Antibiotics - Half Full or Half Empty

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In my job as a consultant to companies trying to discover and develop new antibiotics, I keep my fingers on the pulse of the industry at least to a certain extent.  Today, I wanted to share my growing confusion with all of you.  For some reason, I have had a burst of new business both at the beginning of this year and again within the last several weeks.  This business is coming from everywhere - large pharma, biotech and investors - wanting everything from on the ground help with discovery and development tasks to evaluations of potential products at various stages of development.  But then when I look at the number of large pharmaceutical companies who have abandoned the area and the great difficulties that start-ups are encountering in obtaining funding, I wonder which end is up.  Of course, there are still a few (2-4) large companies still pursuing antibiotic discovery and development.  There are still a few antibiotic indications where clinical trials remain feasible at the FDA (urinary tract infection, skin infection, intraabdominal infection - although several of these are under review - hold on to your hats).

I think I understand the dynamic here.  There is hope.  Many very smart people and talented scientists recognize that we cannot go on with no antibiotic pipeline.  They realize that the FDA will, therefore, ultimately have to see reason.  They also believe that, somehow, a way forward for funding will be found.  Perhaps some of them believe that the GAIN act will be a major positive influence (I am not so sure) in terms of providing an incentive for both biotech and their potential partners or even for public markets to finally get back in the act. Maybe some see BARDA as a way forward (although without an ability to fund phase III, I remain skeptical).  Nevertheless, hope and optimism are good things.  Not only that, but they help keep me in business and, I hope, they will help keep the world supplied with new and needed antibiotics. So today, for me, the glass is half full.

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• Lifesaving antibiotics face doubtful future (eurekalert.org)

Antibiotics in the US - Effecting Change

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Once again I was privileged to be a participant in an ongoing conversation on antibiotic development and the FDA involving experts from large and small pharma, academia and the Infectious Diseases Society of America.  The conversation started with the ironies of FDA statements and their recent draft guidance documents, especially that focused on the development of antibiotics for skin infections.  I will leave that part of the discussion for a future blog.  But the conversation ultimately found its way to the topic of what can be done to ameliorate the situation.  This, after all, is the ultimate conundrum.  We, for various reasons, believe that people will, at the end of the day, be reasonable and rational.  We are always disappointed and surprised when that is not the case.  But anyone who has been living the nightmare of the FDA and antibiotic development over the last decade will understand what I am talking about.  We live in a world where reason and rationale have given way to survival in a hostile political environment.

So – what to do? I think it is too much to hope that the FDA will come back to some semblance of feasible trial designs with realistic and clinically relevant endpoints for antibiotics in the near future. I also think that legislation to provide real incentives for industry and real limits for the FDA is beyond reach this year.  I continue to believe, though, that the way forward lies overseas. 

Americans must be made to realize what the FDA and congress are doing to them as far as antibiotics are concerned.  First, the continued use of antibiotics in animal feed is only going to continue to increase the incidence of resistant infections in our citizens.  If Montana has its way that will be our fate.  Now that we will continue to assure ongoing resistance, we will also assure that we have no new antibiotics to fight these infections.  The FDA has constructed a series of guidances for industry that require either infeasible trials or use clinically irrelevant endpoints or both.  So even if industry wanted to develop new antibiotics, and most large companies have already voted with their feet and abandoned the area, they can’t – at least not in the US.  One of the few exceptions is in skin infections where the trial designs are at least feasible, but where the endpoint is at best of debatable clinical relevance.  The other issue for companies is that the trial designs for skin infections required in the US have nothing to do with those required in the rest of the world – this creates additional (but not insurmountable) challenges for industry.

Where is congress in all this?  They are busy trying to protect cattlemen in Montana by allowing continued and unnecessary use of antibiotics in animal feed.  They are unable to pass legislation to provide for real incentives for companies to develop antibiotics where the return on investment for companies is poor.  And, congress is unable to rein in an FDA gone mad.  Trying to speak to congress about this is a little like swimming upstream in jello.  While the basic concept of the problem we face is easily understandable, coming up with legislation to address the problem is not so easy.  The GAIN act, for example, is going to be too little to really incentivize companies and too weak to effect change at the FDA.  But even that bill is having trouble making it through congress.  A plan with real teeth has been proposed by the London School of Economics and has been proposed as law to the European Commission.  This plan would work – but has not even made it into any sort of bill in the US congress.  All we have is a US-EU Task Force that will make recommendations someday.

In addition to continuing to speak with congress and the FDA, I think the way forward is to actually develop new antibiotics active against resistant strains in the rest of the world.  Companies should negotiate reasonable trial designs in Europe and then present these to the FDA.  If the FDA makes it impossible to carry out the trials – so be it.  These new products will at least be available in other areas of the world where the medical need is great.  Companies can always re-approach the FDA at the time of submission for marketing approval in Europe or even post-approval. I know that this advice will be hard for large companies to swallow since the US market, even though stagnating or shrinking, is still large and therefore hard to give up. Nevertheless, for those truly committed to the development of antibiotics, providing them for the rest of the world is still a very good thing.   And putting pressure on FDA and congress to make approval of new antibiotics to fight resistant infections feasible in the US is also better than not developing antibiotics at all. 

Dr. Margaret Hamburg on Biocentury TV

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Yesterday I watched an interview with Dr. Margaret Hamburg, Commissioner of FDA on Biocentury TV.  In general, the questions were softball.  I think the word antibiotic was used only once.  That was for a comment the interviewer heard from a venture capitalist.  The VC said that he had three no-go areas for investing in pharmaceutical start-ups – diabetes, obesity and antibiotics. At least antibiotics is in good company these days.  Dr.Hamburg responded by stating that she and the FDA are aware of this issue and that her interest remains in putting in place the regulatory science that will allow for trials that can show safety and efficacy such that Americans can have access to new therapies in these areas.  But I have to admit that I don’t know what the “new” regulatory science is. We have used Bayesian approaches to trial design in oncology for years.  We have used validated biomarkers in HIV and for oncology for years. 

During the entire interview, I think I heard the word feasibility once. It seems clear that, at least in some areas, FDA understands that trials must be feasible, but is struggling to find a “correct” scientifically based way forward. The idea of conditional approvals was discussed – but only superficially and nothing new seemed in the offing.

 Its as if the fact that somehow “new” approaches exist means that our old ones are no longer valid. You hear that often at meetings – at least as a subtext.  During the last 60 years, it seems to be assumed that FDA approved ineffective antibiotics and that because so called biocreep towards inefficacy is a theoretic possibility, it must have occurred.  But, to my knowledge, this has never been shown scientifically.  So where and what is the “new” science after all?

If Dr. Hamburg and the FDA want to lay the foundations for new trial designs for antibiotics – more power to them.  But what is the problem with continuing with our “old” trial designs while the new templates with feasible designs are put in place?  Why can’t we grandfather such designs until such time as new and feasible designs are ready for prime time?  If we could do something like that, maybe cethromycin from Advanced Life Sciences would already be approved, maybe doripenem and telavancin would be approved for hospital acquired pneumonia is the US as well as in the rest of the world. In fact, it is clear that if we don’t do something like grandfathering the more traditional designs, Americans will be deprived of new and needed antibiotics for years to come.  The current FDA approach is certain to have a negative effect on the global supply of new antibiotics as well as on public health of Americans. 

It is long past time to rethink.

Sanofi - Breaking the Mold?

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In 1999 Roche announced that they would abandon their effort to discover and market new antibiotics.  This ultimately led to the formation of Basilea and Arpida – two biotechs of which Basilea is still standing. The antibiotic discovery group at Actelion is also made up in large part of ex-Roche scientists.  Of interest, with rare and small exceptions, none of these particular biotechs have yet managed to get anything all the way to a significant market. Since 1999, in terms of today’s mega-merged companies, eight others have followed Roche down the path away from antibiotics.  None, as yet, have reversed course and re-established a serious antibacterial discovery and development effort.  None have even licensed in an antibacterial for development and marketing.

But, as I learned several months ago, this may change.  One brave company may be the first of the large pharmas to go back.  In 2004, not long after Sanofi purchased Aventis, the company made what was, for them at the time, a very difficult decision to spin off their anti-infectives discovery group. They not only released their talent, but they also gave up any rights and they put in a large number of preclinical stage compounds – some more advanced than others. This spin-off was Novexel.  At the time of their purchase of Aventis, negotiations for the spin-off were already underway within that Aventis.  Sanofi hesitated – I think over a year – before finally giving the go ahead for the formation of Novexel. Sanofi hesitated because they were not sure they really wanted to divest themselves of their anti-infectives group.  In spite of the calamity of Ketek (an Aventis product that Sanofi had to bear on their shoulders), Sanofi was not sure that anti-infectives would not be an important area for them.  But, for whatever reason at the end, Novexel was born.  With its birth, Sanofi lost most if not all of its internal expertise in anti-infectives as well as any key anti-infective compounds that might have been in the company.  Novexel was a startling success selling itself to Astra-Zeneca and Forest for $505MM in “biodollars” by the end of 2009.  At the time, they had generated two promising phase II antibiotics and had their own discovery program with interesting preclinical compounds.  Sanofi could have had the same but did not.

After all this, several months ago, I received a call from a headhunter, as I do from time to time.  But when this recruiter told me what they were looking for, I practically passed out.  They were looking for a head of anti-infectives for Sanofi-Aventis.  At the time I knew that Sanofi had initiated a small effort at their facility in Toulouse, France to discover compounds useful for the treatment of neglected diseases such as TB and malaria.  But their current plan was much bigger. They shared the job profile with me.  It called for a person with experience mainly in small molecule discovery either from academia, biotech or pharma. They wanted expertise in microbiology or immunology – vaccine expertise would be a plus.  The person would direct research in neglected diseases, but also for new antibacterials, antifungals or antivirals for MDR pathogens.  Personnel reporting to the new unit as proposed would be located both in France and the US.  There could ultimately be 120 scientists and others in the various groups reporting to this person. Of course, to find a single person with all the required expertise to lead such a diverse effort seemed an unlikely possibility – but to find someone who could start from a strong base and learn all this seemed possible.  Of course, now that Sanofi has purchased Genzyme, the integration may complicate this entire plan. I have been in contact with the headhunter who tells me that they have made an offer to someone – but that was back in April.  I have had no further follow-up.

But I was still flabbergasted.  If this happens, Sanofi-Aventis will be the first company in over 10 years to get back into the field.  Even though I may be critical of the specifics of their plan, the idea itself is, to say the least, admirable and courageous.  They will have to rebuild almost everything from almost zero. I expect this will take years to come to some sort of fruition.  Nevertheless – assuming this comes to pass – cudos to Sanofi-Aventis!

Related articles

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ATTAINing Europe

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Europe comes through again!  EMA and CHMP have recommended approval of Theravance-Astellas’ telavancin for use in nosocomial pneumonia based on the same data package rejected by the FDA.  This should be encouraging to all who are developing new antibiotics and for patients and physicians who so desperately need them.  Of course, I’m not so sure that telavancin will answer these needs, but its approval by Europe is nevertheless a very positive sign. This situation is similar to that for doripenem by J&J where it was rejected for the same indication by FDA but accepted by Europe.  These FDA rejections are based on the new draft guidance for clinical trial design promulgated by FDA whereby the infeasible and insensitive endpoint of all cause mortality at 28 days in the microbiologically documented population in the absence of any prior antibiotics and with a non-inferiority margin of between 5.6 and 10% is required.  Europe has clearly (1) stuck with their policy of having their scientific advice be binding such that once trials are completed, if the agreed-upon endpoints are achieved, the product will be approved and (2) rejected the FDA’s guidance on nosocomial pneumonia at least so far.

The ATTAIN data have been published and presented.  I reviewed their data in a previous blog.  The trials showed that telavancin was non-inferior to vancomycin for the endpoint of cure in the all-treated population where cure rates were 58.9 and 59.5% for telavancin and its comparator, vancomycin, respectively.  Of the 1503 such patients across the two trials, 480 were microbiologically evaluable (had only Gram positive pathogens isolated at baseline).  (Parenthetically, if you add those who had gram negatives – this total becomes 629 or 42% having had a pathogen of any sort at baseline). Telavancin remained non-inferior overall in the microbiologically evaluable population. More than half the patients had received an antibiotic prior to enrollment and all were considered to have been failures at the time of enrollment. 

It is of great interest that Europe would find that the potential benefits of a new therapy for these severe infections would outweigh the risks of telavancin.  Telavancin is associated with nephrotoxicity at a higher rate than vancomycin and there is a fetal risk.  In addition, recent data from the Zephyr trials indicate that linezolid, for similar endpoints, might be superior to vancomycin in nosocomial pneumonia.  Therefore, one could question the comparator choice for the ATTAIN trials (even given that the trial was designed long before Zephyr data became available). I conclude from these ruminations that Europe, unlike the US, apparently believes that having alternatives can only be good for patients.  Europe also will now leave specific marketing negotiations to member countries who will take all of these factors into consideration when thinking about price and conditions for reimbursement for telavancin. This seems to be another difference between Europe and the US. Europe sees the regulatory approval as one thing and national marketing and reimbursement decisions as something else entirely.

Even though one might be critical of the ATTAIN trial data, there can be no doubt that the data showed that telavancin is non-inferior to vancomycin at the pre-chosen per protocol primary endpoint.  They also showed some toxicity risk of telavancin compared to vancomycin, but in this very sick population, it seems wise to leave a borderline risk-benefit decision to the clinicians and their patients who can decide on a case-by-case basis. In my view, Europe made the right decision.  The marketplace, national authorities, clinicians and their patients, will now sort things out as to whether telavancin is a useful addition to the antibiotic armamentarium for nosocomial pneumonia or not. In this regard, the FDA, in my view, and once again, made the wrong decision.

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Antibiotic Trial Design and FDA - a Discussion

The current predicament of antibiotics within FDA can be traced back to the scandal around Ketek.  See my earlier blog on this. The FDA has been backpedaling on antibiotics ever since. Clearly the FDA is caught between congressional critics out for votes and the infectious disease community clamoring for new antibiotics to treat resistant infections.  Most of FDA’s recent guidances for carrying out trials for antibiotics have required infeasible trial designs – catering to congressional pressure demanding a more strict approach to the non-inferiority trials we must use for antibiotics. Of course the fact that requiring infeasible designs leads to an empty antibiotic pipeline is apparently not considered by congress or the FDA. The one exception among recent guidances has been for skin infections where the required design is feasible. 

Starting last week and going through the weekend, I was privileged to be able to participate in a stimulating and reasoned email discussion on the FDA and antibiotic development.  Participants will remain anonymous, but included captains of industry; participants in the Foundation for the National Institutes of Health discussions on trial design issues with the FDA, the Infectious Diseases Society of America (IDSA) and industry; active members of IDSA; academics including experts in PK/PD and pharmacometrics; and finally, most humbly and not anonymously, myself. Keeping the discussants anonymous allows me to summarize the discussion in my own way without having to have the drafts reviewed by multiple people who don’t always agree with each other or with me.  I thought that could be a never-ending process.

The discussion was initiated by several emails noting recently presented results of phase II trials where the FDA’s new early endpoints of halting lesion progression for acute bacterial skin and skin structure infections (ABSSSI) were being compared with more traditional late endpoints of clinical cure. It is clear that there is not always a one-to-one correlation between success at the early endpoint and clinical cure – no surprise to anyone. The participants launched into a discussion on whether the early endpoints were or were not clinically relevant and whether they would predict the more traditional and clearly relevant endpoint of clinical cure in a reliable enough way.  Of course, this discussion could also be relevant to the early endpoints now being demanded for pneumonia trials as well – hence the importance of the exchange.  We then began to try to look into the future . . .

The FDA has opted for these early endpoints because they tie back to measurements made during the pre-antibiotic era when sulfonamides were being compared to placebo or placebo-like treatments (UV light being an example of the latter for skin infections). In these 80-year-old studies, the treatment difference between sulfonamides and UV light in skin infections was greatest early in the course of therapy.  Therefore, the FDA has a way of tying modern therapy back to a treatment effect demonstrated 80 years ago.  Critics of this approach note that the patients are not the same, the pathogens are not the same, the disease is not the same and the treatments are not the same anymore – so why should we tie ourselves to an 80-year-old trial design that was not really placebo controlled anyway?

Critics also charge that the early endpoint is clinically irrelevant. The only relevant endpoint is cure of the infection that is measured at 7-14 days when the patient should have returned to his/her baseline status.  Pragmatics are so relieved that they have a trial design from the FDA that is actually feasible, that they are happy to carry out trials and obtain approvals based on the early endpoints while making clinical cure a secondary endpoint.  Of course, most clinicians would agree that this approach is bass-ackwards. The early response is secondary while cure is primary.  It is clear that the early response is already included in the consideration of cure anyway since a patient not responding to treatment in the first few days of therapy will be considered a therapeutic failure anyway and the astute clinician will start looking for the cause of failure. But the converse – early success – may not always predict cure. Time to response is valuable to the clinician, but not pivotal information.

One way around the entire disagreement is to use more modern approaches such as pharmacometrics to define effect size both early and late.  In this way, one could use the treatment effect size to justify a non-inferiority margin for an endpoint at time of cure.  One could also justify a composite endpoint combining early and late response or one could even define margins for two endpoints, early and late (although that would take some non-traditional statistical approach I expect).  Unfortunately, at least so far, the FDA has been deaf to such arguments.

These arguments are equally applicable to trials for community-acquired bacterial pneumonia where, in the current guidance, the analysis population must be the bacteriologically documented one, the endpoints are again early resolution or improvement in signs and symptoms (but not cure), no prior antibiotics are allowed, and the margins are 15% for parenteral therapy and 10% for oral therapy.  This means that an oral only drug will never be developed for pneumonia since that trial requires 5000 patients and is simply infeasible. Even a parenteral drug will require a diagnosis rate of at least 50% which would be a world record and nothing short of miraculous for a modern trial in order for that trial to be within the realm of possibility.  But, as soon as we start talking about using pharmacometrics to define a treatment effect for cure, we can at least get to a relevant endpoint with a reasonable non-inferiority margin.  Again – the FDA is hard of hearing.

Beyond defining a treatment effect for cure in modern times, we need to look at modern statistical approaches to trial design – more later.

Antibiotics - Yet Another FDA Victim Bites the Dust

The end of Advanced Life Sciences has arrived.  Advanced Life Sciences was formed in 1999.  In 2005, they acquired cethromycin, a ketolide antibiotic, from Abbot Labs that had already undergone extensive Phase II testing.   Ketolides are antibiotics with a structure like the infamous Ketek – the GREAT SCANDAL of FDA’s approach to antibiotics and the most proximate cause of all our current problems at FDA. Ketolides are also active against many antibiotic-resistant pathogens that cause pneumonia. Advanced Life Sciences rapidly submitted a phase III plan to the FDA and began their pivotal trials.  In 2008, they submitted their NDA, which was accepted by the FDA later that same year. An advisory committee meeting was held in 2009.  In the meantime, the FDA held a workshop on clinical trial design in community acquired pneumonia in 2008 and released new guidance for this indication in early 2009 – all between the time Advanced Life Sciences negotiated their trial design protocol with FDA and even after they had submitted their NDA.  This did not stop the FDA from reanalyzing Advanced Life Science’s data based on the new guidelines.

Lets just talk about these new guidelines for a minute.  The guidelines preclude the development of an oral drug for pneumonia.  First, they require that PORT II-III patients be studied – where most PORT III patients will be admitted to hospital and, in many countries, will require intravenous therapy. Second, they do not allow the use of prior antibiotics – certainly an impossible situation for US patient enrollment.  Third, the analysis population is the microbiologically documented population and the non-inferiority margin is 10%.  A quick calculation shows that two such trials would require about 5000 patients – five times the number that Advanced Life Sciences enrolled. 

Only a great deal of good luck could have allowed them to achieve such a margin with that number of patients.  Nevertheless, in the FDA’s analysis, they certainly came close.  But at the advisory committee meeting – it was no cigar.  The FDA excluded all patients who had received prior antibiotics, all those with atypical pathogens (oh yes, the new guidance does not allow you to include these patients either), and all those with PORT scores of I (almost half the patients). Even though, under these terrible circumstances, one trial actually achieved the 10% margin, the other did not.  This was an approach even more draconian than the one that Cerexa/Forest recently survived – but they had an intravenous drug and studied more severely ill patients. The committee voted 11 to 3 that Advanced Life Sciences had not demonstrated efficacy for cethromycin. 

The company went on to acquire grant funding to study cethromycin in various biothreat indications.  They also negotiated what I thought was a very risky and possibly infeasible superiority trial to study cethromycin in pneumonia caused by macrolide-resistant, cethromycin susceptible pathogens. Apparently, many funding sources agreed with me since the company was not able to raise money to fund the additional trials they had agreed with FDA nor to keep the lights on.

This is the tragic story of antibiotics and the FDA today. The door is closed to antibiotics that can only be given orally for the treatment of pneumonia.  And because the agency can change its mind even after previously agreed upon trials are successfully completed and filed, all companies face the risk that they will end up like Advanced Life Sciences unless they have a back-up plan for the FDA.  Here is mine.  Europe.  Forget the FDA.  If you are a small company and you plan to market your product alone – or better -with a small company partner – go to Europe. No one is home here in the US.