FDA's Woodcock Testifies on Antibiotics

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But I don’t get it.

Dr. Janet Woodcock testified before the committee on energy and commerce subcommittee on health in the US House of Representatives in June.  Her full testimony can be viewed and downloaded via the link below: http://energycommerce.house.gov/documents/20100609/Woodcock.Testimony.06.09.2010.pdf. 

Dr. Woodcock is a scientist for whom I have the greatest respect.  She was the originator of the FDA’s Critical Path whitepaper that was an important recognition of the regulatory implications of personalized medicine for drug development.  But I am afraid that her testimony in June is more a political statement designed to shield the agency from congressional criticism rather than a real world assessment of the FDA’s current position in the war against resistant bacteria.

Dr. Woodcock notes that the “FDA is working to provide scientifically sound guidance to industry on demonstrating the safety and effectiveness of new antibacterial drugs, particularly on indication-specific trial designs used to study a new drug.”  She goes on to point out the challenges faced by antibiotic drug development in the sense that non-inferiority trials where one antibiotic is compared to another assume superiority of the comparator to placebo – something that most often was never proven in a placebo controlled trial since these are mostly viewed as unethical.  You can’t not treat someone with a serious infection.

Dr. Woodcock then goes on to cite FDA’s list of recently released guidance or draft guidance documents related to antibiotic development.  We, and congress, are supposed to believe that the FDA has actually made progress.  A careful look at the guidance documents she cites provides more angst than reassurance.  The placebo controlled trial designs required for registering a new antibiotic for otitis media, sinusitis and bacterial exacerbations of bronchitis are all infeasible since no one will be able to get sufficient numbers of patients to enroll in such trials.  Moreover, in the case of moderate to severe exacerbations of chronic bronchitis that are associated with bacterial infection, it would be unethical to withhold antibiotics from patients.

The guidance on trials in community-acquired pneumonia was apparently obsolete upon its release since the FDA had to backtrack after the extent of the response from sponsors and the public.  This guidance is being substantially reconsidered and will almost certainly be revised.  I’m still not sure that we will end up with feasible design requirements at the end of the day.

Dr. Woodcock rightly states that clear guidance will not be enough, but that incentives will probably also be required to assure a continuing pipeline of new antibiotics active against resistant bacteria.  But, if the trial designs required for registering these new antibiotics are infeasible, where are we?  No incentive in the world can overcome that obstacle. 

I am hoping that congress will see through the FDA claims of progress and realize that the only progress we are making on the regulatory front for the development of antibiotics is backwards. I continue to hope that someone, either within FDA or within congress forces a regulatory reboot for antibiotics.  We need to start over.  And the first premise going forward is that required trial designs must be feasible within the world in which we live.  If this simple concept can be woven throughout our scientific considerations, I am sure that those in industry still left working on antibiotics will respond.  But if we don’t figure this out soon, we risk further losses in this very shaky area within the pharmaceutical industry.

Why Avandia Threatens New Antibiotics

To continue on our theme of Avandia and antibiotics, I notice that the FDA has now put Avandia’s safety trial on hold while they sort out their own view of the risks and benefits of this study.  This all reminds me of a situation faced by Wyeth back in 2002.  At that time, Wyeth had just completed reviews of several therapeutic area, including an in depth review of anti-infectives including antibiotics.  While I initially thought that the entire idea to review anti-infectives was a way for management to find an excuse to cut the entire therapeutic area, I was later encouraged by the data we uncovered during our preparation for the review.  We were able to prove to ourselves, and, at least I thought, to management, that antibiotics were going to be an important part of Wyeth’s future in the pharmaceutical marketplace.  To come to that conclusion required months of work by 20 or so people including a consulting group digging through historical antibiotic sales data, determining the effect of generics on the antibiotic dollar volume marketplace (virtually nil), and examining our ability to overcome the scientific difficulties involved in discovering new antibiotics (e.g. tigecycline).  The result of that review was that we had certainly convinced ourselves that antibiotics was a worthwhile endeavor for a large pharmaceutical company like Wyeth.  And, the handshake I received from Wyeth’s CEO at the time, Bob Essner, led me to believe that he agreed with this conclusion.

But then, just 6 weeks after this big review, Wyeth was crushed by emerging data from the Women’s Health Initiative Study showing that Premarin, a $2B product for Wyeth, was associated with increased rates of cornonary disease, blood clotting and breast cancer in post-menopausal women.  These data were totally contrary to earlier studies and Wyeth’s entire marketing position for Premarin. Premarin sales and Wyeth stock values plummeted.  Of course, this followed on the heels of the fen-phen debacle where Wyeth ultimately paid $20B in legal fees and settlements over its diet drugs. 

Wyeth’s response?  What else?  Cut costs.  How?  Eliminate the infectious diseases therapeutic area. Almost 100 people were either fired or moved to other positions within the company.  A skeleton crew of 10 or so was left to support a couple of projects in clinical development.  The most important of those was tigecycline, which was finally launched in 2005 and is now selling almost $500 million per year.

J&J recently severely cut back on their antibiotics research effort after their failure to get ceftobiprole approved by either the FDA or the European regulators.  They are also in the midst of a severe manufacturing crisis affecting key generic products like Tyleonol.   This is also hitting their bottom line and their stock price.  Will antibiotics come back to J&J anytime soon?  I doubt it.

At GSK, Avandia was selling $3B per year in 2007.  Because of recurring safety concerns, sales are now hovering around $1.2B and falling.   GSK’s stock has fallen roughly 25% overall since the beginning of this year.  So, the Avandia scandal is not causing as big a hit on GSK’s bottom line as the Premarin results did for Wyeth.  But, given large pharma’s constant ambivalence towards antibiotics, there is always the possibility that GSK will react the same way as Wyeth and J&J.   While I believe that GSK has come to believe that the antibiotics marketplace is a reasonable one, I think that of all their therapeutic areas, antibiotics remains at high risk within this large behemoth company.  The same is probably true of other large pharma companies as well.

Avandia and the fate of products like Avandia threaten our access to new antibiotics because they cause large pharmaceutical companies to reconsider their priorities in terms of return on investment.  When these giants need to cut costs, public health considerations like the need for new antibiotics are frequently not their first consideration.  Nor should they be.  These companies exist to provide a return for their shareholders, not to provide for public health.  When these two needs intersect, both the company and public health benefit.  In the case of antibiotics, it seems that there is more likely to be a fork in the road than an intersection. 

Antibiotics and Avandia

I have been following with interest the potential scandal over the handling of controversial data on GSK’s Avandia by GSK.  It appears, based solely on various new reports that GSK deliberately tried to cover up negative data concerning the safety of this oral drug for the treatment of diabetes.  Of course, until we have full disclosure we won’t know if this is a scandal or not. But the discussion prodded me to think about the pharmaceutical industry and its ambivalence towards antibiotics.

To many, the pharmaceutical industry is a parasite that does little other than contribute to the rising cost of health care.  The industry may be the source of life-saving drugs for cancer or important symptom-relieving drugs for painful conditions such as rheumatoid arthritis, but the costs of therapy remain unreasonably high.  The public frequently views pharma as greedy beyond belief.  The Avandia scandal does nothing do alleviate these concerns regardless of the ultimate outcome at the FDA.  GSK’s settlement of lawsuits for billions of dollars doesn’t help either.

But GSK is one of the few remaining large pharmaceutical companies actively involved in antibiotics research.  It also diligently pursues opportunities for new antibiotics outside GSK, thus providing opportunities for academia and for biotech in the antibiotics area.   While I presume that GSK is involved in antibiotics because they still believe that the market is a viable one, even if their only or main motivation is humanitarian, I won’t complain.  Some companies, like J&J (who has since abandoned most antibiotics research), have openly stated that their motivation for remaining in the area was humanitarian and societal concerns.  Nothing wrong with that!   But these companies get little credit for their efforts in public opinion.

The Infectious Diseases Society of America has proposed the 10 x 20 initiative – that is – deliver 10 new antibiotics active against resistant bacteria by 2020.  This can probably only be achieved through the auspices of the pharmaceutical industry.  Although this is a great public relations campaign, it is, of course, completely unrealistic.  The initiative is also only undermined by the Avandia scandal. The problem for antibiotic research posed by scandals such as the one around Avandia is that it simply reinforces the already negative opinion of the pharmaceutical industry in the eyes of the public.  That, in turn, makes it harder for politicians to back measures designed to provide incentives for the industry to remain or to get re-involved in antibiotics research and development.  Most of the measures being considered will involve increased monies going, directly or indirectly, from taxpayers to an industry already disliked and distrusted by the public.

The sad thing is that the Avandia scandal may not be a scandal at all.  It is possible that the e-mail messages released by the press have bee taken out of context and that there was never an intention by GSK to cover up anything of any scientific value or validity.  We may get a better idea of what went on in GSK during the next few days and months as the FDA and others examine the case more closely. But the truth is almost irrelevant as far as the damage to GSK’s image and the deepening public distrust of the pharmaceutical industry is concerned. 

As the industry struggles to provide more and more personal care options for serious diseases such as cancer, the more the industry will be resented by the public.  It seems like Alice in Wonderland to me.  The industry provides drugs that work for small populations of seriously ill patients but must charge a high price to provide a sufficient return on investment to their shareholders.  If the industry can show that these prices are justified based on the value provided to society and for healthcare overall, then why should we complain?  There is, in any case, no way the industry can provide drugs designed for very small populations without charging a high price.  They would simply lose money.  So, while I can understand resentment at the high prices being charged, I also think a little injection of reality into public thinking wouldn’t hurt.

I say all this because one future direction for antibiotics is to provide curative treatment for seriously ill patients with particular resistant infections.  This would be another example of a small population where high prices for therapy would be required.  But with the industry shooting itself in its public opinion foot, all I see is the abyss for new antibiotics.

Antibiotics vs. Pricing

I just read a very interesting report entitled, “An Economic Assessment of the Relationship between Price Regulation and Incentives to Innovate in the Pharmaceutical Industry” published by the European School of Management and Technology (ESMT) and sponsored by Novartis (https://www.esmt.org/fm/479/WP-109-03.pdf).  A careful look at the data might suggest that much of the data used by the ESMT came from Novartis itself.   Much also came from the Tufts Center and from other publicly available documents.  The bottom line comes as no surprise to anyone involved in pharmaceutical R&D over the last couple of decades.  The less people are willing to pay for new drugs, the fewer new drugs we will have.  It’s actually quite simple. 

The ESMT report gets much more granular.  They look at various pricing strategies and their effects on pharmaceutical innovation. 

• ·      External Price Benchmarking, according to which the price of a drug in a country is pinned to the price of the same drug in a basket of other countries;
• ·       Internal Reference Pricing, according to which the price of a drug in a country is pinned to the price of similar, potentially already off-patent, drugs in the same country;
• ·      schemes based on a pharmaco-economic assessment, according to which the price of a drug depends on its cost-effectiveness.

One case example they use is Germany.  A better one, at least for antibiotics, might have been Australia.  These counties exemplify situations where, for advances in side effect profiles and ease of drug administration, where the molecule in question is not a totally new or novel class, governments won’t pay – or at least not very much.  In both cases there are examples where new drugs have simply not been marketed.  But if such policies were to spread to other world markets, this would clearly have a major impact on drug discovery and development within industry.

The fact that such pricing strategies are already having an effect can be seen by simply looking at the kinds of drugs in development in large pharmaceutical companies. A perusal of Clintrials.gov or the PhRMA website showed that there are 5-8 times more trials being carried out for cancer than for antibiotics. In the ESMT analysis, under almost all pricing scenarios, antibiotics are placed in the lowest priority among projects at various stages of development compared to all other therapeutic areas in a large pharmaceutical company.  Of course, this is patently ridiculous given what we know about the medical need for new antibiotics.  But it reflects today’s perceptions of pricing in a world where health care costs are government budget busters.

My conclusion is that in a world where drug-pricing strategies are designed to keep drug prices low even when drugs offer clear answers to important medical needs, antibiotics end up at the bottom of the priority list within the pharmaceutical company.  The company tends to focus on drugs where governments cannot argue too much over price – like cancer and Alzheimer’s disease. Antibiotics are not helped by the fact that they are miracle drugs and cure disease.  In fact, because there are cheap antibiotics that still work for many infections, antibiotics are hurt by their own success in most drug pricing scenarios. Even when they meet the medical need and innovation tests to justify a high price, the patient population to be treated becomes so small (Pseudomonas aeruginosa resistant to all other antibiotics) that the market is hardly worth thinking about. 

Reality check – Zyvox and Cubicin are high-priced antibiotics in most countries where they are sold. Cubicin was approved relatively recently.  Therefore, not too long ago, Cubist was able to defend its position during the drug pricing negotiations with most countries.  What this means is that the perception within industry does not necessarily reflect realities on the ground.  I think it also means that the pricing policies of many countries are not very transparent and what they say is not always exactly what happens.

My conclusions.

1.              Pressure on drug prices will, by necessity, mean fewer new drugs.  Period.
2.  Antibiotics, for many reasons, will still struggle to be prioritized within large pharmaceutical companies.
3.    Pharmaceutical companies need to improve their studies to demonstrate the societal and economic value of the antibiotics they bring forward to the marketplace.
4.    Governments need to be much more transparent regarding their pricing policies and their expectations for data justifying higher prices. 
5.     Governments also need to keep the problem of antibiotic resistant infections in mind in developing their pricing strategies for antibiotics in particular.

The day will come (unfortunately), as I noted in another recent blog, where antibiotics active against those resistant Pseudomonas will fetch 10s of thousands of dollars per course of therapy just like oncology drugs.