More on FDA Thinking

In the Oct. 14 issue of the New England Journal, Dr. Susan Okie writes about Drs. Hamburg and Sharfstein’s efforts to “revive” the FDA (an interesting choice of words, don’t you think?).   In this article, Dr. Okie covers the FDA on rosiglitazone, medical devices, food safety, facility inspections and the tension within CDER between their Office of Surveillance and Epidemiology and their Office of New Drugs.  The surveillance folks claim that the new products folks are too focused on approving new drugs to pay sufficient attention to safety risks.  The new drugs folks feel that the surveillance office is too focused on safety to the detriment of valuable new products. Although Dr. Okie cites rosiglitazone as the contemporary example, she could easily have chosen the antibiotic telithromycin (Ketek) removed from the market for certain indications back in 2006.  Of interest, the FDA has apparently contracted with Harvard Pilgrim Health Care to develop and test a data mining system to survey electron medical records to answer safety questions.

Back in 2005, I worked with the Manhattan Institute to frame an approach to Janet Woodcock’s Critical Path proposal.  In this proposal, Dr. Woodcock exhorts sponsors to develop new tools using new genomic, proteomic and other novel scientific methods to push rapidly forward towards a new paradigm of drug development.  In this new paradigm, drug safety and efficacy studies would be informed by biomarkers developed and validated using the new scientific tools.  The task force at the Manhattan Institute examined the proposal and developed a white paper, Prescription for Progress; a Critical Path to Drug Development.  The context of the white paper was within the realm of biomarkers and, mostly, the development of drugs for oncology and inflammation.  But one general approach that we did present to the FDA still resonates for me and, I think, for some at the FDA.  We suggested that a drug could be conditionally approved based on favorable Ph. II data in a life threatening indication or where there was no other therapy available.  One example we used in our presentation to the FDA in 2005 was Vioxx.  If Vioxx were developed for use in patients with rheumatoid arthritis whose pain was unresponsive to other non-narcotic pain relievers in a phase II trial, the drug would then be approved for use only in that patient population.  A registry would then be required for all patients for whom the drug was prescribed to assure that the drug was not being used off label and to assess safety risk.  Thus, the drug would fill an important medical need only within the specific needy population.  The sponsor would sell the drug and recoup some costs while continuing into phase III trials that might study the drug in a wider population.  Before the drug would be approved, though, there would be considerably more use occurring outside the clinical trials than we usually have at the end of phase III.  Therefore, our understanding of the safety of the new drug in a larger population would be enhanced and this would reduce the safety risk going forward.  In the case of Vioxx, perhaps the cardiac risk would have become evident during its restricted use in the rheumatoid arthritis population.  The sponsor might have then been able to argue that the benefit risk ratio is still favorable within that population, and ultimately have had Vioxx approved in a narrow indication as opposed to the very broad indication for pain relief where hundreds of millions of prescriptions were written.

If we could study antibiotics in a very needy population, such as patients with serious infections caused by highly resistant pathogens, perhaps a new antibiotic could follow a similar route.  The questions as posed in a recent blog remain the same.  What would the details of such a study look like?  Will it be feasible or not? 

The article by Dr. Okie in the New England Journal did not even touch on antibiotics.  Hmmmm . . . .

She Speaks!

Hey everyone – I just received my copies of my book as promised by Springer. I think I’ll put them in a safe deposit box. 

But to business.  I have seen a flurry of activity by Dr. Hamburg, Commissioner of the FDA that is relevant to Antibiotics – the Perfect Storm.   And my spies tell me that Dr. Temple has been active as well. Since I am not a journalist, and do not cover Dr. Hamburg’s speaking engagements, and since I am not involved in the FNIH process or other direct interactions with Dr. Temple (outside of the usually advisory committee meetings and public workshops), I have to rely on spies and news reports.  Nevertheless, a story is emerging.

Two recent new reports have reported on Dr. Hamburg’s statements on antibiotic resistance and the antibiotic pipeline.  According to Alicia Mundy of the Wall Street Journal, at a recent appearance at the National Press Club, Dr. Hamburg noted the increasing resistance to available antibiotics.  She laid this at the feet of antibiotic use both for human health and for crops and in chickens and livestock. She called for more judicious antibiotic use.  This comes at a time when the FDA is (finally) poised to act on the use of antibiotics in agriculture. But, according to Mundy, Dr. Hamburg also said that the state of the antibiotic pipeline is “distressingly low” and that “the range of antibiotics is disturbingly limited.” 

It is comforting to know that Dr. Hamburg is at least devoting some of her time and energy to antibiotics.  I know from my days on the Institute of Medicine’s Forum on Emerging Infections, where she was a frequent participant and co-chairman, and from Dr. Hamburg’s history in New York during the outbreak of resistant TB in the 1990s, that she is acutely aware of the issues of antibiotic resistance. I admit that I have been worried (and am still not reassured) that Dr. Hamburg would be so overwhelmed with crisis management within a large and unwieldy bureaucracy that she would have no time to think about the antibiotic mess at the FDA. 

Evidence that FDA management is beginning to get more involved comes from spies.  Apparently Dr. Robert Temple has harkened back to Mark Goldberger’s (ex-Director of the antibiotics division at FDA) suggestion from 2002 that we approve antibiotics based on a small number of high quality cases.  That is, we recruit patients with serious disease caused by resistant pathogens that would be untreated or poorly treated with approved antibiotics, treat them with a new drug showing that it works (is superior).  The devil here, as it was back in 2002, is in the details.  Which infections are OK?  Is bacteremia from any source OK?  The FDA has rejected that approach many times over the years.  Is hospital-acquired pneumonia OK?  If so – what kind of difference would the new drug have to show?  How many patients would that require? How many patients would have to be studied? 10?  20? Hundreds?  Are historical controls OK?  If so in theory, how would you justify the treatment effect for the historical controls?  If historical controls are not OK, is it ethical to not treat patients with a drug that will, with a greater than 50% or even 80% probability, work?  At least, maybe, we are back to considering these approaches at top levels within the FDA.  The basic question remains – can we make anything happen that will speed approval of needed new antibiotics?

The other piece of news, Angie Drakulich reports in PharmTech.com that The FDA and generic drug manufacturers are discussing user fees to speed approval of new generics.  This would allow the FDA to carry out a timely review of generic drug safety and manufacturing standards according to the FDA.  As those of you who have been following my blog know, generic antibiotics has become one of my key issues since the Ketek scandal.  During the Ketek scandal, it was clear that many generic drugs were approved for use in otitis, sinusitis and acute bacterial exacerbations of chronic obstructive pulmonary disease.  But they were approved based on clinical trials that the agency now considers to be obsolete and invalid. At the same time, several of these generic drugs have safety problems.  At the time, I asked the FDA to review these generics and either remove their approvals for these indications or at least change their labels.  Nothing has happened in the last four years.  Maybe user fees will allow the FDA to actually work on this problem.

When it comes to the FDA, I am no longer ever optimistic.  But I am heartened to see that the eye of top management has, at least, been drawn to the very serious problem of rising antibiotic resistance coupled with our shrinking antibiotic pipeline. 

Superbugs, Antibiotics and Drug Safety

I’m back.  Vacation was great.  Now I’m being punished for having taken one. Oh well . . .

Well, NDM-1 has arrived in the US.  These Gram-negative bacteria cause everything from urinary tract infections to brain infections and pneumonia.  The can be treated, usually, by only one or maybe two antibiotics, and sometimes, by none. Of course, as noted in previous blogs, KPC-2 bearing Gram negative bacteria have been here for a long time and have already invaded 35 states that we know about.  Since we do not carry out active surveillance, what we know about these resistant bacteria probably only represents the tip of some undetermined iceberg. A recent report on CBS News shows the devastation these infections can wreak on patients and families to say nothing of their physicians struggling to treat what used to be a fairly simple infection in days gone by.

Of the 90,000 deaths occurring due to infections acquired in US hospitals every year about 70,000 involve antibiotic-resistant bacteria.  These numbers do not reflect resistant infections acquired outside the hospitals which may be much more frequent if sometimes less serious.

With serious infections caused by bacteria that are more and more resistant to the antibiotics we have in our armamentarium, we still face enormous roadblocks to the discovery and development of the new, effective antibiotics we need now.  Our need for new therapies is likely to become desperate in the near future if we don’t act now.

The FDA is entrusted with ensuring that the drugs that are marketed in the US are safe and effective.  But these terms are relative.  The question is, to what extent must we go to prove sufficient safety and efficacy for the treatment of which infections?  The more serious and life threatening, the more we can tolerate adverse events as long as we can pull the patient through. But what about efficacy?  How can we prove efficacy is these patient populations?  They are the hardest to actually enroll in trials because they are so ill.  The results of therapy are frequently hard to interpret because they are so ill.  Is the fact that they survive enough?  Can we compare such patients to historical controls?  How good would the database of historical controls be for KPC-2 infections since this superbug has just emerged on the scene recently, and since there are sometimes at least one or two presumably effective antibiotics left to treat it. For example, lets look at NXL-104 – ceftazidime, a combination of a resistance inhibitor (NXL-104) and an antibiotic that is already marketed that is being developed by Astra-Zeneca. NXL-104-ceftazidime is very active against KPC-2 bearing Gram-negative bacteria. For patients with such infections where there are few if any other choices, is it ethical to withhold what will very likely be effective therapy?  We can predict efficacy for antibiotics so well using preclinical models that many would argue that it would be unethical to withhold such potentially life-saving therapy under these circumstances.  But would the FDA approve, at least conditionally, an antibiotic developed in this way?  Since, presumably, only a small number of patients might be studied – perhaps in the low hundreds, what do we do about a database to establish safety?  These are all questions being debated and discussed by the FDA, industry, the Infectious Diseases Society of America and others. 

A decade ago, Mark Goldberger, when he was Director of the anti-infectives division at FDA, called for high quality studies using a small quantity of seriously ill patients in trials of antibiotics. In the decade that has passed since then, we have rolled backwards in our ability to streamline and improve the relevancy of antibiotic development.  Companies are dropping out of the field right and left.

One major point that must be considered in all of these debates is – a lack of new antibiotics active against key resistant strains is, itself, a safety issue.  The FDA must recognize that acts of omission might also be important contributors to a safety risk for the population.  This key ingredient must be added to the stew of strategic thinking on antibiotic development if we are ever going to get anywhere.