Few practicing physicians, clinical investigators, or bioethicists would argue with the statement that the publication of an article by Beecher in 1966 fundamentally altered the opinion of most that “unethical clinical research” activity was limited to those countries and societies with “deranged political systems.”1 In this landmark article, Beecher described several studies conducted in the U.S. that would not satisfy any objective standard of ethical research, including the intentional inoculation of institutionalized, mentally disabled children with the hepatitis virus; the administration of “live cancer cells” to human volunteers not told of the origin of this material; and the “transplantation” of melanoma cells from a patient to her mother (who subsequently died of metastatic melanoma). Quite appropriately, the Beecher study is, and should remain, a centerpiece of formal clinical research training programs for all individuals participating in research involving human subjects.
A recently published article in the same journal may someday find itself discussed alongside the seminal effort by Beecher as one of the critically significant documents that awakened the international research community to the potential for the exploitation of citizens in the developing world who are being “asked to participate” in clinical trials.2 This profoundly disturbing piece, written by Drs. Nundy and Gulhati, both of whom are Indian physicians, describes clearly how women and men in India are, in the words of Kant, being used as a means (sometimes solely for the financial benefit of others), rather then being treated as an ends themselves.
Descriptions of the lack of ethical oversight for clinical trials (e.g., investigators do not seek nor do they provide any information regarding conflicts of interest), sponsor indifference to the welfare of individual study participants (e.g., the absence of statements that patients responding to an experimental agent will be permitted to continue treatment when the formal study is completed), and potentially inappropriate direct inducements to encourage entry into the study of those living in abject poverty (e.g., paying workers more money per month to participate in a study than they would earn at work, or by providing medication that is worth more than their annual salary) provide a powerful reminder that we must remain vigilant and stand united against the behavior of those clinicians who do not appear to understand that the term “human subject” refers to all human beings, regardless of race, gender, culture, religion, financial status, or country of birth or current residence.
Unfortunately, although the situation detailed by Nundy and Gulhati is most disturbing, of equally serious concern is the fact that economic and other forces in the “developed” world may be unintentionally providing powerful incentives for sponsors to consider conducting trials in the manner described in their article.2 As the costs associated with conducting clinical trials in North America and Western Europe rapidly escalate, perceived onerous regulatory requirements (e.g., “complex” Institutional Review Board [IRB] and the Health Insurance Portability and Accountability Act of 1996 [HIPPA] rules) proliferate, and the number of sponsors competing for limited patient populations increases, some in the corporate arena who mistakenly believe their ultimate audience is their stockholders and the financial markets rather than society may the tempted to ignore or “bend the rules” regarding the fundamental principles of the conduct of ethical clinical research.
Although these concerns are not unique to the field of oncology, the dramatic expansion in the availability of molecular targets and novel experimental antineoplastic agents involving multiple biotechnical and pharmaceutical companies, with the realistic potential for individual drugs to generate hundreds of millions of dollars in sales, provides adequate justification to sound a note of caution regarding the potential for unethical conduct in clinical cancer trials in countries currently lacking a strong human subjects regulatory infrastructure.
What can individuals and groups in the “developed” world, who are concerned about this complex situation, do to strongly encourage the conduct of ethical clinical trials in the “developing” world (Table 1)? However, before addressing this question, it is critical to acknowledge the relevant distinction between the sincere desire of individuals to insure that all people, regardless of their personal circumstances, are treated with respect with regard to their participation in clinical trials, versus a conscious (or unconscious) attempt by one group to assume, in a paternalistic manner, that they must protect those unable to help themselves.
|1. Investigators participating in multinational studies should demand written assurances that informed consent procedures similar to those used in the “developed” world will be employed in the “ developing” world. If such assurances are not provided, investigators in the “developed” world should not participate in the trials.|
|2. When reviewing their institution's participation in a trial also being conducted in the “developing” world, individual Institutional Review Boards should demand assurances that the informed consent procedures in those countries acknowledge the “rights” of all potential study participants. If such assurances are not provided, the Institutional Review Board should refuse to grant permission for the study to be conducted in their own location.|
|3. Regulatory requirements for drug approval in the “developed” world should attempt to avoid inadvertently encouraging less-than-ethical trial conduct in the “developing” world by mandating unrealistic (and perhaps unnecessary) study endpoints.|
|4. During the drug registration/licensing process, pharmaceutical regulatory agencies in the “developed” world should refuse to review any clinical data from research sites that fail to provide clear and convincing documentation that mandatory safeguards for the protection of the rights of all human subjects participating in the trial were routinely and vigorously employed.|
First, all clinical investigators who are asked to participate in multinational trials that include patients in the developing world should demand assurances from the study sponsor that these subjects will be provided a degree of protection that is similar, if not quite identical, to that given to patients in developed world countries (e.g., North America, Western Europe). If sponsors are unable, or unwilling, to guarantee that they will respect the rights of all human subjects, clinical researchers should simply, but firmly and without equivocation, decline to participate in these trials. Furthermore, these investigators should not hesitate to inform colleagues of their concerns, because a unified strategy among the national and international cancer research community may lead to important changes in the plans for the conduct of the study.
Second, IRBs in the U.S. and corresponding ethical review boards in other countries that are asked to review studies in which such multinational involvement is contemplated should formally inquire regarding the rights of patients being entered in all geographic locations. If clear and convincing written documentation of mandatory human subject protection is not provided by the sponsor, the IRB should refuse to permit the study to be conducted at their local site. Such action should send a strong signal to the sponsoring organization regarding its fundamental obligation to insure the protection of all human research subjects, regardless of their place of residence or socioeconomic status.
Third, although it is recognized that the pharmaceutical regulatory organizations in the developed world (e.g., the U.S. Food and Drug Administration) do not have as their primary mission the assurance of the ethical conduct of clinical trials in the developing world, such bodies should do everything in their power to determine that their regulatory approval processes do not inadvertently encourage otherwise highly ethical sponsors to pursue activities that, in their own countries, would be condemned. For example, if survival is the endpoint required for drug registration, the mandated statistical plan hopefully will not require such large patient numbers that the only realistic way for a company to complete a trial in a reasonably timely and cost-effective manner would be for the study to include “subjects” in a locale and under conditions in which there is less concern for the “niceties” of the informed consent process.
Finally, under no circumstances should a study ever be permitted to satisfy regulatory requirements for licensing approval in the “developed” world if there is reliable evidence that any of the human subjects entered into that trial were not treated with adequate safeguards, or that ethically mandated informed consent procedures designed to respect the autonomy and dignity of all people were not employed.