Placebo controlled clinical trials are as ethical as active controlled trials even if effective therapies exist

Placebo controlled clinical trials are as ethical as active controlled trials even if effective therapies exist

Lin, Yeong-Liang

In recent years, placebo controlled clinical trials have often been considered unethical if effective therapies are available when the trials are conducted. This concept was strengthened by the 2000 revision of the Declaration of Helsinki. This article discusses why placebo controlled clinical trials can be considered as ethical as active controlled trials, even if effective therapies are available for the medical conditions concerned.

Key Words: Placebo controlled trials; Ethical; Subjects; Declaration of Helsinki

IN RECENT YEARS, ethics committees and investigators have often begun to consider placebo controlled clinical trials to be unethical if effective therapies are available when the trials are conducted. This concept was further strengthened by the 2000 revision of the Declaration of Helsinki (1), which states that: “The benefits, risks and burdens of a new method should be tested against those of the best current therapeutic methods.” However, because of substantive debate regarding the controversial additions to the revised Declaration of Helsinki (2,3), the World Medical Association subsequently clarified its position on the use of placebo controlled trials. This article further discusses why placebo controlled clinical trials can be considered as ethical as active controlled trials, even if effective therapies are available for the medical conditions concerned.

In determining whether it is ethical or unethical to conduct placebo controlled trials under such circumstances, it is worth scrutinizing the process of clinical trials. Before the subjects are enrolled, informed consent must be obtained. In this process, the possible randomization of some subjects to placebo arms and the potential risks due to the lack of active treatments during the trial period are explained both verbally and in written forms. The informed consent process is the same regardless of whether the trial is placebo controlled or active controlled. Although there are known limitations of our consent forms, as long as they are completed according to the ethical principles described in the Declaration of Helsinki and the International Conference on Harmonisation E6 Good Clinical Practice (4), the consent forms may in themselves constitute an ethical cover. Thus, placebo controlled trials may be ethically conducted provided that subjects are fully informed about the risks of entering clinical trials and the consequences due to the lack of active treatment during the trial period.

Second, when we assess whether the conduct of clinical trials is ethical, subjects’ safety should be the most important consideration. Active controlled clinical trials are more commonly considered ethical because subjects receive at least some active treatment during the trial. However, the toxicities of active comparators are seldom considered. All drugs are toxic; the issue is whether their toxicities are acceptable or not. While ethics committees prefer active controlled trials, the toxicities that the subjects may potentially suffer should never be forgotten.

As we know, in clinical trials, most subjects are recruited by physicians who have special groups of patients or by referral from primary care physicians; some may be recruited through advertising. Common grounds on which physicians decide to recruit certain patients rather than others include inadequate treatment response under present therapies, intolerable side effects, or poor quality of life due to too many drugs used together to achieve the desired efficacy or too frequent dosing. Under the pressure of recruiting adequate subjects to clinical trials in limited periods of time, recruitment of subjects will not be limited to newly diagnosed patients.

In addition, active controls are usually drugs considered standard therapeutic agents for the medical conditions concerned. Under such circumstances, subjects assigned into the active comparator arms in the active controlled trials may receive the active controls that they have taken before, or active controls in a similar class to drugs they have taken. This can be demonstrated by the lack of excluding patients who have been exposed to certain drugs as one of the exclusion criteria, although patients with hypersensitivity to drugs used as the active controls are excluded from most clinical trials. However, placebo controlled clinical trials will not have such issues.

Therefore, while the debate is focused on whether effective therapies are available for trial subjects, the major determinant should be the severity of the medical conditions and whether the transient lack of an active treatment can lead to serious or irreversible damage. If the consequences are the permanent disability or mortality of trial subjects, such as would occur in clinical trials investigating the prevention of fetal transmission of the human immunodeficiency virus in pregnant women (5) or respiratory distress syndrome in premature babies (6), no placebo arms should be used, even though there are no effective therapies at the time of the clinical trials. Under these circumstances, alternative approaches such as an add-on trial may be considered (7,8).

If many effective therapies are available at the time the clinical trials are conducted, placebo can be used in major studies, provided that trial subjects will not suffer irreversible changes during the duration of the trial. Knowledge of the diseases’ courses and data regarding the differences in the clinical outcomes with or without treatment can be used to make this judement (9).

Furthermore, the motives of subjects to enter clinical trials and expose themselves to the potential risks of inadequate efficacy and intolerable toxicity should be considered. Although some subjects do so because this is the only way for them to have access to these innovative therapies, others enter the trials simply because they hope to make some contributions to the understanding of the illnesses they suffer. As investigators, we have to respect this spirit and make the best use of subjects’ sacrifices.

Many authors have explained why placebo controlled trials have more scientific merit than active controlled trials, such as the assay sensitivity problems in active controlled equivalence trials and the lower incentive to minimize errors in active controlled equivalence trials because the intent of these trials is to demonstrate lack of difference (7,10,11). If we fail to conduct clinical trials in such a way that data generated from these trials bring about the best interpretation in terms of the efficacy and safety of investigational drugs, we fail the spirits of our patients. Therefore, placebo controlled trials are not necessarily more unethical than active controlled trials.

In conclusion, placebo controlled trials are not necessarily worse than active controlled trials, ethically. Due to the complex and controversial nature of this ethical topic, no definite conclusion or clear recommendation is made to safely label placebo controlled clinical trials as “ethical.” It is thought that, provided the subjects are not harmed irreversibly by entering the clinical trials, the conduct of placebo controlled trials may be ethical even though effective therapies exist.

Acknowledgment-We thank Dr. Shaw Chen for his help and advice.

REFERENCES

1. World Medical Association. The Declaration of Helsinki. (www.wma.net).

2. Vastag B. Helsinki discord? A controversial declaration. JAMA. 2000;284:2983-2985.

3. Brennan T. Proposed revisions to the Declaration of Helsinki-will they weaken the ethical principles

underlying human research? N Eng J Med. 1999; 341:527-530.

4. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Good Clinical Practice (E6). Geneva, Switzerland; International Conference on Harmonisation: 1996.

5. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Eng J Med. 1997;337:853-856.

6. McCarthy M. US company’s plan for trial in Latin America draws fire. Lancet. 2001;357:691.

7. Temple R, Ellenberg S. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments. Ann Intern Med. 2000,133:455-463.

8. Ellenberg S, Temple R. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments. Ann Intern Med. 2000;133:464-470.

9. Levine RJ. The use of placebos in randomized clinical trials. IRB. 1985;7:1-4.

10. Pledger G, Hall DB. Active control equivalence studies: do they address the efficacy issue? In: Peace KE, ed. Statistical Issues in Drug Research and Development. New York: Marcel Dekker; 1990:226– 238.

11. Fleming TR. Evaluation of active control trials in AIDS. J Acquired Immune Defic Syndr. 1990;3 (Suppl 2):S82-87.

YEONG-LIANG LIN, MD, HERNG-DER CHERN, MD, AND MONG-LING CHU, MD

Reviewers, The Center for Drug Evaluation, Taipei, Taiwan

Reprint address: Yeong-Liang Lin, MD, 1F, No 15-1, Sec 1, Hangjou S Road, Taipei, Taiwan 100 (e-mail: yllin@cde.org.tw).

Copyright Drug Information Association Oct-Dec 2002

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