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Results Wire: US FDA Advisory Committee Narrowly Supports Solithromycin for Community-Acquired Bacterial Pneumonia – NOV 4, 2016 (AMDAC)

Background

On Friday, November 4, 2016, the Antimicrobial Drugs Advisory Committee (AMDAC) narrowly supported, by a vote of 7-Yes to 6-No, with no abstentions, the safety and efficacy of solithromycin capsules and solithromycin for injection, sponsored by Cempra Pharmaceuticals, Inc. (Cempra), for the proposed indication of the treatment of community-acquired bacterial pneumonia (CABP). December 27 and 28, 2016 are the PDUFA dates for the solithromycin capsules and solithromycin for injection NDAs, respectively.

Key Outcomes of Advisory Meeting

A narrow majority of the Committee, 7 of 13 members, voted that the efficacy results of solithromycin for the treatment of CABP outweigh the risks.

Prior to this vote, the Committee voted separately on efficacy and hepatotoxicity risk.

The Committee voted unanimously (13 of 13 members) that Cempra has provided substantial evidence of the efficacy.

The Committee voted almost unanimously (12 of 13 members) that the hepatotoxicity risk has not been adequately characterized. Despite this, several Committee members felt that the efficacy of the drug outweighs the risk, noting the seriousness of the condition and the need for new and effective antibacterial therapies.

The Committee recommended that the labeling for solithromycin should emphasize two points: 1) The only approved use for the drug is for CABP and not for less severe disease; and 2) Treatment duration must be limited to 5 to 7 days. Another condition of approval was that Cempra should be required to continue to assess the hepatotoxicity risk in the postmarket setting.

The Committee members who did not support approval felt that the hepatotoxicity risk needs to be characterized more fully before approval.

The Committee expressed support for also requiring that Cempra obtain more data in populations that may be at greater risk (e.g., patients with liver, renal, and neurologic diseases) and data about resistant pathogens.

Overall Voting Results

1. VOTE: Has the Applicant provided substantial evidence of the efficacy of solithromycin for the treatment of community acquired bacterial pneumonia (CABP)?

13-Yes

0-No

0-Abstain

2. VOTE: Has the risk of hepatotoxicity with solithromycin been adequately characterized?

1-Yes

12-No

0-Abstain

3. VOTE: Do the efficacy results of solithromycin for the treatment of CABP, outweigh the risks including hepatotoxicity?

7-Yes

6-No

0-Abstain

Individual Voting Results

Ellen Andrews (Consumer Rep)    

1) Yes

2) No

3) Yes

1) I voted yes, but maybe not as enthusiastically as others, because I would still like to see patient-centered, patient-supported outcomes - whether people are feeling better, not just what an investigator reports for them. I would like to see a lot more in terms of - I know I'm not supposed to talk about other studies if I voted yes - but looking at lower doses and whether the loading is really, really necessary, and also tracking liver enzymes over time, a study that looks at that. This is a drug that taxes the liver and most people recover from that, but some don't. Can't we find out which ones are not going to and when we can know that as soon as possible and discontinue the drug?

2) I voted no. I agree that we need more, obviously we need more tests, we need more studies with more people, but as Steven (Mikita) just pointed out much better than I could, time means we might catch a few more, we might being more diligent and save some people from liver damage, but how many people are going to die or be harmed because of the disease? The resistance levels are already up to 50% and going higher. How long does it take to do massive clinical studies? It takes a long time. I think it's really important though for the FDA, if they choose to approve this, to be really strong about the studies that they're going to require going forward.

I love the ICD-10 idea, I don't know if that's happening elsewhere, but that's a way to get post market surveillance. Very large groups. Also the connection to payers I think is really important because you can educate the doctors as much as you like, but payers have other ways to influence physicians, and they're prescribing beyond 5 to 7 days. Also to educate them. Value-based purchasing provides an incredible opportunity, opportunities to also get to very large populations, so I think that's exciting.

3) I voted yes. I also worry a lot about that scenario (Michael Proschan’s), that's not an unlikely scenario, and I would feel like we could wait if the bugs would just slow down and not get resistant so fast. Then we'd have time to do the studies. We don't really and there are people who need drugs for these infections.

I do think, I understand the public. It was a scandal at the time, but I think people understand there are no easy answers, that there's always a trade off. I think people can get that. I think we can help people with that confidence concern that you had. I think it's inevitable either way. People are going to feel that you didn't do enough or that you did too much. That's why they get the big money at the FDA.

Lindsey Baden (Chairperson)        

1) Yes

2) No

3) Yes

1) I also voted that substantial evidence of activity was demonstrated. In addition to comments already made, additional considerations - I think the data on resistant pathogens has to be expanded. There is only so much one can do in an initial study given the challenges of diagnostics, but I think we need to be careful in assuming that it works the way we think it should work for different bugs with different mechanisms, with different levels of emerging resistance. Even macrolide resistance as presented had different mechanisms, and that has to be more carefully looked at.

I think the issue of threshold for us, and I think this is important for this compound and important in general for the agency to consider, is one of the problems with antibiotics, is we think they have no side effects and only benefit. Every medicine has risk and benefit, and therefore we really need to push the issue of benefit. That it's the population with the disease that can benefit, and how we can strengthen the label to the agency and strengthen the education to the sponsor that it isn't misused, because then we'll all lose something if it's misused. Drug interactions we didn't touch much on, but it was alluded to. That I think is very important with the 3A4 pathway. Then the real issue was implied already that the dosing needs to be carefully considered with renal issues, and one needs to think carefully in individuals who already have a compromised liver until more data are available.

2) I also voted that the hepatotoxicity has not been adequately characterized. I think the ALT, the evidence of liver injury in the phase 1 as well as the 2, 3 data sets, are concerning, as well as the history of the class. I think that the issue of what sample size is needed to detect idiosyncratic reactions is a salient one, and it may be tens of thousands rather than hundreds. That creates complexity in how best to characterize it, but it doesn't diminish the need to do so. I think the other comments about how different groups maybe at different risks also needs to be sorted out. There's also more than hepatotoxicity, but the hepatotoxicity signal obviously is the one of greatest concern.

3) I also voted yes. I think that there are real safety concerns, which are difficult to answer given the uncertainties of exactly what those concerns are. There is also a real need for antibiotics, particularly oral antibiotics for organisms that are becoming more and more resistant. This is the balance that we have to make and we have to accept the fact that medications have side effects.

I would commend both the sponsor and the agency that, if this is not handled responsibly, then we will relive ketek. On the other hand, if it is handled responsibly, we can have another antimicrobial that we can use. However, it will be difficult to know safety until we've looked at it in a thousand, five thousand, ten thousand, a hundred thousand, a million with all the complexity. It's a very, very difficult balance, and it is very hard to develop antimicrobials, hence, we have so few new ones. Thus, I favored yes.

Demetre Daskalakis

1) Yes

2) No

3) No

1) I'm going to be brief so I don't resay a lot of what's already been said. I voted yes. I think a couple of important points are again, to do whatever we can from the perspective of regulatory and at the pharmacy side, to make sure this is only prescribed for people who have a community-acquired bacterial pneumonia. The 5 to 7 day issue is very important. Those regulatory aspects need to be in place as well at the pharmacy side. I want to restate that I do agree with the no post-IV load, that the loading dose for the oral seems to make sense. Ultimately, I want to then also echo Dr. Baden which is even though we're not being asked about what future studies should happen, I think that studies focusing on multi drug resistant bacteria are critical if we're receiving that this agent as one that has a role in the armamentarium against them.

2) I voted no. I don't think that the sponsor has adequately characterized the hepatotoxicity or the potential for more extreme hepatotoxicity. In terms of additional studies, I think that it is about numbers and sample size. I think that the strategy, in terms of what kind of study that should be, is one that I think needs to be discussed more. Whether that is increasing the phase 3 studies and doing more of them, or doing a phase 4 study after release that has very stringent and very focused observation of hepatic parameters, not only extreme outcomes, but also outcomes that may portend more extreme outcomes, which means liver function testing as part of the story for being in those studies, and aggressively so.

I think it's also critical to better characterize some racial and ethic minorities in the United States. That's really I think sort of sorely missing. Understanding that 10% are African-American, I didn't see any comment on what percent were Latino or Latina. I think it's an important thing to think about in the establishment of the phase 4 or whatever strategy approaches to increase the end in understanding the liver toxicity potential for this drug.

3) I voted no, which was really a no on the side of maybe, mainly because of the fact that we don't really have the full story of hepatotoxicity. I think that that's where I can't really decide and feel confident in a yes, given that that's still missing. I think that the perspective that others could vote for no for this question is not necessarily a vote for no for recommending approval. That's not what this question asked, and so I put that out there to say that I vote for no with the idea that potentially being very stringent and if this drug is recommended for approval, since we do need new antibiotics, especially oral antibiotics for these conditions that produce the risks of some of the other complication for quinolones, I think that it's critical that again, the Phase 4 studies are every rigorous and very clear.

I also want to bring up the idea of is this a place where we think about a REMS, where we sort of create something where we realize there's an associated risk with the drug and that we give some sort of tool to be able to allow patients to access it and shift the risk balance by creating some sort of clear documentation that this a piece of the story of this drug as you use it in your practice.

Michael Green          

1) Yes

2) No

3) No

1) I voted yes. I have some of the same thoughts, has been already mentioned by other members of the Committee, that they certainly met the statistical design burdens that were following the guidances of the FDA. I want to reiterate what Dr. Baden said about trying to get more data on resistant organisms. At least one of the follow-ups that was in the data sets suggested that there might have been a bit of inferiority with MRSA. While there are not that many of those infections, when they occur they can be really horrific.

In terms of labeling, I just want to reiterate the thought that you said to limit it really to just CABP and maybe even in the labeling discourage its use for other things. I think the companies already told us that they are going to follow the FDA's recommendation and not use a second load when they go from the IV to oral, and I support that. Then. I would consider in their package insert, recommending against the use in people with pre-existing liver conditions, because I think it was a contra-indication to enter the study, and therefore we have no idea how this drug will work in that setting

2) I voted no. I think all the infectious disease specialists at this table understand the incredible need for new agents and new drugs. Actually in response to that need, the FDA has created these expedited pathways that allows studies to come for approval with much smaller numbers than they did before. Using non-inferiority as a strategy leads to being able to conclude from an antimicrobial basis effectiveness is found, but the safety side of the equation is not necessarily going to be fulfilled when you use these smaller numbers. While we heard that the certain aspects and the difference in the compound between telithromycin and solithromycin maybe will make it not be a telithromycin-like agent, we also heard that there's a lot of similarity, and so I think we need larger numbers and perhaps creative study designs to really answer the question.

My concern is that if we approve a drug and then it ends up having to be withdrawn again, people's confidence, the confidence of those of us who prescribe medicines, the confidence of the patients that we take care of, the confidence in the FDA, and actually the confidence in the sponsors, will all go away. Rather than making a mistake on small numbers, I think we need more data.

3) I voted no. I've been struggling with this specific balance question since I opened up my CDs from the FDA and started reading about what looked like efficacy that was demonstrated and toxicity that was raised. What do we know? Telithromycin is a ketolide. It's interesting because I think when telithromycin came out they said it's a ketolide. They said it's a new class. We've been hearing about azithromycin. We've been calling it a macrolide, in some ways almost to intentionally separate it from its association with telithromycin and yet structurally it looks a lot alike, although it clearly has some differences. Unfortunately we don't really know whether the differences between azithromycin and telithromycin versus the similarities between these two compounds predict whether or not it will have this signal.

My next concern is that we desperately need antibiotics, and I spent the last 20 years of my career being interested in antibiotic resistance. I do antimicrobial stewardship. I've done resistance epidemiology both in the community and in the hospital setting for my entire career. I'm desperate to see new drugs. We need them for our sick patients. That's absolutely true. One of the things about this particular recommendation and indication they're looking for is it's not just for the patient who's going to be hospitalized, who's going to have the most severe infection. It potentially will also be for the person who's got mild to moderate illness in the community.

It turns out that there are still drugs that are available. You might have to use two drugs as opposed to one. You can use high dose amoxicillin to overcome penicillin non-susceptibility in streptococcus pneumonia. I'm a pediatric infectious disease person, and that is what we do in our setting. We actually have less of a concern or issue with the atypicals, at least in our very young children. For that there's no issue of I think, or no real issue of resistance in the atypicals yet to the macrolides.

Having said that, I actually asked a question which could have swayed my vote. I was trying to give the sponsor a potential out because they were putting this great surveillance in place and so I asked them, "What level or signal will make you pause, make you stop, make you hold, make you withdraw?" I couldn't get an answer. If they would have told me one or two cases would make them pause, I could have voted yes with an understanding that they would try to work out some sort of understanding with the FDA. Although I don't know whether that's even precedented or not. Yet we couldn't get that. I really do fear that we haven't answered the question.

Having said that, I'm not smart enough to know exactly how to do the study to get at answering the risk. I'm ambivalent. I'm absolutely desperate to see new drugs. I'm so thrilled that there are companies that are still trying to do drug development because if they don't do it we won't have them. Yet I think that this is a drug that is a ketolide, and we have not addressed the issue of whether the signal that we see will mean it is or it's not telithromycin part 2.

Barbara Gripshover

1) Yes

2) No

3) Yes

1) I voted yes because I agree with everyone else. I think that it certainly showed that it was non-inferior. I think I agree with you need to make sure like everyone said about the short course, but I think the other thing that we need to also make sure to emphasize is that this is only for pneumonia and not for [inaudible] That's the other way they go down Z-Pak number 2, is broadening the [inaudible, respiratory]. I think it needs that piece need to be clear as well. I agree with [inaudible] on when you go from IV to oral.

2) I also voted no. I feel again that numbers is the biggest issue. Again I'm worried that we just haven't seen enough people treated with this to know. I did think there is one other group that I'm worried about, is [inaudible] people. We know that they're having higher levels, so I think that maybe that gets down more to the next question of risk-benefit, but that's a situation I think we need to study better too.

3) I voted yes, but I also want to echo that it was more like maybe or maybe a partial might even be a better way ... because I think that, in thinking of the risk benefit, I think for oral, I actually think it's more important for oral. We don't have any good oral therapy for community-acquired pneumonia other than quinolonoes right now. Whereas for IV we still can do a beta-lactam or other macrolide. The IV formulation also looks more toxic, so maybe if we started it with oral and collected more data on that and with a Phase 4 we could then feel more comfortable going with IV as one strategy.

Jonathan Honegger  

1) Yes

2) No

3) No

1) I voted yes. Like others, I was convinced that they met the non-inferiority target. The package labeling as well as other mechanisms to directly interact with pharmacies would likely be important to make sure that the short courses are adherent to.

2) I also voted no. I agree that to search for idiosyncratic findings will be difficult, but doing larger studies to at least get us to a point where we feel that the benefit is matching the potential risk. I also feel like this needs to be evaluated in other races, as I mentioned, the effects of re-treatment maybe in healthy controls as well as in people with infection.

3) I voted no. I definitely recognize the urgent need for antibiotics for pneumonia and macrolide-resistant pneumococcus, avoiding excess risk of C. Diff and other adverse affects of the other options for pneumonia. But with the 7% risk of an ALT rise that's significant and the history of ketek, I feel that additional studies are needed in the Phase 3 level for approval. Not in the tens of thousands, or raised necessarily to rule out a rare risk of DILI (drug-induced liver injury), but in the thousands to evaluate for a moderate or high risk of DILI. Then in Phase 4 we can do further evaluations to quantify the risk of DILI if it's lower. Also just a perspective, I don't know where the science of risk benefit is as, but it would be interesting if FDA or even pharmaceuticals would quantify different levels of DILI versus offsets of C. Diff and other adverse affects. Maybe it wouldn't be as meaningful as our own judgment, but it would be nice to see.

Vincent Lo Re

1) Yes

2) No

3) No

1) I voted yes. I thought both the sponsor and the Agency concurred about non-inferiority. I agreed with the fact that for the IV to PO (oral) switch that potentially avoiding the loading dose for PO would be helpful to feel strong about the 5 to 7 day duration. I think there wasn't really enough data on patients with preexisting liver disease. I would echo Dr. Baden's suggestion about getting more data in this population, because potentially, given the prevalence of chronic liver disease, this would be very important to understand. I think given what we've heard about the hepatotoxicity, I think that would be very important to highlight the potential of path toxicity and to assess, to at least include some measurement and timing for liver transferases and liver function tests

2) The question was, has the risk of a hepatotoxicity with solithromycin adequately characterized. I voted no, for a couple of reasons. I felt that the sponsor had suggested to abandon the oral loading dose after switching from IV and I felt like it was really unclear how this might change the drug's hepatoxicity profile. We really weren't presented with data on ALT elevations after initiation of solithromycin among persons who previously used macrolides or other structurally-related drugs or patients with chronic liver disease, and I felt that this was important to characterize the hepatotoxicity profile.

I was concerned that they were relatively small sample sizes within the phase 2 and 3 trials that might not be really sufficient enough to adequately characterize the hepatotoxicity risk. As an infection disease physician I recognize the need for new antimicrobial agents, especially with the rise of antimicrobial resistance, but I think we need to ensure these drugs' safety prior to release into the market. I need to make sure that we first do no harm, so I think we need larger patient samples to really confirm the safety of this drug.

3) Yeah, I voted no. I felt that the risk outweighed the benefits. I was swayed by the FDA's analysis and the identification of hepatotoxicity signal was a major concern for me. In particular, I thought that the evidence of acute liver injury among the healthy Phase 1 volunteers with liver amino transference levels that continued to rise after discontinuation, the imbalance in the ALT elevations within the azithromycin arms compared to the levofloxacin in phase 2 studies and moxifloxacin the phase 3 studies.

In the case of acute hepatocellular jaundice from the COPD trial, especially when no such case existed at what was observed in the telithiromycin experiments made me feel that the risk of this drug might outweigh its benefits. I felt that more evidence to quantify the risk of hepatotoxicty of the drug is needed. Particularly, there's been some discussion about the use of large databases. I felt that without even some guidance on how clinicians should measure liver function tests in real world settings that it's going to be difficult to assess that without that. I feel that if we proceed without better estimating the hepatotoxicity risk and more cases of severe acute liver injury develop after approval, then confidence in the FDA sponsors, all of us as advocates and providers, is going to be eroded.

Marc Scheetz

1) Yes

2) No

3) Yes

1) I voted yes. I think the 13 to 0 vote shows that they've pretty much met the FDA's guidance for CABP. I agree that there should be some hard limiting to 5 to 7 days. I'm a pharmacist, and I haven't practiced in the community for a long time, but I can tell you that when I was there, that's a data-poor zone. When patients transition from the hospital to the community pharmacy, sometimes you're not sure what their name is. Knowing exactly how many days of therapy they received, solithromycin is going to be difficult. I know the FDA has mechanisms that that hand-off goes well, and I'd encourage them to use those.

In terms of the load, we talked about that a bit, it sounds like the load is necessary for the oral-only therapy. I still don't know if I've seen enough data to suggest that it's necessary for the IV to oral switch. If that depends on what day you make the IV to oral switch, I'd caution that I don't know that the serum concentrations are the way to actually make that assessment. I think the current FDA assessment if based on the serum concentrations. I would suggest that I'd probably look at the target concentrations.

2) I voted no. I just felt like there was enough evidence presented that I really had some substantial concerns about the liver safety. I think the FDA's presentation gave me a lot of concern, especially taking not only these studies, but other studies that have used solithromycin. It was mentioned about what would be the confidence in the FDA or the company for that matter. I think that's especially true when people are going to say, "You had this other story here with telithromycin, and you still didn't get it when you saw these signals." I definitely think there needs to be more safety information. I don't call for a clinical trial to rule out the 1 in 20,000. You can't just do that, but I certainly would feel more comfortable if I had another larger phase 3 trial. I'm not talking about tens of thousands, but even a couple thousand per arm. I would certainly feel a lot better than I feel right now. I don't feel any better knowing that the company says, well, you can't predict these things. That doesn't make me feel any better. That makes me feel worse.

3) I voted yes. I really wish I could have voted the mean or the medium here, which is maybe. The reason I say maybe is because I think it really depends on the situation. and I think the labeling will have to define that very carefully. Should this drug bleed into otitis media, should this drug bleed into other areas where there's going to be expanded use, I think the answer is clearly no, not until we have much, much more data. I was fortunate to sit around this table when we discussed the risk of the fluoroquinolones, and even when there's almost infinitesimal risk, that translated to patients standing up out in that audience that had very real toxicities, very life threatening toxicities. I think that can happen here.

I also think that we do need to have a better pathway to approval of antibiotics and there is a true need in CABP. I could very easily come up with multiple scenarios where the patient might not have any other therapy other than this. If it's not available, that patient would be at risk. I think a lot of this has to center around risk-benefit, and I think that there are a number of post-marketing strategies that can be employed to really give physicians that option to use this treatment, but to also know that this is not the first treatment they should be grabbing off the shelves for your run of the mill I think even CABP.

Peter Weina  

1) Yes

2) No

3) Yes

1) I voted yes, with a quick caveat, and that is that the question was stated as substantial evidence. I think a better way of putting it would be adequate evidence rather than substantial. I become concerned with what was already brought up in our discussion, and that is the issue, once the genie's out of the bottle, it's going to end up getting used like the Z-Pak part 2. There really needs to be some adequate controls in place of some type. Whatever you can do. I agree with the loading, with the oral. I think the data's good for that but I have a significant concern about using no loading does on the switch. I think that the recommendations of not going with the loading dose seems ... At least the evidence that was presented is better.

2) I as well voted no. In addition to what was already said, all I would say is just that, what is adequate characterization? I think the taint of the third generation macrolide on the entire class is going to create a problem. I think the suggestion of tens of thousands or even more are going to be really the rule until we even start to feel comfortable with not having that shadow hanging over us.

3) I voted yes. I had a hard time with it until I started to think about what we can do with the labeling. Part of it is, if there was a very strong hepatotoxicity warning on there or potential hepatotoxicity warning or the signal was there, it may slow down this whole idea of a Z-pack part 2 syndrome because people would be really concerned about just tossing it to anything, number one.

Number two, I think it opens up a conversation between the clinician and the patient about the risks associated with it. Unfortunately that's not a conversation that takes place as often as it should. I'm concerned about waiting to get more data. How long is it going to get to get the right number, whatever that right number is? If it's another thousand or five thousand or ten thousand, to get to the answer, I don't think we know what that answer is going to be.

It might be a little better to get to it a little faster, to get to it and be able to settle this in Phase 4 than in doing another Phase 3 and then having to come back. I'm really concerned about having some tools in our toolbox because everything, again, we're left with one drug that works in no time at all and next thing you know everything looks like a nail because all we've got is a hammer left in our toolbox. I like to have the options. We just need to use it with caution like we use other hepatotoxic drugs.

Thomas Boyer (Temp member)    

1) Yes

2) No

3) No

1) Well, as far as labeling, it seems it's 5 to 7 days. It sounds like from what was said, a loading dose appears to be required whether it's oral or IV to achieve level high enough for efficacy.

2) I voted no because I think there are 2 phenomena looking at the data that are going on here, one which I think is reasonably well clarified, and that is this is a direct hepatotoxin perhaps mediated by mitochondrial injury that tends to get better. That doesn't cause me huge concern because there's so many drugs that cause elevations in transaminases that don't lead to serious liver disease. The concern is the one case of jaundice. When you think about it, if you had a 1 in 10,000 risk and out of 800 patients, 1 patient out of 10 patients who've got prolonged exposure, 1 patient turned yellow, what are the odds that in this 1 study, that 1 patient of 1 in 10,000 happened to be in the study, happened to get the drug and have to turn yellow? I think the concern is is that's not the number. That the number is less than that.

I think the FDA is trying to make some estimates of what that risk is, and if you know what the risk is, you can define the size of the study to determine whether or not that risk is real or in fact it was 1 in 10,000, and the company was incredibly unlucky. I'm not going to Vegas with these guys. I think you need more data. You can do it now, to design a study to look at risk. The other thing is, as Dr. Lee pointed out, we need later numbers, even after patients have come off the drug. If you're going to do a trial, you need to document that 2 or 3 weeks later. They don't have a rise in their liver test that might, as we see with clavulanic acid. I think there's some things that could be done to enhance the safety profile and make everybody feel better about the risk benefit for this drug.

3) You could have predicted my vote. When I asked the question of, I just, if this drug were one of a kind drug treating a disease for which there was no other therapy, then I would have felt differently, I think, but I don't feel that way. I think there is a significant risk associated with this drug. I think that outweighs its efficacy.

William Lee, MD (Temp member)  1) Yes

2) No

3) Yes

1) I voted yes as well. I have very little else to add except that the list of 3A4 metabolized drugs is quite long and only 3 or 4 have been tested, so more testing along that line as Dr. Baden suggested is very important, and at least should be listed in the package insert.

2) I voted no as well. It's hard to know where to start with further studies. I think the FDA in phase 4 could require formally a study where there is a larger number of patients enrolled, even just for the 5 to 7 days, with adequate ALT follow-up. Not just during, but post. There's obviously, in the second tier, there's going to be a need for some sort of further monitoring or consideration of when a patient a year later gets re-exposed, and maybe these large databases are the way to go for that. I think that's very important. As Dr. Boyer suggested, multiple exposures often leads to this adaptive immune response.

3) Yeah, this was a very agonizing vote. I think the history of DILI (drug-induced liver injury) at the FDA was that in '99 there were two drugs approved, Troglitazone and Rezulin. Both had to be withdrawn in the next couple of years. Since then the FDA has been incredibly risk averse with one exception. That's cancer drugs. The tyrosine kinase inhibitors get a free ride. They basically know they have toxicity, but every patient has cancer and they usually have metastatic cancer so the FDA tolerance of hepatotoxicity is huge or at least higher than it is with any other drug. Since 1999 there's been essentially nothing, not even telithromycin. It never was withdrawn except eventually by the company. The FDA has not withdrawn a single drug since 1999 because I think they've been relatively risk averse.

Now this drug clearly has a strong hepatotoxicty signal. However, I think we heard Dr. Fernandez say that it took three and a half years to get eight hundred and eighty patients. My concern is that we keep discouraging companies from going forward. Perhaps the FDA has to come up with something different, a provisional approval with the understanding we're in the post-ketek world, we're in the post- ... We're eighteen years since 1999 and we have to come up with a new strategy to allow the Phase 4 studies to go forward. We have much better pharmacovigilance presumably. All these huge databases that we can draw from. I think we need to come up with somehow a better paradigm, maybe stronger labeling, but also perhaps some way to acknowledge that the C. Diff issue is huge, the quinolone resistance issue is huge, and the potential death from the primary disease is huge. We've got to be able to figure out where the balance is.

J. Stephen Mikita (Temp member, Patient Rep)  

1) Yes

2) Yes

3) Yes

1) I voted yes. I believe it's a narrowly construed and straightforward question. I believe like others have said that the sponsor has met its burden, and any concerns can certainly be mitigated by effective labeling.

2) Being the lone dissenting vote, I don't want anyone in this room to come away with the fact that this was a knee-jerk or emotional reaction. I believe that both the sponsor and FDA have proceeded with their expertise and that they have considered the data. I believe that we're kind of raising the bar to a level because with telithromycic [inaudible – specs] were too high, I think that there are risks inherent in these kinds of drugs. I believe that with labeling and with stewardship and with pro-surveillance, that a lot of the concerns can be addressed. I think confidence can be introduced in those practitioners in the communities who know their patients. I think it's unfortunate that the climate is such that there is an invitation for those to develop these drugs, and yet there is such hesitancy over a single effect when many, many patients are dying of this disease every day. Thank you very much.

3) Yes. I'm delighted not to be alone on this one. It takes courage to vote and it takes courage to stand on a wall and say, "I'm going to vote drugs for this particular disease, that I'm willing to put in safeguards to make it as safe as possible." Nothing's 100% certain in this life, and when you're dealing with people's lives there's got to be a trade off because there is a lot of sick people and the drugs that you use are not always 100% safe for 100% of those patients.

In this case I believe that there's an array of worries and concerns that are not surprising, but they can be addressed by a package of labeling and the other types of precautions and safeguards and post-market analysis that can ensure and invite and encourage other drug developers to bring their genius to the FDA and to the patients like me that need it.

Michael Proschan (Temp member)           

1) Yes

2) No

3) No

1) I voted yes. They met the non-inferiority criteria but they also did better than that because, as I said, they ruled out basicallya 5.5% increase. I think there's been no disagreement. The FDA agrees that it worked. Their analysis indicated that it worked. Obviously a sponsor also agreed that it works, so I think that's not a question.

2) I voted no. I just felt like there was enough evidence presented that I really had some substantial concerns about the liver safety. I think the FDA's presentation gave me a lot of concern, especially taking not only these studies, but other studies that have used solithromycin. It was mentioned about what would be the confidence in the FDA or the company for that matter. I think that's especially true when people are going to say, "You had this other story here with telithromycin, and you still didn't get it when you saw these signals." I definitely think there needs to be more safety information. I don't call for a clinical trial to rule out the 1 in 20,000. You can't just do that, but I certainly would feel more comfortable if I had another larger phase 3 trial. I'm not talking about tens of thousands, but even a couple thousand per arm. I would certainly feel a lot better than I feel right now. I don't feel any better knowing that the company says, well, you can't predict these things. That doesn't make me feel any better. That makes me feel worse.

3) I also voted no. This is tough for me because obviously I'm not a physician, so it's very hard for me to judge how much the benefits are of having another agent to use in case someone doesn't get benefit from other drugs. It makes it very difficult for me to balance benefit and risk, but I am concerned enough about the safety that I would feel very bad if I voted yes and the same thing happened as happened with telithromycin, which I see as a real possibility. I had a tough decision, but overall I felt like I had to vote no.

 

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