The FDA and Me

Some of you may remember that last Fall, in the midst of the government shut down, I wrote a blog publicly expressing my desire to work (once again) for the federal government – specifically for FDA.  I offered my services free of charge starting this year since I planned on retiring from my consulting business December 31^st of last year. I also felt that my retirement would free me of any conflicts of interest that the FDA might be concerned about.  I thought that I would provide you faithful readers with an update of my interactions with the FDA on this topic.

I was rejected.  Of course, I feel I have been rejected by more attractive places to work in the past.  In fact, in my consulting business, I found that sometimes, when I gave a negative opinion about a company’s sole asset, I was rapidly fired.  Some companies with more than one asset would listen to negative opinions and stop pursuing whatever avenue I criticized – but that also put me out of a job with them. And, as an academic, trying to publish papers and get grants funded, I can tell you that I’ve had a lot of experience with rejection.  I can take it. But I was particularly disappointed with FDA’s rejection.

My primary motivation for working with FDA was to help the commissioner’s office understand the real world impacts of the policies that the Division of Antimicrobial Products was putting in place through their constantly changing (recently mostly for the better) guidance documents on the development of antibiotics. I felt that the commissioner’s office – primarily Janet Woodcock – had their hearts in the right place.  It just seemed that they did not have the technical expertise to properly evaluate what the Division was doing.  Their main expert, Rachel Sherman, was about to leave the FDA (and has since left I understand). Around this time, Bob Guidos of the Infectious Diseases Society, left his job there and started to work at FDA.  I still don’t know what he does there – but there he is.

I started my contacts with the FDA in late November.  I wrote Dr. Woodcock and we arranged to speak in December – Bob Guidos joined our conversation. Dr. Woodcock pointed out that I would be unable to work for them for free – they would have to pay me.  Well, OK then. I then provided, at their request, a written summary of areas where I thought I could help.  Specifically, I mentioned considerations in the design of small superiority trials in areas of unmet needs and the design and definition of endpoints in more traditional non-inferiority trials.  I emphasized various ways we could use pharmacometrics to help in these considerations. I spent some time on the mortality endpoint for hospital-acquired pneumonia that I still think is the wrong way to go. Over the next month, Bob got back to me asking for more details whereupon I sent him several of Paul Ambrose’s papers with an explanation of the approaches I was considering.  I pointed out that the FDA had much of the data that we would need to carry out the appropriate analyses and that we could always get Paul or George Drusano to help.

And that was that. I have had radio silence since January and have concluded that I have been rejected. Maybe they have hired Paul or George – but I don’t think so. Of course, I really shouldn’t be surprised.  I have been extremely critical of them for years – probably since around 1999-2000.  I thought of it as tough love – and I thought they did too – but maybe not.

Don’t worry. I am now going to pursue other outlets for my desire to continue to be active in the area of policy on the discovery and development of new antibiotics where I think we still have lots of work to do. (Hint – pricing and economic considerations).

Pricing!

Gilead and Hepatitis C Drug Pricing.  Speaking about pricing, I was infuriated to read Andy Pollack’s report of congressional self-righteousness on the topic of Gilead’s pricing for a new, less toxic, more effective and shorter therapy for chronic Hepatitis C infection. Also see Josh Bloom’s article on the same topic a few months ago. Let’s think about this for a few minutes.  Hepatitis C is the most common infectious cause for liver transplantation in the world today. Before Gilead’s Solvadi, the standard treatment was 24 – 52 weeks of interferon plus ribavirin.  Interferon causes fever, chills, depression, low blood counts and a number of other problems.  It has to be administered by intravenous injection monthly. Other drugs have to be used to counteract its side effects. Ribavirin is given as a pill (many pills) and causes anemia among other things.  Sometimes transfusions are required to maintain blood counts throughout a course of therapy. And after you have finished the entire course, the failure rate of this therapy can be as high as 50%. Even though Solvadi has to be given either with interferon And ribavirin or just combined with ribavirin (depending on your type of HCV virus infection), the treatment course is just 12 weeks. There are fewer side effects and the therapy works much better curing about 80% of patients. And when I say cure – I mean cure.  No more need for therapy.

Solvadi, perhaps in the future, could be used with other new, less toxic drugs such that ribavirin and interferon could be avoided altogether.  That is now the holy grail of HCV therapy.

Not every patient infected with HCV has to be treated.  Some will just carry the virus (and presumably could pass it on to others) but will not suffer harm from their infection. About 80% of patients who become infected with HCV will develop a chronic infection.  But only about 15% of them will go on to develop complications from their infection that would require therapy. Some of this 15% will go on to get liver cancer or will require liver transplantation. Because there is a limited population that would require therapy, Gilead needs to charge a high price to recoup their investment in Solvadi (and all the other drugs that failed before Solvadi). Not only that, but it is easy to show that even at the price Gilead is charging, $84,000 per 12 week course of therapy, the reduction in side effects and the greater benefit of therapy is easily worth every penny.

Yet Representative Henry Waxman and other Democrats on the House Energy and Commerce Committee are demanding that Gilead justify their pricing.  While I think this will be easy for Gilead to accomplish, it is frustrating that Congressman Waxman is getting on his self-righteous high horse without adequate knowledge of the situation (I’m being charitable here since I can think of no other rational explanation for his behavior). I am getting on my own soapbox here because this could have implications for antibiotic pricing and the last thing we need is someone putting a damper on this at this critical time in the evolution of antibiotic research.  

Compared to oncology drugs (most of them), treatment with Solvadi or antibiotics against bacterial infection result in CURE!  Not ongoing therapy forever, not in a few months of additional life in the hospital or hospice, but CURE!

Antibiotic Pricing.  In the better news department, an article in Barrons notes that the Disarm act, currently in front of congress, would remove punitive fiscal measures from DRG reimbursements when hospitals use expensive drugs under certain circumstances.  In this particular case, congress is targeting patients with high unmet needs where the drug is limited to restrictive populations.  In other words, the bill apparently is specifically designed to allow the kind of pricing for highly specific antibiotics that would be required for companies to earn a return on their investment.  This means the $15-30,000 per course of therapy that was discussed at the Pew meeting last year would be reimbursed by Medicare, Medicaid and other payers.

Billionaires are NOT Privatizing Antibiotic Research

A lengthy article appeared today in the New York Times entitled, “Billionaires With Big Ideas Are Privatizing American Science.” The author, William Broad, is a science reporter for the Times.  He notes how government funding for research has declined in real dollar terms for years. The chart below shows that in terms of constant 1995 dollars, the overall NIH budget has been falling for the last decade. (Click on the figures to enlarge). This has been paralleled by an ever-decreasing success rate in funding grants from investigators (second chart).  During the years I was reviewing for the National Institutes for Allergy and Infectious Diseases (NIAID), their payline was never over 10%.  That means that less than 10% of the grants we would review would get funded.  At the worst, the payline was around 6%.  One meeting, maybe 30 reviewers met in the basement of a hotel somewhere for two days and scored about 110 grants.  Seven were actually funded. Don’t get me wrong.  In the study section where I was reviewing, there were only a small number of truly deserving applications – but that number was certainly more than 6%. Reviewers typically spend a minimum of two hours reviewing each grant and writing up a report of their review. Of course, someone has to do this work – but it’s no longer me. The point of this is, as Mr. Broad has pointed out, government funding for research is going down the toilet in this great world power of a country. (Caveat – BARDA has been a wonderful exception here).

What appears to be happening is that, increasingly, billionaires are funding research.  According to Mr. Broad, what are the areas most likely to get money? Cancer – especially prostate cancer (most of the billionaires are men and some have had prostate cancer) - surprise. Other subjects popular among the philanthropists include the environment, exploration, aging and genetic diseases. Gee – what is missing from this list?  Oh – antibiotics and antibiotic resistance! The closest thing we get to support for that comes from the Gates Foundation and their work on malaria and TB.  This is wonderful and sorely needed – but what about resistance among Gram negative bacilli?  What about new antibiotics to treat resistant infections?  If we leave this totally up the pharma, we could be in trouble.  Don’t we need to hedge our bet here? Apparently, all the talk of the second coming of the pre-antibiotic era has not been enough to get the attention of the billionaire research patrons.  Why not?

I think it’s all about whom you know and who knows you.  I just don’t hang out with billionaires.  Does anyone out there have a line into a billionaire who might be interested in establishing an antibiotics research institute?  Lets make it non-profit and evergreen. Lets make it competent and staff it with academics who have spent time in industry and with ex-industry scientists with expertise on antibiotics.  There must be a ton of them out there looking for jobs given what’s been happening in pharma over the last 15 years. We could even make the institute, at least partly, geographically dispersed and connected virtually.

In the meantime, we have to hope that more pharma companies will get back into the antibiotic game and that they will do so competently.  I don’t think that there is any hope for a strong presence of government funding here.

Roche; Antibiotics - a Perfect Storm Twofer

This blog is a twofer.

First, I want to talk about Roche’s recent antibiotics deal and what this says about companies who get back into the antibiotic R&D game after having been out for many years. Roche recently reported a deal with a company called Discuva. According to their website, Discuva has a technology (SATI) using transposon mutants of bacteria and bioinformatics to help figure out why compounds that might have antibacterial activity work and potential mechanisms of resistance for compounds that don’t work.  First – a small disclaimer.  I have no knowledge of the specific technology Discuva is using and everything I say after this sentence could be entirely wrong (but I doubt it). To those of us who went through the genomics era of antibacterial research during the 1990s, and that includes people like Wolfgang Keck who was at Roche at the time, this is déjà vu all over again. Unfortunately, most of the compounds pulled out of chemical libraries that have activity, especially those with activity against Gram negative pathogens, are non-specific toxins.  So a target or targets will never really be discovered.  There are those that might be bona fide antibacterials with more than one target.  Many researchers believe that this is a good thing since it limits the possibility for mutational resistance.  But this also means that is harder for Discuva’s technology to identify the targets.

I am not convinced that this sort of approach is any better than the kinds of things one can do in one’s own laboratories with people who know what they are doing. And this brings me to the apparent problem at Roche.  Maybe they don’t. Who would be surprised if, after having pulled out of antibiotic R&D 15 years earlier, Roche no longer has the expertise it did during Wolfgang Keck’s time there? And this is the conundrum faced by companies who want to re-enter this area.  They have lost all their internal expertise.  So hire it, you say.  Right.  But who decides who to hire? Use consultants – like me for example.  Well, I’ve retired, although they never called anyway. But again – who chooses these consultants and who will be considering their advice?  Getting back in is not impossible, in my view, but it will take time and the learning curve will be steep.  I think Roche is in the first phases of this learning curve and I anxiously await further developments.  I just hope Roche of today has more patience than it did in 1999.

 

Next, I want to talk about antibiotic toxicity. 

In an article that appeared recently, Rao and coworkers examined the incidence of all cause mortality and serious cardiac arrhythmias occurring after 5 or 10 days of antibiotic therapy in a group of veterans treated with 1.6 million courses of drug.  This group differs from those in previous studies in that the cohort has more serious comorbidities than most other studies.  The most common problems include chronic lung disease, cardiovascular disease and diabetes – pretty much what you would expect in an aging veteran population. The rates of these events were 15 per 100,000 courses of therapy for amoxicillin given for 5 days up to 71 for levofloxacin given over a 10-day course. The baseline numbers are higher than I would have expected given previous FDA and other data – but this may be related to the higher risk groups studied here. To give you some other examples:  Chloramphenicol, which is virtually never used anymore, caused an irreversible, fatal anemia in about 1 in 50,000 to 1 in 100,000 course of therapy. This could and did occur in young, otherwise healthy patients. Telithromycin (Ketek) caused serious liver toxicity (not leading to death) in 1 in 100,000 to 1 in 200,000 courses of therapy and was withdrawn from use for bronchitis and sinusitis for this reason.  Augmentin – a combination of amoxicillin and clavulanic acid, causes serious liver toxicity at roughly the same rate as telithromycin – but is still widely used. When amoxicillin resistance ranges from 10 to 35% among respiratory pathogens and with azithromycin resistance at about the same level, what should the physician do?  Levofloxacin resistance remains at about 1% in those same respiratory pathogens.

The study by Rao and colleagues is a welcome and needed addition to the database on antibiotic toxicities.  It does not look at other toxicities like serious liver damage. And, it does not consider the necessity or appropriateness of the therapy used.  Until we have a good understanding of risk benefit for all these drugs, generic and branded products, physicians will not have all the information they need to make treatment decisions.  On the other hand, even with the new information, other than pausing before using antibiotics when they are not truly needed, I’m not sure the data provided by Rao will allow physicians to make different antibiotic choices for those patients who need antibiotic treatment.