the ethics of clinical trials of ineffective therapy

The Ethics of Clinical Trials of Ineffective TherapyAuthor(s): Jannes H. MulderSource: IRB: Ethics and Human Research, Vol. 3, No. 5 (May, 1981), pp. 9-11Published by: The Hastings CenterStable URL: http://www.jstor.org/stable/3564140 .

Accessed: 14/06/2014 04:06

Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp

.JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact [email protected].

.

The Hastings Center is collaborating with JSTOR to digitize, preserve and extend access to IRB: Ethics andHuman Research.

http://www.jstor.org

This content downloaded from 193.105.154.120 on Sat, 14 Jun 2014 04:06:11 AMAll use subject to JSTOR Terms and Conditions

http://www.jstor.org/action/showPublisher?publisherCode=hastings

http://www.jstor.org/stable/3564140?origin=JSTOR-pdf

http://www.jstor.org/page/info/about/policies/terms.jsp


May 1981

Among Pattullo's reasons that our institutional assurances should not be as general as OPRR wishes, I find one most compelling. Although the new DHHS regulations are generally supe- rior to the old ones, some old flaws re- main and some new ones have been introduced. Consider, for example, Sec- tion 46.117c:

An IRB may waive the requirement for ... a signed consent form ... if it finds ... that the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of con- fidentiality. Each subject will be asked whether the subject wants documentation ... and the subject's wishes will govern....

Stipulating that the signed form must be the only record linking the subject and the research presents a problem; the existence of records that constitute a threat to a person's privacy does not justify the imposition of a requirement to create yet another. Moreover, while I do not wish to be sar- castic, how else does one discuss a requirement to ask a subject: "Do you wish to create a threat to your privacy? Do you wish to provide me with de- fense against any future allegation on your part that I wronged you or harmed you?"3

In my view, enforcement of such de- fective regulations will be more detri- mental to the IRB's credibility than the establishment of double standards. Prudence dictates that IRBs reserve the authority to develop rational institu-

tional guidelines that IRB members can defend in their institutions and communities and that they impose in- defensible rules only when explicitly required to do so by law.

Robert J. Levine

REFERENCES 'I am not persuaded that intelligent prior re-

view according to reasonable guidelines necessarily restrains academic freedom. Thus, while Yale's and Harvard's state- ments of assurance may be identical, our institutional policies are more likely to differ.

2This point is elaborated in Levine, R.J.: The impact of institutional review boards on clinical research. Perspectives in Biology and Medicine. 23:S98-S114, 1980.

3Space limitations constrain me to present only one example. A more comprehensive ac- count will appear in a book to be published later this year: Levine, R.J.: Ethics and Regu- lation of Clinical Research. Urban and Sch- warzenberg, Baltimore, 1981.

? ETTERS

The Ethics of Clinical Trials of Ineffective Therapy

To the Editor: Under the pressure of public opinion, the Dutch parliament in September 1979 decided to allocate funds for an investigation into the efficacy of the so-called Moerman antitumor therapy. In essence, Dr. Moer- man's diet therapy is a nontoxic metabolic therapy. In contrast to Dr. Moerman and his supporters who claim a tumor-growth-retarding effect of this nutritional program, the medical profession is convinced of the inef- ficacy of the treatment and conse- quently calls it quackery. Convincing animal data for an antitumor effect are lacking and the results of a retro- spective analysis of "successfully" treated patients were inconclusive.

As a medical oncologist, I was in- vited to participate in a protocol writ- ing committee. This committee was a mixed one as the study had to be acceptable to both sides, i.e., "Moerman physicians" and the official medical profession. I suggested in the committee that we do a Phase II study: patients eligible for the Moerman therapy should be those with advanced measurable tumor disease of any type no longer suitable for hormonal or chemotherapy. As you may anticipate, these selection criteria were hardly acceptable to the Moerman physicians,

as metabolic therapy will never have a fair chance of being effective in exten- sively treated end-stage patients. At this point, comparison with immunotherapy (BCG, Corynebacterium parvum and levamisole) was made. If immunotherapy has any effect, it will be in the early stages of the disease or in residual tumor disease but not in the advanced stages.

The protocol committee decided therefore to broaden the patient en- trance criteria; so the study will now also include a second group of patients: those with early or advanced but always measurable disease and who have not been previously exten- sively treated with radiotherapy, hormonal or chemotherapy. Newly diag- nosed stage I carcinoma patients are, for example, eligible for this study. The first point on which I would like your opinion is whether surgeons, ra- diotherapists, and medical oncologists should join in a study in which curable patients are treated with a possi- bly ineffective regimen.

Institutional review boards have ex- tensively discussed the point of in- cluding curable patients in an irra- tional study. Many of my colleagues are generally reluctant to give support to the study of this form. In my opinion there are six conditions to be ful- filled (and they are all specified in the protocol) before I can participate in this nonrandomized trial:

1. A patient is recruited for this study by his own Moerman physician;

2. Each eligible patient will be informed about the study by his Moerman physician as well as by myself;

3. I am allowed to explain the pros and cons of the nontoxic metabolic therapy as well as of the conventional surgery/radiotherapy/ medical treatment

4. All patients must give written consent;

5. My professional role in the study must be limited to regular tumor volume measurements during the study period, which will have a duration of three months;

6. The patient may at any time re- quest conventional therapy.

My own position is that the protection of a free choice of therapy should receive a higher priority than our obli- gation to cure patients, even if someone with a curable malignant disease chooses quackery. Much will depend on the way the informed consent proce- dure is carried out.

The second point I would like to raise is that, for many of my colleagues, the scientific merits of the proposed study are doubtful. Animal data and case studies have not been promising and, notwithstanding these facts, the study will be carried out on 30 end-stage pa-

9



MD _

10

tients and 30 effectively treatable or curable patients. My second question therefore is: should we ignore these scientific facts and simply start the study because the public at large asked for it?

A commentary on the scientific and ethical aspects of our study proposal would be very welcome. Your experi- ence with the laetrile lobby and the medical response to it may be of great help to us here in The Netherlands, although I realize that laetrile medica- tion is not altogether comparable with diet therapy.

Jannes H. Mulder, M.D. Rotterdamsch Radio-Therapeutisch Institute Rotterdam

Dale H. Cowan, M.D., J.D., replies: The questions asked by Dr. Mulder are, as he correctly notes, similar to those raised in the United States with respect to the use of laetrile in cancer patients. To respond to these questions, it is necessary first to consider the medical and ethical issues involved in designing a clinical trial of antineoplastic therapy and in selecting subjects for a proposed trial. Second, it is necessary to consider the nature and scope of autonomous decision making on the part of both patient and physician. Finally, it is necessary to balance conflicting principles to achieve a result that conforms with prevailing societal practices and with existing legal requirements. It is recognized that a response based on Ameri- can medical practices, ethical perspectives, and legal considerations may lead to conclusions at variance with the traditions and practices of other countries.

The ethical conduct of clinical trials requires, as a necessary condition, good research design.' Good research design of a clinical trial ordinarily means that the results of animal studies or prior clinical studies provide some scientific rationale for the proposed trial. In addition it requires a sound statistical basis for the trial. In short, good research design requires that any proposed clinical trial be sci- entifically sound and capable of yield- ing generalizable data; a study lacking these characteristics is inherently unethical. Whether the facts supporting the efficacy of the Moerman antitumor therapy provide a sufficient basis to justify testing it in a clinical trial is one of the issues raised by Dr. Mulder. Dr. Mulder indicates the data are not sci- entifically sound. If this be so, clinical trials of the Moerman therapy lack the necessary condition of good research design and are unethical.

If, notwithstanding the lack of data substantiating the scientific basis of the Moerman therapy, there are reported clinical experiences alleging its efficacy, there may be a basis to pro- ceed with some type of clinical trial to assess it. This.is the apparent rationale for the current testing of laetrile in the United States. Extensive analyses of laboratory and clinical data failed to provide any evidence supporting the claims of proponents of laetrile of its effectiveness in treating cancer.2 None- theless, the National Cancer Institute, responding to considerable social and political pressures, has begun clinical testing of laetrile at four medical cen- ters.

A major issue affecting such testing is the selection of subjects to receive a therapy having no generally recognized efficacy. Ordinarily, new anti- cancer drugs are tested initially in patients in whom all conventional therapy has failed. Such patients are admittedly least likely to exhibit an ob- jective response to the new drug. How- ever, it is generally accepted that it is unethical to withhold from patients treatment of established benefit and to substitute treatment having unknown or no known benefit. Thus, the clinical testing of laetrile is being done only in patients who no longer respond to conventional therapy. This approach conforms with the ethical principle of nonmaleficence and the corresponding duty to avoid inflicting harm. It pro- vides an arguably acceptable resolu- tion of the conflict that exists between the individual's autonomy in decision making and society's duty and interest in promoting the general welfare of the community.

The basis for testing the Moerman therapy in patients no longer responsive to conventional therapy appears similar to that for testing laetrile. It

LETTERS TO IIRB

We welcome letters from our readers and we publish as many as space permits. In general, shorter communica- tions have a better chance of being published. We reserve the right to edit or abridge letters as necessary.

The Editors

may therefore be justifiable in this class of patients. It is not justifiable, however, in patients whose diseases are treatable by conventional therapy. Here, the standards of practice that de- rive from the principles of beneficence and nonmaleficence require that only treatment known to be useful be ad- ministered. Even in an investigational setting it is unethical to compare therapy generally recognized by experts as effective for an intended use with therapy not so recognized absent substan- tial support in the scientific literature for predicting efficacy of the untested therapy. The use of adjuvant chemotherapy and of immunotherapy is based on sound scientific theory and experimental observations in animal tumor models and in humans. These justify their evaluation in clinical trials. I infer from Dr. Mulder's report that no such basis underlies the use or testing of the Moerman therapy. For this reason, there is no ethical or medical justification to expose treatable patients to this therapy.

An additional factor affecting the ethical propriety of the trial described by Dr. Mulder is the fact that the trial is intended to be nonrandomized. A nonrandomized trial cannot be ex- pected to answer the question being asked here. Selection of subjects by other than a chance mechanism will in- troduce variables rendering analysis and interpretation of the data virtually impossible. An adequate and scientif- ically acceptable assessment of the Moerman therapy can only be achieved where there is a control population with similar characteristics that is ran- domly allocated to an alternative "treatment" arm consisting of support- ive therapy, placebo, or no treatment. For the reasons cited, this is only per- missible in patients no longer responsive to conventional therapy. With rare exceptions, participation of any group of patients in a nonrandomized trial is wholly unjustified and unethical since nothing can be learned from it.

It may be argued that it is pre- sumptuous for physicians to dictate to patients what treatments they may or may not have. It is an accepted ethical principle that a competent person has a right to exercise autonomy over his person. Judge (later Justice) Cardozo wrote: "Every human being of adult years and sound mind has a right to de- termine what shall be done with his own body."3

To the extent that a free will and a will subject to moral law are one and the same,4 autonomy is making one's choices in accord with moral principles that are both one's own and universal.



May 1981

Moral principles are derived and pre- sumably attain their legitimacy from shared experiences and tacitly accepted social agreements in particular cultural settings. Inherent in the principle of autonomy, therefore, is the no- tion that there are limitations to autonomous decision making that arise from one's participation in a social order and one's acceptance of the protection and authority provided by society.

The principle of autonomy is at the core of the concept of freedom of choice embodied in the evolving right of privacy. The U.S. Supreme Court found a constitutional right of privacy in decisions deemed by it to be fundamental.5 Recognizing the direction implied by the Supreme Court in its opinion in Rutherford v. United States,6 the 10th Circuit Court of Appeals rejected ex- tending the right of privacy to include an asserted right to choose a particular treatment.' The treatment in question in Rutherford was laetrile. The Califor- nia Supreme Court in People v. Priv- itera8 similarly refused to extend the right of privacy to include a physician's right to prescribe any nontoxic substance without legal impediment. Here again the substance in question was laetrile. The rationale for these decisions is that individual autonomy and right to privacy must be subordinated to the reasonable exercise by Congress of its power to protect the public welfare and to the exercise by the states of their police powers--i.e., powers to promote the health, safety, and welfare of their citizens.

Applying these ethical and legal considerations to the situation confronting Dr. Mulder, there is no basis to assert that the patients have a right to choose an ineffective therapy where presum- ably effective treatment exits. (Under U.S. law, competent patients do have a right to refuse treatment. This is con- sidered from both a legal and a public policy standpoint to be different from selecting ineffective therapy.) It is therefore doubtful whether a physician can ethically subordinate his duty to act in furtherance of his patients' inter- ests to the patients' right to select any therapy, however ineffective. This con- clusion may be viewed as highly pater- nalistic and an invasion of patients' rights. However, there is a legitimate argument in support of some societal control or limitation over personal decision making where the consequences of the decisions affect the overall well- being of society. At the very least, there is no basis for anyone to assert a right to participate in a clinical trial involving a treatment generally recognized as

being worthless. Similarly, there is no justification for any physician to ignore the relevant scientific facts and participate in a clinical trial solely in response to political pressures. The ethics of the profession and the general well-being of society will be better served if the physicians refuse to participate in an activity which essentially legitimizes unethical decision making.

In summary, there is no medical or ethical basis to justify the study described by Dr. Mulder. Even if there is an arguable basis for conducting the study in patients no longer responsive to conventional therapy, there is no justification for exposing curable or treatable patients to an ineffective regimen. No physician should sanction such an activity or be part of it. Finally, a physician may feel he cannot prevent a patient from resorting to quackery. He should not, however, legitimize quackery by incorporating it into a clinical trial regardless of the proce- dures used to obtain informed consent. There can be no informed consent to fraudulent treatment.

REFERENCES 'Levine, R.J., Lebacqz, K.: Some ethical consid-

erations in clinical trials. Clin Pharmacol Therap 25:728-741, 1979. The norm of good research design is expressed in the Declara- tion of Helsinki as the initial basic principle: "Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on

adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature." Human Experimentation: Code of Ethics of the World Medical Association, Declaration of Helsinki. Brit Med J 2:177-179, 1964. It is stated explicitly in the final regulations issued by the Secretary of the Department of Health and Human Services (DHHS) for the protection of human subjects of research. 46 Fed Reg 8366-8392. January 26, 1981, and in the corresponding regulations issued by the Food and Drug Administration (FDA). 46 Fed Reg 8942-8980, January 27, 1981.

2Food and Drug Administration, Laetrile. Com- missioner's Decision on Status. 42 Fed Reg 39768-39806. August 5, 1977. A review of the litigation surrounding the use of laetrile in- cluding an analysis of the legal issues was published recently by J. Brant and J. Gra- ceffa: Rutherford, Privitera, and Chad Green: Laetrile's setbacks in the courts. Am J Law Med 6:151-171, 1980.

3Schloendorff v New York Hospital 211 NY Rep 125, 129-130, 105 N.E. 92, 93 (1941).

4Kant, I. Selections Ed. by Greene, T.M. Chas. Scribner's & Sons. New York, 1929.

5Fundamental decisions were determined by the Court to be those related to marriage: Loving v Virginia, 388 U.S. I (1967); procrea- tion: Skinner v Oklahoma, 316 U.S. 535 (1942); contraception: Griswold v Connecticut 381 U.S. 479 (1965), Eisenstadt v Baird, 405 U.S. 438 (1972); abortion: Roe v Wade, 410 U.S. 113 (1972), Doe v Bolton, 410 U.S. 179 (1973); family relationships: Prince v Massa- chusetts, 321 U.S. 158 (1944); child rearing and education: Pierce v Society of Sisters, 268 U.S. 510 (1925), Meyers v Nebraska, 262 U.S. 390 (1923).

6442 U.S. 544 (1979) 7Rutherford v United States, 616 F.2d 455 (10th

Cir. 1980). 823 Cal. 3d 697, 153 Cal. Rptr. 431, 591 p.2d 919,

cert. denied. 444 U.S. 949 (1979). i Please enter my subscription to IRB: A Review of Human Subjects Research

O INSTITUTIONAL $160 annually (20 copies mailed to the same address)

Additional copies included in same mailing @ $8 each annually (number)

O INDIVIDUAL OR LIBRARY $20 annually (single copy) Prepayment is appreciated. Please make checks payable to: The Hastings Center, IRB

o My check for is enclosed. If you enclose payment, we will extend your subscription to include one free issue. (Please detach the subscription form and mail with check in an envelope, addressed to: The Hastings Center, IRB, 360 Broadway, Hastings-on-Hudson, N.Y. 10706.)

O Please bill. E Please change my individual subscription to an institutional sub-

scription.

Name

Title

Institution

Address

City/State/Zip



the ethics of clinical trials of ineffective therapy

Documents