The FDA’s new clothesBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4897 (Published 23 September 2015) Cite this as: BMJ 2015;351:h4897
All rapid responses
Light and Lexchin write that patients “are said to want” faster regulatory reviews for important new drugs (1). This word choice suggests the authors heard about patients’ views second hand, from sources that they did not entirely trust. Why not ask a few patients and settle the matter? I know some who are, to quote their website, campaigning to “change the drug development process in order to speed up the delivery of life-saving and life-enhancing medicines to people with life-threatening and rare illnesses” (2). I think there are others with similar views. I would be happy to try to arrange introductions.
The $85,000 launch price of sofosbuvir shows why it is a bad thing to have only one breakthrough drug with no “me too” competitors. At long last, some health systems are learning to use competition, via therapeutic substitution (choosing drug a ahead of therapeutically similar drug b), to force lower prices and to improve access (e.g., bevacizumab versus ranibizumab in AMD in France, AbbVie versus Gilead in hepatitis C, competitive tendering for insulin supply to Brazil, UNICEF’s vaccine procurement, Norway’s procurement of biosimilar infliximab, NHS procurement of erythropoietin, etc., etc.). I am therefore puzzled by Light and Lexchin’s (1) negative view of the approval of drugs that are not “any more effective than existing products”. I think health systems need more opportunities to force manufacturers to compete on the basis of price, and not fewer.
The story of insulin in type 1 diabetes has been one of incrementalism for nearly 100 years. No patients today would prefer the breakthrough that Banting and Best offered in 1922. Boeing has produced a series of me-too aircraft since the first jetliner, the 707. Few of us would now prefer to cross the Atlantic in the 1958 original. I am therefore puzzled by Light and Lexchin’s (1) negative view of incremental innovation. I would like to see more frequent incremental gains in the pharmacopeia, not less frequent ones.
I agree with Light and Lexchin (1) that bias is a major problem. As I have written elsewhere, “Phase III trials have become a messy mixture of science, regulation, public relations and marketing.” (3) However, there is a problem with the cost and speed of clinical development, independent of commercial bias (see, for example: (4) (5)). There is also the problem that clinical trials and regulatory decisions lack “ecological validity.” The usefulness, or uselessness, of drugs often becomes clear only after years of real world use (6). A great deal of therapeutic innovation occurs as doctors and patients make the most of the drugs at their disposal (7). The pharmacopeia will improve more rapidly if more acceptably safe “chemical diversity” reaches patients and doctors, at lower R&D cost, and if it is then evaluated in its natural environment. I do therefore see a useful role for some of the expedited programmes in the US, and for adaptive regulatory pathways in Europe. To quote Mao Tse Tung, who I confess is an unusual source of advice on drug regulation: “Letting a Hundred Flowers Blossom and a Hundred Schools of Thought Contend is the Policy for Promoting Progress.”
1. Light D, Lexchin J. The FDA's new clothes. BMJ. 2015; 351: p. h4897.
2. Empower. Access to Medicines. [Online].; 2015 [cited 2015 October. Available from: http://www.accesstomedicine.co.uk/.
3. Scannell J, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012; 11: p. 191-200.
4. Coates A, Halls G, Hu Y. Novel classes of antibiotic or more of the same? British Journal of Pharmacology. 2011; 163: p. 184-194.
5. IDSA. IDSA comments on FDA draft guidance for industry on hospital-acquired and ventilator-associated bacterial pneumonia. Federal Register 73106, November 29, 2010. [Online].; 2011. Available from: http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_....
6. Scannell J. What bad forecasts say about pharmaceutical and biotech innovation. [Online].; 2014 [cited 2015 September. Available from: http://www.accesstomedicine.co.uk/news-and-events/what-bad-forecasts-say....
7. DeMonaco HJ, Ali A, Von Hippel E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy. 2006; 26: p. 323-332.
Competing interests: Jack Scannell is a director of J W Scannell Analytics Ltd., which provides consulting services related to drug R&D to the public and private sectors.
FDA’s new clothes?
Alain Braillon, David Menkes
Senior Consultant, University Hospital, Amiens. France.
Associate Professor of Psychiatry, University of Auckland, Hamilton. New Zealand.
Light and Lexchin’s perceptive editorial about FDA drug approval should have titled “FDA, the king, has been naked for too long!”(1,2,3)
Indeed, this is not a news as it was disclosed by insiders: from December 1992, to July 2010, the FDA granted accelerated approval to 35 oncology products for 47 new indications but clinical benefit was confirmed in post-approval trials for only 26 of these 47 indications and confirmatory trials were not performed as requested by the Agency for 14 new indications.(4)
We suggest a simple solution: accelerated drug withdrawal programs! In half of cases of withdrawal because of deaths, more than 2 years elapsed after the first report of this adverse outcome; withdrawals for commercial reasons are more frequent than those prompted by risk of harms.(5,6) Regarding inefficacy, the inertia is even worse, as illustrated by delays in withdrawing drotrecogin alfa (10 years) and bevacizumab (45 months); in a further example, the FDA banned sibutramine 9 months after the EMA , allowing a further 160,000 prescriptions to be filled in the US. However, the FDA can act quickly, for example when it banned Mimolette (May 2013), a French cheese. Coincidentally, this was when Europe began to discuss banning US export of GMO foods.
Sadly, the problem also concerns Europe. Prescrire’s third consecutive annual (2015) list of “drugs to avoid” (drugs with adverse effects that outweigh benefits, or drugs superseded by others with a better harm-benefit balance), identified 71 such drugs (7). Remarkably, marketing of these drugs is yet to face any action from the EMA or the French agency.
1 Light DW, Lexchin J. The FDA's new clothes. BMJ. 2015;351:h4897.
2. Kesselheim AS, Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ. 2015;351:h4633.
3 Wang B, Kesselheim AS. Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs inUnited States, 2005-14: systematic review. BMJ. 2015;351:h4679.
4 Johnson JR, Ning YM, Farrell A, Justice R, Keegan P, Pazdur R. Accelerated approval of oncology products: the food and drug administration experience. J Natl Cancer Inst 2011;103:636-44.
5 Onakpoya IJ, Heneghan CJ, Aronson JK. Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis. BMC Med 2015;13:26.
6 Prasad V. The withdrawal of drugs for commercial reasons. The incomplete story of Tositumomab. JAMA Intern Med 2014;174:1887-1888.
7 Toussaint B. Prescrire: France’s Choosing Wisely initiative. BMJ 2015;350:h3325.
Competing interests: No competing interests
This is an important set of articles and editorial. Many still look to FDA as the one place we can turn to for independent and good advice - See Response from Larry Sasich to last week's Restoring Study 329. But Kesselheim's articles and this editorial make it clear that the FDA's reviews many of us once turned to are missing in 98% of cases and the data underpinning warnings are missing even more comprehensively.
The information FDA offer is the information underpinning a regulatory decision - such as whether to allow this food to be classed as organic or fresh. It is not medical information. The position we now have is that the information on whether drugs reach "Emission" standards is of ever poorer quality - and that this information is good compared with the quality of information that is needed to underpin the practice of medicine. .
Light and Lexchin point to one light on the horizon - the work of the Mario Negri Institute. See:
Competing interests: I have quarreled with both authors about many things.