The ASGT and Ethical Codes for Clinical Research
Authors: Theodore Friedmann
Journal: Molecular Therapy (2008)

Professional organizations such as the American Society of Gene Therapy (ASGT) have the responsibility of defining the standards of scientific and, to a lesser extent, personal conduct expected of its members. On rare occasions, additional position statements must be developed in response to new challenges and issues, as exemplified by the strong and influential ASGT position statement (April 2000) on principles of financial conflict of interest in clinical research (http://www.asgt.org/position_statements/conflict_of_interest.php). Because the methods and codes that define scientifically and ethically acceptable approaches to clinical human research are a cornerstone of the ASGT's activities, it is vital for the Society to respond to events and issues that may pose important new challenges to those tenets. One such issue has arisen via the recent announcement from the US Food and Drug Administration (FDA) of a final regulatory action1U.S. Food and Drug Administration Human subject protection; foreign clinical studies not conducted under an investigational New Drug Application.Federal Register. 2008; 21 (CFR 312, 28 April)Google Scholar that will implement its plan announced in 2004 to abandon the Declaration of Helsinki, the official human research ethical policy of the World Medical Association and arguably the most important international ethical code of conduct for human clinical research. This final action pertains to the evaluation of data submitted to the FDA by foreign sponsors in support of Biological License Applications. In place of the declaration, the FDA will rely on the standards and guidelines set forth in the Good Clinical Practice (GCP) document of the International Conference on Harmonisation (ICH), which is more a regulatory than an ethical code, drafted by an international but limited group of regulatory agencies (United States, Japanese, and European) and pharmaceutical companies. One of the principal and most problematic tenets of the most recent (2000) version of the Helsinki Declaration seems to have catalyzed this FDA policy change: the requirement that subjects in clinical experimental research studies not be deprived of existing standard-of-care treatments in favor of simple placebo controls, as occurred during the use of placebo-only controls in studies of maternal–infant transmission of HIV in Asia and Africa. Admittedly, the Declaration of Helsinki acknowledged the possibility of ethically justifiable placebo-only controls under “compelling and scientifically sound” reasons. Another area of concern seemed to be the provision that patients entered into studies should be assured of access to “the best proven prophylactic, diagnostic and therapeutic methods identified by the study.” To be sure, the final policy announced by the FDA is complex and driven by many legitimate and evolving needs of the international scientific and commercial communities with respect to human clinical research and drug development. However, the scientific, commercial, and ethical standards for clinical research and the standards for rapid and efficient drug development must not function in conflict with each other; instead, they must work in harmony and aim for the same goals: humane and efficient methods for fostering health, developing new drugs and biologicals, and saving lives—worldwide. Of course, the goals of the ICH to harmonize technical guidelines and minimize unnecessary delay in the global development and availability of new medicines while maintaining safeguards of quality, safety, and efficacy are laudable and must be incorporated into any set of principles for the science, medicine, and public policy of drug development. But without a firm footing in the ethical principles of the Declaration of Helsinki or a similar ethical code, the commercial and regulatory aspects of medicine, drug development, and clinical research are severely weakened and, even worse, potentially given opportunities for serious missteps. Because of the complexities of the issues and the particularly strong impact of mixed ethical, scientific, and policy and regulatory standards of the conduct of clinical research studies in gene therapy trials, the ASGT should take immediate steps to examine the implications of this FDA action for the design and implementation of gene therapy clinical trials and provide explicit ethical guidance to its members on sound scientific and ethical principles in conducting and shaping experimental clinical studies. This task has already been taken up preliminarily by the ASGT Ethics Committee, and that effort should be pursued vigorously by the ASGT to produce a more detailed understanding of the complex issues and to make clear recommendations to ASGT members on how clinical studies can be made consistent with accepted ethical codes of conduct for clinical research studies. I recommend that such action at the ASGT should align the Society solidly with the spirit of the Declaration of Helsinki and require clear and rigorous standards for the probably rare “compelling and scientifically sound exceptions” that might justify placebo controls in place of standard of care. Similar efforts should be undertaken by sister organizations such as the European Society of Gene and Cellular Therapy. We realize that some of those standards will and must evolve, but what must not evolve is the commitment of the ASGT and similar societies to the primacy of the central underlying principles (but not necessarily all the details) of ethical codes such as the Declaration of Helsinki: protection of the health, welfare, autonomy, and dignity of research subjects. Such an ethical position should, of course, be as consistent as possible with the valuable and important regulatory and commercial tenets laid out in the GCP guidelines of the ICH. Perhaps the most pressing current question is whether and under what conditions subjects in clinical research might be asked to forgo established therapies in favor of pure placebo controls. Of course, any policy that is not aligned first and foremost with an underlying ethical code will be deeply flawed and represent a terrible ethical step backward.