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Testimony on Clinical Research Involving Children

Peter Lurie, M.D., M.P.H.
Deputy Director, Public Citizen’s Health Research Group
Testimony before National Academy of Sciences’ Committee on Clinical Research Involving Children

Thank you for the opportunity to share Public Citizen’s thoughts and concerns with regard to ethical aspects of pediatric clinical trials. My comments today will address five topics: a. the pediatric exclusivity provisions and their ethical implications; b. informed consent; c. payments to participants’ parents; d. post-trial dissemination of study results; and e. the internationalization of research.

The Pediatric Exclusivity Provisions

There can be no quibbling with the intent of the pediatric exclusivity provisions: to obtain reliable safety, efficacy, pharmacokinetic and other data specific to children. Similarly, it is clear that due to these provisions there is now more pediatric testing. However, the reliance upon a market-based mechanism to secure these ends has had predictable consequences with worrisome ethical implications. 

The incentives in the Best Pharmaceuticals for Children Act of 2002 are, for many drugs, absurdly generous. According to the Tufts Center for the Study of Drug Development, a research group with funding from the pharmaceutical industry, pediatric studies cost $3.87 million per drug.[1] For many drugs, doing such studies and securing six months of additional patent protection is paid for dozens, if not hundreds, of times over. For example, based on sales in 2000, the six months of pediatric exclusivity granted for Prilosec will be worth $1.4 billion to AstraZeneca and the extension awarded to Pfizer for Lipitor will produce $1.3 billion in revenues.[2] Seniors will wind up footing most of the bill for this pharmaceutical company windfall.

As huge as this incentive can be, it still is not enough to ensure adequate testing of pediatric drugs. Market-based incentives produce market-based corporate responses. Because the adult market for most drugs dwarfs the pediatric market, the strongest predictor of pediatric testing is adult sales. Predictably, companies pursue pediatric testing for their most profitable products, not those for which the pediatric need is greatest. As documented by the Food and Drug Administration’s (FDA’s) own Report to Congress in January 2001,[3] major gaps in pediatric testing remain: generic drugs, those with insufficient sales and those that require testing in more than one pediatric age group (because the FDA typically grants the patent extension after the first age group’s studies are completed). For example, the FDA Report documents that companies had submitted study proposals for only six of the ten drugs the agency had designated as priority drugs for pediatric studies. Not coincidentally, the remaining four drugs were available generically.

Ethical principles require that either the study participants themselves or the population from which they are drawn stand some reasonable chance of deriving benefit from the research. If the primary purpose of a study, from the researcher’s (company’s) perspective is to secure added sales, particularly in the population that excludes the participant (the adult population), the risk-benefit balance that Institutional Review Boards (IRBs) must consider is perturbed in a manner arguably unfavorable to the patient. The risk-benefit equation shifts in the other direction if the drug in question is a true breakthrough drug, compared to the more-usual “me-too” drug. We think it is only reasonable that IRBs accept less risk to patients when considering studies that primarily benefit pharmaceutical companies than for those studies that directly benefit the study participants or the group from which they are drawn.

The obvious solution to this dilemma would be FDA’s Pediatric Rule, which required companies to conduct pediatric studies for certain new and already marketed drugs with “substantial” pediatric use or for which pediatric use would provide “meaningful therapeutic benefit.” However, the Pediatric Rule was successfully challenged in court[4] and is now on appeal.  Regrettably, the FDA chose not to be a party to the appeal.

Informed Consent

A partial (but not sufficient) solution to the problems above would be to use the informed consent process to fully disclose to participants or their surrogates the incentives for companies to conduct the trials. Participants or their surrogates cannot properly balance the potential risks to themselves against the possible benefits to themselves or society without fully understanding the researchers’ motivations. This is a necessary elaboration on the disclosure of funding sources to both IRBs and patients, already required by the Declaration of Helsinki[5] and the Council for International Organizations of Medical Sciences (CIOMS).[6]

Whether the children themselves or their parents are providing consent, tests of comprehension of the information provided should be required. We believe that, in large clinical trials, a pretest sample of participants or their surrogates should be surveyed to see if their understanding of the trial is sufficient to meet a reasonable standard of informed consent.  If adequate levels of knowledge about the trial cannot be demonstrated, the trial’s informed consent process should be redesigned to address the deficiencies identified in the survey. Once the study is underway, each participant or their surrogate should be required to demonstrate a reasonable level of understanding of the trial, its risks and potential benefits.  Instruments to assess participant comprehension of informed consent already exist. In the absence of real measurements of the outcomes of the informed consent process, rather than mere documentation that the process has taken place, the claim that informed consent was given will be an empty one.

Payments to Participants’ Parents

Whatever the benefits of research, facilitating one’s child’s participation in research has undeniable inconveniences. Parents are entitled to compensation for their travel, board, lodging and time. However, because they are not directly participating in the research, they should not be compensated beyond this, lest that cloud their judgment as to whether their child should participate in the study. A parallel, uncomfortable though it may be, can be drawn between any additional compensation and the use of “finder’s fees” conferred upon physicians for referring their patients to clinical studies. This practice has been declared unethical by the American Medical Association.[7]

Post-trial Dissemination of Study Results

The Declaration of Helsinki insists that “Negative as well as positive results should be published or otherwise publicly available.”[5] While some disclosure, in the form of labeling changes after the pediatric studies were completed, has taken place, there is ample documentation of physicians’ failure to heed labeling recommendations.[8],[9],[10] At a minimum, the FDA should require the posting of study summaries on its website and track whether studies are being published in the peer-reviewed literature.

Internationalization of Research

There is a recent trend for pharmaceutical companies to conduct abroad studies that could reasonably be done in the United States. The number of new foreign investigators in the FDA=s database grew from 988 in the 1990-1992 period to 5,380 in the 1996-1998 period.[11] Some of these studies have been marked by severe abuses.  The Washington Post has reported that the apparent local IRB approval of a Pfizer-sponsored pediatric meningitis study in Kano, Nigeriawas based on an IRB document back-dated by one year.[12]  In addition, Public Citizen exposed a study of Discovery Laboratories’ new surfactant in the treatment of neonatal respiratory distress syndrome that was to have been conducted in several Latin American countries.[13] Some patients would have been randomized to placebo, even though the FDA had already approved four surfactants, which have been proved to reduce neonatal mortality by 34%. The ethics of the proposed trial were discussed at an internal FDA Scientific Rounds with the extraordinarily inappropriate, but revealing, title “Use of placebo-controls in life threatening diseases: is the developing world the answer?” A strong statement by the Committee condemning the export of pediatric studies for the purposes of exploiting the lack of ethical oversight or the poverty of pediatric patients in developing countries would be most helpful.

[1] Milne P-F. The pediatric studies incentive: equal medicines for all. Tufts Center for the Study of Drug Development, April 2001.

[2] Public Citizen’s Congress Watch. Patently offensive: congress set to extend monopoly patents for Cipro and other drugs.  November 2001. 

[3] Food and Drug Administration. The pediatric exclusivity provision: Status Report to Congress. Department of Health and Human Services, January 2001.

[4] Association of American Physicians and Surgeons, Inc., et al. v. United States Food and Drug Administration, et al. 226 F.Supp.2d 204, October 17, 2002.

[5]World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, 1964 and revised by the 29th World Medical Assembly, Tokyo, 1975, the 35th World Medical Assembly, Venice, 1983, the 41st World Medical Assembly, Hong Kong, 1989, the 48th World Medical Assembly, Somerset West, 1996 and the 52nd World Medical Assembly, Edinburgh, 2000.   Note of Clarification on Paragraph 29 added by the World Medical Assembly, Washington 2002.

[6] Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Geneva, 2002.

[7] Council on Ethical and Judicial Affairs, American Medical Association. E-6.03 Fee splitting: referrals to health care facilities. Available at: http://www.ama-assn.org/apps/pf_online/pf_online.

[8] Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride. Journal of the American Medical Association 2000;284:3036-9.

[9] Graham DJ, Drinkard CR, Shatin D, Tsong Y, Burgess MJ. Liver enzyme monitoring in patients treated with troglitazone. Journal of the American Medical Association 2001;286:831-3.

[10] Willy ME, Manda B, Shatin D, Drinkard CR, Graham DJ. A study of compliance with FDA recommendations for pemoline (Cylert). Journal of the American Academy of Child and Adolescent Psychiatry 2002;41:785-90.

[11] Office of the Inspector General. Recruiting human subjects: pressures in industry-sponsored clinical research (OEI-01-97-00195). Department of Health and Human Services, June 2000.

[12] Stephens J. Doctors say drug trial’s approval was backdated. Washington Post, January 16, 2001, pp. A1, A17.

[13] Lurie P, Wolfe SM, Klaus M. Letter to Tommy Thompson, Secretary of Health and Human Services regarding unethical surfactant trial in Latin America. Public Citizen’s Health Research Group, February 22, 2001. Available at: https://www.citizen.org/hrg1558