The Bay Area Reporter - July 3, 1998
Bill Snow, ACT UP/Golden Gate Writers Pool

Safety and efficacy trials

The cornerstone piece of human experimentation is the clinical trial, which carefully measures the effect (which must be statistically "significant") of the drug or vaccine. Trials must be done in enough people so that statistically the result cannot be by chance (usually up to a very high level of reliability, or statistical "confidence"). Since the Thalidomide disasters of the 1960s, the U.S. Food and Drug Administration (FDA) and similar agencies in other countries require such scientific proof of safety and efficacy. This is why it takes so long and costs so much to license a new medical product.

The process is not foolproof however, and AIDS activists and pharmaceutical companies have put pressure on FDA to make it faster so lifesaving treatments (and corporate profits) can be available sooner. Politicians supportive of less government control have facilitated this positive change, but now we are hearing of drugs taken off of the market because safety problems arose after approval and marketing. Protections, proof of efficacy, and access must strike a delicate balance.

Personal health and public health

We can get an indication if a drug is helping by testing it in a smallish number of sick people. If doctors believe it may or will work, and it has some benefit over existing treatment, many have little difficulty recommending it for their patients while it is still experimental, and patients can enroll in clinical trials with some hope of a benefit. That is one reason many AIDS patients and activists follow the drug testing process so closely.

Human trials of preventive vaccines pose a much more difficult problem because they are tested and ultimately used on healthy individuals for HIV, because there are other ways to prevent infection, and because no vaccine is 100% effective. In addition, scientists are in genuine disagreement about what is likely to work, so at our current level of understanding big trials with thousands of at-risk individuals will be required to even get an indication, if any approach has any value at all.

Three levels of approval

The Nazi doctors who performed terrible experiments on prisoners were only an extreme of medical exploitation, often in the name of science or mankind. Our own country also has a history of running questionable experiments on vulnerable groups, and usually the experimenter believes in what he is doing, so much that he may not be an objective judge of its scientific merit and ethics.

So, since the Nuremberg trials there has been an international effort to protect the rights of individuals, while at the same time being able to conduct important human experiments, which have the prospect of improving the human condition. The ethical principles for this effort were defined in a 1979 report by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research called the Belmont Report. The three principles are respect for a persons (autonomy), beneficence (doing no harm, maximizing possible benefits, and minimizing possible harms), and justice (equitable distribution of risks and benefits).

In the U.S, the FDA must first approve the complete protocol for any human trail, and then an Institutional Review Board (IRB) at each site must approve it locally. The requirements for IRB membership were designed to ensure various points of view, some measure of objectivity, and expertise. There are seven distinct criteria IRBs are to follow based on the Belmont principles, including careful attention to informed consent documents and process. Yet only last month, federal investigators determined that clinical trials were often unsafe and unethical because these boards are overworked, often unqualified, and didn't do their job well enough. There is ample evidence of misleading recruitment and advertisements that don't mention the risks and experimental nature of human trials. So let the "buyer" of research beware!

Informed consent: the personal level of approval

The Belmont principle of respect for persons includes treating individuals as independent decision-makers, and protecting those who are incapable of making independent decisions. All existing codes of research ethics, and regulations in the U.S. and many other countries, require obtaining the individual consent of each participant based on respect for the person's autonomy, independence, and freedom to choose. The Council for International Organizations of Medical Sciences (CIOMS) defines this as "consent given by a competent individual who has received the necessary information; who has adequately understood the information; and who, after considering the information has arrived at a decision without having been subject to coercion, undue influence or inducement, or intimidation."

Federal regulations specify what elements must be included in informed consent. These are usually covered in a written document signed by the participant and by a witness, who represents the study team, and who should be responsible for explaining the study and answering all questions. That is the letter of the law, which often is as far as informed consent goes.

Essential information

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.

2. A description of any reasonably foreseeable risks or discomforts to the subject.

3. A description of any benefits to the subject or to others, which may reasonably be expected from the research.

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.

6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and if so, what they consist of, or where further information may be obtained. (The international guidelines require that therapy be provided free of charge for specified types of research-related injury!)

7. An explanation of whom to contact for answers to pertinent questions about the research and the research subjects' rights, and whom to contact in the event of research-related injury.

8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

You can pretty much count on these legal guidelines (and probably these very words) being met in any informed consent document, though often in a perfunctory way.

A higher standard

The international guidelines also specify that informed consent represents more than just a legal document with a couple of signatures to protect investigators and their institutions. They state it is the duty of the investigator to:

* communicate to the prospective subject all the information necessary for adequately informed consent;

* give the prospective subject full opportunity and encouragement to ask questions;

* exclude the possibility of unjustified deception, undue influence and intimidation;

* seek consent only after the prospective subject has adequate knowledge of the relevant facts and of the consequences of participation, and has had sufficient opportunity to consider whether to participate;

* as a general rule, obtain from each prospective subject a signed form as evidence of informed consent; and

* renew the informed consent of each subject, if there are material changes in the conditions or procedures of the research.

You should insist on all these points when you think about enrolling in any drug or vaccine clinical trial, or you should walk away from the "opportunity." If you have any doubts, you shouldn't hesitate to call in the primary investigator. CIOMS guidelines specify that informed consent is ultimately the responsibility of the investigator, and that the information be provided in "language that he or she (the participant) is capable of understanding." Often the attitude and openness of the investigator will help you decide if you want to enroll in the trial.

If you want to know more about ethical issues in the development and testing of a preventive HIV vaccine, see AIDS Vaccine by Christine Grady, 1995. She actually proposes a fourth level of consent, at the community level, which seems like a good idea for vaccines that benefit the community, but which is difficult to define, let alone accomplish.
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