Vaccines and Related Biological Products Advisory Committee – 12/17/2020

Good morning, welcome to the 163rd meeting of VRBPAC I am the facilitator, being broadcasted its entirety, YouTube Twitter and a variety of other live streams Today’s event is also being recorded and will be posted on FDA VRBPAC webpage along with all materials and today’s meeting I will be [ Inaudible static ] sponsors and speakers as to whether they are to post at their allotted time and assisting them on need and just a reminder to everyone that was called upon, please manager mute and activate your WebCam and note to all members and participants, we are aware of the adverse weather conditions that we are experiencing We have taken precautions If we encounter any issues we may have to take an unscheduled break and at this time I would like to now kickoff the meeting and introduce Dr. Arnold Monto acting chair who will now provide opening remarks, Dr. Monto, please go ahead, activate your camera and take it away shipment I would like to add my good morning greetings to the microphones, again this is the meeting, 163rd meeting of the vaccines and related biological products advisory committee affectionately known the VRBPAC, we have one topic for today a topic to discuss and vote on and the emergency use authorization of the Moderna COVID-19 vaccine for the prevention of COVID-19 in individuals 18 years of age and older First, I would like to turn the floor over to Dr. Prabhakara Atreya the designated financial federal officer and she is of the VRBPAC will give us administrative announcements and introduction of committee and conflict of interest statements, go ahead Please mute your personal phone I will start again, good morning, everyone this is Dr. Prabhakara Atreya and it is my honor and great pleasure to be designated as the designated officer for today’s 163rd vexing related biological products advisory committee meeting on behalf of the FDA, center for Biologics evaluation and research and the committee I would like to welcome everyone for today’s virtual meeting and the topic of today’s meeting is emergency use authorization, EUA of COVID-19 vaccine for the prevention of COVID-19 in individuals 18 years of age and older During the meeting the topic will be in the federal noticed that was published on December 3rd 2020 I would like to acknowledge the excellent contributions of my team present in the team, Dr. Kathleen Hayes is my backup providing support in all aspects of conducting this meeting other staff are Christina Bert, Jeanette DeVine and many kill who will deal with the additional report Thank you for your support and any media questions, FDA [ Indiscernible – low volume ] FDA OMS

at FDA HHS.gov and the issues for today’s [ Indiscernible – low volume ] we will begin today’s meeting by taking a formal roll call of the committee mentors and the temporary members when it is your turn, please turn on your video camera and mute your phone and then [ Indiscernible – low volume ] and when finished you can turn your camera off so we could proceed to the next person [ Inaudible static ] begin with the chair, Dr. Arnold Monto, Mike, can you present the first slight swell I am Arnold Monto, Professor of epidemiology in the School of Public Health at the University of Michigan Dr. Mehta Cohen? You have to unmute your speaker phone Thank you, good morning I am Dr. Amanda Kohn chief medical officer at the national Center for immunization and respiratory diseases at the CDC Great [ Inaudible static ] Dr. Dr. Chatterjee Good morning I am Dr. Chatterjee being of the Chicago medical school and vice president for medical affairs at [ Indiscernible – low volume ] pediatric infectious disease specialist by training and background and my interest in the field of vaccines Grade, Dr. Cody Meissner? Good morning My name is Dr. Cody Meissner, I am a professor of pediatrics at Tufts University School of Medicine and Tubbs Children’s Hospital, thank you Dr. Gregg Sylvester? Good morning, my name is Dr. Gregg Sylvester on the nonvoting industry representatives and I am the chief medical officer at secure and a pediatrician and general preventive [ Inaudible – static ] Dr. Holly Ganz? Dr. Gans? She is re-logging back in so let us go — [ Indiscernible – overlapping speakers ] Okay we can move on to Dr. Michael — [ Indiscernible – overlapping speakers ] This is Haley Ganz, can you hear me? Go ahead, Haley This is Dr. Haley Ganz Professor pediatrics and pediatric infectious disease from Stanford University, good morning Dr. Kula? Good morning Michael Carrillo, pathologist by training and I am the director of the division of clinical innovation within the national Center for advancing translational sciences within NIH prior to that I was at the national Institute of allergy and infectious disease working on vaccine drug and diagnostic development and prior to that stint in industry doing drug development and then my Pesek spirits in academia doing clinical microbiology Thank you, Dr. Paul off it? Good morning, I am Paul off at a professor pediatrics at Children’s Hospital in Philadelphia [ Inaudible – static ] at the University of Pennsylvania, thank you Mr. Sheldon Tobin? Good morning, my name is Sheldon Taubman and I am and attorney at New Haven legal, New Haven Connecticut where I represent voting individuals mostly in the area of active healthcare and I am here today in my personal capacity as a consumer representative Thank you, Dr. Steven Pergam? Hello, I am Dr. Steven Pergam associate professor University of Washington [ Indiscernible – low volume ] cancer research Center in Seattle Washington infectious disease physician by trade Thank you Next slide please

Mark? Next slide please, thank you, Dr. Fuller? Good morning, I am Oveta Fuller associate professor at the University of Munich in — Michigan in the [ Inaudible – static ] member of the is TEM and is deaf at the [ Inaudible – static ] and I am a [ Indiscernible – low volume ] by training Okay, Dr. David Kim? Good morning, David Kim I’m the division director at the vision of vaccines in the Office of Infectious disease and and — and HIV policy in the Office of Assistant secretary health, HHS, think you have any Dr. Irick Ruben? The morning I am Irick Ruben, and welcome from very snowy Boston I am microbiologist at the Harvard [ Inaudible – static ] public health infectious disease position at the Brigham women Hospital and editor-in-chief of the England journal of medicine Excellent, thank you, Dr. James Hildreth? Good morning I am James Hildreth President and Chief Executive Officer of [ Indiscernible – low volume ] College and also Professor of internal medicine and viral immunologist by training, thank you Thank you Next Dr. Jeanette Lee Good morning I am Jeanette Lee [ Indiscernible – low volume ] Arkansas for medical sciences and happy to be here, thank you Thank you, Dr. Mark Sawyer? Good morning I am Mark Sawyer Professor of pediatrics at the University of California San Diego and Grady Children’s Hospital San Diego and a pediatric infectious disease specialist Thank you Dr. Melinda Wharton? Good morning I am Melinda Wharton director of the immunization services division at the Centers for Disease Control and I am an adult infectious disease physician by training, thank you Thank you, Dr. James need 10 Good morning this is Jim need 10 a professor of biostatistics in the cool public health at the University of Minnesota Grade, Dr. Pamela Macrinus Good morning my name is Pamela mechanist [ Inaudible static ] national Center for [ Inaudible – static ] sciences and one of the NIH institutes Thank you, Dr. Patrick Moore? Good morning on Patrick Moore, Professor at the University of Pittsburgh Cancer Institute and also in the department of micro allergy and micro genetics Thank you Dr. Robert Schooley? Good morning I am initially Professor [ Indiscernible – low volume ] University of California San Diego Thank you, Dr. Stanley Perlman? Good morning I am Stanley Perlman at the University of Iowa pediatric infectious disease and microbiology and I have long-standing interest in current viruses and immunology Okay, thank you Now I will do introductions for the FDA staff and I would like to introduce Dr. Marion Gruber, director Office of Vaccine was say a few welcoming remarks, Dr. Gruber please turn your camera on [ Indiscernible – low volume ] everyone can see and hear you, thank you, Dr. Gruber Yes,, good morning my name is Marion Gruber directing [ Indiscernible – low volume ] research and review and center for biologic evaluation research at the FDA I would like to welcome the committee members, Moderna and the public to today’s meeting and I want to thank the members for convening again today from VRBPAC and we are looking forward to your comments regarding the scientific evidence it will be presented by more dharna and the FDA We also look forward to your perspectives on the benefits of Moderna COVID-19 [ Indiscernible – low volume ] support authorization of the vaccine and then for prevention of COVID-19 in individuals 18 years of age and older so I look forward to the discussions and thank

you Thank you, Dr. Gruber and now I would also [ Inaudible – static ] and Dr. Philip Krause deputy Office of Texans at this meeting who may chime in as needed at a later point in the meeting and also [ Inaudible – static ] will join us as we complete the meeting [ Inaudible – static ] to make his remarks Now I will proceed with the [ Indiscernible – low volume ] thank you The administration [ Inaudible – static ] on December 17, 2020 163rd of the vaccine related biological products advisory committee also known as VRBPAC and [ Indiscernible – low volume ] Federal advisory committee act [ Inaudible – static ] of 1942, [ Inaudible – static ] Arnold Monto will be the acting voting chair for today’s meeting Today December 17, 2020, the committee is meeting and open session to discuss the emergency use authorization EUA of Moderna vaccine for the prevention of COVID-19 in individuals 18 years and older The topic is determined to be a subject matter involving specific parties With the experts in the industry presenting to the members outstanding and temporary voting members of the VRBPAC are appointed special government employee, SG, regular government employees, RGE, other agencies and that subject to federal [ Indiscernible – low volume ] [ Inaudible static ] regulations The following information on the status of the committee compliance with federal ethics and [ Indiscernible – low volume ] including but not limited to [ Indiscernible – low volume ] do 08 is provided to participants at today’s meeting and to the public We would like to have the discussions today, our members RG in our is G [ Indiscernible – low volume ] financial [ Indiscernible – low volume ] their own [ Inaudible – static ] including those [ Indiscernible – low volume ] minor children and for 18 zero [ Indiscernible – low volume ] these may include investments, consultant, [ Inaudible – static ] contracts and grants, corporate [ Inaudible – static ] agreement teaching, speaking, writing, paint [ Inaudible – static ] employment, this may include but is current part of the negotiation FDA has developed that our members of the advisory committee vote regular and temporary members are in compliance with the federal ethics and conflict of interest law Under 18 section 208, Congress is authorized FDA to grant waivers to special government employees who have financial interest of committee [ Inaudible – static ] special government employee [ Inaudible – static ] conflict of interest payment they may also be [ Inaudible – static ] of the regular government employee is not [ Inaudible – static ] deemed not likely to have the integrity [ Inaudible – static ] government may expect from their employee In this agenda and all financial interest, reported by the committee members, and consultants, there have been one conflict of interest to date that was issued under 18 you was quite 200 08 in connection with this meeting We have the following [ Inaudible – static ] temporary voting members at this meeting today [ Inaudible – static ] David Kim, Jeanette Lee, [ Indiscernible – low volume ] Patrick Moore, [ Indiscernible – low volume ] Mark Prior, Dr. Robert Schooley and Melinda Watkins Among these consultants Dr. David Kim [ Indiscernible – low volume ] has been issued a waiver from the consultation today and [ Inaudible – static ]. We have posted on the FDA website for public disclosure Dr. Gregg Sylvester [ Indiscernible – low volume ] industry [ Indiscernible – low volume ] for today’s meeting Industry has presented [ Inaudible – static ] special government employees and so only as nonworking members of the committee Industry representatives of this committee [ Indiscernible – low volume ] [ Inaudible – static ] do not have voting [ Indiscernible – low volume ] act on behalf of all the regulated industries and bring general industry back to the committee Mr. Sheldon Feldman [ Indiscernible – low volume ] committee and [ Indiscernible – low volume ] special government employee and therefore agreed and clear [ Indiscernible – low volume ] in the meeting Working members of the committee Today’s meeting has one external speaker, Dr. Steven Goodman who will start as a guest speaker and he has been asked to disclose any financial interest he may have related to the product before the committee The disclosure of conflict of interest of guest speakers well applicable by law but

regulations and FDA guidance, FDA [ Indiscernible – low volume ] participants including [ Indiscernible – low volume ] speakers to advise the committee of any financial relationship that they may have with any of the [ Indiscernible – low volume ] products and if known [ Indiscernible – low volume ]. We would like to remind standing and temporary members that if the discussions involve any of the products transformed not really [ Inaudible – static ] [ Indiscernible – low volume ] financial interest the participants need to inform the DSO and include them in further discussions and inclusion will be noted for the record This concludes my routine of the statement of conflict of interest and at this time I would like to invite Dr. Peter mark to make a few remarks, please could you turn your camera on and the speakers can unmute your speakerphone and the floor is yours now Thank you Good morning Go ahead Thank you I would like to take a moment first of all to welcome you all and also to provide a brief overview of advisory committee and the role they play in assuring transparency in FDA decision making process ease FDA uses advisory committees to obtain advice from experts who work outside of the government It does so while working towards an open and transparent government by presenting information under consideration in a public forum and encouraging patients, healthcare providers, and other interested people to share their views during the open public hearing or submitting comments to the docket A key part of FDA mission is to evaluate new therapies and determine which are safe and effective for their intended uses This complex job often involves many areas of expertise and sometimes FDA turned to outside experts were council such as for the COVID-19 vaccine under consideration today Advisory committees weigh the available evidence and provide scientific and medical advice to the FDA on the safety effectiveness and appropriate use of products that the agency regulates FDA advisory committees are just that, advisory in nature It is important to note that the advice that the FDA receives from the committee does not represent the position of the FDA, rather the FDA weighs the advice that it receives when taking actions on medical products FDA ultimately makes the final decisions on all matters that come before the committee Also to set expectations, for today’s meeting, we have organized the agenda topics slightly differently than last week’s meeting to allow the committee members to have sufficient time for robust discussion of the questions before them We invite the public and the committee to review the presentations and recordings of December 10 meeting for more information on COVID-19 epidemiology, vaccine safety and effectiveness monitoring and operational distribution plans as those will not be covered in depth today as they were at the last meeting As we begin today’s proceedings, I want to take the opportunity to say thank you to all of you including all of the advisory committee members for the insights that they will provide and also think the FDA staff, the sponsor, and those presenting at the open public hearing today for participating Your contributions are very important in helping us at well reasoned cited science-based decisions Thank you very much and we look forward to the meeting today the Thank you, doctor, now I will hand the meeting back over to the chair, Dr. Monto, Dr. Monto,

takeaway Thank you very much, Dr. Prabhakara Atreya First we are going to hear from Dr. Doran Fink, deputy director of the division of vaccines and related products applications at FDA, who will give us a presentation on emergency use authorization Dr. Fink? Good morning Is the AC staff would make me a presenter I will begin my presentation In the meantime I would introduce myself, I am Doran Fink, deputy director for clinical review In the division of vaccines and related products applications office of vaccines research and review, Center for Biologics Evaluation and Research at FDA The COVID-19 pandemic continues to worsen in the U.S. and worldwide As of the week ending December 15, there have been a total of 16 million cases, and greater than 300,000 deaths in the U.S. to date and 1.5 million cases and greater than 17,000 deaths just in the past week On December 11, just last week, FDA issued an emergency use authorization for the Pfizer behind tech COVID-19 vaccine and this vaccine is authorized for active immunization for prevention of COVID-19 to make to SARS Kelly to in individual sexting years and older the EQ it was issued after December 10 VRBPAC meeting to discuss the vaccine and data informing its benefits and risks and plans for further evaluation On November 30, Moderna therapeutic submitted EQ a request for the vaccine other known as mRNA-1273 This like the Pfizer vaccine is an mRNA lipid nano particle vaccine and it is administered as a two dose regimen 28 days apart The requested use for this UK is for active humanization to prevent COVID-19 caused by stars Kelly to and individuals 18 years of age or older The information submitted with the request include safety and efficacy data from a large randomized blinded placebo control phase 3 trial FDA has been conducting a comprehensive review of the Moderna COVID-19 vaccine UA submission received on November 30 As with the Pfizer request, review has been comprehensive, and conducted over a short period of time We have verified clinical data integrity and integrity of Moderna’s analyses and conducted our own independent analyses from data sets provided in the submission With conducted ongoing review of manufacturing nonclinical and clinical essay information including information that is coming in the last few days We have reviewed and worked on revisions of prescribing information and fact sheets necessary to inform vaccine recipients and healthcare providers We have had multiple information request to Moderna to address our questions I need for clarifications and of course we have prepared for today’s data six meeting This sounds like a bit of a broken record but I say it again because it is important Today’s VRBPAC committee [ Indiscernible – low volume ] that is transparent, scientifically sound, and data-driven As a reminder, from material presented last week that legal authority for emergency use authorization was established in section 564 of the Federal Food drug and cosmetic act It allows for FDA authorization of unapproved medical products — approved uses of — unapproved uses of approved medical products to address public health emergencies related to biological, chemical, radiological or nuclear agents HHS Secretary Azor issued a declaration on March 27 justifying emergency use authorization of drugs and biological products to address the COVID-19 endemic which is a necessary prerequisite for issuance of an EUA Here again are the criteria for FDA issuance of the EQ a Agent referred to in the EU a declaration must cause a serious or life-threatening disease

or condition again we know this to be true for COVID-19 The medical product must be effective — must be believed to be effective to prevent diagnose or treat the serious or life-threatening disease or condition calls by the agent Known potential benefits of the product should outweigh the known and potential risk of the products and also there must not be any adequate approved and available alternative to the product for diagnosing, preventing or treating the disease or condition As I explained last week there is only one FDA approved product for COVID-19 which is remdesivir approved for treatment and not for prevention As I mentioned at the beginning of my talk the Pfizer bio intact COVID-19 vaccine is now available under EUA, for prevention of COVID-19 But it remains unapproved and its quantity is not sufficient for mass vaccinations needed to address the pandemic in the US U.S. therefore a fourth criterion is still met FDA explained in guidance and in a VRBPAC meeting on October 22nd our exit patient for data and other information to support issuance of an emergency use authorization for COVID-19 vaccination This information includes data to demonstrate manufacture in quality and consistency and similar to the case with the Pfizer vaccine last week FDA has reviewed the manufacturing information provided by Moderna and found it to be adequate to support issuance of the EUA We expect clear and compelling safety and efficacy data to support a favorable benefit risk of the vaccine went rapidly deployed for administration to millions of individuals including healthy people And finally we expect plans for further evaluation of vaccine safety and effectiveness including ongoing clinical trial active and passive safety monitoring during use under EUA and observational studies Last week I had a number of slides outlining more details of these expectations and in the interest of time I am going to skip those today If EQD were to be issued for the Madonna COVID 19 vaccine it would specify the conditions of use for which benefit risk has been determined to be favorable based on review of the available data These conditions include the populations to be included in the EUA, conditions for vaccine distribution and administration and requirements for safety monitoring and reporting of adverse events Vaccine made available under EQ it will also be accompanied by vaccination for vaccine recipients and healthcare providers by way of prescribing information and fact sheets in these well described that the vaccine remains unapproved and under investigation under IND and date will describe the known and potential benefits and risks of the vaccine and will also discuss available alternatives with the option to refuse vaccination As I explained last week, and EQ a that is issued may be revised or revoked for a number of reasons If circumstances justify the EQ a no longer exist, if criteria for issuance are no longer met, or if other circumstances are arise that wearing changes necessary to protect public health or safety for example based on new information concerning vaccine safety or effectiveness, vaccine manufacturing or quality or for COVID-19 epidemiology or pathogenesis I want to pause here to address the issue of anaphylactic reactions or serious allergic reactions following vaccination While today’s discussion is about the Moderna vaccine at last week’s meeting we reported on anaphylactic reactions that occurred in the United Kingdom in two recipients of the Pfizer vaccine which is also mRNA and lipid nanoparticles vaccine and also relevant to today’s discussion Both of these vaccine recipients had a medical history of serious allergic reactions Though not as far as we know to any of the vaccine components Yesterday as has been reported in the press, two healthcare workers in Alaska experienced allergic reactions minutes after receiving the Pfizer vaccine and one of them on anaphylactic reaction resulting in hospitalization All of these individuals were treated with appropriate medical interventions and thankfully

all are recovered or recovering We anticipate that there may be additional reports which we will rapidly investigate We learned of these cases through established safety surveillance systems that worked exactly as designed FDA is coordinating with CDC to further investigate the cases in the USA to communicate our findings in a timely manner with faxing providers and recipients FDA and CDC are also in close contact with public health and regulatory authorities in the United Kingdom as they continue their investigations While the totality of data at this time continue to support vaccinations under the Pfizer EUA without new restrictions, these cases underscored the need to remain vigilant during the early phase of the vaccination campaign To this end FDA is working with Pfizer to further revise the fact sheets and prescribing information for their vaccine to draw attention to CDC guidelines for postvaccination monitoring and management of immediate allergic reactions This revision will be in addition to the information already included in the contraindications and warnings Including the facilities where vaccines are being administered should ensure that medical treatment for managing serious allergic reaction is immediately available We do the same for the Moderna vaccine — vaccine should it be advised for use under EQ a Here is the agenda for today’s VRBPAC and as was mentioned we have a lighter schedule than last week to allow for more robust discussion You will see that some of the presentations from last week are absent because the information is not materially changed We will have a repeat of Steven Goodman’s talk on considerations for placebo-controlled.– probe design if unlicensed vaccine becomes available I will explain the reasons why on the next slide Following Dr. Goodman’s talk we will hear a sponsor presentation of the data for the Moderna COVID-19 vaccine and we will then have an open public hearing followed by a lunch break and finally an FDA presentation of our EQ a review discussion items and questions for the committee to discuss and vote We have just one question today for discussion without a vote This question is similar to what we ask last week we were phased it in a way in that we hope will focus the discussion The reason we’re coming back to this question is because it is important in the case driven vaccine trial conducted in the midst of a pandemic that very quickly demonstrates clear evidence of efficacy at least in the short term, can allow the vaccine to be made available under you a On one hand this has a very positive effect of helping to address the pandemic On the other hand widespread vaccine availability can interfere with conducting the trial to completion To be clear, FDA had never insisted that placebo recipients enrolled in ongoing trials who want vaccines be made to wait be on when the vaccine would otherwise be available to them under the conditions of EQ a prioritization recommendation and available [ Indiscernible – low volume ] whether we have been asking those as possible for conducted 19 vaccine trials to think carefully and creatively about how to continue trials after vaccine becomes available under EQ a and to preserve whatever societal value can be preserved and to ensure sufficient data are ultimately approved to support vaccine licensure payment this includes encouraging study participants who are willing to remain in blended follow-up for the same altruistic reasons that prompted their enrollment in the first place to do so Later today you will hear about Moderna’s plan for their trial The question that we would like you to discuss is in considering Moderna’s plan for on blending and cross over a placebo recipients please discuss the most critical data to further inform vaccine safety and effectiveness to support licensure and that should be included in either ongoing clinical trials with the Moderna COVID-19 vaccine, or other studies such as additional clinical trials or observational studies with that vaccine Following this discussion, which again will not have any vote, we will have a single question,

for VRBPAC discussion and vote That question is, based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 vaccine out wait it’s risk for use in individuals 18 years of age and older? Thank you very much [ Inaudible static ] Thank you, Dr. Fink, we have a full 20 minutes for discussion here and I think we should restrict our discussion to the EUA process and its characteristics since we are going to be hearing from Dr. Goodman about some of the other issues, we probably should restrict questions or discussion about that until after he presents So raise your hands please, if you would like to make a comment Dr. Cody Meissner? Thank you, Dr. Monto First I would like to express my gratitude to Dr. Fink, Dr. Marks, Dr. Gruber, and their colleagues at the FDA, for the extraordinary amount of work that has been put into this issue over the last few weeks and months I think that all the citizens of the United States should recognize the enormous efforts that have been put into this Thank you My question is as follows, and it is somewhat similar to the question that was asked that I asked last week, it is important that we move a vaccine from an EUA to a BLA because there are a number of advantages to have a vaccine licensed and recommended by the CDC Is there anyway you can anticipate how soon that might happen and does the availability of a second messenger RNA or vaccines with a similar mechanism of action — will that facilitate the decision in any way for the FDA, over Thank you for the question I believe I responded last week, we are actively working with the vaccine manufacturers, both Pfizer and Moderna to arrive at a data package that would support vaccine licensure This data package would include some additional follow-up from clinical trials as well as data approved from use under the you a as well as some additional manufacturing information for vaccine that is intended to be produced following licensure payment so it is our go to arrive at a licensure application as quickly as possible, as the data allows And in terms of your other question, certainly two vaccines that are similar in platform, although not exactly the same, will be considered relevant to each other and will inform our assessment of those respective vaccines Thank you Dr. Kurrila? Thank you Doran, I want to make sure I understood what you said payment you seemed to imply that the issuance of a second EUA was partly dependent on the fact that there was inadequate supply of the initial EUA for mass vaccination, is that a criteria that would potentially impact the decision on future EUA for other vaccines? Thank you for the opportunity to clarify that question Actually the supply of Pfizer vaccine is the secondary at this time for considering issuance of EUA for different vaccine and that is because the Pfizer vaccine is not approved

Consideration of available alternatives requires that those alternatives both being approved and adequate So the fact that the Pfizer vaccine is not approved means that there is currently no approved, available and adequate preventive vaccine for COVID-19 Thank you Dr. Rubin? Thank you, Dr. Fink, for the very clear presentation and I’m curious what FDA will do with the discussion item on Dr. Goodman’s proposal Is it likely to end up as an FDA requirement or a strong recommendation to proceed to BLA for the manufacturers? As I explained before, we are working actively with the vaccine manufacturers on accruing data that would be necessary to support a Biologics license application This includes discussions around the contours of their ongoing clinical trials going forward We are hoping that the committee discussion will help to inform those discussions with the manufacturers Dr. Perlman? So I just have a question about one of the last things you were talking about, so the anaphylactic reactions have clearly been a big deal in the present I and probably others get lots of co-judgment calls about what it means and I think the FDA recommendations talk about allergies to components of the vaccine yet the components of the vaccine actually are not obviously to meet allergenic So do you have any sense for how the FDA will finally recommendation? The UK has different recommendations then the FDA came out was so do you know how this will play out and what the components are in the vaccine that could be inducing this? At this point, we and CDC are continuing to investigate these cases and consider data At this point, we do not have enough information to make definitive recommendations one way or another And as we continue to investigate and evaluate the data we will consider whether additional recommendations need to be made Dr. Steven Pergam ? Thank you, Dr. Fink, for the clarity and again for the short presentation because we have a lot to discuss today Had a question, he brought up the issues of a couple of separate questions in addition to the main EUA question we will be reviewing unrelated to what other studies need to be done etc And I want to be clear, is this for both vaccine since we did not get to review those and give those recommendations to the Pfizer BioNTech team and are their discussions for additional studies are work that needs to be done and are those going to be relevant for both factors and candidates as well they certainly will be relevant for both vaccines We like this discussion today to focus specifically on Moderna’s plans But clearly the ideas discussed will be relevant to both vaccines Thank you Dr. Moore? For the long-term safety, meaning beyond that years even decades long safety for this vaccine and the other vaccines, requires obtaining the centralized resource that allows us to know who is vaccinated and who is not Is at being planned to be collected for outside of the randomized controlled trial? Is there a plan to collect that information to securely store it so that you can do the linkage analysis with say cancer registries or autoimmune registries? So as discussed last week, the U.S. government is planning a number of studies leveraging healthcare claims databases to evaluate vaccine safety over the longer-term payment with the use under the you a and I am not the expert under the studies and I would have to defer comment on the detail for those who are spearheading it Dr. Fuller?

Thank you, Dr. Monto and thank you, Dr. Fink, for your explanations The question that may be addressed later but I will ask you, how will the FDA or CDC or other state health agencies monitor the potential adverse events that happen like the allergies that you mentioned in Alaska? If it were a continuing clinical study, those would be picked up by the researchers, but in this case, how will that be done? Could you please share a little bit more? Sure, this was also explained last week in one of the presentations by CDC, that we do not have today but I will refer you back to that and refer the public back to the recording of that presentation We have robust safety surveillance and reporting systems that have been in place for a long time Including VAERS, Vaccine Adverse Event Reporting System, in addition vaccine recipients under the EUA will be asked to participate in a program called be safe, which is an electronic safety reporting system that the government is using to track vaccine safety with the use under the EUA All right, thank you Dr. Neaton swap thank you, Dr. Fink My question is actually similar to Dr. — Dr Steven Pergam and have you considered aligning some of the future protocols for these two vaccines in a manner and also the current protocols with the purpose of being able to combine the data from the two studies or two federal studies as well well, yes, combining error or pulling data involves complicated statistical considerations, but what we have done and we discussed this at our October 22nd VRBPAC meeting and also in our guidance released in June of this year, as we have recommended standardized case definitions that will help to evaluate efficacy results from trials of different vaccines and not necessarily for comparing one vaccine to another although that is one possibility We hope that this standardized approach which as we explained in October is not a requirement for the primary end.but the recommendation we have made for inclusion in all of the phase 3 trials and we hope that this will facilitate the type of broad and robust data analysis that everybody might be thinking of Thank you Dr. Gans? Thank you very much Thank you, Dr. Fink I had one question about — I realized today we are entertaining the Moderna vaccine and we have now entertained the Pfizer one Revis Lee and I wonder in the context of other vaccines that are coming to market all of which will have different adverse events as well as different populations in which they should be used and I am wondering in the context of equity in terms of how we roll some of those out and coming to obviously into use before others, and I just worry a little bit about how we should think about that in the context of the broader field of different vaccines that are coming that have different profiles Have you had any thoughts on that or how the FDA and CDC are thinking about those other vaccine models in the context of this one? Sure So just to be clear, FDA’s responsibility is to evaluate data concerning the benefits and risks of the vaccine in the context of the emergency use authorization request payment –. Once FDA issues emergency use authorization then the responsibility falls to CDC and the advisory committee on immunization practices to set prioritization recommendations and other recommendations for use of the vaccine, considering its benefits and risk and populations included in the emergency use authorization

Okay Dr. Archana Chatterjee? [ Inaudible static ] good morning, I have a question with regard to the BLA applications that may be coming from the manufacturers In the past, from my experience anyway, usually BLA application comes in after the clinical trials have been completed For these vaccines, is there a plan and I cannot quite understand from your explanation, Dr. Fink, whether there will be enter into him dead analysis and we will not have to wait until the trials are completed before the BLA application will be entertained by the FDA Thank you for the question and the opportunity to provide clear vacation It is actually not unusual for a clinical trial to be ongoing for longer-term safety and/or effectiveness follow-up When a biologic license application is submitted At this point, we do have interim data for two COVID-19 vaccines, one of which we have authorized for emergency use and another which we are considering today At this point, the data would not be considered quite sufficient to support a biologic license application, but as I mentioned before, we are working with both manufacturers to approve the data that would be needed but the goal of getting these vaccines licensed as soon as the data allows We heard from Pfizer last week that they are anticipating potentially submitting a Biologics license application sometime in the spring of next year and that plan is certainly within the realm of what we would consider possible Thank you very much Dr. McGinnis? Dr. Fink, I have a question regarding the status of infection of facility and the reason I think this becomes important for us to have some sense of where you all are in this, was the availability of information on the news about an unexpected volume left in syringes so while that may very well just be due to residual volume in syringe and needle of a particular type for what might be seen in another situation, it does bring up the question of the confidence in the manufacturing side and the manufacturer and the fill and the consistency and while I appreciate that a full sure of that is not required under EUA, I would like to have some sense of sort of confidence of the FDA in that particular set of data So I can repeat that we have reviewed extensive manufacturing information for this EUA request and do feel confident that we have enough information to justify issuing an EUA for this vaccine, should everyone a great that the benefits outweigh the risk aced on clinical data I cannot speak in more detail about facilities inspections and I invite other FDA colleagues who might be on the line to chime in if they have something additional to say The other thing I will mention about the volume issue for the Pfizer vaccine is that if you look at the instruction, they are to add 1.8 ML’s of the world went to 0.45 ML’s of vaccine that is already in the multidose bio and that gets you to a total of 2.25 ML and so with a dose volume of 0.3, ML’s, it is not actually at all unexpected that there would be more than five doses in those vaccines Or in those files, over

Any further FDA comments? Okay, for the final question, Mr. Tubman? Thank you for the excellent presentation, Dr. Fink I have a question about the FDA review of effective data and use light indicated a November 30th position from the EUA and the [ Inaudible – static ] documents indicate that Moderna submitted another set of documents on 12-7 and that included several closed dated [ Inaudible – static ] 11-21 and in the briefing document you indicated FDA had reviewed some and verified some of that more recent data but not all and just briefly explain what that actually means and there has been reports in the press about how the FDA process is more rigorous than the British review process for example But it [ Inaudible – static ] second, to confirm that you have been able to verify the efficacy data in the second [ Inaudible – static ] as well as the important secondary [ Inaudible – static ] disease? Yes, we will hear more about that in our FDA presentation this afternoon, but I can verify and can from firm that the FDA has examined, verify the integrity and confirmed the efficacy, analyses from the later time point from the November 21st time point, both for the primary efficacy analysis and for the secondary analysis of severe cases What we have not done due to time constraints, is more in-depth probing of the data to do our own independent analyses on some questions that we look at that aren’t maybe not so central but of interest So all this to say that we have verified and confirmed Moderna’s analyses for both the interim and final efficacy analysis and those that we consider to be most critical to confirm the benefit risk assessment and we have not done quite as comprehensive a dive into those data as we did for the interim analysis But we do not think this should hinder in any way our confidence in the data to support an assessment of benefit and risk Thank you Okay We are moving on now to the presentation from Dr. Steven Goodman He will be telling us about the considerations for placebo-controlled trial design if an unlicensed vaccine becomes available Dr. Goodman, associate Dean of clinical and translational research at Stanford University school of medicine Dr. Goodman Wah good morning? Good morning, can you hear me fine? Yes Okay, terrific Thank you so much for inviting me and in fact particularly for inviting me back again I think the reason for that was pre-staged by the questions and talk just given, which is that the issues will be or we will be considering here are not just relevant for this vaccine, but for many trials currently ongoing and those in the future so this arguably has potentially more long-lasting and or an effect than even that EUA today I don’t want to scare you with this title which looks exactly the same as last week and I am in fact not going to be giving exactly the same talk I will be picking up from where we left off last week and taken a hit of a deeper dive to give you more material for your discussion This is the outline and I will very briefly remind you where we left off after last week and then go into the Moderna consent and proposal and then we will take a bit of a deeper dive into the deferred vaccination design which we talked about last week Then I will discuss the evidential and ethical effects of both partial and complete and blinding of the placebo group which are both under consideration right now and I will have a final single slide on the evolution of design Which is a perspective I hope you will consider in your comments and I already heard a suggestion

from Dr. — Dr. Gans in her last question so just going very briefly where we were last week and we had a ethical summary where he talked about the issue of ethical dilemmas as being a choice between two right actions are justified in different ways which is certainly what we will be facing today even more starkly and the importance of trust in the whole vaccine development process and prioritization which enables us to do these clinical trials and it could be withdrawn at any time and we talked a little bit about the issue of context for the ethical calculus depends not only on what we know and what we don’t but the availability of vaccine and we talked about ethically relevant benefits in the sense that whether the placebo group was taking on such a risk relative to the vaccinated group, that they were owed something just by nature of that benefit and the argument was that they were not, even though there was some very, very small deficit but of course you don’t know that when you sign up for the trial and we only know that in retrospect In terms of the epistemic or evidential summary and I will use the word evidential more even though epistemic even though I am talking about the same thing which is that all designs can generate valid — valid evidence although be it with different efficiency and degree of [ Indiscernible – low volume ] randomized controlled trials and was experience with observational designs and pain knowledge of mechanism in biology which guides a light of the interpretation of the empirical design And finally the RCT are best to assess some properties are vaccine properties but not necessarily all There are very good for something but we have to partition between the things that it is good for and not And finally, the idea that there should not be any bright lines drawn either on the ethics or epistemology fronts and we should not be declaring anything particularly unethical What we are really saying when we say the word is that we believe one can spell out why another and the word unethical sort of disenfranchise people on the other side and [ Indiscernible – low volume ] does not lead to good discussions as well as restricted hearings to randomization when that is not necessarily or when that is not necessary Let is go to the Moderna consent a proposal, the consent is at the beginning exactly what you would expect It mentions voluntariness with that’s my particularly important that the document may or may not benefit from participate in the study but it is designed to help others in the future That they can leave at any time and this will not affect their future care Then we get into some of the questions which state and very plain language what the participants should expect and it says what will happen at the end of the study and basically you will just be discharged from the study by your Dr. and will you be informed of information becomes available? Yes, and certainly as was Leslie the EUA is part of the and this is the most important class at the bottom, can continue getting the study vaccine after the study? This is what was told in the consent If you choose to withdraw from the study or are taken out of the study, you will not continue receiving the study vaccine Also, if the study is terminated early, or when the study is ended, the sponsor will not continue providing the study vaccine That will be highly relevant to the actual proposal which we will contest here So first of all, and observations made, that there is going to be a large number of folks who are eligible for early vaccine administration and in particular 25% of the enrollees are healthcare workers Here’s the proposal, they will proactively re-consent participants who received placebo and then offer them the vaccination And they will be observed unblinded for the rest of the entire two years Adverse events will be captured But basically they are proposing to simply unblinded and immunize the placebo group This is importantly different from last week’s proposal, which was to wait until there was or they were eligible for receipt otherwise and then if they ask, they would then be unblinded

and immunize and that all participants would be encouraged to stay in the randomized trial as long as possible and that everybody would be immunize at the end of six months So this is different in multiple ways First it is done immediately and second of all that they be unblinded and that actually is common to both But that we do not wait for eligibility outside the trial This is a very, very, very important difference and something that — as I will argue — consequence not just for this trial but for other trials of other vaccines This is exactly the same of what we talked about before and what is owed to placebo participants in this really is what is the obligation? Something that can be asked of the investigators or the company Because it is owed to them And the simple answer, what is in the consent? That is with his owed to the placebo participants and the condition upon which they rolled and of course all the adherence to the [ Indiscernible – low volume ] ethical principles The certainly would want to expect, and they would not be denied vaccine, if it came available to them, which could be done through an exclusion of EUA but I don’t think that is actively being considered And potentially reciprocity which is really a form of gratitude and not obligation, could be operationalized through higher priority for vaccine within their priority group when they become eligible But there is not an ethical obligation of investigators to unblind on-demand It is if there’s a medical reason but not for others And not immediate vaccination [ Indiscernible – low volume ] outside the trial and actually reflected in the consent, if this was an ethical obligation to immediately vaccinate once there was interim results showing efficacy or even within EUA, this would’ve been the consent and it was Let a snout take a deeper dive into the vaccination — let is take a deeper dive into the vaccination design and I show this light last week and really two alternative designs at this point that might be considered for this or future trials and one is deferred immunization which is a blinded crossover design and second is active control designs and I will not focus on those but I will talk about the implications of the guidance on this placebo group for the future of active control design but very important and of course everything comes with active and passive observational studies of almost every aspect of the vaccine and not just safety, the vaccine properties So both approaches are going to require some give on the evidential and ethical sides So this is a picture you saw last week and this is the deferred vaccination arm and on the top you see the arm that gets immediate vaccine and that is in blue and it narrows and the narrowing looks like slow waning of the vaccine efficacy and of course we don’t know if or when that happens but this is just to have a schematic of showing you how they could still be compared if we crossover blindly On the bottom, you see placebo arm and the point at which there is early efficacy establish which is roughly where we are today and still in period one And then the proposal is that at some point, if we are going to — if somebody’s going to become eligible for a vaccine, that if they are in the vaccine aren’t that they get up placebo injection and if they are in the — I’m sorry placebo arm they get up placebo — I will get the straight If they are in the placebo arm they will get a vaccine injection So everybody ultimately gets immunized but they still don’t know whether they were in the immediate vaccination arm are in the deferred vaccination arm And this preservation of blinding, even with the immunization of everybody in the trial, allows a number of things that I will talk about in a minute and I mentioned last week This is another way to represent what is going on and here we are measuring efficacy not as the thickness of a bar but in terms of the attack rate and that is on the vertical axis and what you see is the attack rate you would expect under placebo in the early days and on the bottom is just time It would be high here just anomaly index at one

That would be the attack rate and the redline of the placebo group and at the bottom would be the attack rate in the vaccine group In fact this turned out to be much, much lower roughly 95% lower than the redline And we watched them over time and the vaccinated arm, if vaccine efficacy starts to wane, if and when, what you would seek or see is a slow rise in the attack rate in the vaccinated group and the blue line is starting to ramp up But of course there are other things going on in the world that affect the attack rate including prevalence in the community, community restriction measures so there is a lot of things going on in calendar time that need to be controlled for Which is why we cannot just observe what happens over time We will not know if the attack rate starts to go in the back seem exactly what it is due to So this is where the deferred — preferred vaccination could still help us recover the vaccination and that vaccination occurs with a big drop at the point of deferred vaccination from the redline down to the blue line and we watched this attack rate for a while and if there is a difference between the attack rate and the early vaccinated group, versus the late, that is finding there is waning affect us the and this could occur at every.and they could be at the same.[ Inaudible static ] the early vaccinated is start to — their efficacy starts to wane and attack rate goes up over time and does not have to be right at the point of crossover So this is what it looks like and this is how you can recover this really critical information about how long the immunity lasts which will be a major question and we will also see a few other things we can do with this design I want to make the point, the crossover can occur whenever and individual participant becomes eligible for an available vaccine outside the trial It is not occurring for everybody at the same time, which the schematic suggested It is occurring for each individual potentially at a different time and I will talk more about that issue of design There is also some unexpected benefits and one is the blinded crossover and allows for more safety assessment through self-controlled design and you will see here on the bottom that the placebo arm, we are looking very, very carefully at adverse event incidents in the post placebo appeared and that serves as a control for the AE scene in the vaccine arm which I sort of erased up here I am only looking at the placebo arm and you will see why and then when they crossover blindly, of course they don’t know that they are crossing over, we can then watch very closely adverse event incident post vaccine and we can compare AE after the vaccination to before and particularly in a powerful way which would control within each individual This is not just comparing overall incident rate which is like what is occurring in the first period It is self-controlled design which controls for compounding in a particular powerful way So this is a nice benefit of this design because they are being watched carefully and that first period so this is very solid AE information We could ask people if they had a recent stroke or heart attack or whatever before entering the trial, but for certain AE’s they may not remember it very well and certain once might prevent somebody from enrolling This guarantees that there is absolutely no five-step included and there is another bonus which is as vaccine efficacy wanes, if it does Wayne’s, the deferred vaccination allows the booster trial sort of right on top of the trial infrastructure and is — in that sense it is an added benefit if we find that a second booster third shot is needed and this can be piggyback right on top of the deferred vaccination structure This again is a very nice add on if needed Now last week that Dustman something was asked whether they were amenable to doing this and they pointed to the logistics of maintaining the blind and they said it was very difficult and maybe not worth it but I will say there are additional logistics and it will be up to you to explore the yield and to give FDA advice on whether this is determining whether

it is worth going, worth instituting So there are mandatory crossover serology less a dummy shot and there is another dummy shot for both arms because neither one could note what arm they were in and there is possibly more blood draws and these have to be synchronized between the two groups They should be done or checked on the same schedule so serology is comparable Finally there is re-consent but this is necessary for any major design change including unblinding Administration of Vaccine so this is not necessarily an additional logistical barrier But what is really article is in theory no one knows their assignment All the parameters and all the same reasons we do the RCT apply here in preventing bias in and ascertainment of the whole bunch of AE’s, efficacy endpoints and even crowd participation as I will mention This is a complicated [ Indiscernible – low volume ] I will not go through in detail but I will point out one thing and this is a list of all the things we still want to learn about the vaccine that is not really captured very well at this interim point which includes duration of immunity after two months and this actually under certain circumstances can be enhanced by the difference it would make even over continued placebo control even though I think that is off the table and the other thing that is enhance which is really critical on this is the link to the future is correlating of immunity because we are now doubling the vaccinated arm and doing so in this randomized way and we can enhance the finding of markers started Marcus up [ Inaudible – static ] absolutely critical for active control designs in the future and I mentioned a variety of things here that are partly preserved and we will be able to get some information but not necessarily the vindictive information Now finally effective complete or partial placebo unblinding both on the evidential and ethical scale In terms of partial unblinding which would be done if we gave the vaccine to those who at the point they became eligible so we would never completely unblinded the group until maybe sometime.in the future as Pfizer recommended but not as Moderna is proposing and it is important to mention the same fraction [ Inaudible – static ] unblinded because when the as to be unblinded or when they become eligible they don’t know what group they are in so people in either group would be unblinded and we lose them both at least to the randomization and the remaining cohort will probably be at lower risk and the high risk ones be the ones that we will either potentially — they will request unblinding or we will offer the unblinding because they become eligible and once a vaccinated person realizes they have been vaccinated, they will probably engage in high-risk behavior, which will for at least the one-2 months after the unblinding will make them a more difficult comparison group to the placebo group And finally, not finally put patient reporting outcome for the unblinded group can be bias in terms of how people interpret various symptoms and there will be impaired ability to evaluate waning the vaccine and advocacy in the first 6-8 weeks after crossover and after eight weeks everybody knows they have been vaccinated, but before this time, that vaccine efficacy is uncertain and it has unpredictable [ Inaudible – static ] particularly safety assessment there is crossover because once you do the unblinding [ Inaudible – static ] coming back giving information but we do not have the same sort of bonding for the trial in the sense that it is adherence to the dictates — actually critical for validity and if we ran completely unblinded with the placebo group than we lose a lot from the evidential site and there is no comparison group to compare rates or comparison or [ Inaudible static ] much more poorly assessable, very unpredictable effect on retention in effect the trial is over Quality of evidence for licensure will only be marginally different than that for the EUA because of what we are giving up And actually it weakens the scientific value of the trial that is pledged to the participants on enrollment This can easily be done if for good reasons but should not be done if there are good alternatives

if we want to give them the vaccine anyway Finally this may make the Siebel controlled trials more difficult for of the vaccines We have a very strong interest in developing good information for those of the vaccines Because there will be a President that as soon as something has been shown to the — effective and be available that it is ineffective to ask people to wait anymore time to be immunize in any way and this is a President you may not want to set I have a couple of slides here on what the value of having more slides for the vaccine [ Indiscernible – low volume ] I think this committee knows it very, very well and they could have different immunization properties and there are [ Indiscernible – low volume ] better in combination and they might have different safety profiles and acceptance and they may have different distribution and updates But I’m not going to go through this but you have these slides available so I want — last few slides I want to bring up the ethical impact of unblinding and for the trust the whole trust system and immediate unblinding vaccination could become a precedent in the de facto execution [ Inaudible – static ] ongoing or new placebo-controlled trials and a sense could take hold of even temporary was holding vaccination within a trial is unethical because it was done in proceeding trials I would suggest the images of — we have to remember what happens what we are doing here if we do unblind is we are disturbing the priority set and that is we are going to be vaccinating young, low risk trial participants and this will get out in the community very different than the pictures that we saw after the authorization last week where it was healthcare workers and others so the image of young, low risk trial participants being knowingly vaccinated [ Indiscernible – low volume ] community members could adversely affect trust in the fairness of the vaccine testing system and the allocation system and we will then start looking very closely at the trial recruitment enrollment procedures of all trials to see how we are choosing people who work in the trials who work then or then will jump the queue and that is a scrutiny we may or may not want to have done so aggressively that the enrollment in the trial is in a sense a privileged position with regards to trials and vaccine administration And it may be dangerous to have different ethical evidential trade-offs meet in each trial by each company and there are a lot more coming as you know and those priority setting [ Indiscernible – low volume ] generally regarded as fair partly because the processes that created them is perceived as fair If these are overridden in individual trials to the very unpredictable effects of perceptions by groups underrepresented in the trials and by the public And if these trade-offs are trial and company specific then there will be a rush by some current and prospective participants to game the system in their favor because everybody will be looking for the trial that does better by then thereby undermining the ethos that we are all in this together and we need to act collectively for the greater good So the trial by trial resetting of the ethical priority and prioritization I think is something that we have to think about from a larger with the white Lance and here is the whitest lens The evolution of designs that we are going to be experiencing as these ways are issued [ Captioners transitioning ]Last week moving to the area where there are some EOA available in some vaccinations that are available and then we might preferred vaccination from the inception and not this conversion and will become the standard and we believe we can ask people to put off vaccinations for a few months but in the consent it will say [ Inaudible ] vaccinated And believe we will rapidly move into that in that asking for these trials to be in that category will be a great president to allow that transition for future studies to be designed for that Finally once we get the issues, the approval, we probably will have to move into an era

of maybe sooner than later when the and when were able to do in populations that have the vaccines available and active control that RCT and for these we need good surrogate endpoints and [ Inaudible ] of immunity and that is what we got that we have the opportunity to get right now and if we undermine that it will weaken the interpretability of the later active control I would like to strongly encourage you to look, a Longview a look at the vaccine development ecosystem and if we can keep the same standard for all of the trials particularly the priority setting for vaccine administration and as I mentioned none of the current international party settings agreement include participation in a trial as a priority unless of course you fall in traditional high risk group If we are consistent across all trials they are more comparable and enhance truss system inconsistent across the board and start making company by company trial exceptions we will run into rather quickly trial adrenaline with trust and retention That I will thank you for listening and yet again and I went to in particular thank the participants in the trial so far who have enabled us to have a conversation today and whose contribution was and will continue to be a tremendous gift to all of us Thank you Thank you very much You went over a bit but this was a very important presentation for our further thinking I want to reiterate what you have said and that is the crossover is not really just one design, it is a design which will vary by when the crossover is done Am I correct in that? Yes One thing I will also add, it doesn’t necessarily have to be for individuals but it could be about crossover is staged by priority group Preplanned every two weeks or every month and the next priority group will come in but yes it does depend on when it is done and you want to maintain as long as you can and as long as it is practical This could be part of future consent force? You don’t have a logistic challenge and [ Inaudible ]? Yes it could be present as the design of the trial that the trial from inception in the design and it seems inevitable but placebo-controlled trials is hard to imagine and with the possible trials going forward but I think that is what we will evolve to and something you can discuss We have about 10 minutes for discussion but we will circle back and re-discuss all those actions we hear with the sponsor’s presentation Okay Doctor [ Inaudible ]. Is it difficult to maintain the blind in any of these crossover trials device that you talk about, because of the different adverse events and vaccines that are clearly much more crinoline than the placebo but at least the recipients and presumably the people conducting the trials would be [ Inaudible ] which [ Inaudible ]. That is absolutely — first subset of folks there will be able to guess more often but there is a overlap in symptoms that is even things like tools which you think would be vaccine specific So it’s true that that symptom occurs more often and absolutely in the vaccine group

but necessarily on blind and still it won’t be as complete and on blending but all relative you tell people this is what you got 10 people may well suspect that and I don’t think they necessarily act in ways that assume they were vaccinated That happened maybe people in the current trials or future trials when we got those reactions would go out with high risk behavior and that’s what we are trying to avoid Absolutely All I can say it will occur more with on blending then with a continued blind and we will try to preserve as much as we can for valid interest but you are absolutely right, this is also therapeutic trials as well and it is a relative issue and not that it’s completely unblinded with the blinding, it is perfect but much better and also the other sense of staying within the experimental framework and not leading the trial and making possibly talking about further follow-up and retention with other endpoints You are right about that but I think it is preferential from both evidential point of view than basically telling everyone which arm they are in Barber miser Doctor Goodman I would like to thank you again for a thoughtful and clear presentation on this difficult issue As a former chair of the vaccine injury compensation program, it’s important to have careful in understanding as we reasonably acquire with the longer-term follow-up of vaccinations The compensation program has an enormously favorable impact on the uptick of vaccines in the United States and resulted in the highest uptick of vaccines history So I would certainly encourage the blind crossover design you have partook dust proposed because that may give some opportunity to evaluate long-term complications between a vaccinated group and unvaccinated And so I would like to support that and the second question I have and may not be answerable but has Pfizer made any decisions as to how they’re going to follow subjects based on your first presentation? That will have to be, the last question what Pfizer will do and today not about that but you can assess some question about what the consequence will be and turn but that is a question for the FDA and I don’t know the nature of their conversations with either of these companies about the requirements That’s where this will play out and not necessarily in the EOA but in the subsequent request for the information they would like I don’t know what is happening as a consequence after last week’s meeting and probably not know after this week meaning that is something for you to ask the FDA and representatives what they are working for or what they think they can ask Doctor Carrillo That has to be one of the most insightful trend want to listen to so think you for that The question I have concerns the ongoing trial if we were to do a 100 crossover and I’m thinking

and wondering how two populations would be handling in the first is who Copeland and what to do? Are they done and do they just fall out or the other population because of the unreliable serology in this regard that unless you catch it in the post acute phase and recognize will be an increasing percentage within both arms from asymptomatic infections and they may be contributing to immunity that will complicate and I’m wondering how you go forward it can be handled appropriately with those populations Fantastic question It was a line in the slide what we could learn that the infection for the ability to prevent infection which is asymptomatic and other designs may be needed So it won’t necessarily capture that unless it is frequent [ Inaudible ] and as you say the serology is not perfect We can capture a little bit of that particular if we increase the number of serology and almost certainly cannot do that if they are not retained with semi-randomized study That is all I will say I think that is something for the FDA to think about for both observational designs going forward but it is something that can be done better within a blinded crossover and I think more successfully not blinded Incredibly important question to get partial information out of it better blinded but not perfect and I think we will have to lean heavily on other designs as well Thank you The other people who have their hands raised, circle back and we will have more discussion later and Doctor Ruben Inc. you Thank you for coming in speaking with us twice and of course very compelling infancy way think for the end verse of events and I think [ Inaudible ] leaning immunity in observational trials but it does preserve the ability to look at [ Inaudible ] and clearly I think it is the way that we should have been designed but the logistics of implementing now, for the Pfizer vaccine that we receive in the UA, people are getting vaccine and getting vaccines in specific groups and so high risk looks like they’re getting it first and we may be already using those people but as a practical to implement the design? As I mentioned, it keeps the groups equal and so all healthcare workers at the beginning, you lose them from both the possible arm and vaccine arm in terms of lighted art But then you have a period of time before maybe the folks in the older risk groups and lose them slice by slice and whether in terms of logistics with you do that on an individual basis and simply say this will be crossover two weeks after and 2.5 months after the two-month of observation placebo group Next one three weeks later the next one three weeks later and you see sequentially you may lose from the blinded part that from follow-up the highest risk patients that you can still learn a lot from those who are left correct but the cohorts change in the state the same in stay comparable in the two arms Thank you Doctor Goodman Please stick around what will be late morning for you for the discussion later on Now it is my pleasure to introduce representatives of the sponsor and we are going to hear from Doctor Tal Zaks and [ Inaudible ] Good morning

My name is Tal Zaks Doctor [ Inaudible ] and behalf of myself I would like to thank the committee opportunity to present data today We carefully watched in was in the meeting and preparing presentation for today [ Inaudible ] proactively address many topics at the meeting and the date that follow Developing [ Inaudible ] and with the goal to see global licensure for the prevention of coca 19 disease ended here today seeking emergency use of — based on phase 3 safety and efficacy data I don’t need to belabor and continue to on health and indirectly on the society and the way of life The pandemic began, we moved rapidly to leverage the advantage of the [ Inaudible ] platform and been working closely with colleagues from the national Institute of health to develop the vaccine We’ve done so in a very transparent manner with the phase 3 clinical trial protocol as well as improving metrics and let me briefly explain the merits of our vaccine 1273 is based on messenger ornate and fundamental to the biology of every living cell and serves a blueprint for [ Inaudible ] synthesis from the vaccine body’s own cells to activate the immune system and enables the cells to make only part of the virus is critical for the immune system to recognize and in this case spike protein Partly the vaccine protein has inherent safety features in the [ Inaudible ] does not self replicate and does not enter the nucleus and does not integrate into the DNA The manufacturing [ Inaudible ] itself and does not use products of animal or human origin and does not contain preservatives or [ Inaudible ] avoiding potential concerns of older vaccine technology It’s not the first infectious disease vaccine and in fact we’ve been in early trials conducting clinical trials in general over 1700 healthy volunteers Virgo two is the ninth largest accounts which are [ Inaudible ] have a listed neutralizing antibodies and we have not seen a significant safety concern in any of the trials to date The companies consumption we been investing heavily understanding the critical quality attributes of the [ Inaudible ] and we have been using these insights can you improve the process and manufacturing capability we love [ Inaudible ] at the start of the pandemic to develop a product that remains and stable and cultured shifting in storage conditions that are widely available in hospital pharmacies and assisted-living skilled nursing facilities At the point of care can be deployed in a multiuse bio with no further mixing Ordovician and while remaining stable up to 12 hours at room temperature Phase 3 study which is the basis of the presentation today was conducted in collaboration with NIH and in accordance with clear FDA guidance In and rolled over 30,000 participants in believe the results support [ Inaudible ] authorization and NRA 73 eight exceeds recommendations and eventual licensure in the vaccine rate for symptomatic COBIT 19 infection was 94.1% with a 95% confidence interval lower bound of 89.3% in these results are clinically meaningful and highly statistically significant The efficacy observed is probably [ Inaudible ] subgroups Importantly we also observed the dramatic reduction in severe cases and all of the 30 severe cases observed at the time of primary analysis occurred in people given placebo and reduction in total symptomatic cases, predict reduction in cases leading to hospitalization and intensive care and death Finally data from nine weeks of [ Inaudible ] exposure and more than 15,000 people vaccinated with 21 1273 have characterize the short-term safety profile and we see generally good tolerability and most [ Inaudible ] reactions is systemic events were reported as mild-to-moderate and result quickly

It’s important to note and to educate people that we see an increased rate of severity of expected systemic systems like headache and myalgia after the second dose Review these as consistent of a specific immune response in transient and self-limited and do not see a significant safety risk These results support acceptable benefit risk for broad population vaccinations to help prevent COBIT 19 infections We acknowledge the need for longer-term safety and effectiveness data We continue to transparently share data and the independent will continue to monitor safety as well as monitoring duration of immunity and effectiveness We will continue to leverage the phase 3 trial even as we amend to enable access to participants who receive placebo In this regard we face unique circumstances and first as it relates to vaccine supplies, none of the trial participants would be quote unquote jumping the line a bit of others because we have clinical trial supplies available that in fact expire and go to waste if we don’t use them Second, all the participants are increased risk of infection and many have risk factors for severe disease One of the participants on the placebo arm died from COBIT 19 during this trial It was a 54-year-old male whose sole risk factor was diabetes And I work for to Doctor Bateman to describe the proposed steps on the trial which will continue to be overseen by the DSM B and provide significant additional ETA on both safety and effectiveness Beyond the phase 3 trial [ Inaudible ] will conduct additional studies in active [ Inaudible ] and workouts prints of understanding of the vaccine risk profile over time and we initiate pediatric clinical trials and national Institute with [ Inaudible ] people with cancer and continue to collaborate with FDA and other agencies together with additional long-term safety data And with the agenda for the rest of the presentation Good morning my name is Melissa Moore and I am a chief scientific officer at the proper research were due to Over the next three minutes I will walk you through a description of the Madrona vaccine platform and specific COBIT vaccine 1273 As the basis of the vaccine we created a messenger RNA or am RNA that only contains the instructions to make the stars COB to spike protein We manufacture the in large quantities and self three process that utilizes no ingredient of human or animal origin and within formulate the two [ Inaudible ] LMP and as can be seen in the electron micrograph to the bottom right the GMP manufacturing process yields a highly consistent product about 100 nm in diameter In in addition to MRNA and lipids the only other ingredients in the vial are water, glucose and two FDA approved pharmaceutical buffers Importantly the vaccine is no preservatives no antibiotics and components are rapidly cleared from the body When the vaccine entered muscular it’s big enough in the [ Inaudible ] with notes by specialized immune cells known as antigen presenting cells or APC Once inside the antigen presenting cell instructor sells protein synthesis machinery to make the spike protein which has been displayed on the cell surface In the note this allows B cells and T cells to interact with the spike routine and develop an adaptive immune response This adaptive immune response includes production of antibodies and development of two cell responses with the protein resulting in both immoral and [ Inaudible ] memory Once the MRA has been done it’s degraded Importantly the mRNA vaccine has no capacity to alter DNA First the externally delivered MRA constitutes only a tiny fraction of [ Inaudible ] molecules

in the cell Second it’s transient and remains in the [ Inaudible ] until lemonade by the natural MRA K process The alter DNA and RNA gain access to the nucleus and be reversed transcribed Seminary contains no singles for nuclear access and no known signals for reverse transcription So in summary, mRNA 1273 directly educates the immune system by instructing antigen presenting cells to synthesize the stars Kobe spike protein In this way it officially drives the adaptive immune response by protein expression Institute Annually MRA neither enter or interact nor integrate into the DNA Thank you I will now pause in hand the presentation over to Doctor Miller to discuss efficacy My name is Doctor Jaclyn million of the senior vice president therapeutic area had infectious diseases at Madrona When pleased to share with you details of the clinical development program in the key [ Inaudible ] efficacy results Before moving to our clinical program, I would like to review the key nonclinical results Generated an extensive nonclinical data package, three different animal models, including nonhuman primate or NHP or data demonstrates [ Inaudible ] 1273 induces humoral and cellular immunity including review cells in vaccinated animals We also challenge these animals [ Inaudible ] virus and found that the vaccine fully protect animals with sub therapeutic doses and no evidence of the vaccine associated enhance these Recently completed the developmental and reproductive toxicology study indicated no safety concerns Development of mRNA 1273 has been accelerated given COBIT 19 pandemic and nonetheless a full development program including phase 1, two and three studies have been executed and 101 phase 1 dose ranging [ Inaudible ] study affected across three age [ Inaudible ] 18 to 55, 56 to 70 and over 71 years of age [ Inaudible ] was a phase 2 [ Inaudible ] study The primary focus of the presentation will be phase 3 COBIT 19 — COVID-19 as it is enrolled over 30,000 participants approximately 15,000 of whom MRNA 1273 Study 301 study the vast majority of safety and efficacy and so let’s begin with study 301 The slide summarizes antibody induced by 100 terms of MRNA 1273 across three age strata Data error represents a panel of Tyler’s from convalescent [ Inaudible ] taken from individuals recovery from COBIT 19 disease — COVID-19 disease A benchmark to care between the doses and samples 54 days after diagnosis Neutralizing antibodies were induced in participant day 36 for one week And they were comparable across the three age strata and completing participants in the older age strata and persisted until day one — 119 [ Inaudible ] were further evaluated for teenage one anti-age to phenotypes and T cells were thought to be associated with enhanced [ Inaudible ]. The panel represents teach one [ Inaudible ] and the bottom panel is teach to and CD4 cells are induced by day 43 across age strata Minimal detection of the teach to phenotype This analysis showed no evidence of enhance I would now like to present the image in the city results In the study 201 The blue bars represent on hundred microgram dose in the gray bars represent placebo By day 43 there was more than a 50 fold increase in geometric [ Inaudible ] in the vaccine

and in the placebo group DMT’s remained below the level of quantitation In summary, phase 1 and phase 2 study show the induction of neutralizing antibody titers in all participants by one week following the second dose DMT’s were observed to be higher than those of a panel of convalescent [ Inaudible ] and neutralizing antibodies persisted for three months after the second dose across all three age strata [ Inaudible ] Donovan response was also observed across age strata and consistent with the findings animal models Now let’s look at the efficacy data from study 301 Study 301 was designed to evaluate the efficacy and safety and turn one of [ Inaudible ] 1273 compared to placebo and adults at least 18 years of age who are at risk for COVID-19 30,420 participants were randomized one-to-one received two doses of vaccine or placebo Participants received the first dose on day one and second dose one month later on day 29 Disciplines have been monitored for efficacy emergent mess of the and safety and points throughout the study It includes the measure of finding and neutralizing antibodies at the indicated time point Imagine the city samples will also be used to assess for asymptomatic zero conversion and non-vaccine antigen And if data were not available for the emergency use submission and not to be discussed [ Inaudible ]. Efficacy surveillance occur throughout the study And once diagnosed with COVID-19, participants went under daily close medical follow-up and participants were also given Paul six examiners to manage the oxidation and measure their oxen that oxygen daily Study 301 — occurred in certain negative participants and demonstrate success the lower limit of the 95% confidence interval for Rebecca seen has to be greater than 30% Secondary endpoints for efficacy include severe disease and death and COBIT — COVID-19 using CDC case definition and COVID-19 cases occurring after the first dose . Also a secondary objective to evaluate asymptomatic infection but the results are not yet available Please let me review the case definition for COVID-19 , severe COVID-19 Per Mary efficacy endpoints of adjudicate disease that occurred less than 14 days after dose number two And to be considered a case save COVID-19 in participant have experienced two systemic symptoms or at least one respiratory sign or symptom or clinical or radial graphical evidence of pneumonia and confirmed [ Inaudible ] infection from at least one [ Inaudible ]. And study 301 also analyzed efficacy against severe COBIT 19 — COVID-19 The meet all criteria for the primary endpoint and have at least one of the four following criteria Systemic illness or respiratory failure and respiratory distress syndrome or evidence of shock or significant acute organ dysfunction where admission to ICU or death To ensure adequate safety monitoring and to enable the interim efficacy analyses, the study has been monitored by a data safety monitoring board or DSM be It was chartered and convened by the national Institute of and completely independent from the company In addition an independent efficacy endpoint committee was assembled and determined if the case definition for COVID-19 severe COVID-19 were met . Many adjudicated cases for the primary efficacy endpoint and continues to adjudicate as they occur and ultimately adjudicate all cases reported

30,420 participants were randomized in study 301 and including 15,000, 10 subjects to the group The full analysis set include 15,000 and 181 participants that receive at least one dose of MR and a 173 and a modified intense to treat population with participants who had no evidence and infection prior to receiving the first dose of study vaccine or placebo It includes participants in the MA TT who receive both plan doses and have no major vertical deviation and 92% of participants vaccinated in both treatment groups are part of this population Now let’s return to the efficacy results One stratified to ensure we study participants most at risk for COVID-19 At least 25% of the study population would include participants over 65 years of age or subjects between 18 and 65 with [ Inaudible ] medical conditions and we were successful and enrolled a total of 42% of the study population in these two categories and let’s review the study [ Inaudible ] by gender and age Approximately equal proportion of male and female participated And the mean age was 51 in the range is 18 to 95 years 25% of the study population was over 65 years of age and half of those individuals were over 70 Age and gender distribution were well-balanced This trial included approximately 10% African-Americans and 5% Asian Americans and 21% of participants who identified as being Hispanic This is the breakdown of the comorbid conditions reported in the study 23% of participants overall reported at least one pre-existing condition And included 9% with diabetes [ Inaudible ] 7% severe obesity and 5% each with significant cardiac disease or chronic lung disease And specific inclusion criteria participants had to be for [ Inaudible ] and overall 25% of the study participants are healthcare providers and substantial proportion of the remaining subjects meet the definition for essential workers that the participants depicted on this table represent more than 50% of our study population And here are the numbers contributed to the endpoint by demographic subgroups 33 cases in the elderly and 10 of the severe cases 42 cases occurred from communities of color that have been disproportionately impacted by COVID-19 . This slide is the primary efficacy result for the prespecified interim analysis Primary efficacy hypothesis event Maxine after the second dose was 94 point Maxine after the second dose was 94.5% and lower limit of 86 point lower limit of 86.6% Difference between groups was statistically significant and the P value less than .0001 The incident rate in the vexing group was 1.8 and as compared to 33.4 to 33.4 thousand person-years in the placebo group This interim analysis was submitted as part of Trenton by the E UA The second analysis was performed when the full prespecified cohort of 151 cases COVID-19 accrued and two-month median follow-up time point had passed This analysis was predefined in the protocol as the primary efficacy And 196 cases, 11 of which occurred in the vexing group then 185 occurred in the placebo group Mouse — vaccine efficacy was 1.9% lower level of 90 — vaccine efficacy was 1.9% lower level of 93% and difference between the groups was also statistic Is it rate was 3.3 in the vexing group and compared to 56.5 [ Inaudible ]. Now I would

like to show you a forest plot of various subgroup analyses performed on the primary endpoint stratifying the population by age gender, race and risk factor Also did analyses with the primary analysis lending confidence to the generalized general ability of the efficacy And also evaluated is the efficacy of MRNA in severe COBIT 19 the secondary object and read severe cases have been adjudicated at the time of the primary efficacy analysis [ Inaudible ] reported in the placebo group Also evaluated efficacy [ Inaudible ] which required only one clinical symptom from an expanded list And a swab positive for [ Inaudible ] virus the point with this definition, 95.1% finally consistent on the primary C hypothesis Also investigated the efficacy against cases of COBIT 19 and 14 days after dose number one of a secondary objective 11 cases in the vexing group compared to 225 cases in the placebo group in for an overall estimate of vexing fricassee 95.2% The result is limited by the fact that not all cases are adjudicated for the 96% of participants receive their second dose We analysis included cases occurred after the second dose Nonetheless the fact that but because the estimate is consistent with the primary analysis and [ Inaudible ] cases that occurred in the modified intent to treat cohort since randomization is shown on the site and supporting the secondary efficacy analysis for efficacy after the first oxidation Based on this we also evaluated the percentage of subjects in the modified intent to treat cohort according to the CDC case definition which after randomization occurred These are the cases reported in each group stratified by two-week intervals up to the second dose Overall prior to 14 days post dose to their 62 cases in the placebo group as compared to a cases in the vexing group Most of the cases of vexing group were reported in the first two weeks after vaccination and taken together the analyses that projection may be prior to dose number two but for excellent protection the doses [ Inaudible ]. The protocol specified analysis and efficacy against asymptomatic infection is not available at the time [ Inaudible ]. However pre-dose number one and predose to portray one virus, and have performed a descriptive summary and curing positive swabs as a way to estimate asymptomatic infection Among baseline negative participants, or tenet of the vexing group and 38 in the placebo group had evidence of stars infection at the second dose without reporting comes And nearly 2/3 fewer positive swabs in the vexing group as compared to the placebo group as the predose to time points and thus the possibility prevention of asymptomatic In conclusion [ Inaudible ] 1273 demonstrated clear and compelling evidence against symptomatic [ Inaudible ] was 94 point [ Inaudible ] was 94.1 and the lower limit of the 95% confidence interval of 89.3% successfully meeting the primary efficacy hypothesis and exceeding FDA guidance At the time of the data cut off, 30 cases of COVID-19 occurred in the placebo group and no cases occurred in the MRNA group . Efficacy against severe disease reassuring about the lack of enhanced disease and participants in this trail will continue to be followed

for breakthrough [ Inaudible ]. All key secondary sensitivity and group analyses were consistent with the primary analysis Underscoring the performance of the vaccine across high risk population Given the high and consistent efficacy [ Inaudible ] 1273 offers the potential to address public health crisis of COVID-19 Thank you . I would like to invite David Martin to discuss the safety data Good morning, when we name is David Martin and I am the vice president from coal objects and Madonna The study represents 97% of total mRNA 1273 vexing exposures I will present the nine week median exposure follow-up data using the same November 25 data [ Inaudible ] is the primary efficacy analysis This provides 6579% years of safety data and represents 20% more follow-up time than previously available in the E UA which is a seven-week medium Let’s look at the study 301 safety data More than 30,000 participants were enrolled and received at least one dose In both groups compliance with getting a second dose was high and about 97% of participants receive a second dose and as of the data cut off, more than 60% had completed two months follow-up Now moving to the data, getting solicited adverse reactions, turn one for the entire population, overall more solicited reactions reported in the MRA 1273 than in placebo with a consistently higher occurrence after the second injection Here are the data for solicited local adverse reactions after the first injection As you see, the most commonly reported was pain 87% of participants in the MRNA 1273 18 to 65 and 19% of the same age range in placebo group experienced pain And participant 65 and older 74% of the [ Inaudible ] and 13% of the placebo group had pain and similar patterns but much lower rates were seen for [ Inaudible ] swelling and [ Inaudible ] swelling or tenderness These reactions were most mild to moderate in severity represented by the dark green shading, great number one in the lighter green shading grade 2 Grade 3 reactions shown here in orange occurred at lower rates and no grade 4 reported an overall local reactions were short-lived for the median duration of 1 to 3 days And a similar pattern was seen for solicited local adverse reactions after the second injection and again most commonly reported was pain Higher percentage of participants in the MRA 1273 groups experience the symptoms with an increase after the second injection compared to the first Again grade 3 reactions occurred at low rates and no grade 4 events were reported Here we look at solicited systemic adverse reactions after the first injection [ Inaudible ] myalgia were the most commonly reported and they were mostly mild to moderate Grade 3 reactions occurred at a low rate and grade 4 were even lower Great for reactions aren’t visible because they were reported in 0.1% or less in both groups The reactions were also short-lived lasting medium 1 to 2 days Here on the data for solicited systemic adverse reactions after the second injection As you see there is an increase in grade 3 reaction after the second injection in the MRA 1273 group Again the grade for reaction occurred at very low rates Overall most reactions were still mild to moderate and resolve within 1 to 2 days I will now review the unsolicited adverse event

An unsolicited adverse events were reported in the overall stage of the trial and comparable to the groups between There were seven [ Inaudible ] in the placebo group In this figured depicts medically attended adverse events by system organ class These two were comparable between and the rates were [ Inaudible ]. And here we see serious adverse events by system organ class and these were comparable and infrequent with no terms reported in more than 0.25% of participants Deaths were balance between groups and assessed by investigators not related MRA 1273 This slide shows solicited adverse reaction rates after any dose by baseline [ Inaudible ] status of group Rates are shown being local adverse reaction to the left and systemic adverse reactions on the right These data indicate individuals who were positive at baseline did not experience higher rates of solicited adverse reactions and baseline serum negative We have actively scrutinize the safety data to identify and analyze possible cases of anaphylaxis and we found no cases suggestive of anaphylaxis mRNA 1273 It’s important to note participants with a history of anaphylaxis [ Inaudible ] or other significant hypersensitivity were not excluded from study 301 and two anaphylactic reactions reported unsolicited adverse events and one in placebo and one in MRNA arm . Placebo occurred 10 days after the first dose attribute it to radio contrast I am the participant received the second dose of placebo MRNA event occurred 63 days after the second dose [ Inaudible ] asthma and allergy to [ Inaudible ]. We also ran as measure query and reviews events occurred within 48 hours of vaccination Non-met Brighton collaboration in a flexible case definition criteria Of course we continue to actively monitor for the events And I will now review the safety monitoring activities with the post-authorization period Maternal works hard to have a vaccine monitoring system that complements US government and other established programs And focused on identifying safety signals as rapidly as possible in the system has three goals One to monitor adverse events of special interest and other concerns associated with vaccines in general We will of course look for [ Inaudible ] patterns but we will also actively monitor ASI in real world healthcare data as I explain in a moment With respect to safety in the event of vexing exposure during pregnancy, developmental and reproductive study was completed in December 2020 with no adverse findings Given the limited human exposure to date in the phase 3 trial, we will establish a registry that includes a cohort recruited from the general population The second broad goal is to monitor long-term vaccine effectiveness in the study and integrated healthcare delivery system Third, we identify and assess unanticipated safety signals as rapidly as possible and again my monitoring adverse event reports from the US and from other countries In addition using real were dated its anticipated safety signals to the vaccine monitoring system as I will describe Given the recent events in the United Kingdom, we know active surveillance system using a large status course is critical to capture rare adverse events We will identify expected rates of ASI prior to vaccination using a cohort of 45 million adults from a large claims data source In this case visual you see how the sample with women and in red and men on the right

is US population The cohort complements but does not duplicate the large electronic health data surveillance system operated by the FDA and CDC Next, after observed rates postvaccination, we will follow new vaccine administrations providing data updates every two weeks and this will enable analyses comparing observed to expected rate We will also include linked open claims data for early visibility on vaccination that can be connected to subsequent adverse events In addition to ASI, we rapidly add new safety signals to the monitoring program for assessment In conclusion I would like to point out that collaboration is key to a successful global safety monitoring system in a worldwide pandemic and maternal risk management plans are currently being reviewed by the FDA as well as international regulatory agencies We will interface with vaccine safety stakeholders to learn from the safety signal to pension program and to share information and these will include the US FDA CDC as well as international regulatory public health agencies Working together we can enhance public confidence in the vaccine through robust collaborative robust monitoring and I will now turn the lecture over to Doctor Lindsay [ Inaudible ] who treats COVID-19 patients and will share clinical perspective on the ongoing phase 3 trial Can you hear me? Yes we can serve I am Doctor Lindsay made in and an investigator at the Brigham and Women’s Hospital at Harvard medical school Medical journal editor in one of the co-three principles and investigators of this trial As coprincipal of the study I am funded by the NIH for this work I received no funding from Madrona and share my views but they are informed by many discussions with colleagues at NIH and any ID and co-VPN and maternal studies PIN site staff and study participants among others Efficacy data from the two large all done phase 3 trials are compelling They’re not lost on many of the study participants How many more severe illnesses will we have and we have about 2 to 3 per weekend that we need to convince ourselves of the short term efficacy? It’s important we carefully consider the volunteer viewpoint as we navigate fairness, equity, trust, transparency as well as a larger societal interest Without them clinical research cannot function and we have unique obligations to handle the study properly and as either likely the large-scale data from a high-quality randomized allocation and process Future observational work will be invaluable but will have methodologic issues required challenging analytics to get correct There are many ethical challenges in trial conduct in the core one is a study volunteer should not be disadvantaged Principles of research require our informing participants of new information such as a clinical available perception effective which Severe illness and by doing this we build trust and research broadly We need to communicate with the study participants in the clear and understandable manner and their intelligence and informed and in boat with their feet and we are currently 21 since UA authorized last week having substantial dropout study participation given the increasing available of vaccines, the dropout undermines the data integrity what can be learned We must be proactive to ensure the best choice is for the participants to remain in the study and continue to make sacrifices that they have done and must ensure our ask of them is reasonable and respectful This requires moving with haste and ensuring all are treated fairly Those who are more health and health system savvy and vocal be treated differently than

those who are more passive in the process The study enrolled rapidly especially in Caucasian and healthcare provider communities Given efforts to enhance diversity participants enrolled later in the study were from more diverse communities The communities enrolled earlier in the study be treated differently than those communities enrolled lady — later in the study? And the majority of those in this trial as already mentioned fall into CDC priority groups 1/8 through C CM do use numbers on the image need to be interpreted carefully as one a and B are mutually exclusive but not with group 1 and see This reminds us the majority of the volunteers hubs essential risk for suffering significant health car consequences from COVID-19 Maintaining the volunteer in the research trial, not just for the next three months but the next 18 months is of value To this end, they have informed me us that they have residual search label vexing product which is due to expire soon which could be used for an open label crossover redesign of the study The vaccine product will likely be unavailable for the purpose giving time and regulation The next image shows, many possible piles With the original double-blind for six months unlikely to be successful due to volunteer dropouts and double-blind crossover in open label crossover as we see in this image Going to come at the moment on the double-blind crossover And it is my favorite design and I am a co-author in the paper and discussed it extensively with Doctor Foreman and others as we have thought about redesigning the path forward since efficacy data emerged from the DSM B meetings someone — a month ago The problem is it’s impractical at this point If we lose the volunteers than the ability to learn anything further will be substantially impaired We must carefully consider the merit and risk of the different path forward but we do have to choose a path forward and one that hopefully builds participant trust and enables us to gain more knowledge as to how the vaccines work In this image as a pragmatic path forward, what one sees is re-consenting of all volunteers and informing them of the new E you a and taming serology from the double-blind RCT component of the study and allow us to make an assessment of the vaccine on asymptomatic and sub- clinical infections and we need high compliance with the data point At this point the volunteer can choose to stay in the study as designed double-blind placebo-controlled or crossover to an open label format with placebo recipients now being vaccinated All will be followed the original study design including assessment of safety you know tenacity and [ Inaudible ] so research continues and this is not clinical application that this is a continued research study evolving to an open label format from a double-blind format The volunteers in the late vaccine recipients will allow systematic knowledge to be engaged including a potential identification of a car lots of protection By using vaccine research there’s no impact on the clinical [ Inaudible ] deployment and I’ve known about two thirds of the volunteers would make it to the six-month double-blind placebo-controlled follow-up in March Crossing over to an open label format in the next month or so would lose about two months of volunteer blinded follow-up We carefully balance the value of collecting data from a double-blind format with the ethics and participant interest which will translate into study retention or loss to follow-up and the impact on data and knowledge that can be gained In the proposal on this line, all volunteers are treated equally and the enterprise continues to build and maintain the trust of the communities and society gains knowledge The proposed design balances obligations to both volunteer and society We must continue to learn from those who are in this with four and six months ahead of us and there are many more questions over the next month in years that these volunteers

can help us answer Only if they stay in the study and if the volunteers leave the study particularly for nonrandom reasons than future knowledge will be fundamentally undermined I would like to now turn the lecture back to Doctor Zaks Thank you I will briefly conclude In conclusion the data study 301 supports emergency use authorization and expected it to support licensure and adrenaline role characteristics need to be characterized and occurred on trial and using [ Inaudible ] surveillance during real world deployment For further on bearing [ Inaudible ] and clear and timely guidance of FDA and look forward to the opportunity to rent [ Inaudible ] with [ Inaudible ] 1273 and also appreciate the efforts of this committee for reviewing the data and look forward to answering questions Thank you for your attention and turn it to [ Inaudible ] to moderate Q&A session Doctor Miller, I think I am the one that is supposed to moderate Q&A session There will not be very much time to do it now, we have a few minutes for the start of the Q&A I want to remind everybody that the open public comments is a fixed part of this meeting and it will start at Eastern time and go for one hour and we also need to have a short break before that time Especially for technical reasons We can only have a couple questions now Will circle back and I’m sure you all will remember the questions you have stored and have a question session starting at one Eastern so a couple questions now that I see many hands raised and I will do the first few right now and put the rest of them off till 1 PM Doctor off it? In the 11 breakthrough class — cases you showed data that you have [ Inaudible ] collected at the following dose So what I’m trying to understand the characteristics of the 11 cases and it may be that there is [ Inaudible ] which Doctor Baden said that it’s important to know so it’s great to have the data but it sounds like you don’t have them yet, is that true? Yes we expect them in January Is there any other characteristics that distinguish them from those who were protected by the vaccine? Nothing in particular These were cases that were relatively even given the small sample size between male and female, three were Hispanic and eight were white and non-Hispanic and they ranged in age from 29 to 72 Okay thank you very much Doctor Ganz? Thank you very much and thank you for the illuminating presentations One was a continuation of the breakthrough cases that Doctor [ Inaudible ] raised and not only [ Inaudible ] trying to understand protection he expected but one of my questions and it alludes to the breakthrough is [ Inaudible ] immunity was only evaluated not to in phase 3 and I don’t know of those samples are also being included and in particular relevant to the phase where the breakthrough, my other question which you can either in an hour later is what about other adverse events like those policies which we did note and of interest because it seems to be a signal not only with the vaccines but the others Thank you for those questions Given the review of last week we look carefully into the data and have four cases souls policy that three of them occurred in the vaccine group and one of them occurred in placebo group and this will be part of the postmarketing safety surveillance so in addition to continuing to monitor through the phase 3 trial, as a vaccine is hopefully authorized for EUA and

expanded, this is one of the key safety endpoints that will be in the signal [ Inaudible ]. Question about the T-cell immunity, the T-cell work, it’s done in collaboration with the NIH in phase 1 clinical trial and in terms of looking for a [ Inaudible ] production the search for Corlett, it has focused up until now on the neutralizing and finding antibodies responses I mentioned the breakthrough cases that we observed will go towards that analysis and as we continue to accrue data in the trial additional breakthrough cases will be added to that analysis The samples in phase 3 as they require special handling for T-cell immunity and as we were implementing across hundred US sites T-cell immunity was not part of what we instituted in phase 3 The Corlett work that we collaborate with NH will focus on the finding Doctor Moore Also I want to thank you for presenting the data even though it was [ Inaudible ] data on the asymptomatic I feel it’s certainly important for control of this epidemic And could determine the widespread use of one vaccine versus another Although it symptomatic is the surrogate measure for [ Inaudible ] and a common sense measure or shedding at least So if you break blunting, do you anticipate Reese wobbling all the participants before hand and what are your plans for a second swab? I know you measured them) or the second dose and is there a plan for having another nasal swab? Thank you for the question You are correct it was the predefined swab that both pre-dose one and two that enabled us to be able to do that analysis and a free transition swab certainly can be implemented into the phase 3 study The way we predefined the surveillance for asymptomatic infection was actually through serology against the anti-[ Inaudible ] protein so is a certain logic evidence immunity to [ Inaudible ] and to your point swabs and a lot of importance in additional data Further data not available at the time of the E EUA include swabs that we obtain frequently from subjects too were found to be COVID-19 positive The intent is to look at the viral shedding and burden of shutting comparatively So we should have additional [ Inaudible ] The sequence of the virus? Do we have any idea whether the virus escape from when you ask and? We are deep sequencing the virus as part of the surveillance of the breakthrough cases and I’m going to ask Doctor Darren Edwards — we have time for exactly one more question We will circle back and I will call on you again to answer the sequencing in question which is a big one Doctor [ Inaudible ]. Your final question I was concerned about the lower efficacy in the lower age group and if you only thoughts about [ Inaudible ] hard dose or additional injections and comments about that? The older age group, I want to mention, let me bring up the slide That efficacy is based on a relatively small sample size with a wide 95% confidence interval It completely overlaps with the competence and a roll to the overall efficacy and it’s based on 33 cases and if you were to evaluate the efficacy in those above 75 years of age and an even greater risk their seven cases all which were reported in the placebo group

and it highlights and certainly very helpful to look at the subgroup analyses to ensure were not seeing dramatic differences We have to keep in mind there are not multiple adjustments for the multiple endpoints and the view is actually efficacy in the elderly is indeed consistent with the efficacy in the overall population Thank you all Thank you to modernity and don’t forget you have to come back and answer questions at 1 PM Now we have a break until the open public hearings which starts at exactly noon Eastern time We will take us to break Hang on one second

We are clear Tony, start bringing them in

In the meantime, Doctor Mildred, do me a favor we are doing double duty, I can clear the

countdown timer, let’s check your camera again I’m showing your camera was not connected Should I sign out and sign back in? Do you have a window closing it? Before you try that, if you and mind it is not covered because it looks like it is active block? It is not blocked Make sure if there is a start sharing button usually in the top left — I disabled it Then thirdly where you see the WebCam icon it’s a circle on top of the triangle in the top left-hand corner If you select the drop-down arrow to the right, you should see an option and make sure the camera that you select is a camera you want to have an external 10 maybe selecting a different one Do you have an external camera you are using? Know, it is only one camera — Greetings to all those joining the meeting right now Please keep your phone silent while we call in all speakers Please make sure you are muted and we will do a audio check after we get everyone in and we are also doing technical stuff in the meantime Doctor, go ahead Opiates you are calling in and we will go over all that after we get everyone in but there is a lot to call in I think at this time if you would exit the application and log back in and when you come back in, for activating the camera, you will get a notification from your machine that saying this application is trying to use your camera and make sure you allow that Let’s try that next Give us a moment while we get everyone dialed in and I will test all OPH audio feeds Then we will go from there Please stay muted or silent for a moment [ Captioner standing by ] FDA encourages you if you don’t have any such financial relationships, and if you choose not to address the issue of financial relationships, at the beginning of your statement it will not preclude you from speaking Over to you [ Inaudible ] to lead the discussion Good afternoon everyone Think you for joining us today I will [ Inaudible ] and when I call your name you can start speaking and when you are finished please meet your phone so we can call the next person [ Inaudible ] thank you The first name is Doctor Winston Wong Go ahead please Thank you for the opportunity to provide public comment I am the chairperson and acting CEO of the national Council patient specific [ Inaudible ] position I have no relevant financial disclosure to share and I speak on behalf of the national Council that was informed 10 years ago to provide application voice for actively committed healthcare needs in public health [ Inaudible ] federal agent specific [ Inaudible ] in need of Hawaii communities [ Inaudible ] can you please go to the next slide which shows the local national Council? In the context the impact of COVID-19 in API community has been under recorded and impact on the community, mirrors that of other of color and can you go to the next slide which talks about underreported story? For example, according to the recent report from the Kaiser family foundation, derived from epic electronic health records from 52 million patients across 32 states, Asian Americans were less likely to get tested for COVID-19 and more likely to have a positive test results require a higher level of care at diagnosis Moreover, more likely to be hospitalized and I compared to all other racial ethnic groups in cording to ethnic data I referenced So the spec drop [ Inaudible ] the news of [ Inaudible ] vaccine with caution optimism The communities need the protection offered by the promise of this vaccine With that in each and API community must incorporate critical components that are both relevant and unique to the population and go to the next slide which starts with the title critical issues and deployment and therefore the organization recommends number one, data for the broad

category of the AA NH PI and efficacy and potential adverse vaccine events and recognition that this category is comprised of dozens of subgroups An important differences can be lost when data is not broken down The next light has numeration As the vaccine is deployed the immigration status of Asian Americans individuals should not be a very are for [ Inaudible ] and those the vaccine itself may be free of charge to US residents in the special status of individuals from the specific jurisdiction such as Micronesia should be accounted for As the modernity Maxine is deployed every effort should be made to provide information about background in a culturally competent and [ Inaudible ] accessible manner Many AA in API individuals travel to and from Asian countries and also obtain information about COVID-19 other than those that originate in the mainstream and or American [ Inaudible ] effort should be made so that there is no confusion or misinformation about individual vaccine stops Decisions and other clinicians from Asian-American native Hawaiian subsonic Hawaiian communities like those amenity health centers, could be supported is critical ambassadors that advocate for the [ Inaudible ] vaccine Thank you for allowing me to have the updated comment on the important issues relative to the Asian-American native line community as we look forward to the approval of the modernity Maxine — Madonna vaccine Butler Executive Director Hello minus test my name is Lisa Butler [ Inaudible ] at this time I have no financial [ Inaudible ] conflicts of interest to disclose and thank you to the FDA for this opportunity [ Inaudible ] syndrome is acute inflammatory disorder of the [ Inaudible ] urban characterized by the rapid onset often paralysis of the legs arms [ Inaudible ] muscles and face in this paralysis is [ Inaudible ] the cause is unknown and we do know about 30% of cases occur shortly after Michael [ Inaudible ] section or viral bacterial and some are simple and common as flu or food poisoning and miniseries suggest an autoimmune trigger Over 19 pandemic flurry of incentive for healthcare for nationals and [ Inaudible ] application in the community [ Inaudible ] increase with triggered by Cove in 19 fortunately despite a handful of [ Inaudible ] cases happening around the [ Inaudible ] infection that have not been any indications increase risk from COVID-19 infection . And confirm there’s no epidemic association between the COVID-19 There should not be any increase risk GBS from the COVID-19 vaccine and see the chart on the slide permitted 76 apparent association between influenza vaccine and GBS and since then several studies research the risk of GBS after influence vaccine and found no or very small increase was someone contracting GBS after influenza vaccine And it’s highlighted by article [ Inaudible ] and musician safety office of the CDC Additionally leaving [ Inaudible ] experts remain confident that any cases resulting from mask vaccination of the global community are coincidental and likely and learn what the expected rate of [ Inaudible ] and regardless of the science devious community expresses understandable [ Inaudible ] towards vaccination Safe and effective vaccine across [ Inaudible ] a beacon of hope for many Americans The Hamburg syndrome community feel the renewed sense of worry and panic that the news of this expedited miracle and though the data is still quite limited the foundation Global medical advisory board in [ Inaudible ] are hopeful that the relative risk of GBS infection is not significant and there’s no reason to turn on the vaccine would cause it The foundation urgently hopes that the partnership with FDA to collaboratively instill necessarily [ Inaudible ] community regarding [ Inaudible ] vaccination especially the COVID-19 vaccination

so we continue to rely on experts for their assessment of science and safety In conclusion we are a nervous patient committed and optimistic for the future and thank you for your interest Thank you The next speaker is Doctor Diana Ackerman We scrutinize safety don’t accept funding from companies that make products of my expertise is based on training and epidemiology as well as a former faculty member and researcher at [ Inaudible ] yell and Harvard and former fellow [ Inaudible ] at Penn I also worked at HHS and [ Inaudible ] Next slide Focus on three concerns Number one, the two month meeting and follow-up is too short and so [ Inaudible ] is proposal to immediately underlined and offered to vaccinate the entire placebo group should be rejected [ Inaudible ] recruited a diverse group of participants but only four cases were black and even fewer were other racial groups We can’t assume the vaccine would highly [ Inaudible ] in demographic groups with so few cases And 25 cases among participants with comorbidity which is slightly more substantial Number three, glad to see that unlike Pfizer, modernity provided a total number of participants who reported one or more adverse events That’s important Unfortunately the total severe systemic adverse events, after the second dose was 17% for the vaccine group compared to 2% for placebo There were 30 severe covert cases after the second dose and none in the vaccine group This is a strong finding and nine required hospitalizations but 12 or based on the questionable criteria of at least slightly low blood oxygen saturation Long-term care patients were not included in the study 1300 people over 75 were in the study but only three were cases We want to save their lives but with no data it’s not possible to provide useful and conform consent with nursing home patients and that puts a tremendous burden on those patients and family members We need longer-term data on benefits and risk The vaccine is clearly effective but doesn’t last too months or four months or one year To learn that FDA needs to ensure the blinded RCT is continued Last slide In conclusion FDA initially target authorization to priority population and if the EO and he is given for all adults, celebrities and others who are well-connected will cut in line and we have already seen that [ Indiscernible – multiple speakers ] Under FDA expanded program and we need at least one year of blinded randomized controlled data I agree with Doctor Goodman’s proposal that FDA should delay access to vaccines by placebo group members unless they are in priority population Blinded crossover is better and not continuing a blinded control study and if that is the only alternative thank you for the opportunity to speak today Next speaker Good morning I am Doctor Charles Lee and next slide please I represent the American College of correctional physicians and speaking on behalf of correctional workers in those incarcerated There are no conflicts Look at the numbers there are 2 million people incarcerated in the United States and 500,000 workers working within correctional facilities The infection rate among those incarcerated is six times that of the general population 1700 folks have died Why so many? The inability of inmates to follow CDC guidelines and why?

Not socially distant and unable to get proper hand sanitizer is because of the alcohol content And the inability to get [ Inaudible ] tested and many of the facilities are eight and 19th century and may not get mask and realize this varies from facility to facility Increase vulnerability, the inmate has [ Inaudible ] medical age of 20 years younger than that of the general population Someone 50 incarcerated his body equates to that am someone 65 and increase percent minorities within correctional facilities So patients who have core ability reliabilities and asthma cardiovascular disease and increase [ Inaudible ] out of necessity they have close contact within and extremely demanding working conditions Fortunately [ Inaudible ] may get sick and thereby unable to probably manage the facility increasing danger of the correctional facility Consequences of this, increase death and series of patients that they die from coronavirus As a result of this increase community infections and 90% of inmates are released at some point in time and workers go home daily and increased use of community [ Inaudible ] and hospitals were patients incarcerated become sick in the modernity vaccine has certain advantages that may be extremely applicable with correctional population And as a result the American College of correctional positions recommend approval of [ Inaudible ] modernity vaccine Thank you very much Thank you Doctor Lee Next speaker is Doctor Ojikutu My name is Doctor Ojikutu and I have no financial disclosures I’m provided in Massachusetts which has one of the highest death rates in the country and [ Inaudible ] Massachusetts General Hospital and I’ve been working directly with what community members for the last few months for the coded data COVID-19 mixing as many have . Many community members that I work with have suffered personal losses and secondary [ Inaudible ] so this is an important issue to them In the process working with the black committed I have attended numerous town halls and had many meetings and discussions and I think it is important to of the size in this trust are government and pharmaceutical industry and those recent poll shows willingness and acceptance may be increasing and still believe it will delay the mistrust and completely inhibit uptake in these vaccines While it’s highly unlikely we make our institution more trustworthy over the course of the next few weeks the vaccines are rolled out and I and others believe the same amount of effort and funding that was placed into the development of this and other successful vaccines needs to be directed towards ensuring uptake and promoting vaccine competence specifically within black ethnics in communities who are most proportionately [ Inaudible ]. First we need better messaging It will resonate [ Inaudible ] diverse individuals Second we need more intensive community engagement I’m well aware initiative that quite frankly easily [ Inaudible ] and what has been done thus far is nowhere near enough In terms of messages first we need complete transparency in laying which was side effects and need to be honest Can emphasize many unknowns and much work needs to be honored Secondly the government institution and industry need to consistently acknowledge systemic and equity in structural racism have led to this mistreated trust Third we need to reframe vaccination of empowering the community and fighting back Lastly we need to explain the process of the process that we are part of today to the community

People want to know, who’s looking out for them in the best interest and in the interest of people who look like them and who is at the table — Vaccine development process and not engaged early enough and that’s a problem Going forward we must change that dynamic People of color will begin to trust the process in the process of other vaccines if they feel they are truly part of it Therefore community engagement and committee investment must be enhanced and amplified and fully supported I believe this is necessary and we continue to see racial and ethnic disparities and not end the epidemic Thank you The next speaker is Doctor David Berger My name is David Berger and think you for the opportunity to address the community again I have no conflicts of interest I’m a board certified pediatrician and [ Inaudible ] from the available data it appears Madera and vaccines are quite effective in minimizing the [ Inaudible ] trend to disease and this is an accomplishment that will help aid in [ Inaudible ] of the virus Vaccine has [ Inaudible ] healthcare community and public at large and full transparency can reduce [ Inaudible ] and as more manufacturers apply for authorization, I urge the NCA to provide timely information for review and meaningful in what is [ Inaudible ] given two days to review manufacture data for addressing the committee or when data is released after deadlines pass for submission [ Inaudible ] are one of the first target populations to receive COBIT vaccines and if only 816 [ Inaudible ] were included in the reported data, Madera data subjects over 65 years old build distinction of the participants over 75 years old The team found minimal data on pregnant women wear those with pre-existing allergic [ Inaudible ] autoimmune condition and that is not available it’s hard to for individuals to weigh the risk of an offense which is fundamental to making informed decision As for the Pfizer vaccine [ Inaudible ] report incidents of those all the number of cases with a small fraction we monitor this to see if traffic for this and other [ Inaudible ] conditions Please provide long-term data and outcome who may develop and significant may take longer than two months to become evident please provide quantitative standards for the antibodies and people can determine if they have immunity and if there is immunity is persistent Our team has not discovered significant differences in efficacy or adverse events between the Pfizer and Moderna vaccine and we comment on other manufacturers as apply for emergency authorizations and it’s awful to have comparative data to guide decision-making process between rants The vaccine consideration project is a central repository health and safety concerns and the national network of medical graduate students are compiling and analyzing [ Inaudible ] data and evidence-based information to help address concerns We are inviting all interested students and professionals and others to join supporting efforts by connecting with us with vexing considerations It’s critical that rigorous mechanisms maintained and given complete transparency with data and closely monitor and report on unique subpopulations such as different minority racial communities, elderly and those with allergies and autoimmune and hyper inflammatory conditions With such actions FDA indexing manufacturers have the opportunity to provide Americans information they need to make the most informed decision possible for themselves and loved ones Thank you Next speaker is Doctor Khanasekaran — Stanford University California I am here at the physician to advocate for vaccine access Patients and also [ Inaudible ] conducting COVID-19 research No conflict of interest to disclose . COVID-19 is a global public health crisis More than 290 More than 290,000 deaths in the United States alone

Patients with chronic medical conditions like cancer and heart disease and obesity experience worse [ Inaudible ] COVID-19 in taking care of the sickest patients with chronic [ Inaudible ] diseases and compromised patients I have personally seen the devastation that COVID-19 has caused for patients and [ Indiscernible – accent speaker ] the vaccine local relief for [ Inaudible ] patients and chronic medical conditions As discussed by earlier speakers the vaccine has been shown to be effective in preventing COVID-19 and I looked at the data I was happy to see among the 30,000 participants in the study 7000 were over 65 years and 5000 were younger than safety five years and they had underlying medical disorders obesity cardiac disease and overall 42% of the cohort consist of the medically high risk groups and this is reassuring to me and these are the very patients who are in dire need for this vaccine Moving on, I would like to [ Inaudible ] that communities of color have been affected during COVID-19 . The CDC probes has been X are at more than 2.5 times the risk for death with COVID-19 then They show [ Inaudible ] factors in medical community play a huge role in this I’m happy to see the study cohort 11,000 people amenity of colors with 6000 Hispanic and 3000 black and I believe these communities will benefit greatly with the vaccine approval I reviewed the safety profile of the vaccine and the vaccine was generally validated asking [ Inaudible ] listed here and in my opinion the benefit far outweighed the risk versus investing especially in patients with communities Next I would like to end with these points and number one safe and effective vaccine need of the hour, burnable populations will be especially well served with the vaccine approval Thank you for the opportunity to speak Thank you Next is Doctor Marie Garlock Good morning I am Doctor Marie garlic and a board member of the Abbasid group and not funded by [ Inaudible ] industry in any way and completely independent Hundreds of members across the nation are patient caregivers and advocates for drug and device safety and efficacy and affordability A letter submitted to the doctor has less [ Inaudible ] main concerns and action items and I would like to say before we moved to the next slide trend when given recent project oversight reporting to start with a note and deliberation must take time to transparently include all expert member questions [ Inaudible ] an explanation Today is not about PR is about public health seriously commitment on which FDA should must make good Next slide trend on stopgap standing clinical trials must continue Here’s the basic part, do you want to control and we have to control the group going in anything less accountability for industry and FDA, we need public trust in [ Inaudible ] axioms and only come from transparent mayors how they in turn and what that means possible groups must continue along these trials Metrics that matters in the vaccine from its transmission and severity with hospitalization and death and next we need to incorporate the national vaccine injury compensation program and folks can go to [ Inaudible ] and then we need for health media elected officials and FDA and Moderna are not FDA approved and we need transparency on that and [ Inaudible ] to not ever be president for future similar or [ Inaudible ] devices should be rust [ Inaudible ]. [ Captioners transitioning ] Because this population is so vulnerable how many of these other frail population The need to understand that after getting the vaccine [Indiscernible] they need to understand racial and ethnic difference Given systemic differences with COVID-19 health disparities we need besides numbers for black,

indigenous, Pacific Islander, Hispanic, and in order those folks in comparison to their white counterparts they are three times as likely to die from COVID-19 and four times as likely to be hospitalized with severe COVID-19 In a framework called structural competency we know that systemic racism helps with parallel health challenges for the insurance coverage and directly affecting COVID-19 severity and hospitalizations and deaths We need Nuance on the numbers and in these specific groups and placebos first phase for four They meet standards that have a systemic fix We commend Jonah — Moderna but it should not be [Indiscernible] thank you so much and I would like to ask the FDA to focus on meeting the nuance on the numbers and keeping the control groups going and knowing the integrity requires adverse event reporting and structure and that action means action FDA must ensure safety and infection practice Thank you Thank you The next speaker is Mr. Gwen Schell My name is Gwen Schell I represent a community of rural populations and I work for a public health district I want to describe the impact that COVID-19 has had on rural populations and touch on the value of the vaccine We have very limited nursing staff in this part of the United States and in a rural population that nursing staff is covering an area of about 500 miles We have noticed an uptick in people being sent home from the hospital who are not meant to be home All of the local assisted living and skilled nursing facilities are very particular about who they take A vaccine would not only benefit those who are at risk for contracting COVID-19, but would also benefit the health population at large I wish to express our excitement and gratitude for treatments that are coming I forgot to mention that I do not have any financial ties I just wanted to bring to light the impact that a vaccine will have on rural populations Thank you Thank you The next speaker is Dr. Douglas Dietrich Thank you I am Dr. Douglas Dieterich I work at Mount Sinai health system in the professor of medicine I am here as a patient, actually, not as a professor Even though COVID-19 causes significant liver disease and significant mortality in patients with pre-existing liver disease I think it is important to recognize that there is a space between life and death The deaths are extraordinary, 3600 yesterday, and the number of people infected I was infected in mid-March as was about two thirds of my clinical team I was hospitalized for about a month and sent home on six liters of oxygen Subsequently I discovered that I had severe peripheral neuropathy in my feet and severe fibrosis, pulmonary fibrosis which I am still getting treated for Actually both of them Of course, my sense of smell is completely gone

I think it is important to recognize that as good as our treatment is now, prevention is clearly much better There’s a lot of long-term effects of COVID After I was at home for a few months I develop some severe atrial arrhythmias When they subsided I developed severe hypertension which I am still battling Of course, I am still taking medicine so that I can feel my feet and hopefully recover some of my sense of smell I think the important thing is that there is a real price to be paid for getting COVID, whether it is severe or not There are long-term side effects and I think the vaccine is the answer to prevent COVID-19 and not to get it As good as the treatment is now days In addition, even though my antibody levels remain extremely high, I will get vaccinated when my time comes I think that is an important thing to recognize as well I wanted to thank the Moderna people in the other vaccine makers for helping us prevent this disease so that other people don’t suffer like I have Thank you for the opportunity Thank you The next speaker is Dr. Jasmine Marcelin Thank you I am employed by the University of Nebraska Medical Center My comments do not represent my employer I have no conflicts or disclosures to report After reviewing the available information about the vaccine developed by Moderna, I am encouraged by the medical % effectiveness demonstrated and review of expected adverse effects I would advocate for continued long-term monitoring of clinical trial participants to evaluate for the long-term effectiveness and safety However, I am encouraged for this vaccine to receive EUA status with prioritization for those highest at risk We still need data regarding pregnant people and children and we hope that there will be more sharing of these outcomes as people become pregnant I noted that there were 36% of the participants from communities of color and few reported cases from these participants Considering how and what we know about the disproportionate rates of COVID-19 in black and brown communities, I urge vaccine discussions to avoid centering mistrust of the black and brown community as originating within this communities and instead acknowledge the fact that the healthcare profession has previously betrayed these communities through centuries of structural racism including grievances that are happening today Therefore, we need to have open listening and understanding of the concerns of these communities and trusted healthcare professionals from communities of color need to be engaged and ensure that the approach continues to align with equity and cultural congruence I would also comment on the importance of funding campaigns with appropriate messaging and community engagement in the rollout to emphasize safety and efficacy for laypeople to encourage vaccine confidence and appropriate messaging about expected side effects so as to not alarm people and they occur Finally, hoping for an equitable distribution plan that ensures that people in rural, low income, and communities of color have adequate access to the vaccine, including follow-up for second injections Thank you for the opportunity to participate in these open comments and I am looking forward to seeing what this vaccine has to do for communities in the future Thank you The next speaker is Dr. Robert long It afternoon I have, flicks or disclosures Thank you for giving me an opportunity to speak today and share my thoughts on the importance of timely and equitable implementation of this COVID-19 vaccine My name is Robert Wong I’m and clinical associate professor of medicine at Stanford and a practicing gastroenterologist and hepatologist serving U.S. veterans at the VA healthcare system in northern California In addition to my clinical practice which focuses on management of patients with complex liver diseases, my clinical research is focused on health care disparities, particularly among ethnic minorities, vulnerable populations, and underserved safety net health systems

Even prior to the COVID pandemic, ethnic minorities and bonobo populations suffer significant health care disparities from receiving timely screening and surveillance exams to delays in access to life-saving treatments Specifically for patients that I serve, my research has demonstrated disparities and timely receipt of high quality care including access to viral hepatitis treatments for patients with chronic hepatitis B and hepatitis C, as well as timely screening for liver cancer among cirrhosis patients In the past nine months since the pandemic began in the U.S., we have seen these disparities exacerbated as our attempts to deliver high-quality care have been disrupted by this pandemic Patients avoiding care due to fear of medical visits or labs for imaging or cancer screening and healthcare systems transitioning to telehealth delaying nonurgent procedures and trying to balance the risks of delaying diagnostic and treatment procedures with the risks of our vulnerable patients being exposed and infected with COVID These vaccines present some hope that the end of this deadly year Many of us have lost not only patients but close friends While these vaccines will not be a magic bullet to reverse all the damage this pandemic has cause, it gives us hope that one day in the not-too-distant future, some semblance of normalcy will be within our reach While I have no doubt in eventual approval and dissemination of these vaccines, I would like to encourage all of us to be particularly cognitive of ensuring equitable access, particularly among those underserved and vulnerable populations whose existing health care disparities have been disproportionately exacerbated by this pandemic Thank you all very much for taking time to hear my comments Inky Dr. Wong The next speaker is Dr. Joseph Bick Good morning My name is Joseph Bick and an infectious disease specialist serving a statewide director of healthcare services for the California Department of Corrections and rehabilitation I have no financial disclosures to report I would appreciate the opportunity to speak to the committee regarding the importance of those who work and reside in our jails, prisons, and detention centers in the first phase of COVID vaccination Over 2 million people are incarcerated in this country, over 500,000 individuals interact with them on a daily basis as correctional officers, nurses, cooks, respiratory therapist, teachers, and others More than 260,000 inmates and 58,000 correctional employees have been diagnosed with COVID, resulting in at least 85 employees and 1700 and made COVID related deaths The death rate due to COVID among the incarcerated several higher than what is seen in the community Case needs are higher than those seen outside of incarcerated settings Many of the outbreaks in the country have occurred in correctional facilities Many facilities do not routinely test for COVID and these numbers underestimate the true burden of COVID in these settings Most inmates are housed in large, overcrowded congregant living environments in which consistent physical distancing is not possible Many of these settings suffer from insufficient ventilation and hygiene contributing to the likelihood of widespread COVID outbreaks Inmates are disproportionately people of color and often have multiple comorbidities to increase the risk for serious illness, hospitalization, and death if they become infected with COVID Delaying vaccine distribution to inmates exacerbates the disparate racial impact of COVID-19 Advanced ages one of the greatest predictors of adverse reactions and it begins to rise in the 50s The average age for inmates in this country has risen significantly over the years Currently over 10% of the prisoners are 55 years of age or older Many of them are essentially nursing homes, long-term care facilities, and skilled nursing facilities Jails, prisons, and detention centers are often major employers in rural settings when employees knowingly introduce COVID the disease can be rapidly amplified and subsequently fuel large outbreaks in the community Inmates are required hospitalization and quickly overwhelm bed capacity in surrounding community healthcare facilities Cases among staff animate and inmates are surging to unprecedented numbers overwhelming

local resources not including correction staff and high risk inmates and vaccination phase 1 will result in preventable illness and deaths and unsafe jails and prisons and increased pressure on overstressed community hospitals In closing, I urge you to include high risk inmates and front-line correctional workers in phase 1 a for this and all future COVID vaccines Thank you Smack thank you Dr. pick The next speaker is Doctor Donald Middleton Thank you I am unofficially speaking to support EUA approval of the Moderna MRna vaccine I serve on a Moderna MRna advisory board . My background is in vaccine education and I am one of the developers of a free vaccine app for iPhone and android called shots by AAFP COVID-19 is ubiquitous It’s in the air, doorknobs, in computers, in the trash Even when social distancing policies are followed to the fullest infection still occurs The number of infected persons is staggering The number of deaths more so In the U.S. 300,000 A number that is difficult to grasp Basically, the city of Pittsburgh is wiped out As we have already heard, recoveries from COVID often take months or is incomplete Most days when I walk into UPMC St. Margaret, my true home a community hospital with about 200 beds, I wonder how many COVID patients do we have? Is this the day, is this the one when I will become infected? Others who work here sure that fear, but it does not stop thousands of our hospital employees from doing their jobs The hospital staff always keeps in the forefront that the patient is important Something that the statistics failed to convey We used to have maybe 5 to 7 COVID patients daily Now we have 60 60 out of 190 in patients Nine out of 10 patients in the ICU had COVID and seven were on respirators The 70-year-old woman on a respirator how to communicate with handwritten messages Just before being sedated to improve her oxygenation, she scribbled a note, I love you all My life is in your hands A heart was attached to the bottom of the note Endless lights, noise, strangers in the room You cannot release it to talk with patients even though the staff does there work daily they are working in The Madrona — Moderna vaccine has published evidence of lasting immunity to help keep it at bay Please advise the FDA to give this outstanding vaccine full EUA status Thank you very much Thank you The next speaker is Mr. Sidney Wolfe Good morning I am Dr. Sidney Wolfe During the October 22 meeting seeking data from Pfizer or Moderna vaccines they pointed out that deployment of a weekly deployment could result in more harm than good It could do so by providing a false sense of security to introduce measures such as wearing a mask, other PPE, and social distancing Both vaccines are highly advantageous There is still concern about the danger of those getting vaccinated if they no longer adhere to the proven public health measures such as wearing masks and social distancing

The FDA 2017 EUA guidance included requirements for an FDA improved patient fact sheet to accompany the use of all EUA products to ensure the recipients are informed about the product they receive and to inform them of any available alternatives to the product and the risks and benefits of available alternatives This 2017 EUA had been granted prior to the Pfizer vaccine, but providing written information about proven health measures such as wearing masks and appropriate social distancing is clearly necessary and appropriate for COVID vaccine recipients Flashing back to last week, less than 24 hours after the EUA for the Pfizer vaccine was granted, the FDA posted a Pfizer fact sheet for recipients and caregivers intended for recipients of the vaccine The fact sheet accurately states the Pfizer biotech vaccine may not protect everyone Unfortunately it contains no mention of the need for wearing masks and appropriate social distancing For further information, they suggest asking the vaccination provider or local or state government, health department, and lists websites that do not state such preventive measures should accompany vaccination Though necessary, it is a part of the EUA submission such fact sheets were not included in packages provided to the public or advisory committee for today’s our last week’s advisory committee meeting This morning it was mentioned that the FDA review yielded — the FDA mentioned that the review and revision of fact sheets for vaccine recipients were part of what happened when the FDA looked at the EUA submission This is at least mentioned in today’s meeting which it had not been before I hope that your advisory committee urges that important public information such as that must immediately be added to vaccine fact sheets before millions more people are vaccinated Thank you very much and I hope that you will ask the FDA questions about this It does not seem to be in their presentation for this afternoon Thank you Thank you, Dr. Wolf The next speaker is Dr. Roberta Luskin-Hawk Smack thank you I am speaking as a private citizen today and I have no relevant disclosures I am a physician with extensive experience in conducting and analyzing clinical trials In addition to overseeing healthcare delivery across both urban and rural settings My current role as Hospital chief executive serving a remote area in northern California provides unique perspective on the potential impact of emergency youth authorization of MRna 1273 COVID vaccine on rural communities The current surge in COVID-19 is having a devastating impact across the country and the demand for care is starting to exceed capacity and parts of the healthcare system with further increase in cases forecast in coming weeks While the numbers of patients of COVID-19 in rural communities may seem limited, even small numbers of cases or illnesses among healthcare and workforce can threaten the fragile healthcare infrastructure and limit the ability to provide critical care to people in these communities Intervention is needed and we are fortunate to have had a robust response from the scientific community It is therefore essential that we rapidly deploy those that are found to be safe and effective to both rural and urban communities across the country The data provided on the Moderna COVID vaccine demonstrates exceptional vaccine effectiveness and the reduction of symptomatic COVID-19 across all ages In addition, the potential impact on the severity of disease It also has a favorable side effect profile in the evaluation Use of this vaccine will not only save lives but will help relieve ICU capacity available for the care of patients with other acute medical conditions The fact that storage requirements can be met by healthcare organizations without access will have an added benefit to many small rural hospitals and clinics Vaccination of 21 million U.S. healthcare workers in vulnerable populations is urgently needed to protect healthcare workers, infrastructure, and to change the tide of the pandemic Rapid and broad distribution will require EUA and eventual approval of effective COVID

vaccines I urge you to provide emergency use authorization for MRna 1273 which has met the necessary safety benchmarks for data I personal believe that this approval is needed to support our healthcare workers and to save lives Thank you Smack okay The next speaker is Ms. Veronica Holloway Smack good afternoon and thank you for the opportunity to speak today My name is Veronica Holloway I am from the Illinois department of health I have no conflict of interest I want to recognize Dr. Damon Arnold who has been dating conversations about COVID-19 vaccine on behalf of Illinois COVID-19 task force To ensure that this is impacted in urban and rural communities of color are informed and engaged in the process of building trust with an awareness promoting the importance of vaccination and creating equitable access and distribution we launched several initiatives We engaged with a diverse group of community partners including people with disabilities, homeless, refugee and immigrants, those in the LGBT communities, to discern the need for special assistance We launched a community ambassadors program to ensure confidence with directed messages around the COVID-19 vaccination These conversations made clear that education and targeted communication regarding misinformation and rebuilding trust and active collaboration with the community is key Accurate and timely information concerning the safety and efficacy of the vaccine from the manufacturer and scientific community is vital National and state data shows that COVID-19 kills more males than females and black males already have a life expectancy 8 to 11 years shorter than their white counterparts Special outreach efforts should be made to engage black males in order to improve participation in both outreach and vaccine uptake Messaging must be consistent with community and perceptions about the vaccine We can collect perspectives from communities mentioned We noted that both cultural and linguistically appropriate language is essential for effective communication and delivery of quality healthcare Providers appear to require additional training with respect to cultural norms and implicit bias Providers must be intentional bladder about engaging with local community members about the vaccine The pandemic also underscores the need for a more diverse healthcare workforce perspective of the communities they serve In closing, there’s concern that the access and distribution of vaccines will encounter hurdles in an already negatively impacted rural and urban communities of color The federal, state, and local support as needed much as additional funding to support the use of tools and the vulnerability index which combines the CDC social vulnerability index with epidemiological and health factors to target those most likely to be impacted Thank you for your time and attention to this important matter Smack thank you The next and last speaker of this session is Dr. James Woody Hello I would like to thank the FDA for the opportunity to speak I have no financial disclosures., Pediatric immunologist and Biotech executive that in a prior life discovered and developed a drug called [Indiscernible] I would be interested to see how they do with your vaccine better that is not why I am here I want to talk about what I see as the optimal format for deploying a COVID vaccine for the Navy and Marine Corps My comments are my own and do not reflect in any way the Navy or Marine Corps., Retired U.S. Navy captain who spent 20 years in the U.S. Navy as a medical officer I ran a worldwide Navy medical R&D One of the jobs was to look at infectious disease risks anywhere that we might port By way of experience as a former commanding officer of the Navy medical unit, a facility in Cairo, Egypt, for four years My team did surveys for infectious disease over the entire eastern Africa region They included HIV, hepatitis, Ebola, Valley fever, and serious stuff

As you know well, space on Navy ships is very confined and it is always limited Transmission of infectious diseases is a concern We have shut down ships in the past due to chickenpox outbreaks As you have seen in the press, over 190 Navy ships have had COVID cases representing about 65% of all Navy ships at sea Likewise, the Marine Corps recruits live in congested facilities and have also had significant numbers of COVID cases Should the Marines be required to deploy on ships which is the usual sequence? The overcrowding will be even worse and they will be at higher risk Assuming they will work to provide the protective community, what is the best use for format by the Navy and Marine Corps? Common sense needs to prevail In situations where multi-doses are required, the smaller shore based clinic facilities and the shipboard facilities must have similar kinds of storage equipment and capacity so that once a Marine is deployed with the first dose they can actually get a second dose That can be administered anywhere on shore or in the fleet So most shore-based facilities have the usual -20 degrees refrigerator freezer Vaccines could be stored in any of these locations and the second dose be administered quite easily These are the much lower temperature specialized freezing of -100 is not a reasonable option as such kinds of equipment is only available on very few, very large ships or shore-based hospitals In summary, from somebody that has actually been in the trenches, common sense needs to prevail here Simpler is better Thank you very much for the opportunity and listening to my talk Thank you I would like to thank all of our speakers for making the comments This concludes the open public hearing session Now I would like to introduce Dr. Peter Max He wanted to speak as well Are you ready? Thank you very much Thank you to our public speakers I just wanted to take a moment before we move on to further questions and the FDA presentation and deliberations later on, there was not an exact perfect time to thank everybody today, but this may be a reasonable one just to thank everybody for their participation This is somewhat of a historic event to have these advisory committee meetings so close together We really thank all of the advisors for taking the time to go through a very large amount of material I also need to thank the FDA staff who have worked tirelessly going through an amazingly large amount of material over the past week That was only made possible because they had worked for several months with the company’s internally and with stakeholders to prepare things so that this relatively rapid EUA review would be possible Incredible thanks to our colleagues and thanks to all of you that are tuning into this process I also need to call out the advisory committee staff which has done a remarkably great job in putting together this meeting I will not hold this up anymore and I will turn it back over thank you Dr. Monto, the floor is yours thank you We are going back to questions for the sponsor I see that Dr. Miller is ready and I will re-address the question that I interrupted when we broke and that was about sequencing and the rest you are a muted Thank you for the reminder that I was still muted

Apologies for that Thank you, Dr. Monto The question was about whether we were intending to sequence the samples we receive from breakthrough cases The answer is yes We are in the process of deep sequencing virus from those cases and I was going to invite Dr. during Edwards who was at the head of the clinical group to address the work we have been doing to assess the effectiveness of the vaccine against emergent need Dr. Edwards Thank you for that In addition to sequencing of cases in the phase 3 trial we are also performing additional assessments and research assessments These are animal or human sera The ability to break through these these are through internal efforts as well as collaborations We have thus far identified five variants that are key concerns At this point we have assessed both mouse and nonhuman primate sera that were vaccinated with 1273 to protect against these variants In the future, we are also performing assessments on humans Thank you and I hope that addresses your question thank you Let’s go on to Dr. Sawyer I believe you have a question thank you Thank you for the great presentations Given our new and unexpected focus on anaphylaxis, I just wanted to ask if you have seen anaphylaxis in any of the other eight vaccines that you had previously developed and given to a small number of people, whether you have seen allergic hypersensitivity reactions in any of the animals and whether you have done or are planning to do any in vitro studies to see if this MRna lipid platform has interactions that would predict allergic type reactions Dr. Sawyer, thank you for that question We have been doing a very rapid review of the overall clinical database in light of the information that has come forward about the other MRna vaccine As you mentioned, we do have a clinical database across eight other vaccines which includes approximately 1700 recipients of a similar lipid nanoparticles with specific MRna sequences In those cases we have had one other report of anaphylaxis It was a woman with soy allergy and more than a few months outside of her vaccination I should clarify that although participants have been excluded on the basis of an analogy that is one of the components of the vaccine they are not routinely excluded participants that have a history of allergies The second question was about potential in vitro studies In fact, we have been in discussion with leaders at the NIH and so forth to talk about what additional activities we might collaborate to better understand this Thank you Dr. we — Lee I wanted to talk about potential unwinding There was a [Indiscernible] that would not interfere with supplies for the general public if it were to be granted My question is, these have a limited shelf life My first question related to that is how long do you think that supply will last

Related to that is, would you have enough doses to vaccinate two doses for all 15,000 placebo participants, where they all asked to do that? Thank you for your question about the vaccine supply and yes it is true that we have sufficient supply to be able to vaccinate the placebo participants The supply will actually be expiring relatively soon By the end of next month the supply will be expired so they cannot be used for emergency use Thank you Dr. Cohn thank you . I can’t [Indiscernible] including how many days after vaccination it started to occur and how long after it occurred and if the patients were covered thank you for that question , Dr. Cohn Those cases occurred between 17 and 32 days after vaccination They were either resolved or resolving at the time of this presentation and they were three nonserious and one was serious Dr. Carrillo thank you You began counting after the second vaccine dose but it begins to diverge after about two weeks after the first dose Your immunogenicity results in the phase 1 say that even two weeks after the first dose there is no neutralizing titers and there does not seem to be any bump in T cells which suggests that there is a nonspecific antigen vaccination mediated protective effect potentially going on The question becomes, how long does that actually manifest and do you know what that is? I would presume it is inflammation and interferon NK cells and that sort of thing I’m wondering how much that will be bleeding into the primary efficacy influence analysis thank you for that question We did show a difference in the reported cases after randomization, as you mentioned We do know that the vaccine induces innate immunity with the first dose and clearly increases with the second dose Understanding this phenomenon a bit further is why we looked into that one dose efficacy in several different ways Looking at it in terms of the time when the MRna kisses might be reported as well as looking at PCR swabs and the ability or the differences between the vaccine and placebo group in terms of the positivity I am going to also ask Dr. Melissa Moore if there was anything that she would like to add about after the first dose thank you I would like to send that question over to Dr. Zaks Thank you We see the binding antibodies come up quick and well everybody focuses on neutralizing antibodies I suspect what happens here the binding, will it be a boost That will be the reason for the discrepancy that we see between the neutralizing antibodies that are clearly measurable after the boost, but the sense that protection may start as early as that It is concurrent to that that was reported last week While there is some potentially innate activation I think the potentially is for the quick antibody

binding and total response easy after the first dose with maturation and further increase for the neutralizing titers It is supportive evidence overall Coming back to the fact that we really studied and what we see is clear boost across all age groups and hopefully that will be durable I would say that first dose efficacy is supportive evidence to remind us all that we actually need both doses to achieve a high level of protection Thank you Dr. Sylvester thank you I wanted to briefly revisit that blinding versus unblinded issue You don’t need to convince me that a randomized double-blind clinical trial is the gold standard However, I do not believe this would be the first study that would be the first RCT that would meet the primary endpoint and vaccinate the placebo group before the protocol described timeframe and I believe that HPV for and the pneumococcal conjugate vaccine and their placebo group after the primary endpoint was met and the data showed overwhelming evidence of benefits similar to what we are seeing here today I do not know Dr. Dayton but I share his concern about losing a significant portion of the study population without offering the COVID vaccine I think is open label continuation seems like a practical solution Thank you Dr. Meisner thank you for a fascinating presentation First of all, why do you think you were successful with this particular MRna vaccine whereas the previous eight are still in development? Number two, when we see adverse reactions in the first 48 to 72 hours following administration of the vaccine, do you think that is a reaction to the messenger RNA, and along that line is their understanding that these are proprietary issues Can you say anything about differences in the lipid nanoparticles between the Moderna vaccine and the one that we spoke about last week Finally, why did you select a 28 day time interval between the first and the second dose? Was there a reason for that? Thank you Did you meet your phone? I did I apologize Thank you for those questions What I was saying is I’m going to start and then I will pass it along to the chief medical officer, Dr. Zaks With respect to the development program for MRna 1273 on the other development programs that we have ongoing , our company has been working for about five years Most of the programs have been in the clinic for about two years The difference between the 1273 program and others forces the unique circumstances in which we find ourselves, and the strong medical need which the vaccine requires We have expedited many elements of the development program, including conducting the three phases

of the study staggered but also much of this has been done in parallel That is required with absolute focus and collaboration around their focus as well on the scientific restaurants that have been raised throughout the course of development For example, what safety data do we need to have available to move from one step to the next step With respect to your question about the component of the vaccine that is responsible for the reacted in the city, I will ask Dr. Zaks to join the call now Server, you are muted I apologize for that For the vaccine, I think it is also important to note that we are in the midst of a pandemic and for a case during trial, the cases are occurring proportionally That’s why we delivered information so quickly As it relates to components This was a discussion yesterday with the expert panel This is about the anaphylaxis, people look at three elements here There is the component which is actually not just that it is connected to a lipid Than the attached lipid in the vaccine that is different than the Pfizer vaccine The second potential culprit is the amino which we and Pfizer use very different proprietary amino lipids The other components are probably in oculus The final element is the particle [Indiscernible] we know that these can actually immune responses themselves because of the physical properties I would expect the chemical nature of the particles will actually be very different than Pfizer I actually think that as far as the component it is likely to be the culprit here I would not necessarily assume that We will be looking very carefully as has been noted and continue to collaborate to make sure that we understand this as the picture involved I think the last question you asked was about the 20 day interval I don’t think that there is a big difference We have always done that between [Indiscernible] that is based on immunological first principles of vaccination We understand that when it starts to be optimal [Indiscernible] I would note that the window for this vaccine the protocol is reasonably wide We say four weeks but there is some room there When we did the analysis we made sure to include all of that I doubt that is [Indiscernible] thank you Can I ask a follow-up I am in the unenviable position of having about eight pounds raised and five minutes to go We will have to put that off until later Thank you The data is impressive I am still nervous about the nine weeks median data I will try to put myself in he is one is in regards to the supposition of advanced disease [Indiscernible] but we really need data Pfizer did not really have data on that They have a few cases You have 30 cases in the placebo group and none in the [Indiscernible] group which is great I assume that you know how many cases there have been Enclosed on 11/21 how many have been reflected in that My other question is related to the unblinded This is really important because we do not have enough data and maintaining the placebo-controlled studies is a way to get more data Your plan is specifically to end that The arguments, we heard a bunch of arguments for that like we don’t want to disadvantage trial participants relative to others and there are supplies that have been set aside

that you can use for all of the trial participants I think that that is kind of behind the point What is the expectation I understand that he indicated that the participants of the trial were not told that they would jump the line and be entitled to get the vaccine before others in their state and demographic If that is true, they have no expectation of getting it different from anybody else in the group Is there any other ethical reason why am Moderna thinks that the participants with the placebo should be getting the vaccine which Pfizer it appears has rejected the crossover study, according to this letter that they just sent out to a trial participant in my state that it is only healthcare workers and the rest are being told will be at a later date I would like to know if there is an ethical reason [Indiscernible] and the rest would be later That would maintain the controlled studies Thank you for your questions I will start with the first question about additional data As we reviewed in this presentation, we made two submissions to the FDA The first was on what was intended to be a first analysis There were so many cases reported in November that we achieved the final primary analysis approximately five months earlier than we anticipated We have continued to collect cases since that submission on December 7 We currently have over 450 cases that are actually making their way through the adjudication process You can imagine that the adjudication physicians have also been working extremely hard to keep up with this tsunami of data that is becoming available I do not have that available for you today but we intend to continue to make data cards and update the efficacy analyses That should be in the weeks to come The second question was really about the ethical basis for the proposal to unblinded placebo recipients I think that some of your questions really speak to the interface with trial participants I will turn the floor over in a moment but the one thing I would say is that we do have one death that has been reported in the trial in a case of severe COVID that occurred in a placebo recipient That death weighs very heavily on me I do understand that it occurred at a time when we did not understand if the vaccine was going to have the efficacy that it does and we did not have a clear understanding of the benefit risk profile I think that the 450 cases that I just mentioned, additional severe cases and deaths are a question more of when than a question of if I think that the knowledge that it may be waiting in some of the trial participant future weighs heavily on me Would you also take the floor and discuss this question? Thank you for raising those issues I think the question is, not that they were promised We should not disadvantage the volunteers, but we have to be practical of where we are Unblinded is going on The vaccine is available Availability will rapidly extend to multiple groups It is not as this this will take place over six months to a year This will be days to weeks in terms of extending the vaccine supply two additional groups I think that what we need to do is keep the volunteers in the study Keeping it in the study there is not only one flavor of study It is not just a double-blind study There are other formats that can enable us to learn, particularly to learn about asymptomatic transmission through the serology at the transition point, the nasals want to look at contagiousness and infectivity If we don’t come up with a plan that is easily understood and practical for all of our volunteers, some of whom are very health savvy and some of whom are not, it will become very confusing

and disruptive and corrosive I do not think it is an issue of a double-blind study or nothing There are different formats of an ongoing clinical research trial that leverages or accepts the reality that we are facing over the next 2 to 6 weeks in terms the transition as vaccine becomes more available We will have to go on to Dr. Fuller Let me say in advance that we are going to eat into our lunch I’m going to try to break for at least a short time because we have no breaks scheduled from now until the end of the meeting We will take a break for a short period of time maybe for 15 minutes Since I’ve got a lot of hands raised, I will continue to go Dr. Fuller, please Thank you Thank you to mature and your study and what seems to be a very well-crafted study I have to hopefully quick questions You mentioned you will be doing surveillance in the follow up and phase 4 not only through CDC and FDA but your own system of real-time global monitoring of events The first question is will that be done in conjunction with other vaccines that may be approved For example the one that has ever been approved through Pfizer? The second question is probably a little bit more theoretical You noted that you have third-degree pain for the second injection than the first injection I have been wondering about these vaccines where they boost specific communities What happens when people are exposed over and over again to the virus in a circulating pandemic when they have been highly boosted to something that binds to, say in this case the receptor Do you have any idea why there is more pain in the second injection? And do you have any thought to this idea of having highly boosted immune systems in the middle of a pandemic where they are continually challenged Thank you for both of those questions I will go to the second question first Afterwards I can turn it over to Dr. David Martin who can speak to the Reporter: of vigilance plans that we have in conjunction with the safety surveillance systems at FDA and CDC and also the study that we intend to undertake ourselves Your question about the reacted gene city with the vaccine and cut that have to do with vaccinating during a pandemic What we have observed in terms of the vaccine really parallels what we see with it immunogenicity The increase after the second dose really goes along with the increase in neutralizing antibody that we see in all participants and the induction of the T cell responses We had to put 2% of the population in the study who did not have a history of COVID-19 to disease but when we tested the baseline swab and we tested the serology for existing antibodies were found to be baseline positive In fact, the observed reactor tonicity was lower We think it can safely be given to people that have deviously been exposed and think it is more likely that the increase in immunogenicity our are related to the pattern of reacted gene city Dr. Martin would you like to talk about the post-authorization safety study that we are proposing Before you go to the second question just a quick follow-up So in the next few minutes with the virus circulating, the boosted immune system should not have any systemic effects because of exposure to the virus? I don’t know the answer to that I don’t know if anybody does I think that you are right You bring up a good point Only 2.2% of the population were baseline sera positive in the study That is another important reason to both keep the clinical trial ongoing and also follow the patient’s that might get vaccinated in a crossover design for the safety event but

also to conduct the postmarketing safety surveillance that we are proposing to do Perhaps, Dr. mine do you want to talk to the study that we are going to conduct Briefly, please Absolutely Thank you for the question as you are mentioning, visibility for the Pfizer vaccine as well as the Moderna vaccine, there are vaccine specific administration codes which are brand specific The U.S. FDA and CDC surveillance systems which have described their activities publicly in the last few weeks, they will be able to observe both vaccines in a brand specific manner and aggregate if they choose to do so Moderna, as is customary will primarily focus monitoring on its own product and will obviously work bilaterally if contacted by the FDA We have been notified by the U.S. government that we should expect communications regarding safety signals from the FDA So that is customarily how these things are done Okay Dr. Hildreth We are not hearing you Make sure you are not on the mute Now we can hear you Thank you I apologize for not being able to get my camera to work My question relates to the minorities in the study My understanding is that many of them or large numbers of them are [Indiscernible] in the process I wonder if you on the same follow-up for them I do not have the specific data about minorities and the follow-up in each of those groups It is true that they were enrolled a little bit later in the process That was really because we invested in working with community leaders to understand what we needed to do in order to make participation in clinical trials something that those communities, again to the previous point, building trust with those communities and ensuring that the benefit from the clinical trial in which they have so generously donated their time and willingness to be examined is really critical to encouraging minorities to participate in future clinical trials We will continue to follow as we would propose to transition to an open label study we will continue to follow those individuals for further Prechter cases and for their safety outcomes to generate this very important data Thank you Dr. Brohman, please I just have a relatively quick question This vaccine can be kept at room temperature for some number of hours? Since it is a MRna vaccine, how much degradation occurs during that time I worry about it going to places in which conditions will not be perfect How long is it really stable? To speak to the stability studies I will ask our expert to take that question Hello Can you hear me? We started with those studies very early in January when we started developing the vaccine We have demonstrated a significant amount of stability which we have shared with the FDA including the stability in temperature which were provided to the FDA to be able to make the shelf life claims that we are making In the recent documents it has agreed with the package [Indiscernible]

Is there any degradation? MRna has degradation of the time . It is different from temperature We characterized it and ensured that the product remains potent and maintains the quality attributes to maintain effectiveness Also during this we actually put [Indiscernible] in the study representing the quality attributes of the product Final question before we break Dr. leaving, Ruben [Indiscernible] how long does the MRna stick around for ? I apologize I missed the first part of your question The audio took a moment to come up Would you mind repeating that? Sorry Which cells do you think are important for antigen presentation and how long does the MRna and last you Mark To answer your question, I will ask Dr. Melissa Moore to come up in a minute . The cells that we believe are important for the antigen presentation are the [Indiscernible] and subcapsular macrophages Dr. more — MRna 13 ‘s, Moore I’m showing on this slide this takes up the liberal nanoparticles and expresses them in the draining lymph nodes These are the monocytes and antigen presenting cells In terms of how long the RNA sticks around the peak presentation is about 48 hours and is gone by 72 hours The MRna is generally gone around 24 hours The protein sticks around longer than the MRna Thank you Okay I am going to have to call a mercy rule here for everybody I apologize to the six people with their hands raised right now Your turn will come later on We are about 15 minutes late To allow everybody a little bit of time off, let’s start at 2:05 A 20 minute break right now

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Welcome back to be vaccine and related biological products advisory committee meeting We just came back from the break and now we will go to the last portion of the agenda With that, Dr. Monto, taken away I would like to introduce next for the FDA presentation and description of the voting questions to Rachel Zhang who is our next presenter Good afternoon everyone Here’s a brief outline of what we will cover today I will start with an introduction of the Moderna COVID-19 vaccine and a quick run through of the clinical development program to date and then we will take a dive into the efficacy and safety data from the phase 3 study We will discuss the plan for vigilance plan and enhance for future studies and finish with the benefit risk assessment and contact with the proposed used under FDA A quick introduction The Moderna COVID vaccine is based on the glycoprotein antigen encoded by RNA formulated in lipid nanoparticles It is an intramuscular injection Each dose is 100 micrograms The use is for active [Indiscernible] caused by SARS-CoV-2 and 18 of years of age individuals and older Really quickly looking at the clinical development program to date There are three ongoing studies for the Moderna vaccine One study was cosponsored by the NIH In the open label the study the individuals 18 years of age or older The phase 2 study is a randomized placebo-controlled dose confirmation study also is individuals 18 years of age or older The phase 3 data from phase 1 and additional safety data for phase 2 helped inform this for phase 3 Phase 3 study which will talk about more in-depth is a randomized placebo-controlled efficacy study in individuals 18 years of age and older Looking at the phase 1 study, we enrolled a total of 120 participants in three age cohorts There were 60 between the ages of 18 and 55 30 between the ages of 50 and 60 and 70 3071 years of age and older There were four levels tested ranging from 25 micrograms to 250 micrograms The immunogenicity substance from the study shows that two doses of the neutralizing antibodies

and teach one bias response was solicited The safety profile supported further clinical development and there were no concerning safety findings As of the time of the EUA request there were no serious adverse events reported from this study The study was staggered and design with the younger cohorts enrolled earlier than the older cohorts Some doses were later added onto the study so there is a range of follow-up At this time all participants from the study have had at least three months of follow-up after the second dose and a very small number have had a six-month follow-up Now looking at the phase 2 study The participants have between the ages of 18 and 54 and have age 55 and older They were randomized to either the 50 microgram dose, 100 microgram dose, or placebo Similar to the phase 1 study, two doses induced comparable binding and neutralizing antibodies for both age cohorts No concerning safety symptoms were found As of the time of the EUA request there were three FAE’s that were reported in the vaccine group but none vaccine related The immunogenicity and safety data are from the day 57 data which is about one month after the second dose SAE’s are reported more in real time They are current as of the beginning of September Moving on to the phase 3 study In this study, 30,351 adults 18 years of age and older were randomized one-to-one and vaccinated with two doses of the vaccine or placebo 28 days apart Random and Jason was stratified by age and risk factor for severe COVID-19 into one of these three categories Those 18 to 64 years of age without risk factors, those 18 to 64 with risk factors and 65 years of age or older regardless of risk factors The protocol specified that the later two categories should make up 25 to 50% of the total population The risk factors for severe COVID-19 specified in the protocol are chronic lung disease, significant cardiac disease, severe obesity which is a BMI of 40 or greater Diabetes, liver disease, and HIV Also solicited for adverse reactions seven days after each dose Unsolicited adverse events for 28 days after each dose and adverse events for the entire study duration The plan to study duration is two years This is a graphical depiction of the study timeline in terms of scheduled visits and also when are the two efficacy analysis time points occurred Starting on the left-hand side, subjects were administered two doses of the vaccine or placebo one month apart A nasopharyngeal swab for SARS-CoV-2 recollected as well as blood for immunogenicity There were further studies for safety and immunogenicity studies Throughout the study subjects are given weekly E diary prompts as well as safety phone calls Looking at the top of this graph you will see the dates of the two analyses that contributed to the data that we will look at today This slide shows the case definitions used for the efficacy endpoints Starting from the left-hand side the primary efficacy endpoint COVID-19 disease case definition is positive SARS-CoV-2 PCR plus at least two of the following symptoms fever, chills, myalgia, headache, sore throat, olfactory and taste disorders I will just keep going At least one of the following respiratory signs or symptoms Cough, shortness of breath, or difficulty breathing or clinical or radiological evidence of pneumonia Let me know if I need to click something Just give us a second Somebody accidentally hit stop sharing so let me pull it back up It will just take a moment here

I just need to check the names This will just take a moment Did you try to hit the arrow accidentally? Was that it there? I did not touch anything What is the title of yours? Hold on This is going to be a small — we will take a quick little break Just while we pulled this up I want to make sure that we get it Here it comes I will load it in right now I apologize for that, Dr. Zhang To my cohosts and all of that, please make sure we don’t hit the stop sharing button on the corner of the presentation because that is what happens It is loading It’s just a large file No worries That’s all right It gives us a couple minute break Should be pulling up soon Tell me when you see it I see it Go ahead and advance to your slide Okay Go ahead and take it away All right On the right-hand side is the case definition for severe COVID-19 disease which is confirmed case meeting the definition to the left plus at least one of the following symptoms Severe systemic illness based on vital signs, respiratory failure, shock, significant acute renal hepatic or numerological dysfunction, ICU admission, or death This slide shows the primary efficacy endpoint and how it was analyzed The primary endpoint is confirmed COVID-19 occurring at least 14 days after those two and participants without evidence of infection prior to those one Baseline SARS-CoV-2 status with serology prior to does one For the primary endpoint and independent, blinded adjudication committee whether this met the case definition and should be counted Vaccine efficacy is defined as % reduction versus placebo in the hazard of the primary endpoint The primary objective would be met with vaccine efficacy less than 30% or is subjected at any of the interim analyses There were two protocols specified interim analyses time points The first after 53 cases on the second after 106 cases have occurred Because of the rapid rise in cases around the time that the first interim analysis triggered, there were actually 95 cases included in the interim analysis Similarly, for the primary analysis which is specified in the protocol to occur at 151 cases, there were actually 195 cases

These are just two of the key secondary efficacy endpoints included in the study The first is efficacy against severe disease, using the definition we looked at a few slides ago starting 14 days or later after dose 2 and participants without evidence of SARS-CoV-2 infection prior to does one The second is a less restrictive definition COVID-19 based on the list of symptoms by the CDC Similarly these are cases confirmed 14 days or later after dose two and participants without evidence of SARS-CoV-2 infection prior to does one Cases of severe COVID-19 are reviewed in real time by the DSM be to monitor for possible respiratory disease and the protocol specified study stopping role will be triggered if the one-sided probability of observing the same or more extreme case split was less than or equal to 5% when the true incidence of severe disease was sustained for the vaccine or placebo participants This was not triggered for this study These are the key analysis populations defined in the study The full analysis sets are all randomized participants who received at least one dose of vaccine or placebo Disappearance are analyzed according to the groups in which they are randomized They are all participants in the full analysis that who had no evidence of prior infection before the first dose The per protocol sector all participants in the modified set that received planters as per schedule and have no major protocol deviations The safety sets are all randomized participants who received at least one dose and, sorry for the typo here That is the full analysis set In the safety said they are analyzed according to the treatment they actually received This slide will hopefully make it easier to see the distance and medium follow-up duration for the two different analyses that we looked at that we will look like today On November 30, Moderna submitted data from the interim analysis to support the EUA Annually orange bars the medium follow-up for safety and efficacy in these at the time of the interim analysis was seven weeks after the second dose To align with the expectation for a minimum of two month follow-ups, Moderna later submitted on December 7 official data from the final analysis as an amendment to the EUA As you can see in the blue bars the median follow-up for safety and efficacy at the time of the final analysis was around nine weeks after dose two The majority of the slides that I will present today will show data from the interim analysis unless otherwise specified as final analysis data However, I just want to note that we have independently verify the vast majority of the analysis from the final analysis and this includes the primary endpoint and associated subgroup analyses with the primary endpoint The key secondary endpoints and solicited and unsolicited safety data We have not identified any notable differences in terms of efficacy or safety profile with these additional two weeks of data Data did not alter the conclusions that we had already arrived at after a thorough review of the interim analysis data Moving on to the efficacy data This table shows the demographic characteristics of the study population and you can see that it was very similar among the vaccine and placebo participants The median age was 53 with a range of 18 to 95 around 25% of participants were 65 years of age or older looking at race and ethnicity we have 9.7% of subjects self identified as African-American, 4.7% Asian, 0.8% American Indian or Alaskan native 0.2% Pacific Islander 20% subjects identified as Hispanic or Latino Around 25% of study participants were healthcare workers Based on protocol defined risk factors for severe COVID-19, around 22% of study participants had at least one high-risk condition present This is a subjective position table Looking at this you can see around 8% of subjects were excluded from the protocol for the primary efficacy analysis

The primary reason was the subject being positive or having an unknown baseline as far as SARS-CoV-2 status prior to does one Around 95% of the subjects completed two doses in the per protocol set Discontinuation from the study was where with only 0.2% from either Now here is the primary efficacy endpoint at this scheduled final analysis If we can look at the top line in all subjects, there were 11 cases of COVID-19 in the vaccine group compared to 185 in the placebo group with the vaccine efficacy of 94.1 and a confidence interval of 89.3 to 96.8 Dividing that up into the age subgroups in the 18 to less than 65 years age group the vaccine efficacy point estimate was 95.6 Very similar to the efficacy and the overall population In 65 years and older age group, the vaccine efficacy slightly lower at 86.4% However, the number of cases are small and the confidence interval overlaps with those in the overall study population This is a subgroup analysis of the primary efficacy endpoint broken down into further age categories and stratification categories You can see that vaccine efficacy in each subgroup was comparable to the overall study population Again, going through these next few slides showing here is the interim analysis that we have verified the final analysis for the subgroups and there is no notable difference This is the subgroup analysis of the primary efficacy endpoint by race and ethnicity As you can see, efficacy was uniformly high across the groups I want to point out that for many of the subgroups the sample size and case numbers are small and that limits the interpretability of the individual efficacy This is the subgroup analysis of the primary efficacy endpoint by the protocol defined risk factor for severe COVID-19 It also includes at the bottom an analysis of obesity with the BMI greater than 30 Again, you can see efficacy across the board is consistent with what was seen in the primary endpoint For some of these groups it is again limited by the small number of cases in the population This is a subgroup analysis of the primary efficacy endpoint by baseline status This is based on [Indiscernible] and serology prior to does one Just over 2% of the study subjects were positive at baseline You can see that there is just one single case There is not really any sufficient data to make any conclusion on vaccine efficacy in participants with a prior history of SARS-CoV-2 infection This is the secondary efficacy analysis of severe COVID-19 and the scheduled final analysis Looking at all subjects, there were 30 cases in the placebo group and nine of these cases resulted in hospitalization One resulted in death In the vaccine group, we note that there was one severe case in the vaccine recipient which occurred two months after the second dose requiring hospitalization but had not been adjudicated by the time of the data this is the cumulative incidence curve of COVID-19 following randomization You can see the curve starts to diverge a little bit after the two week mark the divergence becomes more prominent as time goes on and more cases that accumulating in the placebo group This is a post hoc analysis of COVID-19 cases from time of randomization in the full analysis set That means all participants who had received at least one dose of either placebo or vaccine and regardless of baseline status Such as looking at the second line, efficacy any time after the first dose to before the

second dose was around 69% This could suggest some protection after the first dose but data is limited by the very short follow-up so around 28 days The majority of the subjects received a second dose Now moving on to the safety data This again is a graphical depiction of the scheduled safety visits and safety calls throughout the study Just as a reminder, all solicited adverse events are collected from all of the subjects via an E diary for seven days after each dose Unsolicited adverse event are collected for 28 days after each dose and [Indiscernible] are captured throughout the entire study This is a subject his position table You can see the vast majority of subjects completed two doses and very small percentage discontinued the study and it was similar between the vaccine and placebo The next few tables will show the solicited local and systemic reactions Again, before we dive into this I want to reiterate that all the data shown are from the interim analysis data, we have verified the data from the final analysis and there was no notable difference compared to the interim analysis data shown here Looking at the solicited local reactions after dose one, you can see the most commonly reported local reaction was pain Grade 3 events were rare after the first dose and something that you see through the next three tables is a lower rate of reactions in the elderly cohort compared to the younger cohort This is looking at solicited local reactions after dose two It is slightly higher than after dose from one Grade 3 events are still pretty low Now switching to systemic reactions after dose one similar to the local reaction There is a lower rate in the elderly compared to younger After dose one grade 3 or four events were rare Finally, looking at solicited systemic reactions after dose two, you can see that there is a higher rate compared to does one including a higher rate of grade 3 events For example, fatigue and myalgia is around 10% grade 3 Overall, based on the review of these last four slides there were no [Indiscernible] of the safety data Shown here is an overview of solicited safety by baseline SARS-CoV-2 status The rates of solicited adverse reactions were comparable or sometimes slightly lower in participants with the baseline positive SARS-CoV-2 status but this group is much smaller in size compared to participants with negative status [Captioners Transitioning] Those which are related and considered serious and medically related adverse events and also broken down by baseline status in the rates of these events are comparable and lower in those baseline will be compared to those negative at baseline but again some group population is small Unsolicited adverse events in general are comparable between the vaccine group and placebo group In FDA conducted standards messenger using FDA developed software to evaluate for consolation of unsolicited adverse events with onset allowing dose were and SM twos worth for terms that were various conditions and including but not limited to allergic neurologic inflammatory and immune disorders Here we highlight the unsolicited adverse events which have a higher frequency and vexing group versus placebo and starting with hyper sensitivity events there was 1.5% in the vexing group is 1.1% in the placebo group and the most frequently reported in the hypersensitive estimate you were [ Inaudible ] rash or trick area and [ Inaudible ] ration we thought this had a possible relationship to the vaccination and also no anaphylactic or severe hypersensitivity

reaction with close Temple relation and with an uppity related events and 0.6% of placebo recipients The most frequently reported some cues were injection site and [ Inaudible ] again without this had a possible relationship to vaccination We also noted delayed localized injection site reactions with onset after seven days and mostly after dose one and this was noted in 1.4% in the vexing and there was a numerical imbalance [ Inaudible ] case with three cases in the vexing group and one case in the placebo group The case and placebo group is 17 days after dose one and three cases in the vexing group occurred 22 to 28 and 32 days after dose to The observed rate was consistent with background rate in the general population and no basis upon which to conclude cause of relationship at this time Moving on to adverse events and deaths As of December 3 there were 13 thus in the study six and vexing in imminent placebo and none of the deaths were access related and in the vexing group the first three participants listed all had underlying cardiac disease in the first of died of cardiac arrest 21 days after dose one and 77-year-old Dido myocardial infraction in 70 years it was found deceased at home 5070s after dose number two Next participant was 56-year-old subject with hypertension and chronic back pain treated with opiate pain medication and found deceased at home 37 days after dose one in the official cause of death was head trauma Then we have a 72-year-old participant with Crohn’s disease who was hospitalized 40 days post goes to [ Inaudible ] and acute kidney failure and later developed complications during the hospital stay with her for it also that [ Inaudible ] organ failure and death 59 days after dose number two in Leslie we have 65-year-old participant who died to suicide 21 days after dose number one there’s three SCEs that related by FDA and one is a 65-year-old for this event with a history of severe headache and nausea requiring hospitalization who developed [ Inaudible ] vomiting and hospitalization one day post dose to Both of these subjects have a prior history, thermal filler and the chicken one subject it was about two weeks before vaccination and for the other subject it was about six months before vaccination Also related there was one subject who had [ Inaudible ] about two days after vaccination and that subject also had a prior filler injection Interestingly that subject reported similar reaction after previous influenza vaccine I want to point out for these three subject to mention the two with the Fisher one and one with lip swelling, the swelling was only localized No systemic symptoms observed Women were screened for pregnancy prior to each fascination in a positive case resulted from an exclusion or discontinuation from vexing — vaccination Six of the vexing and 70 placebo Vaccination occurred prior to the last mantra period into vaccines and three princely bills Vaccination occurred within 30 days after LMP and to vexing recipients and three action vaccination 11 placebo recipients LMP is not known in one vexing recipient and in terms of outcomes there is one case of spontaneous abortion and election abortion in the placebo group Otherwise the other pregnancies are ongoing and outcomes are not known at this time in summary for the efficacy totality of the clinical data submitted with the EA you just EUA request

meets the petitions for duration of follow-up final analysis, vexing sissy or two days post dose with confidence interval of 89.3 to 96.8 and 10 participants without prior evidence of SARS-CoV-2 infection Efficacy outcomes were consistent in the 93% across demographic subgroups In the schedule final analysis they were 30 severe cases of COVID-19 in the placebo group and one still on the adjudicated case in the vexing group — Vaccine group Interpretation is limited because all participants received a second dose As far as safety totality of the clinical data submitted with the EUA it’s the wreck expectation greater than 30,000 participants Richter Genesee was more frequent after dose number two and all age groups in mostly mild to moderate and less frequent and severe in adults 65 years of age or older There were no safety concerns identified in subgroup analyses by age, sex race, [ Inaudible ] covered 19 or — COVID-19 or prior SARS-CoV-2 infection — Delay to localize injection site reactions was onset after seven days of more frequent in the vexing group appear to placebo and mostly seen after [ Inaudible ] one and hypersensitivity are frequent in the vexing group but no [ Inaudible ] severe hypersensitive reaction in Temple relation to vaccination After scheduled while houses three cases were reported in [ Inaudible ] and one placebo recipient and all there’s no clear basis which to conclude a causal relation at this time FDA recommends further surveillance authorized for widespread use Moving on to the pharmacology guns plan [ Inaudible ] submitted a [ Inaudible ] plan to monitor safety concerns that could be associated with [ Inaudible ] 19 vaccine and sponsor identified [ Inaudible ] associated including mixing associated respiratory disease and anaphylactic reaction including anaphylaxis Use in pregnancy and breast-feeding women, pediatric population, long-term safety and effectiveness, immunogenicity and ministration with non-COVID-19 vaccines Including adverse event reporting under EUA mixing recipients, vaccination providers or the sponsor First mixing responses are notified and adverse event [ Inaudible ] and fact sheets — recipients is the VSA program which is smart safe program text messaging from web service to from web service to check in with vaccine recipients for health problems after vaccinations Reports from vaccine recipients are voluntary Providers and sponsors is mandatory Both sponsor and [ Inaudible ] modernity COVID-19 the following information associated with the vaccine and administration airs whether or not associated with adverse event in areas adverse events respectable traditions [ Inaudible ] multisystem in cases of COVID-19 hospitalization or death . In addition the applicant will also conduct periodic aggregate review of the data and each periodic safety report is required to contain the narratives early analysis of adverse events committed during the reporting interval including interval accumulative counts by each group, special population [ Inaudible ] and adverse events of special interest Newly identified safety concerns interval and actions taken since the last report because of adverse [ Inaudible ] FDA and CDC will take a collaborative and complementary approach to review adverse events FDA will individually review all [ Inaudible ] events on a daily basis FDA will also examine the other sources for adverse event such as literature, and will perform data mining to determine if adverse events are disproportionally reporting for the candidate vaccine compared to all other vaccines

Any potential safety [ Inaudible ] identified will be investigated The sponsor provided description of studies that are currently planning on contacting me one good completion of long-term follow-up from ongoing clinical trials and as well as to plans safety surveillance studies for pregnancy cohort and sponsor plans to establish a [ Inaudible ] registry to monitor vaccinations during pregnancy with populations expected to receive vaccines under you a and submit a protocol review and approval The study is a safety surveillance study conducting retrospective analysis of medical and pharmacy data to [ Inaudible ] 23 prespecified adverse events of special interest and descriptive analyses of observed versus expected rate and self-controlled risk and a roll analyses that will be conducted if certain criteria are met from the descriptive analyses FDA will provide feedback on these days after further review of protocol when submitted the sponsor Post revisions to the ongoing study 301 is still in discussion we still have not yet received a revised protocol for review direct in general they are proposing there’s no changes were participants who choose to remain blinded For participants who choose to be unblinded, they will proactively read consent and offer vaccine for those in the placebo group Regardless of whether the participants remain blinded or unblinded or which treatment they receive, all participants will continue to be followed for two years Finally we were not going to the benefit risk assessment The non-benefit of the vaccine, reduced risk of COVID-19 at least 14 days after completing two dose vaccination regiment in individuals without prior history of SARS-CoV-2 infection Reduce risk of burn severe COVID-19 14 days after completing two dose vaccination regiment in individuals without prior history of SARS-CoV-2 infection . In the subgroups efficacy findings are consistent across subgroups by age race at the city and comorbidity Local and systemic adverse reactions are reported at a higher rate after second dose and a higher rate when compared to older participants There were three SAE without related to vaccinations and they were all temporarily associated biologically plausible and this is one subject with history of severe nausea and the two cases of facial swelling in subjects that had prior [ Inaudible ] filler Suicide protection reactions have not been reported but have been reported in clinical experience with Pfizer and RNA vaccine Specific safety concerns were identified analysis of subgroup including prior SARS-CoV-2 infection Limitations of the risk assessment include short follow-up duration and pregnant women were excluded Here to remind everyone the question we would like the committee to discuss, and considering [ Inaudible ] for unblinded crossover of placebo recipients, please discuss the most critical data to further inform [ Inaudible ] safety and effectiveness to support licensure that should be approved in ongoing clinical trials with COVID-19 and other studies such as additional clinical trials for observational studies with the Madera — Moderna COVID-19 vaccine In this is the end of my presentation and I welcome any questions Thank you Doctor Zhang for being so synced and keeping us to time I propose first we entertain questions for Doctor Zhang of her questions and then go into her in the sponsor with issues related specifically to the vaccines and vaccine trials

as has been reported We should reserve the discussion about the unwinding issues to be later, just comprehensive discussion that the committee has which will go on for a couple hours including the voting discussion First must ask questions, if you have them for ZhangDoctor and I’ve alerted them to be ready for this questions when we get into the committee discussion about unblinded we need to focus on that issue because we have a hybrid discussion last week and for those who are on with the committee and I think we want to avoid that and focus on the FDA discussion point Thank you for clear presentation I just want to follow up on [ Inaudible ] which is briefly Bell’s palsy and I understand we look through the small numbers that derive from large database and you can determine [ Inaudible ] small numbers and I’m glad you’re doing follow-up and with what we see with the Pfizer and [ Inaudible ] trials are background written if you look at Pfizer for cases of Bell’s palsy and a group of 22,000 vaccines in its eight cases Dashwood also works out to eight cases per 10,000 per year If you look at the one placebo case and add the two placebo groups roughly 37,000, that over a few months and it works out to about 1.2 case for 10,000 per year which I read the background rate That in combination with the fact that it has been reported to be a cause of Bell’s palsy and a handful of people presenting and then [ Inaudible ] offers biological plausibility and it may be true that it’s more common cause and we find this will follow up but I’m not sure how we are so comfortable this was a background And this is something we look into and think a lot about and just based on each of the individual studies we look at the cases that there is still no clear cause with the relationship but we see your point with the two studies combined and numbers and something that we are looking into and thinking much about Thank you I am interested in the three cases associated with the prior injection of the dermal fillers and how long did those well in reactions taken should the product be authorized and will the information be included in the information for healthcare providers? I can give you a little bit more information on those cases All three of the cases that I mentioned is localized with swelling in the cheeks and the lips And they resolved with either antihistamines or a steroid of course and again those systemic reactions were noted and what’s interesting, one participant who reported a similar reaction afterward previous vaccine and we did a literature search and it seems like this is something that has been reported in with a thermal filler injections there could be interaction with a moon — immune response with an extra response in like illness With dermal fillers that create temporaries selling them to resolve pretty quickly with the steroids or by itself We are planning to note this in

the prescribing information Thank you Thank you for that I had one question about clarification that you noted some of the regular [ Inaudible ] that will happen in terms of adverse events and you listed it only under E UA which is what we consider now and wanted to clarify those function will continue as we move out of this, — which we should still look at adverse events and vaccines But wanted to make sure it was not specific to EUA? Yes if you member the business lead with a lot of boxes and arrows, the survey and follow-up for EUA is not any less than a regular BLA so they will continue Doctor Sawyer My question relates to the anaphylaxis story and you described it in balance in hypersensitivity reactions between the vaccine and placebo groups but no cases of [ Inaudible ] and want to know if you can characterize with the hypersensitivity events are because I wonder if some of you immediate reports are reflecting hypersensitivity reactions that are not truly anaphylaxis and things like simple hives or until those get fully adjudicated Thank you for that question I mentioned research by the FM queue, the most common preferred terms event that we found under the hypersensitivity related events were injections by [ Inaudible ] and injection site rush or hives or itching Nothing that are even close to anaphylaxis Thank you for the presentation I wondered, a couple things on safety I noticed for safety cohort that was looked at and access to draw consents [ Inaudible ] and did you notice that and was there anything or reasons for what draws that can make you question the blind or due to adverse events? It was a little bit in balance in terms of withdrawal by subject but not due to adverse events or position decision due to medical English test conditions or anything Overall the numbers are still very small The difference of 60 subjects looking at the overall safety set, it doesn’t make any [ Inaudible ] ‘s of the difference I was thinking about which seems potentially not due to [ Inaudible ] so when the question was in the FDA book you provided more information about the duration of some of the solicited symptoms and I noticed for example a lot of this you take myalgia for example, there’s a pretty street just pretty striking difference if you look at solicited difference but the differences very small with unsolicited symptoms Do you think that’s primarily attributable to when measurements were made? Yes solicited symptoms were [ Inaudible ] and that’s when we expect most of the symptoms like myalgia and fatigue and things like that to occur Medication provided or recommended — recommendations for some symptoms were recorded? I don’t have the data offhand but there is use of [ Inaudible ] was also collected in the [ Inaudible ] Thank you

This is about the potential for qualitative protection out of this trial There was no immuno [ Inaudible ] as part of his phase 3 but as phase 1, particularly in the elderly population with 2 1/2 months period, there was rather substantial drop-offs in both the total allies as well as neutralization titles that were measured and I am wondering from your presentation, it looked like there was a blood draw a 57 but not another one till 209 Wondering if there’s an adequate measurement of immuno treatment Corliss of protection I will ask Moderna to see how they are planning to address Sure happy to do so The core little protection as you noted are the [ Inaudible ] not yet available at the time of submission of the EUA The analysis should be available in the coming months and trial actually ritually got blood samples at various time points and turn one dose one imprint dose to NT 57 which is one month close and three months and six months and 12 months afterwards And the idea would be we would first [ Inaudible ] analyses and we have breakthrough cases to be able to perform [ Inaudible ] analysis that will be done as well and actually working in collaboration with the NIH and Doctor Holman and Doctor Peter Gilbert to pull together the analysis and that will be done with NIH essays in order to be able to look at other products Doctor Fuller Yes thank you There are side effects which are expected with most vaccines and part of what happened Especially in this time when COVID-19 is such a major issue , what is FD or CDC or Moderna have a plan for informing people of what to expect? In other words we can handle things if we know this is part of what is expected and only going to be a few days and we have over two reported to think otherwise I don’t remember the plan for how people will be informed of what the side effects might be as they go to take this vaccine Can you help remind me? I do know side effects will be described in detail in the sheet for providers and for the recipients I will open up for other people to chime in for other things I guess I’m asking if there is a campaign to make sure that we all get vaccines with medicine or whatever and [ Inaudible ] sometimes we do and sometimes we don’t sometimes on the person is taking a but something like this it would be helpful and build trust if there is a major effort to say that this is what you should expect in these are seen often and these have not been seen That I think will give you a lot more confidence So as you heard we have an intensive survey surveillance set up for distribution of vaccine under UA We will monitor the system closely if we detect any signals and investigate those rapidly If we conclude there is a need to inform vaccine providers or recipients to the general public about a risk that has not been previously appreciated, we will do so in revision to labeling or sooner through safety alerts if we determine that is warranted Thank you

My question relates to the fact that every diagnose case are probably other others that go on diagnosed and wondering if by giving the person [ Inaudible ] a single injection of the vaccine that serves as a boost and giving two injections of the vaccine and otherwise infections serve as the prime and one maxes nation will serve as a person that something that Moderna or FDA has considered as a possibility? Just curious This was not in the scope of the data or study design Just to make sure that I understand your question, are you asking about interchangeability about the vaccine with other MRA whether you can get little of both? Referring to the fact that tens of millions of Americans who have already been infected by the country and they can get reinfected and we also know all of them antibody response to the virus But it appears not to be protected and it can be reinfected When I ask is if you took the ones who have been infected and give them the injection of your vaccine, could you possibly serve as a boost for the infection itself is served at the time? Okay thank you for that clarification If something that we may be able to [ Inaudible ] and we had only 2.2% of the study population that indicated they were previously SARS-CoV-2 positive and we intend to evaluate and as we review and something we can look at and once the [ Inaudible ] data are available, we will be able to see what the initial vaccination would look like in the MR [ Inaudible ] group We don’t have data unfortunately to share with you today but we are anticipating data in the coming week Thank you Don’t go away, we are expanding the discussion and Doctor Meiser has been waiting to ask questions One question I would like to ask is about the stars plot on figures 7 and eight and I realize you don’t have this right in front of you but my question is there were approximately 9000 white subjects in the placebo arm and 5000 in communities of color The rates of infection were 16 per thousand versus eight per thousand in the community of colors Means that was lower and usually we think of COVID-19 causing more disease in the community of color Is there a ready explanation for that or perhaps small numbers and you think it’s truly representative of minority groups? Thank you for the question Attempting to pull up that slide now to reorient to everyone to the discussion we are having So to the question about the small numbers, it’s true that enrollment of minorities was a priority and lots of help and advice from the collaborators and from thought leaders in those communities Nonetheless the study was not designed to look at individual efficacy estimates in various demographic groups and so indeed the number in specific groups are quite small and powered only for the systematic COVID-19 disease . Regardless of what happens with the evolution of the clinical trial we will continue to follow the participants who have been vaccinated with vaccine placebo or crossed over four COVID-19 using the same method we used up until now . I think the trial has been successful at picking up the cases of COVID-19 that occur

and overall it was 56 across but does approximately per thousand years and close to reported rates in the literature Hopefully with continued follow-up we will be able to further add to those numbers and get more refinement Would like to ask a question, in regard to sterilizing immunity The pulmonary figures are very, sing The vaccine may reduce infectious virus and the risk of transmission of fully replication [ Inaudible ] virus Has it been any effort to look at antibodies in respiratory [ Inaudible ] in the upper respiratory tract or lower respiratory tract because if this is in fact true, the injection stimulated sufficient circulating [ Inaudible ] IDG so that it gravitates out into the mucous membrane, is that’s reasonable? You are correct it is certainly reasonable to expect IDG is playing an important role in what we see from and efficacy perspective Don’t have data on the IGA but what we will have and hopefully be able to help us better understand viral shedding of infection are the viral shedding samples that were taken from cases confirmed by [ Inaudible ] to be [ Inaudible ] in the subjects submitted a sample every few days over the month of their convalescence and we will take those results and compare in the breakthrough cases what viral shedding [ Inaudible ].. After Meiser, that something you may want to bring up in the discussion about other studies and the sponsor might be asked to do and Doctor [ Inaudible ] Thank you for a great presentation My question is specifically around additional data transparency and a lot of what you talk about is things that are coming down the line and trying to figure out additional shedding data and additional follow-up that you talk about and Moderna has been transparent and curious what FDA approach will be in presenting the additional data to the public and other community members? I think that was a question for Doctor Zhang But what to make sure We will continue to update the prescribing information and it’s appropriate as we get new information and determine the information as necessary to inform vaccine providers and recipients and about the benefits and risk of vaccine of course we will include as part of the review process for any licensure application and transparent review of the data to support that application as well Had a question about the vaccine adverse events and respiratory disease in general systemic problems that could occur and it’s mentioned to the protocol but there are not very many details of what will actually be looked at in the fact that it’s so efficacious that it makes it less of an issue What’s the exact plan for measuring adverse events? In the respiratory disease? I can take that and speak to the various ways in which we measure safety in the protocol After vaccination subjects had an electronic diary which they record solicited local symptoms

so the exception reaction and solicited systemic systems like fatigue, headache and myalgia The E diary as well as safety phone calls from the site prompted subjects to respond back about unsolicited adverse events and these were any adverse events that may have happened to them and we follow those 28 days after each vaccination Then for specific categories of adverse events including medically attended EE as well as serious adverse events, we will continue with the safety phone calls throughout the duration of the study for the subjects and capture that information and so that is really the framework in which the respiratory illnesses you speak about will be captured and as part of the efficacy surveillance there’s also the surveillance for COBIT 19 — COVID-19 and those subjects who are not COVID-19 positive will look at the respiratory panel of viruses to try and understand the respiratory disease and against some of these endpoints are not yet available to be reported out but we intend to continue that surveillance throughout the study Thank you We will have two more questions and then we will shift and go to a discussion among the committee of FDA questions Doctor [ Inaudible ] next Thank you I have two questions The first one is with regard to [ Inaudible ] particles, I think we heard today about the rate of [ Inaudible ] and the protein [ Inaudible ] but what about nanoparticles? How long do they hang out? Nanoparticles have been evaluated in biodistribution studies and they hang around for approximately 48 hours In the following question to that is is there a theoretical possibility that the body will amount in immune response to the nanoparticles itself and if that happens would it then preclude the use of nanoparticles for any future reference that are developed in the same manner To answer the question, I’m going to ask the chief medical officer Doctor’s to take that one Not as far as we know Let me make a few comments, particles and traces are gone by 48 hours They hang around for a few hours but the components as were his renewal are not immunogenic in the sense that as I described, most of us are walking around [ Inaudible ] and not meaningful in preventing drugs and nanoparticles both by and other companies are being used for routine administration and so far without any evidence of that reactor I don’t think we have any date to expect on preclinical data from our experience on the history with these LMP medicines used in other applications and those applications are much larger quantities And in short I don’t believe that is the case Finally, Doctor can This is a question for Doctor Miller And in your brief material for phase number one you outlined your consideration for comparing micrograms to 25 and 200 and 250 µg and in study 201 you concluded the data support of two dose schedule of either 50 µg or 100 µg for rapid induction and functional antibodies and selected [ Inaudible ] dose for phase number three What other considerations did you weigh in selecting [ Inaudible ] over and I assess

question because reports of any local reduction to the hundred that were 72 that were 7280% of phase 3 and wonder what the safety protocol might look like otherwise Thank you for the question I would like to emphasize at phase 1 study was ongoing and when we had to select the dose to be able to start phase 3 the data was not yet available Nonetheless it’s hard to look backward and say what you would have done but I’m not sure we would have taken a different decision and at the moment we are quite comfortable with the consistent and high efficacy we observe but at that point in time all we knew we were in the myths of the pandemic and want to be sure if we were undertaking this large scale safety and efficacy trial we’re going to expose people to a novel vaccine that we had the best possible chance of demonstrating efficacy in the report and point at the 50 Mike [ Inaudible ] in particularly subject over 71 years of age or was an indication hundred microgram dose was more important and knowing the older group is a group that is significant to the risk for severe complications and COBIT right 19 — COVID-19 it was another reason [ Inaudible ] in the final reason is duration of efficacy will be important as we hopefully ultimately exit the pandemic and believe the highest possible antibodies might lead to the longest possible duration for protection for all those reasons the hundred microgram dose was selected and recognizing we are in the pandemic and now that we have data from phase 2, that’s why we put emphasis on the correlated protection that we do in phase 3 study to see if there’s maybe possibilities for emerging based on that Thank you Thank you and thank you to the FDA for your presentation Now we move on to the items for committee discussion without a vote and is it possible to put up the questions I will read them off while I have them in front of me in considering Moderna plans for unwinding and crossover of placebo recipients, please discuss the most critical data to further inform vaccine safety and effectiveness to support licensure in that should be accrued into this one at a time Ongoing clinical trials with ongoing clinical trials with the Moderna COVID-19 vaccine . Then we will talk afterwards about additional studies This is the ongoing study Doctor Ganz Thank you Ongoing critical data, we still have multiple time points which we Moderna will collect blood and I think it is a missed opportunity particularly if they are collaborating with the NIH and ability [ Inaudible ] which is very important to maintain our [ Inaudible ] immunity and its importance so there are two elements to this moving forward which are critical And any time points which you collect [ Inaudible ] mentioned [ Inaudible ] and further put specifically it’s very important to give the parallel treatment because [ Inaudible ] will be important to understand and it could be potentially distant so in both of those it’s critical data in which to move forward and be able to understand what’s better and the other critical piece ongoing information will be very important, to look at the idea of whether people who are vaccinated and continue to be [ Inaudible ] and looking in household contact to see if there is disease and those individuals who are not her ties to receive vaccines but very important and following those forward and lastly doing the final studies

that are needed to be done within the vaccine population and continue to do those surveillance and the PTR for RNA but also important only to look for the positive but negative trend where we can understand [ Inaudible ]. So outside of the population that we already talked about in terms of [ Inaudible ] critical things that are important Thank you Doctor urban — Ruben Thank you I echo that and a couple things with antibodies that look at [ Inaudible ] communities because it’s a very helpful in the further development vaccine and for following [ Inaudible ] community so I think the logic stays continue to be important And of course monitoring asymptomatic infection is critical And it sounds like it’s already in plan and looking at a [ Inaudible ] for loss of neutralization by the antibody I don’t have a back road to Doctor Goodman start because that’s part of the sand in the current [ Inaudible ] it seems to me at least the trial should have been designed as a blind crossover from the start And my guess is it’s relatively impractical at this point to do it And disappointingly because it’s so late in the game I would encourage FDA and I know it’s not quite a level playing field but as sponsors come in I encourage FDA to do that going forward and for now I think they are stuck with [ Inaudible ] study and [ Inaudible ] outlined Thank you for bringing us back to the question Doctor Wharton I’m continued interest in the follow and with duration and critical factors that maybe taking into account as the study continues Any suggestions? There will be opportunity to learn more based on other studies being done but in terms of ongoing clinical trials, it is important that the safety follow-up be continued and that there be attention for the duration attention question Doctor Neaton I want to go back to the presentation that Doctor Goodman gave this morning and I guess it’s all in reference to speaking to [ Inaudible ] and the vaccine So it seems whether going to do a blind crossover as suggested by Doctor Goodman but are you going to do an open label approach that Doctor Bonds thought, given the situation and practically to be done right now but an opportunity to at least do immediate versus deferred vaccination of the vaccine which identify as different risk But healthcare workers in high risk [ Inaudible ] people and so I take advantage of that Because right now there’s only 17% of participants that have many days to follow up And I think additional follow-up which I guess is occurring right now and another couple weeks, I think we need more follow-up with this vaccine versus placebo to understand the durability of protection That’s what I suggest doing

Thank you Doctor Schooley Thank you I also want to emphasize, I think this plan crossover study is a great opportunity to get some of the data about [ Inaudible ] immunity in a structured way and I encourage these sponsors to consider carefully constructed cohorts representative of the population that are the most interest Ranging from age and gender and ethnicity and look at decay of both human employer [ Inaudible ] a crossover to reset the clock and to incorporate [ Inaudible ] models to look at the kinetics based on [ Inaudible ] in the individual people and decay across different groups based on demographics and hypotheses about different patient population And in brick through cases not just [ Inaudible ] but quantitative data to get a good idea and a better idea about immunity and think about how it might play into studies later about when to boost on 12 when to boost on 123 vaccinate because we know about the readability in general and no reason for this to be any different Doctor Chatterjee Thank you There are pediatric trials going Dutch ongoing on so it’s not in reference to the trial that we discussed today but certainly would encourage those trials to continue and for us to [ Inaudible ] data As far as pregnant women, but understanding again is that according to the criteria for inclusion, efforts were made to not include women and potential but critical given the workforce and the role that those women have in our workforce and high risk that they incur during preparation with COVID-19 that the studies be also conducted in the population Doctor Wawyer We have ongoing treatment is similar in a significant percentage of the participants are healthcare workers In many healthcare systems are starting now to do routine testing of healthcare workers and my system it is every week and I encourage the sponsor to try and collect that data and make comparisons between vaccine and placebo groups Doctor Pergam Two things that makes this to me is I hope that if there is the crossover design they can continue to do additional viral testing with those individuals goes it’s a critical piece about potential transmission And particularly to look at viral load and that is sometimes a difficult process But when we think about transmissibility and the levels of virus that are there and maybe one advantage of potentially advantages of the vaccine I’m also curious within this study, the dharna asked if Moderna can speak to us how many are in the study that are healthcare workers have already opted out because they know they might be eligible to get the Pfizer vaccine and maybe too early to know that an interesting piece of data for us to know what expectations might look like for other groups who may be deciding to go and get the actual available vaccine What I am hearing from our members is to streams of discussion Additional studies that can be done and whatever the specific design unbinding open label and a crossover design and additional studies that might be done

I’m not sure how to bring the two together What I think we might want to do in our discussion is to focus on what happens with the issue that I think is troubling to some of us the inevitable loss of placebo group which occurs what ever we do whether unbinding and open label or a crossover design without unbinding We focus on that And then get back to [ Inaudible ] shutting And this is a very difficult thing to do for us to do and if we were around the table talking to each other we can address these issues much more efficiently Let’s try to talk about the placebo group 1st Doctor Ganz are you going to talk about the placebo group? Yes thank you I want to raise an important point that I think it has not been raised yet We are all concerned about losing that [ Inaudible ] group and the integrity of the data moving forward but I think we do realize it is something that is going to be offered to individuals who got the placebo so the only way I see that we hold on to the integrity and continue learning something is to continue the blinding of the study It doesn’t impact the participant that are vaccinated within six weeks and everyone will actually know that they have been fully vaccinated and we know that that is the sufficient [ Inaudible ] and for this to be efficacious And so everyone gets what they want and you can use the vaccine that actually is now coming to expiration and do it on a planted manner and you uphold the integrity and ability to look forward and it will change everyone’s behavior otherwise It will actually impact the result So that is what I plea to the Moderna and to say that it’s things that everyone gets what they want at that point Thank you Mister Toubman I’m thinking of a broader view that the study was funded in part by the taxpayers And the government does have ability to impose the rules and it seems to me that the assumption will be be unblinded with the entire group and it doesn’t have to be that way We haven’t been asked to vote on it but we think it’s a — it’s not acceptable for the Moderna to move forward if it is granted in the UAE and an example it can be either to exactly what Pfizer is doing and Pfizer ignored [ Inaudible ] to the blind and crossover and not doing that and instead unblinded and offered for the healthcare workers and other E percent stay in placebo so that’s one option and another option is the blended crossover But if we are not clear that we think strongly that that is what should happen, one or both or one of the other, what will happen is Moderna will do what they do . And I would strongly urge we discussed the possibility of having a vote or directing what we think for the advisory But if the committee felt strongly, this is the way it should be handled and because of the worry, that it would have significant impact with FDA and FDA [ Inaudible ] dollars and could say these are the conditions that we’ve been granted and maintain a certain

way New raise specific questions and I urge the members to try and address some of these questions so we get a sense of the committee Doctor Meissner I think it’s a very reasonable suggestion Take a boat and maybe give some support to Moderna . Maybe the importance of having a blinded cohort in the study because eventually this will go for a BLA Then be added to the vaccine and composition table And it will be so difficult to add this to the table without their well-established adverse reaction if they occur And without a blinded trial it will be for blinded group, it will be difficult to answer that question What I like to do is ask Moderna if they have a sense of how soon they might submit BLA through the FDA because once it happens it will be the end of any randomized trial And how quickly by the FDA turnaround the BLA that they receive from either of these two companies Think you We might need guidance from FDA and perhaps from [ Inaudible ] as well I want to make a comment regarding Doctor [ Inaudible ] suggestion to join this discussion point into a voted question I believe we had discussed that if we should do this but we decided, because of the complexity of the situation and as you said we have not only one but two companies and do not turn this into a vote at this time and didn’t ask this discussion point to be a boating question but I think what we would like to hear from the committee and I have heard from committee members and clearly some said the support, the open label, design or crossover about Moderna and others are pleading with entertaining a blind crossover so if we hear committee members to speak out on the specific issues, what they suggest and what they think should be done is I think we have guidance on the committee on how to proceed with the respective companies over the next couple weeks In terms of BLA and [ Inaudible ] applications and how fast we can move to that and what data we need, we realize the placebo control is the [ Inaudible ] of every study conducted and at the same time we realize it may at a certain point may not be feasible but we will be working with the companies over the last nest next couple months what do we need to support and what can be done Not only [ Inaudible ] not only the chemical data but also the manufacturing information and facility information that will be critical here and will make and a deciding factor which we would be able to move to accepting the biologic license I urge the committee members in their comments that are coming out and to recognize to speak to some of these points, were trying to get a sense of the committee without a vote about

some of these issues, unbinding, blinded crossover or continuing whatever we can with the blinded placebo control Doctor Fuller So yes that is exactly what I want to comment on it is a research and you want to get the best data you can and you must have the control but in this case these are people who may decide they don’t want to stay in the study because it is a severe issue and even if we kept the study as a blinded study and they’re not there then we wouldn’t have the data that we want So I think Moderna has done a great job of designing the study so far and if his that is what they recommend than the people in the study remain available and acceptable to get whatever data we can, I would probably go with the unbinding to keep them in the study to get what we can and the second point — When would you unblinded, before or after? I think I would unblinded when the study has gone from them what they need in terms of the timing If I were a study and they told me, you are eligible in three weeks but if you stay in and in five weeks or six weeks, we will be able to get this much information and we can make sure you get this vaccine I guess it is communication to me And quickly want to reemphasize the importance of having pregnant and lactating women study because that is a huge piece of the population However we do it to make sure the people are kept in Thank you Doctor Kurilla In terms of what we get out of the ongoing study, I think we need to take transmission off the table and it needs to be a separate study Two issues that I think we derive information about are the potential asymptomatic infection and because if we actually induce sterilizing immunity but if we convert mild infection based asymptomatic, that is good but not as good because there may be still ongoing transmission The other morn thing is duration and one thing I’m concerned about with limited data and with blinded crossover would allow us to continue to collect duration data which I think is important but not going to permitted asymptomatic data to be accumulated so we lose that and if there’s going to be a quote pseudo-blinding crossover that would be the way to go Thank you Next is Doctor Moore One question I have, not necessarily question the comment and I don’t have an answer for With two large vaccine trials that are now currently blinded and ongoing, that will be shortly released publicly in some way or Pfizer has been released That suggests there will be some people that are blinded and for example in the Moderna study who are in a study because they are personally tremendously afraid of getting COVID-19 They may move over to get vaccinated but if they are vaccinated they have a risk of over vaccination and also adverse events occurring that we don’t recognize or actually the fact that people are not being vaccinated according to the protocols we have I don’t have an answer as to whether it’s to blind or unblinded that question but the other point is a degree with Doctor [ Inaudible ] that I do agree transmission is perhaps

the most central think that we need to address and right now in this pandemic and to try our best along that and probably not the [ Inaudible ] antibody but rather direct detection of [ Inaudible ] and that’s why I’m pushing forward and more importantly that perhaps is [ Inaudible ] transmission, is that I hope both [ Inaudible ] and Pfizer would work with public health officials to try and establish what their cohort [ Inaudible ] protocols for [ Inaudible ] vaccination that we can use that will work or have the best chance of working? Ultimately we anticipate that by next summer we will have a low rate transmission and then we will be putting out fires and we need to know how to put out those fires with these vaccines if they do interrupt transmission May I respond quickly to Patrick’s comment? [ Inaudible ] [ Indiscernible – multiple speakers ] trial design I understand Having done a lot of observations studies and I tend to agree with you It is a difficult thing to study unless you are studying [ Inaudible ] that subject Doctor Cohen I want to add to Doctor Fuller’s comment that I agree Moderna plant sound — sounds reasonable and especially given the logistical challenges that a study sponsor would potentially say in terms of when a particular individual in the study becomes eligible and I think given the variability that will happen at the state and local level in those criteria, it would be hard for them to implement that across-the-board I also believe given the large number of observational studies that are being implemented in combination with multiple different groups, some of the questions while it’s not perfect, a clinical trial blinded would be ideal and I think you can look at these questions from a multitude of other observational studies and we will be able to understand and answer some of these questions through similar degree of competence Doctor Offit To that point there’s an ongoing trend went on college campuses where people will be exited or not and those that are mixed in will see if they are [ Inaudible ] or contagious with [ Inaudible ] which is the best way to do it Then look at the [ Inaudible ] secretion to see if you can eventually have a biomarker and what it is but that is being planned and funded Doctor Miller Again let’s try and get a sense of the committee about the unbinding rep crossover issues Doctor [ Inaudible ] I really like [ Inaudible ] I like the idea of continuing blinding portion of the crossover design because of the advantage it gives you following placebo individuals but the real realistic piece of the challenge that entail for the differential groups in terms of when they get access to vaccine will make it difficult

to do and I worry in terms of different states and approaches to this that it will be difficult I was leaning towards who would be doing blinded because it would provide advantages and in some ways this realistic aspect of this makes us difficult and maybe impossible to approach that side I think in an ideal world, we would like to keep a blinded portion of the crossover design but I think the reality of what happening me be too difficult to do Doctor McGinnis I’m in favor of the crossover and I think we have more time than we actually think I can imagine the way that you could articulate the priorities and could be on a state level I don’t think there is this much vaccine floating around for a few weeks Even the people may want to walk and get in the queue to get [ Inaudible ] and I’m not sure what the supply will look like and you may have a little bit more time Then we think I think in principle I like the blinded crossover and I think it is powerful and maybe the best that we can get in terms of being able to continue assess safety I think the crossover could be [ Inaudible ] particular geographic area not saying it’s easy to do but I entertain it in my third point is we’ve been talking about [ Inaudible ] and I want to iterate when I think we are talking about is pregnancy exposure and not actually proposing [ Inaudible ] but for exposure of FDA regulated products Those are my points Thank you Doctor Toubman has a suggestion for us No ethical issue is not in what is having to unwind this works The issue is rolling down to what is practical And I guess when people say it’s not feasible, nonparty groups and the blinded study, you say that what Pfizer is doing is completely practical because that is what they are doing but [ Inaudible ] in my state is that the vaccine transmission often volunteer process offers all participants [ Inaudible ] in the placebo group option to transition to the vaccine group and interested participants can transition to time points to determine the order in which participants can begin [ Inaudible ] Pfizer and [ Inaudible ] are following the guidance of US and disease control for immunization practices which has prioritized healthcare workers [ Inaudible ] contact and now there’s also commentary that we got and hundred and 48 current file participants who specifically recommend they are fine with saying that and as a developer, it should be permitted and encouraged to unbind members placebo arm who would naturally call for vaccination under their state mixing distribution plan They pointed out I understand that but all we need is a few more weeks and if we can get a few more weeks of data by maintaining placebo control for those who are not in the party groups and that will be in this case [ Inaudible ] 25% will go out to healthcare workers and then it is feasible and if you say it’s feasible than what Pfizer is doing is not feasible and the last point is there’s a reason to have deformity because the different sponsors and since sponsors are doing this there’s no reason and no ethical problem with having [ Inaudible ] vaccine practice And protocol So my suggestion is that we recommend that Moderna do what Pfizer does and with a few weeks that are hopeful and secondary thing would be support for the blinded crossover So I have been asked by the committee members if we are going to have a vote on this?

My sense is that you rather we did not and just give you the sense of the committee Am I correct? Yes You are correct And I really think — I think the committee for being clear over the last few minutes And speaking on the preference It is complicated and I was trying to keep a tally alone bit on here what I was hearing and [ Inaudible ] and great difficulty Because there are nuances Again I feel that I’m speaking here for the office of vaccine but at the same time, I have not had a chance to confirm with my colleague so if you could give and continue the discussion, for a bit longer because I don’t think all the committee members really [ Inaudible ] and like to take a minute to get some responses because I asked the question of my committee members and of my people to weigh in with their opinions as well If the event a couple more minutes discussing this very important question We will talk amongst ourselves about this but I want you to think about if we do have a voting question, what that would be because I’m not clear, this is not a black-and-white issue And I’m not sure what the votes would be about So please, if this is a voting question, let’s have a clear question because I’m not sure, we don’t want a lot of that extensions, we defeats the purpose That’s why [ Inaudible ] Can I ask all hands to be lowered and those people who have not spoken on this question, because that is what we are hearing Please try to tell us what they would think about I see Doctor [ Inaudible ] I comment? We are looking for opinions and opinions are pretty cheap What Mac I want to express my strong support for [ Inaudible ] and an open label crossover because we still get a lot of information about safety and as a matter fact I agree with him that the participants who got the placebo should not be disadvantaged because we are still under a national health crisis and its to get a vaccine that can be used [ Inaudible ] so I have a strong opinion that not unethical for us to get the vaccine [ Inaudible ] recipients And this would be right now or a priority group when it comes up Either way When the group comes up Even opportunity to get the vaccine, I want, I feel strongly and if we don’t do that we will lose the placebo participants and do harm for future participants I think I agree with the plan and open label crossover that’s why I recommend to the FDA Doctor Sawyer They brought up earlier the [ Inaudible ] side effects of the vaccine I think now that information is being widely publicized in the media and people are going to figure out whether they got vaccine or placebo If you got two injections and each time your arm hurt and you got valleys the next day

then you will figure out that you got the vaccine Behaviors are going to be modified based on that and so my opinion is blind is already eroded to the point where it probably won’t matter so I will support the crossover approach and prefer the crossover approach to allow people to be vaccinated when — The crossover is blinded I am supporting non-blinded Your supporting open label Ask But when the people come up and in their tear Okay Doctor Wharton Since I didn’t really specifically address this point when I spoke earlier, I want to say that although the blinded crossover is seeming powerful and has a lot of [ Inaudible ] Bible Right now help coal workers being vaccinated in many different parts of the country has asked the 24% of healthcare workers and placebo group to go unvaccinated while a blinded crossover change in the protocol is implemented It really doesn’t seem feasible to me and it’s kept in the study and best to be done by offering vaccinations in the appropriate tiers that they come up and additional data can be collected on the vaccinated person as the study continues That is my suggestion Thank you Doctor Ruben I will echo Doctor [ Inaudible ] but want to say that the open label study is seems like the only choice but not a terribly good choice so I think we should better to keep in the study but for future sponsors in future trials you can get drive a lot more information are out of the crossover design Especially where we learn more about A favor that in the future but supportive of an open label trial now I agree The problem is we deal with unprecedented and few things that people didn’t think about going in Doctor Sylvester Thank you I agree I think it’s not a perfect world and ultimately open label makes sense of the point time and maybe in the future we ought to think about the crossover that is blinded I’m worried also that greater than 90% vaccine efficacy with people enrolling in future vaccine trials knowing you’re not going to be a to get it so I think inevitability towards the crossover makes sense and let’s work on this one at this point I am favor of open Doctor Meisner Any further comments? After listening to this discussion, it’s hard to reach a conclusion and I will say this will be if we don’t do the blinded crossover, this will be the last opportunity because once the vaccine is licensed, no more placebo-controlled trial We will be throwing out that opportunity If I can interrupt, that’s one of the reasons that we have questions or discussion item number two What in the world we do to collect in the future placebo control data? At least in the United States — That brings up another question

Also, what does this mean for the other vaccines when they start their? Or in their phase 3 trials? Will they follow the same regiment that Madonna — Moderna and Pfizer follow it will be the action of a blinded crossover because why would a subject participate if he or she could get an authorized vaccine? Anyone who wants can go and get a antibody test to get a vaccine or placebo and so it’s not — And I think Doctor Cohen comment, about practicality is important And I would still prefer a blind randomized crossover but it’s also going to be very hard to do that Doctor Perlman I agree with all past discussions but want to give my opinion I like the blinded crossover but I found is not going to be feasible because of this ability for people just walking to the vaccine in particular people with healthcare settings If it can be instituted really that would be [ Inaudible ] but it doesn’t sound like that will happen in [ Inaudible ] was thing this morning it was logistically going to be difficult to do that so that’s why the approach may be the best Doctor Kim I don’t have any specific reason to add to the discussions that have taken place but I want to go on record and say that I support the open label After the EUA or individual parity group comes up that [ Inaudible ] Pfizer Let’s move on to Jim Neaton I prefer the party based on blinding this morning was played out that there’s nothing in the consent about you get the vaccine once the study is over with if you are in the placebo group and accepted All sense have a requirement to explain the data to the people from the trier and implications for that And the Pfizer trial and it makes it difficult plus the local circumstances with healthcare workers being vaccinated and I think to maintain the blind between the vaccine and placebo as long as possible and medicate the people the core hurt because you want to follow everyone for another two years and practicalities are a stage party to have a setting if people can structure it that way Doctor schooling? As much as we like to see things from the perspective of realities and vaccine availability, we need to realize [ Inaudible ] and they will walk if they don’t know anything is important to keep it address so I support on blinded crossover I think we have to also, complicated to understand when the vaccine will be available in each location with the way the country works And taking time to get the logistics and the unblinded crossover set up in a synchronous way starting today so I favor going ahead and beginning to make the changes in the market see and do it when it is in place an asynchronous way the best we can

Doctor: and the final word before we look briefly at the second point Just to clarify what I said earlier, you can very easily separate out the healthcare workers from other groups but there’s not going to be this person will be eligible now Health departments are opening up vaccinations for different groups more organically so if you can vex the healthcare workers now and like [ Inaudible ] said, to the blind for majority [ Inaudible ] for several more weeks and if a person believe they are in a group that is now being recommended for vaccination, the sponsor should not be policing that Similarly to how I don’t think health departments will necessarily be policing that that clarifies my previous comment Doctor Lee I agree with open label, normally I suggest fire is Asian, I agree with Doctor school that it is a hodgepodge and practical in the other consideration I think we need to keep in mind is starting as soon as possible that I do have [ Inaudible ] that apparently they have available and used for this purpose which has something with an expiration date but I favor the open label crossover Doctor Chatterjee [ Inaudible ] was about the other studies — Why don’t you wait for a minute while I recognize [ Inaudible ] and you can kick off that discussion That’s not Doctor, it’s just Mister Toubman It sounds like people are okay with open label but no objected to the prioritization meaning yes you are on blind but you do it [ Inaudible ] and we heard there is obviously problems with it and healthcare workers are a clear group and the other group is when we get to them are not so clear but Pfizer believes it’s doable We can at least try and a contrite and if it doesn’t work it doesn’t work but in the meantime people are going to be able to access that anyway for [ Inaudible ] and then we gain something and yes open label but when the group comes up avoid any [ Inaudible ] Doctor Gerber do you have comments? Yes I want to make a brief comment I had to confirm with colleagues and the consensus is as a stated before we will keep this question as a discussion point and should not be voted on thank you Doctor Chatterjee you had a comment and can you start us off on what happens when we don’t have clinical [ Inaudible ] placebo group and what other additional studies can be done? And we agree we don’t want any open discussion of the observation studies to learn about how vaccines work Focus on this current issue of the lack of the placebo group When I was going to talk about was additional studies such as code administration of the vaccine and –. I didn’t want to get into transmission and things of that sort Please Please go ahead

[ Inaudible ] include older adults and those who are 75 and above and the numbers of participants in the group are relatively quite small But also residents and home care facilities, I’m not sure those folks were included in these trials Thank you Very helpful Doctor Hildreth I agree with the previous comment people living in specific facilities [ Inaudible ] and [ Inaudible ] group Doctor I agree with Doctor Chatterjee, a small number of elderly patients in the 75 and older and in we need to expand and — What was the design, you cannot do a placebo control? I would study it to say immunogenicity alone and it’s probably that we can do a placebo control design but you at least have the data from the primary trial to see what immunogenicity looks like between the two of us probably the best you can do Also true in the suppressed population I know they are working on the trails but I think it is important and the ability to do placebo controls and that something you have to look at immunogenicity as well it cannot produce robust immune response and see how much less response you get in this group That is really important study for the larger population It will make up for a five or 6% of the entire use population Thank you Doctor Gans A couple points that have not been raised, I know that there is a lot of overlap The other studies that we haven’t talked a lot about our looking at other conditions and we talk about the policy with the other neurologic outcomes that I think have to be high on the list and we need to consider especially when we go down into the children studies themselves, want to urge those particular dings to be looked at in the other part is the cardiac findings and most of this likely from [ Inaudible ] receptors, they may be specific to the [ Inaudible ] so we haven’t figured out logic or not and we are seeing a lot of different cardiac manifestations of this needs to be studied not only as potential outcomes of the disease versus the vaccine, but also in the cardiac disease That is an important piece to keep in the forefront of moving forward to think critically about In terms of studies that need to happen, again we talked about in me logic studies and in children they will be particularly important because we cannot extrapolate particularly studies that we’ve done in children where [ Inaudible ] not follow the same pattern as each other and as an adult because they have different natural vision of potentially [ Inaudible ] responses and therefore it will be important as we understand to reiterate, doing the study is ongoing Thank you Doctor Sawyer One of the things we learn is what happens if you get one dose of the Pfizer vaccine and second dose of the Moderna or vice versa and that mistake will have a lot as we start to disseminate vaccine around the country The interim guidance is issued so far is immunization registries is to word dose and to assume even though you are mixing products

is an adequate immune response and at some point it’s nice to know if that is really true Doctor Rubin I know were not supposed to propose other studies but [ Inaudible ] protection will be actually important [ Inaudible ] and it’s important in interpreting these tart trials because of the lack of placebo What were difficult in assessing safety and no easy way to do that when we have no placebo control but we can at least get advocacy if we have some idea what protection looks like Doctor Lee One of the interesting things that we might want to consider is noninferiority trial of two doses versus one I think you have a certain trend that doesn’t get the second dose and if you have reasonably good vaccine efficacy is, really big about that and we look at pretty much of the incident of COVID-19 and noninferiority would be want to think about How about different doses? Questions raised about the doses? Especially for children I’m trying to get a discussion — discussion going, it’s hard virtually Thank you Let’s go back to Doctor Ruben’s point about the protection This is probably one of the most critical features and not just in this vaccine but for future vaccine trials that will make other vaccines realistically approachable in terms of their clinical trials going forward if they can move towards an accelerated approval That the immunogenicity would be a good endpoint in that work The other thing in regards to the one versus two dozen, that is important trial but would like to of a size in the follow-up what’s being done to surveillance for under the gi you a it’s aggregated data to look at who only got one dose because there will be people who will not come back for the second dose and see whether there are clues that may be quite informative without having to go through a formal trial to get an assessment is whether it is a feasible approach Doctor Schooley I just want to reemphasize the population because they are a place that we have a wider spray of [ Inaudible ] to look at and might get lots of many data and if they start a lower point of the terms of vaccine immunity Recurring theme and it looks like we may be lost [ Inaudible ] that this vaccine which we have now seen with other vaccines and clearly that is a message that [ Inaudible ] are paramount Doctor Gantz I just want to follow-up that I mentioned that [ Inaudible ] started out with [ Inaudible ] investigating this disease further and we know that hopefully population get recognized and an important [ Inaudible ] will be to look at the adverse event as they follow natural disease versus adverse event that follow vaccination because as we know vaccination is highly protective although often not hundred percent but as long as they reduce the actual events of the severe adverse events than actually it should be an issue of protection that is studied

ongoing so [ Inaudible ] policy and other outcomes that we see Doctor Sylvester Doctor mentor you raised an interesting question about the timing between doses and there is interesting studies or that we have seen in the vaccine world where the longer you wait for the second dose the higher the antibody may be the practicality of that in a pandemic is maybe difficult People are going to want to line up and Pfizer will have a three-week window and Madonna now has a four-week window and I don’t think many people will say I will just wait eight weeks or 12 weeks before I get my second dose I like the question and it is a great and make Dominic question but not a practical one Doctor Pergam The dose issue is important one that I want to come back to because again thinking about population that tend to have less response to or less side effects, it looks like the older population has less complications from the second dose of the vaccine which might suggest they tolerate a higher dose and we have seen in other vaccines that higher doses are more beneficial for whether it is influenza or beneficial and a real value in targeting those populations with a slight difference in the community and immunocompromised or older population as targets to do studies looking at higher dose I had the 250 was the highest I think that is the right Maybe to try and see if that’s better with immunity from the higher dose of the vaccine in those groups Doctor Perlman I just want to reinforce doing a pediatric trial in pointing out problems because children don’t get much particular sickness with this It’s very important to think about whether we measure serology [ Inaudible ] and culturing and children this is very hard but I think this is important because it may be the major group that is unvaccinated in a short time Doctor Fuller Final comment before we discuss the voting question Looking for here a couple questions which have to do with duration of protection, what will happen if this vaccine is a lifelong vaccine which we expect it is not and how do we know when someone needs to boost or if they are protected against new strains that may evolve from COVID-19 and I know that is not the study that’s easy to design but I want to put it out there because of you want to coexist with this virus and variations thereof we need to think about those things Think you all for this — thank you all for this vigorous discussion We have given FDA a sense of our turn that we could do and a crossover wind design and realization that it may be impossible We know what Pfizer has proposed and FDA will be negotiating with Moderna about the way they will address this problem I think we have really have the time fortunately to go over this and the detail that it needs [ Captioners transitioning ] I will ask the committee members who wish to explain their boat To explain their decision A question is based on the totality of scientific evidence

Based on the totality of scientific evidence available due to the benefits of the vaccine Doesn’t outweigh the risk for use in individuals 18 years of age and older For commenting as you wish on this question You are the first Thank you Thank you for allowing us the time about this really important topic I think this is a really opportune time for us to move science forward I would say the evidence that has been studied in great detail on this vaccine highly outweighs any of the issues that we have seen I think it really supports us with the pandemic in our background really move forward and finally provide a safe and effective way to get to herd immunity Again, understanding this is for 18 years and older Obviously we need to be able to provide this to all of our population to get there It is a first step Thank you Thank you I had some serious reservations about this question We have been discussing This whole meeting has been focused on the emergency use authorization for this vaccine Not for full approval The question really does not reflect that It could easily be seen as full approval There was quite a bit of confusion Not only in the general public but many in the media reports talking about this panel approving the vaccine or recommending this vaccine for approval We even heard today during the open public hearing session several medical professionals who talked about approving I think the distinction between a product which is still investigational product and the full approval with the BLA is a distinction we need to maintain I think we are losing that simply by looking at this as a age-related Anyone over the 18 years and older, it does not strike me as really addressing the emergency which is severe and serious life-threatening disease in specific populations I have a lot of problems This could be interpreted as is recommending full approval Not only adequate evaluation of this vaccine but other future and ongoing vaccines in development Thank you I appreciate your concern I wonder if they could address amending the question The intent is really to do this under emergency use authorization The question does not release date that When we published the agenda, the topic is the committee will meet in open session to discuss emergency use authorization of the vaccine for the prevention in individuals 18 years of age and older So that is the topic of today’s discussion It is to discuss emergency use authorization That is what the agenda says We raise this question because as was stated A vaccine authorized is a product that has not been approved It is a nonapproved product In order for us to issue it, we have to make a determination that the benefits of the product

outweigh the risk What if we just add the words EUA to this question Would that be possible? From the totality of scientific evidence available due to the benefit of the out phase, the risk for use under a EUA and individuals 18 years of age and older You have to take this to your lawyers? Can you make a determination We can say for use under the EUA 18 years of age and older if the committee meets that clarification Then I think we can safely do so Yes please The question is very clear Do we think this vaccine benefits outweigh the risk If we think that that the FDA will make a decision That is not what we are deciding on We are deciding on whether the benefits of this vaccine outweigh the risk That it is up to the FDA to make a decision Do I think the question should be left exactly as it is I completely support that I have a little trouble with the way it is written as well It is going to be very hard to study other vaccines when a person looks at this sentence When I was suggest Is that we write through two months of follow-up Up with some qualification in their that defines the length of time that it has been evaluated This is the blanket statement Everybody should get it This is the question that is phrased the way it is phrased because we want to know if the product is still considered a nonapproved product but we could still be given during the public health emergency if the benefits of this product outweigh the risks It does not imply If we determine It can be given to 18 years of age and older That does not equal that the product is approved A lot of people will not understand Could use at least the experimental vaccine I think once we start qualifying in terms of the duration, it is going to be so confusing because it duration make it longer Let me just say we have a question now We are advisory to FDA They have put in a question they feel comfortable with Am I correct? That is what we are voting on If it is not in favor, then we can discuss this further How should we proceed? I would like to proceed with keeping the question May ask a question? Doctor Hildreth? Are required to go back and retrospectively change the question?

That is another issue I was thinking of How would I explain that we have a different question How would I explain that I get it Matt ask a question not related to the phrasing but a very important one? Yes please They will try to go in order It is a lot easier to manage I definitely hope this does not happen What if there is some adversity That if we think the benefits outweigh the risks How does this get withdrawn? That we can no longer do this They had elaborated in his introductory remarks Saying this last week That it can be revoked They can be double reasons It can certainly be that if we see the risk outweigh the benefits of the product That we can revoke them Right now they are looking at benefits based on the data available to us We will have continued follow-up after the safety follow-up of the risks If we would determined the risk That the risk rated benefits The FDA would do that? Yes Thank you for the clarification Let’s just go by recognized individuals I think the question that is being asked Do we have enough evidence to say the benefits of this vaccine outweigh at the moment a theoretical risk I think the answer to that question is clearly yes It is Wendy know know That is as big as any general pediatric vaccine trial We do not know whether or not is going to be affected six months from now We do not know whether or not it is going to have a rare serious side effect Frankly given what we know so far about what we have with the T helper cell We can feel pretty comfortable that this vaccine is going to have a benefit that last for more than three months or so You cannot qualify things as being experimental because you could always say that With the HPV vaccine, we can say with think it is okay for seven years That is all we have data for I think the answer to this question I completely agree It is clearly yes Thank you Doctor: We are going to be discussing this until 5 PM Eastern At that time, we’re going to put it to the boat There is also another chance to explain your decision afterwards I which is going to ditto what he just did I completely agree it is the right question The data clearly suggest that The data clearly shows the benefits outweigh the risk > I completely agree I think the preponderance of data is totally in support of moving this forward I do not see any value in changing the terminology I also think this idea that the process is going to change future vaccine trials feels a little bit strange to me We’re talking about a pandemic which is not very common what we really need to move this forward There is the effort to get this done quickly I do not see much of a risk in the long term that this will be used I think we need to focus on what is in him Mr. Chairman My cameras not coming on but can you hear me? Yes I am fine with the question as is It is based on the totality of scientific evidence available Based upon that The strong data I think it is worth it I did have a concern I’m glad there is discussion about whether to change the question or not I was troubled by the fact the FDA was reined in again on changing the question Basically we have been told by the independent committee That they file question should be changed It does not seem to be the willingness here I think that is the committee’s decision The answer he gave First to my question then after that That in reality does not read work You decline people the opportunity This happened last time There was strong feelings about including 17-year-olds Because that was not presented, people are forced to make a choice I think the committee should be independent In this case I think it is mine Doctor Meisner I did not realize my head was still love Thank you Unless you have something burning to say I agree with what everyone has said I am in favor My only point I do not want people to interpret this the same way they would a license vaccine

Based on the available evidence That is limited If everyone else is comfortable with this, I am totally comfortable In reality, whatever we say, the media is going to interpret it in whatever way they want Yes Doctor working? The question is how we think about EUA Based on the totality of scientific evidence I strongly support the benefits outweigh the risk Doctor needing? The answer is yes to the question You do not have to explain your decision afterwards Then finally Doctor Ruben We will vote the question Inc. you I just wanted to follow-up on several of these previous members that have commented on this I understand the difficulty summer having with A scientist we tend to be very precise in what we say As to the point as possible What is not mentioned in the question We are making this decision during a pandemic It is a really unique circumstance that is forcing us in some ways to work the question in this way and to answer the question in this way I would send comfortable with the way the question is written Thank you Finally, Doctor Ruben Thank you You can hear me? Yes we can I’m glad to be recognized Just want to remember why we’re here We are here to provide for two reasons I can think of To provide the FDA The advice they want Can still get hung up on the question The second reason we’re here is to inspire confidence to the public that we look carefully at the data When we worry about the details of the wording I am not sure where helping people understand what will almost certainly be a very strong vote in favor Thank you Doctor Ruben It is a delight to come to the end When I do not see any hands raised That was not the case last week So now, let’s call the question We are going to be voting They will have a chance to do so by raising their hands Thank you Can everybody hear me okay? Yes we can Our temporary members as seen on the next slide Excluding the industry representative will be voting in today’s meeting He will read the question for the record Afterwards all members will cast their vote by selecting one of the voting options You will have two minutes after the question has been read Was they have been placed we will broadcast the results and read the individual ones allowed for the record You can change your vote within the two minute timeframe All will be considered final Does anybody have any questions before we begin? I do not see any questions Would like to go ahead and read the question The question we are voting on is based on the totality of scientific evidence available Due to the benefits of the vaccine To the outweigh the risk for use in individuals 18 years of age and older Thank you You have two minutes to go ahead and cast your vote I want to point out Correct This is the wrong one You are correct I was busy trying to find where the voting was We will take in the revolt Can we do last week’s? My might be different conclusions That is the right one up now I believe the question has been updated We will restart the timer and clear out the current results We have 30 seconds remaining Our two minutes is up If we could go ahead and close it and broadcast the results I will read the individual not for the record We have a yes from Doctor Cohen Doctor Sawyer yes Doctor Ruben, yes Doctor Perlman, yes Doctor Schooley, yes Doctor Lee, yes Doctor Moore, yes Doctor Chatterjee, yes Doctor Meisner, yes Doctor Fuller, yes Doctor Hildreth, yes Doctor Wharton, yes Doctor Ken, yes

Doctor., Yes Doctor McInnis, yes Mr. common, yes That concludes the vote Is like we have a favorable vote I will pass the floor back Thank you for putting in your vote today Anybody who would like to explain their vote should raise their hands Mr. Tom and his first They can I voted just because it is strong Can you hear me? We can It is strong for approval Last time I did recommend that we not grant them broadly but rather limit it to priority groups to allow for further data to be collected Since there is limited supply anyway That would be to preserve the data we would get That was not accepted When they moved forward, people who were nonpriority groups would be maintained in the study That was really important to me I am very concerned about the proposal It does sound like One of the FDA did not want to vote on that I can see why It seemed like there was strong support If they’re going to unwind, they should do it on the basis of when it comes up Which is what McDonough has proposed Finally, I did want to say thank you They put a tremendous amount of work in this At the beginning of the meeting In terms of very long hours per Working with this sponsors They have been under tremendous pressure Even improper political pressure I think they valiantly resisted that The hard-working FDA folks Thank you You like to explain years? Yes I would Thank you First of all I want to thank the FDA for the incredible work they have done The transparency that went in today Having more time We are in an unparalleled crisis I did not think it was the way to go Since the train has left the station, I appreciate they have given up the thorough study that even from the beginning seem to be very well organized with getting people with underlying conditions Monitoring activity throughout the study With including the nasal swabs which are not completely analyzed at the moment but which have great potential Then the care for the study participants throughout including a plan for monitoring adverse effects as well as what to do with people who may want to move in from the placebo I appreciate the where they have conducted a much more transparent and clean study I know that now that we have vaccines available, that we still have to use the protections that are available We can keep each other safe as we go through getting the type of protection however long it lasts I want to think the FDA and all of you for helping with this discussion today That is why I said yes Thank you Thank you Doctor Fuller For the final word Doctor Hildreth Thank you Arnold I abstained because I am very uncomfortable with the language In the mist of a pandemic and with limited vaccine supply available, a blanket statement for individuals 18 years or older is just too broad I am not convinced for all of those age groups the benefits outweigh the risks I would prefer to see it more targeted towards people at high risk of serious and life-threatening

disease They have that information We understand to a certain extent those high risk groups It could be targeted Then I would’ve preferred to seeing rather than emergency used authorization, expanded access program I think it would have given up a lot more opportunities to continue to collect the data My concern about future vaccines was not on non-coronavirus vaccines but other coronavirus vaccine candidates in various stages of development Thank you Doctor Hildreth? Thank you Sorry about the train I just want to make the point The scientific achievement this is To say thank you to all the scientists present and past that have contributed to this The vaccines available in December It is a remarkable achievement Thank you Thank you Doctor Hildreth You have echoed my feeling about what a remarkable achievement has been reached Having the sequence less than a year ago I just wanted to make one or two comments the foreclosing Our vote was even more overwhelming tonight than last week I do not think anyone should interpret the difference in the vote being one way or another Comparing the two vaccines that we have considered Academics have a way of getting involved in details and what we have done for the last eight or 9 hours was to go over the details Some people took the issues last week

Especially those involving different age groups The 16 and 17-year-olds to drive the decision that they made which clearly was made based on that issue and not on the overwhelming evidence for the risk being less than the benefits The clear benefit with these vaccines I just like to close by thanking the committee members Thinking the FDA for giving us a agenda which allowed much more open discussion which I think benefits all of us Including trying to advise the FDA on some of these very tough issues That we are facing and congratulations to us all for achieving this emergency used authorization for a second vaccine which along with other events would eventually and sooner break the back of the pandemic Now I would like to hand the floor over To formally close the meeting Your phone is muted I’m sorry Thank you all You did a great job Thank you for the report This meeting is adjourned now Thank you very much Have a good evening Thank you Good night everybody Thank you Thank you all and with that we will officially adjourned We will now kill the feeds Thank you so much A great job Hold on one second I appreciate all of those We will have some of those technical things We are clear Thank you so much everyone

You are great Arnold you jinxed us This was a lot better Arnold you jinxed us We had two major issues We had one person stop Sharon Kathleen and I went through every slide one by one We went through it last night That was too funny Thank you Thank you so much This all went very well today Mike you need to get up and stretch please I just want to say thanks to Arnold and the FDA for listening to some of the comment as well I think this went a lot smoother If you give us the time Exactly When you see 10 hands up Yes Arnold you did a masterful job Thank you Thank you Great job everybody Thank you so much Goodbye Like I said, thank you all A lot of work went into this Like I say let’s get people healthy With that, we all need a break You have a great rest of the night We will see you all sometime in January Is not like it is in January This is Kathleen No kidding Let’s all take a long break Like I said this was awesome Did you want to say anything? Hello Mike Good job I am signing off See you later Thank you It sounds like it will not be Like I said, we are all clear Great night and we are out of your I’m turning this meeting reminder Thank you so much The not everybody Talk to you later