Report on Drug Safety and the US FDA by the Institute of MedicineAnthony W. FoxConsulting Editor, International Journal of Pharmaceutical Medicine

COMMENTARY Int J Pharm Med 2006; 20 (5): 289-2911364-9027/06/0005-0289/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

The Institute of Medicine (IOM) was engaged by the USFood and Drug Administration (FDA) to investigate drug safetyin the US and what the Agency could do to improve it. A corollaryreport was issued in July 2006 and concentrated on drug safetyin the context of point-of-use issues, such as bar coding andclinical error. This later and definitive report was issued as adraft, on September 26, 2006, and is entitled The Future of DrugSafety: Promoting and Protecting the Health of the Public.[1]

The IOM committee involved had a professional secretariat,and a membership of highly regarded academics, medical admin-istrators, clinicians and one foreigner, namely Sir AlasdairBreckenridge, who chairs the national competent authority (Med-icines and Healthcare products Regulatory Agency [MHRA]) inthe UK. A second committee comprised of many who are well-known for their participation in US regulatory affairs, and includ-ing at least one former FDA staff member who has held seniorposts in drugs, biologics and devices, as well as a staff memberof the European Medicines Agency (EMEA). This second com-mittee reviewed and commented on the draft, but were not askedto endorse the report, nor saw this next-to-final draft. The person-nel on this report can only be described as very sound. The IOMhas a reputation of independence and credibility, and there isnothing in this report that indicates otherwise. In this report theyconcentrated on what could be done in Washington, DC, ratherthan in the drug cart on the hospital floor.

There was quite a stir on the day the draft report was issued,if measured by the number of news reports on the wire. As earlyas the 22nd of September – a few days prior to the public releaseof the pre-publication document – a USNewswire report had atitle that screamed IOM’s scathing report on drug safety systemshould send wake-up call to Congress.[2] Other news organis-ations used the verb ‘blast’ to describe IOM’s treatment of the FDA.Even presuming they had early access to the report, one stillwonders whether these reporters had actually read this draft reportwhose main text is 265 pages long.

Three official statements followed the release of the draft

report; one came from the Department of Health and HumanServices, and two from the FDA itself.[3-5] Mr Michael Leavitt,the Secretary of the Department of Health and Human Services(which is a cabinet-level post), and a former insurance executiveand Governor of the State of Utah, took the opportunity to callon the Senate to appoint a permanent FDA Commissioner (echoingthe report itself) and to ask Congress for information technologyfunding.[3] For the FDA, one statement came from Dr Andrewvon Eschenbach, the Acting Commissioner, and the other fromDr Steven Galson, the Chief of the Center for Drug Evaluationand Research (CDER). The former generally ratified what theIOM came up with, and stated his enthusiasm for pursuing thosesame goals in the future.[4] The latter noted 25 recommendationsin the report, and drew attention to what he had already done insome of these same directions.[5] Since the FDA leadership hiredthe IOM and set the statement of task, it would, perhaps, havebeen surprising had they been dissatisfied with the final product.

So after all the posturing, what is really recommended, is itactually radical, and what are the practicalities and necessities forimplementing the recommendations?

First of all, the report is not scathing of the FDA. Nor shouldit have been. Nor would it have been useful, had it been. In itsstatement of task, the FDA deliberately asked for identificationof both strengths and weaknesses. The fundamental motive hereis to improve patient safety. The underlying theme is that the FDAshould have more resources to pursue this laudable goal. Nobodydisagrees with that. In fact, the Biotechnology Industry Organi-zation, among others, is supporting a new organisation with theexpress objective of lobbying Congress to provide the FDA withthe funds it really needs.[6] The report goes out of its way todefend the FDA from those who believe that a postmarketingdrug withdrawal automatically indicates a regulatory failure orthat someone erred by letting such a product on the market in thefirst place.

The FDA, hitherto, has been in the business of post hoc (i.e.,after-disaster) labelling changes, black box warnings and product

withdrawals. It has not been active in establishing mechanismsthat aim to prevent disaster. This contrasts with the government’sapproach towards the food supply in the US. At the site of slaughter,the US Department of Agriculture inspects every single carcassthat enters the human food chain. Meanwhile, during the autumnof 2006, the FDA (and the Centers for Disease Control) couldonly investigate outbreaks of Escherichia coli enteritis due tocontaminated Californian spinach after the outbreaks had firstoccurred, and then actually been detected. The FDA approach tolow-frequency, postmarketing adverse drug effects has essentiallybeen much the same. Parenthetically, we might ask why the FDAand not the Department of Agriculture is still sorting out prob-lems with spinach – after all, the London Apothecaries separatedthemselves from the Guild of Grocers centuries ago!

If the FDA becomes more proactive in postmarketing drugsafety, is the the pharmaceutical industry going to resist? Obviously,they must speak for themselves, but senior management in com-panies whom I know would gladly have a real-time, propter hoc,safety clearance system for their products, rather than post hocsecond-guessing.

The problem is how can this propter hoc philosophy be accom-plished? At the end of the day, patients’ exposure in the market-place is always more diverse than those in the new drug applica-tion (NDA) or marketing authorisation application (MAA). ThisIOM report basically recommends drawing the discipline of phar-macovigilance yet closer into the centre of the drug approval andrisk-management regulatory process. Again, none can argue withthat.

Risk-management plans, post-launch, are available to theFDA under the so-called sub-Part H regulation and also by vol-untary agreement with sponsors who are usually very willing tocooperate in order to get their NDAs approved. So one could askwhy these are not mandatory for every approval, as is the case inEurope. This IOM report essentially recommends that this shouldalso be true in the US. Again, the best among large pharma arealready doing it.

The report recommends restrictions on advertising newly ap-proved medications, especially direct-to-consumer advertising(DTCA); only New Zealand and the US currently permit DTCA(and surely this was at the root of the rofecoxib withdrawal).1

Again, among the best in large pharma, a voluntary embargo onDTCA within 12 or 24 months of product launch is already inplace. The FDA has also announced a redistribution of resourcesbetween NDA approval and postmarketing review of promotionalmaterials.

Like many regulatory initiatives, this IOM report recommen-dation against DTCA is nonetheless a blanket remedy to certainparticular problems. Drug patents are exploited over far shorterintervals than, say, patents for mechanical devices because of thesignificantly longer development cycle. Not even the governmentof the richest country in the world is going to develop drugs athigh cost and large failure rates; private enterprise has to performthat role. With such massively greater up-front costs, yet moreuncompensated restrictions on marketing seems unfair if a financialbasis for innovation is necessary to ultimately enhance the publichealth. If restricting advertising reduces the return on investmentfor the first 2 of the 10 years on average of patient exploitation,then some sort of compensation would seem fair. This could eas-ily be accomplished by extending the system of exclusivity alreadyused as a quid pro quo by legislation concerning the paediatricresearch initiative and generic drugs in general.

Many of the 25 recommendations in this report are of a technicalnature. These include cross-assignments of staff within the FDA,and somehow getting a permanent Commissioner appointed bythe US Senate. The under-representation of pharmacoepidemio-logy on advisory committees is another identified problem. How-ever; it is not clear from where a good supply of such specialistswilling to work for the government in Washington, DC, mightcome. The IOM committee pleads for more scientifically rigorousrisk-benefit analysis and better epidemiological staffing at theFDA, along with clinical trial registration, even if this is tangen-tial to the remit of the report (and, again, already practiced by thebest in the industry). Various legal/legislative changes are rec-ommended that are consistent with these clinical goals. Lastly,while the committee recommends better communications withconsumers (i.e. patients), it is notable that the committees did notthemselves included representatives from patient- or disease-advocacy groups. The black triangle used in the UK compendiafor recently introduced drugs is also recommended.

The major aspect of public heath that the report does notcover is the false-negative drug review. When approved drugs getwithdrawn, the NDA approval might be termed a false positive.When the FDA rejects an NDA, and some toxicity is subsequentlyidentified, then that is a true negative. A drug that survives in themarketplace until it sees generic competition is a true-positiveNDA review. But it can equally be argued that when the FDArejects an application, and/or requests further animal or clinicaltrial data, only to later approve the drug for release, then that firstreview was arguably a false negative, and the public may havebeen denied a good drug for a few years. But the FDA is never

1 Since March 2006, the Ministry of Health has been reviewing options for the regulation of direct-to-consumer advertising of prescription medicinesin New Zealand.

290 Fox

© 2006 Adis Data Information BV. All rights reserved. Int J Pharm Med 2006; 20 (5)

held accountable to that eventuality. The IOM report does notconsider this type of scientific error in the drug development andpostmarketing pharmacovigilance process.

If this IOM report is taken to heart by senior regulators, itwill be good for patients and, incidentally, for the regulatorsthemselves and the industry. The report propounds excellence indrug safety and all are agreed on the need for that. Let us hopethat an implementation committee of an equally high calibre tothe reporting and reviewing committees will now be appointedwith a mandate that spans all three domains (drugs, biologics anddevices) of the FDA. Meanwhile, this is a report that is full ofwisdom and could well serve as a manifesto for good phar-macovigilance worldwide along with guiding further develop-ment at the FDA.

Acknowledgements

No sources of funding were used to assist in the preparation of thiscommentary. The author has no conflicts of interest that are directly relevantto the content of this commentary.

References1. Baciu A, Stratton K, Burke SP, for the Committee on the Assessment of the US

Drug Safety System. The future of drug safety: promoting and protecting the

health of the public. Washington, DC: National Academies Press, 2006 [Pre-

publication edition]2. IOM’s scathing report on drug safety system should send wakeup call to Congress;

Consumers Union urges IOM recommendations be included in legislation and

acted on [online]. Available from URL: http://news.aol.com/topnews/articles/

_a/ioms-scathing-report-on-drug-safety/n20060922140309990014 [Accessed

2006 Sep 27]

3. US Health and Human Services. Statement by Mike Leavitt Secretary of Health

and Human Services, on the Institutes of Medicine Report on the future of drug

safety [online]. Available from URL: http://www.hhs.gov/news/press/2006pres/

20060922.html [Accessed 2006 Sep 28]

4. US Food and Drug Administration. Statement by Dr. Andrew von Eschenbach

Acting Commissioner of Food and Drugs regarding The Institute of Medicine

future of drug safety report [online]. Available from URL: http://www.fda.

gov/bbs/topics/NEWS/2006/NEW01461.html [Accessed 2006 Sep 28]

5. US Food and Drug Administration. Statement by Steven Galson, CDER Director,

regarding The Institute of Medicine’s “Future of Drug Safety” Report [online].

Available from URL: http://www.fda.gov/cder/news/IOM_statement.htm [Ac-

cessed 2006 Sep 27]

6. Rubin R. New coalition urges more money for FDA [online]. Available from URL:

http://news.aol.com/topnews/articles/_a/new-coalition-urges-more-money-for-fda

/n20060925081509990023 [Accessed 2006 Sep 27]

Correspondence and offprints: Dr Anthony W. Fox, EBD Group, 2032 Cortedel Nogal #120, Carlsbad, CA 92009, USA.E-mail: awfox@ebdgroup.com

The Institute of Medicine Drug Safety Report 291

© 2006 Adis Data Information BV. All rights reserved. Int J Pharm Med 2006; 20 (5)