Panel recommends emergency authorization for molnupiravir oral capsules for COVID treatment in high-risk adults
The committee will discuss Emergency Use Authorization submitted by Merck & Co. Inc., for emergency use of molnupiravir oral capsules for treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalization.
productive for you, will you? Yes thank you. Dr Brennan the vote results are now displayed. I will read the vote totals into the record. The chairperson will go down the list and each voting member will state their name and their vote into the record. You can also state the reason why you voted as you did if you want to. However you should also address any sub parts of the voting question. The vote is 13 yeses and no zero abstentions. Thank you. Thank you. We will now go down the list and have everyone who voted state their name and vote into the record. You also may provide justification of your vote if you wish. We will start with DR Eastmond. Mhm. Thank you. I'm assuming you can hear me Yeah I voted yes. I feel like the potential risks and benefits. I mean benefits outweigh the rest in this case. I do. I guess the you know I'm comin I don't I think that you should not approve it for use in pregnant women. Been a really exceptional circumstances. Um I do think they should limit the use of this drug to high risk individuals. I believe the FDA has chosen the risk mitigation approaches that they have proposed seem reasonable to me. I would advise that the company engage in post exposure monitoring for mutations in treated patients. The evidence indicates that this drug does not cause mutations in vivo but it would be useful to verify that in patients. Thank you. I think. Let me thank you doctor Creegan. Alright this is Janet Craigan. I voted yes. Um I do think that FDA should require pregnancy testing for individuals before treatment has begun or at least nonpregnant status being verified if someone is pregnant. I think they must be referred or obtain counseling from a knowledgeable provider before they fill the prescription. But the only limitations I have. Okay, thank you. Dr Greene. Thank you. This is Michael Green. I voted yes. This was clearly a very difficult decision and I think the death signal, what was most impactful in my decision making. Um I would also say that the potential concern for lack availability of an alternative therapy for those at high risk, perhaps including the possibility of loss of efficacy of monoclonal cells with the emergence of variants not attributable to use of this medication. I would use it in high risk non vaccinated individuals and looking at the data that we have obesity looks Um uh like a good signal age. Although the outcomes less than 60 and greater 60 were similar in the information provided to us by the sponsor. I would consider it in those with multiple risk factors that are present. I'm uncertain about whether I would use it in transplant recipients, but I would possibly do so because its mechanism of action should actually perhaps decrease the likelihood of emergence of a mutant strain rather than increase it. And studies in that population would be of value for pregnancy. I would only use it if there is no alternative therapy available and I don't think I would use it in the first trimester. I agree with the multiple mitigation strategies proposed by the agents as well as those that were added in the discussion including emphasizing the importance of household contact trying to limit their exposure to positive patients which I counsel families on on a daily basis anyhow. And finally, okay comments speakers should an alternative oral agent become available that had a better safety profile and equal to or better efficacy profile. Uh The agency might reconsider its authorization. Thank you. Thank you. DR ready? Cannot hear you. DR ready? Sorry? Sorry, can you hear me and hear you know I voted yes and I would like to stick with the high risk criteria that was in the original trial. So unvaccinated page. Focus on unvaccinated patients or patients who had a sub optimal response to the vaccine. There's a lack of an efficacious alternative therapy. So if there is an alternative therapy that's efficacious like monoclonal antibodies currently or a future medication that would be the priority. And then in terms of pregnancy, you know, I think the risks outweigh potential risks, outweigh any benefit in the first trimester. So would make that clear. And then um you know that's the only alternative for pregnant page individual on discussing the potential risks and Ben beyond the first. Um and then I strongly recommend getting more data on the U. S. Population um in all patients and then you know the pregnancy surveillance, making it a stronger surveillance. You know not depending upon providers to voluntarily provide that information. Thank you. Dr swamy Nathan. This shank are swarming nothing. I voted no. Um I felt that the overall absolute effect in the total trial population was modest at best. Um The risk of mutagenic effects on the patient uh is not firmly established or characterized and given the large potential population affected uh the risk of widespread effects on potential birth defects, especially delayed effects on the male has not been adequately study. Thank you. Thank you Dr Dublin. Yes, can you hear me? Yeah I voted yes. I agree with others. This was a difficult decision. I think that for me it was important to consider the results of the clinical trial in total and not get too obsessed with why the second half of the trial looked different. And I think that the population will be really important to get it right and I totally agree with people as they have said that this needs to be a really high risk population. And with that in mind I would favor sticking pretty close to the trial population and not expanding to be as broad as the current population of all high risk individuals listed in the CDC guidelines because that gets pretty expensive. For instance, it seems to include people who are even overweight rather than just abuse. I would not recommend a limitation based on age. They limited to people over 60 as got suggested some of our discussions. I agree with the general approach. Several others, like Dr Craven has suggested for pregnancy where I wouldn't recommend it, but I think it does need to be available and you know, very extreme situations where there is no alternative in a woman's life is really in danger. And I think shared decision crucial. I favor approving it for individuals who are unvaccinated or agree with DR already vaccinated individuals who we predict have a very poor immune response Which could be based on factors such as age over 75 or being immuno suppressed. And I think other really important points would be to continue to do efficacy monitoring by viral played and understand if there truly is a real finding of much less efficacy against delta virus, that would be important to know ideally. I would love to see a head to head trial against an alternative such as monoclonal antibodies. Um I think the proposal to minor for many patients after exposure is important tying into Dr Swaminathan, concerned about the potential risk of mutations that could need to delay birth defects. I agree with DR cranium that we should require pregnancy testing before treatment and I agree with the prior suggestion that if another medication becomes available under anyway, this the way should be revisited and have the potential to be withdrawn. I also like the comments that were made earlier about this may end up being a situation where a multi drug strategy is advisable and the idea of combining the drug with another as part of a multi drug strategy should be kept in mind for the future. Thank you. I will just say it's 5:00 now. We're likely going to go 15 or 20 minutes over um Doctor Burgess. The nativity burgess. I voted no. Uh it was a challenging decision. Yeah, I was persuaded. Uh we both know on the basis of the very difficult to explain different in the population and peace. Are there too evaluated after the interim analysis as well as some apparent heterogeneity in the a parent beneficial effect. For example with the risk factor of diabetes. Um and I think there are concerns with respect to the uncertainty about risk for geno toxicity. I certainly recognize the need for additional therapeutic agents to be available, particularly with the emergence of uh huh of developing clay AIDS. And strange but on the as the question was articulated on the basis of the available data, I voted no thank you. Thank you. Dr lee jennifer lee I voted no likely coming from the clinical pharmacologist inside of me. I appreciated the pharmacologic safety is generally more evident. Post marketing surveillance. Yet the pre marketing studies that we've seen here demonstrate highly relevant signals for safety concerns. So in light of multiple safety signals, appreciate it and discuss today and also coupled to the modest benefit for mild to moderate and I know not severe symptomatic covid 19 especially against the delta strain in reducing hospitalization and or death. I voted no. Based on the currently available data, I think I just mean more efficacy and safety data perhaps by with more subjects against people or other treatment strategies before I can um voted yes. Thank you. Dr Wina Peter Wanna. I voted no because I was not convinced that the potential benefits of a 3% decrease in overall hospitalizations and death outweighed the known and potential risks of the post treatment. Even under the protections of the U. S. A. The number needed to treat of around 34 means that a potentially large amount of virus is going to be exposed to the drug for every potential benefiting patient. And this relatively large number needed to treat concern plays into the questions surrounding the immunogenicity of the like proteins and potential for creating variants as an outpatient therapy. There's really no effective way to control the manner in which the patient is taking the medication and may potentially transmit the family or their close contacts while taking the medication or soon afterwards. Another issue that assisted in formulating my decision included the questionable and contradictory benefits seen in the diabetic group and that called into question at least in my mind the possible benefits and other high risk groups not included in the trial. That was used to support this application. There would be real difficulty in defining the high risk group potentially benefiting from the therapy without a large departure from the current criteria list for high risk population. Bye. Thank you. Dr hardy. We cannot hear you dr hardy. We still cannot hear you. We can go to Dr Shoni and when Dr hardy gets audio we will have his comments. Sorry. Dr hardy. Well your on button again. Um Dr Hardy from Los Angeles. I voted yes Because 2019 is still a emergency situation as a front line clinician and treating patients both inpatient and outpatient. There is a need for something like this. Um This is the first opportunity that an oral outpatient medication for mildly symptomatic tomato symptomatic persons would be available. Although I do have questions about its overall longer term longer from efficacy, it did meet its pre specified um statistical bounds of showing 48% improvement in terms of possible ization and death. Um I think as far as mitigation strategies there doesn't need to be a a warning about using this in pregnant women. But also give it up to the a discussion between the woman and her physicians as well as the fact that pregnancy should be tested for. So that that discussion can occur if his former does not know she's pregnant and particularly if she's in the first trimester that could be a concern. Um It should be indicated for persons who are high risk. Um And who are outpatients and we'll see what happens as time goes on. Thank you. Dr Hildreth and that. I'm sorry dr Shoni I I got confused Dr Shoni please. I apologize. No problem. This is rita Shoni. I don't okay. Uh huh. Excuse me attention by any like oh immunogenicity. Mhm. All the mhm. That people needed to naturally is. Yeah but an enormous cancer that is from the as far I think that the highway bacteria that you understand me child are appropriate. I feel that the mitigation strategies that have been proposed by the agency are also appropriate. I would suggest that it's led the author to pregnant individuals and that simply made with yeah the position and the present individual. Mhm. Only as there seems to be um alternative two pregnant individuals would not limit um Run into people over six. And I think that we'll do it. Thank you. Thank you. Dr Hildreth thank you. Dr Payne. I voted no easy vote for me to not know. I think the the general toxicity data, neurogenesis the data more questions than answers. I also think that the potential for this drug to drive some very challenging variants into the public is a major major concern. And for those reasons they're being more questions than answers cannot comfortably vote yes for this or that you know. Thank thank you. Dr Gillespie mm. So I didn't know um mainly I agree with all the no votes. Oh my biggest biggest reason was dad, I know that there is not enough investigation on changes that could be our second cause. Um it all push um I don't think don't think that the benefits are high enough do for the Yeah thank you. Dr Baden. I voted yes and I agree with all that's been said by both the yes and no voters. I see this as an incredibly difficult decision and has already been stated. There are many, many more questions than answers. However, as I see the regulatory framework, are there circumstances where the risk where the benefit may exceed the risk? And I think the mortality data I found compelling. I think we saw at least three studies the impatient study where it did not work and maybe the mortality went the wrong way. The Phase three trial where a part a had tremendous efficacy and part B went the wrong way. So I think that speaks to the right patient population, the right virus at the right time. But for me that at least suggests that there are populations where there may be benefits that then puts a burden on the agency and on the applicant and on the community to continue to vigorously study so that we can better define who's likely to benefit. It's a not hospitalist individuals. It's early and ill. I think the CDC criteria for increased risk makes sense for very practical issues have had to roll this out. But I I would ask the agency to consider adding a supplement to say strongly encourage the criteria associated with the study. We need to understand the behavior with variants. Uh huh. And the assumption that it will work evenly across variants may be true but that needs to be tested and understood. I think the unvaccinated population is very important as well as those who have not had prior infection. And those are parameters that will have to be better understood since they may modulate the efficacy. But overall I trust our practitioners um that if we educate them properly they can deploy this properly. I think there are several mitigation strategies to be considered as already discussed. I think there needs to be studies and vaccinated individual studies and those with prior infection studies and the compromise particularly to understand safety and the multiple cycles of replication and therefore the risk variant emergence of concern and that needs to be quantified. I think the pregnancy issues have been discussed and I think the question of secondary transmission also needs consideration more to prove the negative because I think the presence of data that's reassuring will be reassuring. And it's the absence of data that makes many of us uncomfortable and that will need to be generated. But I can see scenarios where there are benefits and therefore having this available for those scenarios. Makes sense to me. Thank you dr walker. Thank you dr bait and you took the words out of my mouth. um solely under the E. U. A consideration is why I voted yes. This was a very difficult decision for me. I I literally toggle back and forth as I know. Um Everyone has on this. Um While data of this magnitude can you know show of emerging hope for more for more covid vaccines or therapies to come. You know there is room for the efficacy of the overall risk within the population to be fully addressed. Um I do think and this has been stated time and time again. This should really be provided to high risk individuals who have not been vaccinated. Um I think it was stated that in order um for a patient to even receive this drug you know they have to show some type of symptoms I think that needs to be addressed. Um and they have to receive a prescription. So I don't think this study did full justice or it really took into consideration. The minority population that may not have full access to a primary care physician in order to receive a prescription um in order to take the drug. Um Aside from going to an emergency room. Um So I think more data is needed on this subset as well as the effect on pregnant women especially me as a woman of childbearing age. Um I don't think I would want to take this drug not knowing the effect that could have on my unborn child post exposure monitoring. We'll also uh you know, needs to be done um as well as a separate evaluation of immuno compromised individuals. Um And more data is needed on individuals who have have had transplants such as bone marrow transplant. Additionally, when it comes to monetary strategies um you know, it's still fully unknown what would really be employed to ensure that five day regimen will be taken in its entirety once the patient receives the prescription. You know, uh what check ins are being done to ensure that on day three that patient is taken. Um the drugs um it will also be vital to ensure proper language is fully disseminated so that patients fully understand the risk uh in the benefits um proper training and education for uh for clinicians is needed to ensure that they do take into careful consideration um Who this drug should be administered to. Thank you. Thank you. Dr Poor air. Yes, thank you. I believe that. So I voted Yes. Okay. And I believe that the appropriate authorized population should be individuals Age 60 and over. I do not believe that this drug should be used in pregnancy. However, if the agency does decide to lose in the pregnancy, um I would recommend that they consider um the lactating women be given the same mitigation as women of childbearing age and pregnant women and also consider men who are interested in becoming father. Um I think in the case of individuals who are immuno compromised the mitigation um steps that we discussed earlier should be employed and also that there should be virus testing at various times after the initiation of therapy so that they can really learn how long that that virus last. And finally I think at this point the gina toxicity situation is still a black box. Um but I would hope that in the future when there's more data available that the that the agency would reconsider jobs. The situation. Thank you. Thank you. Dr Murphy. I think dr Murphy you're on mute or you may not be connected. In which case we'll go to Dr sid berry and we'll come back to dr Murphy when he is available. Dr sit very high school insider Yeah. Ah A lot of it. I wanted to see a production at the point estimate in reduction in hospitalizations and deaths. The preliminary to the final data set. Final data set still represented a 30% reduction in hospitalization and death. The separate significant reduction in death that motivated me towards the yes vote was clinically well tolerated. I think the evidence shows that there's a very low risk of clinical immunogenicity, especially for a drug taken for only five days. I agree with Dr baden that the CDC high risk criteria should be used but we do need to take into account immunization status and then what's known about current and emerging circulating variant course, the main concern, I'm sorry. I would also suggest that instead of putting an age of 18 the label simply the EU a indicate this is for adults. Girls uniformly closed their growth plates by age 16. And many boys do before age 18 as well. So I recommend just leaving this as adults without a specific age. The reproductive toxicity is a obvious concern. I would say this is a safety signal that needs follow up and represents a potential risk, not a known risk and one that deserves a lot of further evaluation. And also clear counseling when it comes to women or people who are pregnant or may become pregnant. So I agree that this is not for routine use in pregnancy. But I do not think people who are pregnant should be stopped for being able to use this if they meet the criteria for being at high risk of progression for severe disease or death. They need to be informed of the pre clinical findings that raised concerns and only use this if an alternative treatment is not available accessible or acceptable. Thanks very much. Thank you Perez rico Perez Cleveland via I vote for the emergency use authorization of this oral agent because it can serve as an alternative to monoclonal antibodies where these may not be available. I think the eligibility criteria used in the study are valid for its use adding the immuno suppressed category with the caveat that you know the dynamics of fire. All Koreans need to be studied in this population and in regards to the question of uh women of reproductive age pregnancy test is indicated and then unvaccinated pregnant women without access to an accord antibodies who made a deal with the criteria. We would need to have shared decision making with their providers. Thank you. Thank you. Dr Horton Daniel Horton from Rutgers. I voted no um like DR bid and I agree with members who voted both either yes or no. For me. I was struck by a kind of a modest benefit in the highly adherent trial population. Um and then the um unclear benefit, unclear efficacy, particularly in the latter half of the trial when you had increasing circulation of of the delta variant. Um and that is also the impressive mortality benefits seen early on was no longer a parent and I worry about even lower levels of effectiveness in the setting of real world youth and particularly lower levels of here. Ints overall also I was concerned about safety, particularly potential mutagenic effects, especially when used in large populations as well as the possibility for increased pressures for viral evolution. Again in the setting of lower adherence um in the real world. Um and I agree with with others about the importance of additional data on on safety and efficacy. Uh and as well as effectiveness is if this is authorized including comparative effectiveness if thank you Dr Hunt's berger telling entrepreneur, I voted no, I agree with pretty much everything they know, people have said, I just want to emphasis that I think it's a pretty minimal benefit and I have concerns about the change in the placebo rate from the beginning to the end and, and so I don't really think we know what groups this is benefiting if it's benefiting. So I think really another study should be done. If it gets the way then I don't think that would happen. So that would be a big reason. I would like to vote. No because I still have equipoise in whether it's beneficial or not. Thank you. Thank you Dr coffin. Yes, I've got it. Yes. And like the speakers before me, I I also agree with almost everything that has been said so far and I have little to add. I do think that the issue of pregnancy and you genesis needs to be evaluated further and I would favor limiting right uh, the at least the initial authorization to high risk groups other than other than pregnancy and Perhaps only two individuals over 60 or so. Um, as one of the previous speakers suggested, I didn't, since it's dry as a longtime HIV researcher, I've been waiting for a long time to see it, small molecules treatment available and I'm not sure that this is really the one we've been waiting for, but it's all we've got right at the moment. And um, so that, that said, I think, you know, inappropriate, high risk population. I think this will be this is a benefit and the issues around them you get the genesis. So I may not be as severe as they might be impending further further research. I also uh and as I suggested in the question and I think it would be a good idea to at least consider broadening within the high risk group with the highest risk group. Broadening the uh the the criteria for administering the drug to everybody who tests positive whether whether symptomatic or not because we um the early it's very clear that the earlier the drug is the greater the benefit was likely to be. Um And so that's that's my stand up. Thank you. Dr Fuller. Yes, this is a Vida Fuller. I voted no. The reason being that I would really love to have and effective drugs that can reduce virus replication uh and we reduce hospitalizations and disease that can be taken at home. However, with the efficacy that we see and the many questions that were left unanswered, such as what's the rebound effect? What's the effect on host? Both males who cannot take a pregnancy test as well as females who may want who may be pregnant or may not know they're pregnant. There were too many questions for me to be able to release a free agent that even in the most remote possibility of helping to the virus evolved because this is a respiratory spread virus that has no boundaries. We can't separate. You can't usually stop it. I just felt that there were too many reason for the Too many risks for the level of benefits that we see at a 30-40% reduction in hospitalizations. When there still are other options. This would have to be for the unvaccinated for the not pregnant. For those who would be completely compliant for those who would have no rebound effects. There were just too many things that tilted me to the no. Even though I would love to have something that would work in the way that this possibly could. And I want to thank Merck and others for their studies and hope that we will continue to make this better. Thanks. Thank you. Dr Murphy. This is richard Murphy. I voted no. It was a difficult decision. I think it came down to the fact that under the most ideal circumstances, it had a very modest efficacy with a number needed to treat that probably over 30 and very uncertain efficacy against delta. Um, I think edit to that of the logistical difficulties of getting drug to persons within the first five days. Art therapy but an alternative one. Monoclonal antibodies are not available or not active against the circulating variant. And I think it is an alternative agent comes along uh with better efficacy uh and fewer safety concerns that this way should be immediately reconsidered. Thank you. Thank you. So um, I will recap as succinctly as I can. What I think I heard the It was 13 yeses, 10 knows there were some who think it's absolutely no some who are very inclined to Yes, most in the middle where the big questions are how to interpret the efficacy and on the yes side, the efficacy uh outweighed the risk and the unevenness in the data reported where an efficacy signal was apparent, albeit with issues that have to be weighed, the post exposure monitoring is needed. This needs to be focused on high risk individuals. The pregnancy question I think has been discussed uh substantially. The one of the important factors is the limited availability of alternative treatments. And so in that context, the uncertainties about the geno toxicity, the muto genesis um way less because there aren't alternatives and there may be a mortality benefit, which is different than other settings. Where this might be considered. In that risk benefit ratio would be different. The role that displays in high risk patients such as transplant patients need to be better investigated how to look at any unvaccinated or those with sub optimal immune responses with different variants of concern circulating and its activity. However, overall the benefits outweighed the risk for the nose. There are just too many uncertainties. The efficacy signal is wobbly and different measures of it, such as the first half and the second half of the study came to different conclusions. The geno toxicity, the immunogenicity, the impact on viral replication and viral escape. And we're all very important considerations, and the data are lacking to fully inform these risks.