American Journal of Law & Medicine

The globalization of health law: the case of permissibility of placebo-based research.

If any trend can be confidently predicted for the next millennium (or, more modestly, for our lifetimes) it is the globalization of health law. We live in an age of global markets and global communications. While care of the individual patient has remained largely local, national borders are quite porous to health care professionals. The cross-border flow of patients is a significant factor in some regions, and the development of telemedicine and interact pharmacies is radically expanding the possibility of cross-border medical practice.

The most important effect of globalization on health care, however, is probably found in the international market for drags and medical technology. Large pharmaceutical firms and medical technology companies have long operated at the global level. Increasingly, moreover, they conduct research on an international basis for producing new drugs and products. Though individual nations have a legitimate interest in protecting their own populations from defective drugs and devices, it is also essential that nations cooperate to assure that new drugs and devices can be made available to patients promptly once they are established to be safe and effective.

The research that grounds the development of necessary drugs and devices requires the use of human subjects.(1) Thus, this research raises important ethical issues, indeed human rights issues. Research is increasingly taking place on an international basis as large, multi-center, trials become more common.(2) Though there are international expressions of principle that address these issues, most notably the Revised Declaration of Helsinki on Research Involving Human Subjects (or "the Revised Declaration").(3) research, including international research, is also addressed by substantive regulations governing at the national level.(4) These regulatory instruments reflect different approaches to the ethical issues grounding human subjects research.

If international research projects are to be effectively overseen, it is important that international protections be afforded. For this to happen, however, it may be necessary for national principles to be harmonized. This, in turn, requires an understanding of cross-national similarities and differences. Globalization thus requires the application of both international and comparative law.

An ideal case study for understanding the globalization of health law is the regulation of placebo-controlled human subjects research. The word placebo comes from the ecclesiastical Latin, meaning "I shall please."(5) It came to be used in medical practice as a term describing "all medicine prescribed more to please the patient than for its therapeutic effectiveness."(6) In modern clinical research, placebos are inert substances, prepared so as to appear identical to the active substances being tested. They are provided to a control group in a randomized trial to give the control group an experience as similar as possible to that of the investigational group, except for the presence of the active ingredients being tested.(7) In theory, any differences in response between the placebo control and investigational group (if the members of the two groups are assigned randomly and their identity is blinded both to the researchers and to the participants) are due to the active ingredients tested and not to a placebo effect or to chance.(8)

Placebo-controlled studies are often championed by drug or medical device companies, who are often more interested in demonstrating that their product works than in comparing its effectiveness with that of existing drugs or devices. The studies are, however, also often demanded by regulatory agencies, who believe that placebo-controlled studies offer the most unassailable evidence of the effectiveness of a product.(9)

Those who oppose the use of placebos in clinical trials argue that the use of placebos violates all four of the principles generally thought to underlie bioethics--beneficence, nonmaleficence, respect for personal autonomy and justice.(10) First, controlled trials in which placebos are administered to a control group deny potentially beneficial treatment to that group.(11) This argument flows most directly from the Revised Declaration. It is ethically permissible to test a new drug or procedure on humans only if there is some reason to believe that it is efficacious.(12) If this is true, intentionally denying a possibly beneficial treatment to one arm of the research study is at least potentially problematic.(13) Moreover, even when persons who receive the placebo experience an improvement in health from the placebo effect (as often occurs), they may experience confusion and embarrassment when they later learn that they received a placebo rather than active treatment.(14)

If the control group is not only administered a placebo, but is also first deprived of standard treatment--i.e. subjected to a wash-out period--the research might violate not only the principle of beneficence, but also the nonmaleficence, or "do no harm" principle.(15) This may also be true if a clinical trial is permitted to continue beyond the point where it becomes clear that the proposed treatment is in fact efficacious, or if participants in the trial are not "rescued" if their health deteriorates dramatically while under placebo treatment.(16) Administering potentially effective treatment to one group, while intentionally denying it to another, also raises justice issues.

The final cluster of arguments against the use of placebos in controlled trials is based on the principle of autonomy. A general argument against placebos in treatment is that their use is deceptive.(17) It is commonly argued that this is not true when the placebo is used for research, because participants in placebo-controlled clinical trials are informed at the outset that they may be receiving a placebo.(18) Though the research subjects are deceived, they are partners in the deception.(19) Nonetheless, there is often a question as to whether participants in clinical trials who receive placebos fully understand and accept the possibility that this will be the case.(20) One study found that over forty percent of subjects in psychopharmacologic trials failed to recognize that some patients who wanted treatment would not receive it, and nearly seventy percent had little or no concept of what was meant by random assignment.(21) There is also an element of duress that makes consent questionable in situations where participating in a placebo-controlled trial is the only chance a subject has to obtain potentially helpful treatment.(22) The validity of consent is particularly problematic when vulnerable subjects, such as psychiatric patients, children, or persons in developing countries, are the subjects of placebo-controlled research.(23) Some of the worst abuses of placebo-controlled research have occurred in the context of research involving psychiatric conditions. …

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