Darrow, Avorn, and Kesselheim on the new FDA category of "Breakthrough" Drugs.

This weeks New England Journal of Medicine includes a terrific article by Darrow, Avorn, and Kesselheim: New FDA Breakthrough-Drug Category- Implications for Patients, 370 New Eng. J. of Med. 1252-1258 (March 27, 2014).  (the full text is available free online at http://www.nejm.org/doi/full/10.1056/NEJMhle1311493).  The authors point to the relatively high rate of post-market safety issues as well as non-efficacy issues that have surfaced in recent years with respect to drugs approved on the basis of accelerated approval using surrogate endpoints.  There is an important balance to be maintained between expediting access to life-saving new drugs and the hasty approval of new drugs that pose serious risks that outweigh their benefits.  The authors make a strong case that this balance has been lost, and that we may well be doing more harm than good for some of the most vulnerable members of our society-- patients affected with life-threatening diseases for which there are few if any therapeutic options. As the article points out, in the case of accelerated approval with commitments for post-market studies (referred to as Phase IV studies), NDA sponsors have generally been very slow in conducting those studies and gathering data. In one of the worst such examples cited in the article: "Gemtuzumab ozogamicin was approved in 2000 for the treatment of pediatric leukemia on the basis of limited data, but it was withdrawn from the market in 2010 after confirmatory trials initiated in 2004 showed increased mortality and no efficacy [citation omitted]." In other words, children with leukemia were treated for 10 years with a drug that in fact increased their risk of dying. In another example cited in the article, bevacizumab (Avastin) was approved for metastatic breast cancer on the basis of accelerated approval using surrogate endpoints. The post-approval data showed no increase in survival, and, given the serious adverse effects of the drug, the FDA withdrew approval for the indication. This subsequent FDA action was nevertheless met by significant opposition from patient groups, which evidences the understandable desperation of terminally ill patients and their loved ones.

Tu, Holman, Mossoff et al. Make a Valuable Contribution to the Often Wildly Inaccurate Discussion of Gene Patents.

There has been a great deal of hyperbole and plain old inaccuracy in public discussion of gene patents. One would have hoped that the Supreme Court's decision in the Myriad Genetics case, Association For Molecular Pathology et al. v. Myriad Genetics, Inc., et al.) (12-398, Decided June 13, 2013) would have put an end to some of the most inaccurate discussions, which wax on about how the human genome is largely covered by patents and science has been stymied. However, the media still repeats those assertions and, remarkably, they even continue to be made in peer-reviewed journals. GENOME MEDICINE recently published another one of those "the end is near" articles and fortunately, just published a well-written and thorough response by a group of law professors who actually know what they are talking about: Tu et al.: Response to ‘pervasive sequence patents cover the entire human genome’. 6 Genome Med 14 (2014). It has been my opinion that whole genome sequencing largely rendered the problem moot, at least for genetic testing, and that other uses of genetic material, for therapeutic purposes in gene therapy or for protein production for biological therapy should continue to be patentable. Truly workable gene therapy methods are undoubtedly patentable because they are still to be invented and clearly non-obvious. However the patentability of the use of genetic material for protein production for biological therapy has been cast into some doubt by the Supreme Court's regrettable resurrection of the product of nature doctrine in the last two years. I believe that in the context of recombinant protein production this is somewhat less troubling than it might otherwise seem, as there just do not seem to be very many naturally occurring, non-immunoglobin proteins left that can be used therapeutically. Other than in the case of very rare Orphan diseases, there have been no recombinant proteins approved for therapeutic use in the U.S. in a number of years. It appears that the low hanging fruit that was brought to market in the days of Epogen, Neupogen, Humulin, etc., may have been the only fruit worth harvesting at all. From a pharmaceutical policy perspective, the message is clear. Gene patents simply are not an issue of importance.

An Estimate of Pharmaceutical Industry Product Liability Costs

In a previous post I discussed the Generic Pharmaceutical Association's (GPhA) commissioned study of the potential costs of a proposed FDA rule that would allow generic drug manufacturers to update safety warnings and expose the manufacturers to liability. I criticized the methodology used by Alex Brill, of Matrix Global Advisors who authored the GPhA study. Brill arrived at an estimate of $4 billion annually in product liability costs and the GPhA has opposed the proposed rule change citing that figure. My critique of Brill's methodology was principally aimed at his use of early 1980's data for liability costs, and that data was not industry specific. Brill's estimate was thus based on data that would seem to be of very little use in understanding current liability costs or projecting future ones. So, with that introduction, let me explain how I arrived at my own estimate of liability costs for the branded prescription drug industry.

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The FDA Proposes a New Guidance About Distributing Scientific and Medical Publications on Unapproved New Uses: It Doesn't Address the Problem of Publication Bias

On Friday, February 28th, the FDA made available a new proposed Guidance on the subject of pharmaceutical companies' distribution of published materials that report on studies of their drugs for "unapproved" uses.¹ The marketing of pharmaceuticals is a huge enterprise. According to a study by the Pew Charitable Trusts Health Initiative, pharmaceutical companies spent $29 billion in 2012 to promote the use of their drugs, with $15 billion of that spent on direct marketing to doctors by pharmaceutical reps, a practice known as "detailing." For some drugs, a major portion of the promotion effort is aimed at generating "off-label" use, which is the prescription of a drug for diseases or conditions for which the FDA has not received sufficient evidence to determine the drug's safety and efficacy. Until the mid-nineties, the FDA took a hard and fast position limiting the ability of pharmaceutical companies to promote off-label use of their drugs. The FDA's position was straightforward: placing a drug on the market for a use which has not been approved by the FDA is selling the drug without adequate information about its safety and efficacy for that use, which renders the drug "misbranded" in FDA parlance and the marketing illegal. If a drug maker wanted to promote a new use of an already approved drug, then the FDA's view was that the only proper way to do so was to do studies that were reviewed by the FDA and sufficient to support adding that use to the drug's label. Then, in a series of decisions, the District of Columbia Court of Appeals ruled that drug makers' dissemination of information about unapproved uses was commercial speech and merited protection under the First Amendment. That view was partly adopted by statue with the Food and Drug Administration Modernization Act of 1997. Since then, the FDA's efforts have been directed at defining the appropriate limits on off-label promotion, consistent with the First Amendment.

The FDA's proposed rule changes for generic pharmaceutical labels and the GPhA response

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Following the Court's decision in Pliva Inc. v. Mensing that generic drug makers were shielded from liability for inadequate warnings because of their inability to easily strengthen those warnings, the FDA began a rulemaking procedure to change the rule governing generic drug labeling. On November 13, 2013 the FDA published its proposed rule to provide an opportunity for comments by industry and other interested parties.¹ The proposed rule is intended to remove the restrictions on generic drug labeling that lead the Pliva majority to rule that it was impossible for a generic drug company to comply with a state court's determination that generic drug was unreasonably dangerous because the label failed to adequately warn doctors and patients of the drug's risks:

The proposed rule would create parity among application holders with respect to such labeling changes by permitting holders of abbreviated new drug applications (ANDAs) to distribute revised product labeling that differs in certain respects, on a temporary basis, from the labeling of its reference listed drug

The FDA explained that because generic companies that received approval to market a drug under an ANDA, just as the sponsors of new drug applications receiving approval under an NDA, "have an ongoing obligation to ensure their labeling is accurate and up-to-date" and that therefore:

tension has grown between the requirement that a generic drug have the same labeling as its RLD, which facilitates substitution of a generic drug for the prescribed product, and the need for an ANDA holder to be able to independently update its labeling as part of its independent responsibility to ensure that the labeling is accurate and up-to-date.

At the time this is written, the FDA had not closed the comment period, so the rule is not yet in its final form. However, the FDA is clearly taking the position that the potential for tort liability is an important incentive for pharmaceutical companies' efforts to monitor the safety of their drugs, and that the decision in Pliva, by shielding generic manufacturers from liability, undermined their incentive during an important period in a drug's use. In its statement in support of the proposed rule, the FDA cited its own study of the safety-related labeling changes made in 2010, which found that the "most critical safety-related label changes, boxed warnings and contraindications, occurred a median 10 and 13 years after drug approval."²