Experimental Drugs and Clinical Trials

Drugs become accepted by physicians and the FDA on the basis of sci­entific proof of their effectiveness and safety. Scientific proof is obtained through a series of tests called a clinical trial.

While a drug is being tested in a clinical trial, it is considered ex­perimental. If the drug proves effective and is not too toxic, it is then li­censed and made available to the public.

For people with HIV infection, participating in clinical trials has both advantages and disadvantages. Clinical trials are experiments with human lives, and special safeguards are necessary to guard both the peo­ple and the scientific procedure. These safeguards, plus the options and aspects of participation in a clinical trial, are spelled out to the partici­pant in painstaking detail. Some trials can be seen as especially risky: they involve taking a drug with unclear benefit in place of a standard drug with established merit. With other trials—for instance, the com­parison of two drugs, both of which are known to work, to find out which works better—the risk is lower. The motivation to participate is an individual decision. For further discussion, see below, “Advantages of Participating in a Clinical Trial” and “Disadvantages of Participating in a Clinical Trial.”

Anyone worried about the safety of a clinical trial can be reassured that the trials are conducted under the strict supervision of the FDA with substantial safeguards (see below, “Supervision of Clinical Trials”). If the drug being tested proves significantly better or worse than the drugs in standard use, the trial is promptly discontinued.

The Steps of a Clinical Trial

All drugs used for medical therapy in the United States must first be re­viewed and approved by the FDA. The FDA is responsible for assuring that all drugs, before they are sold, are sufficiently safe and effective. Ac­cordingly, the FDA dictates that certain steps be followed from the time a drug is discovered until it is finally licensed. The process of testing drugs has several stages: a drug is tested first in the test tube and in an­imals, then in a few people for a short time, and then in a larger group of people for a longer time.

Preclinical trials. A new drug is first tested not in people but in test tubes and in animals. These first tests are called preclinical trials because they precede tests with people, which are called clinical trials. Preclini- cal trials determine the drug’s toxicity, its pharmacologic properties, and its effects against certain microbes. Of all the drugs tested in preclinical trials, only about one drug in a thousand is ever tested in people.

If a drug shows promise in the preclinical trials, the FDA grants it the status of an Investigational New Drug (IND). IND status must be granted before the FDA allows the drug to be tested in humans.

Phase one clinical trials. Phase one clinical trials are the first round of tests in humans. Phase one trials are designed to determine the safety and dosage of a new drug. These trials usually involve a relatively small num­ber of people, usually between 20 and 80. The drug is given only for a short time, usually for not more than a few weeks, and sometimes only a single dose is given. Participation in a phase one trial may require stay­ing in a research unit of the hospital, or the participant may visit an out­patient clinic, which carefully monitors the trial. Participants in a phase one trial don’t benefit much when the trial is for an infection like HIV because the treatment lasts for such a short time.

Phase two clinical trials. Phase two clinical trials are the second round of tests in people. Phase two trials usually involve 100 to 300 partici­pants and last for months or years. The purpose of these trials is to de­termine the schedules for doses, to collect additional information on tox­icity, and to test, at least preliminarily, the drug’s effectiveness. With HIV infection, the effectiveness of a drug may be determined by the effect on CD4 cell counts, by the numbers of HIV in the blood, by the delay in progression of disease as indicated by medical complications or devel­opment of AIDS, and by how the participant feels. People often partic­ipate in phase two trials for access to the drug before licensing. Or if the trial is relatively short and benefits to the participant relatively brief, peo­ple participate for payment or altruism. With some studies, the distinc­tion between phase one and phase two is blurred, and the resulting clas­sification is phase one/two.

Phase three clinical trials. Phase three clinical trials are the last phase before the FDA reviews a drug for licensing. Phase three trials often in­elude 2,000 to 3,000 or more participants and run for months or years. In this phase, the drug is given to participants in the doses and at the in­tervals that the FDA is likely to consider acceptable. The purpose of these trials is to get additional information about the safety and effec­tiveness of the drug. People usually participate in phase three trials for access to the drug before licensing.

NDA review. The next step is to take all the information gathered dur­ing the previous steps and submit it in a New Drug Application (NDA) to the FDA. The FDA reviews the NDA and decides whether to license the drug, what the dose should be, how the drug should be administered, which side effects require specific warnings in promotional material, and what conditions the drug is useful for.

It should be noted that the FDA approves drugs for the specific con­ditions indicated in the package insert and in the PDR. Despite this la­beling, once a drug is in pharmacies, it may be prescribed for any med­ical condition. Some physicians are reluctant to prescribe beyond the labeling limits for fear of malpractice suits. The FDA acknowledges the limitations of its labeling, and most physicians believe that “standards of practice” should be the guide. Another potential problem is that some third-party payers limit reimbursement coverage to FDA indications. Such decisions are unusual because most third-party payers do not know a person’s medical condition when he or she is an outpatient. When lim­itations are imposed, it may be possible to appeal the decision. But an appeal requires a fight with bureaucrats who often know little medicine and are paid to keep costs low.

Phase four trials. Phase four trials may be conducted after the drug is licensed in order to determine new dosing schedules, or to collect addi­tional information about effectiveness or toxicity, or to compare the drug to other drugs. People participate in phase four trials of drugs, even though the drugs are already available in the marketplace, in order to have access to the best medical care and (sometimes) in order to receive free care.

Streamlining clinical trials. The process described above has estab­lished high standards for determining the safety and effectiveness of new drugs. Unfortunately, the process is also expensive and time-consuming. The average new drug in the United States costs $1 billion to develop and requires an average of twelve years to move from the laboratory to licensing.

AZT was the first drug to be evaluated under some of the provisions of this streamlined process. The phase two trial began in February 1986; in September 1986, the first analysis of data showed the drug was clearly beneficial; the drug was then made available to people with AIDS through a Treatment IND, and the drug was licensed in March 1987. The entire process took thirteen months instead of the customary twelve years. The drug was approved based on studies of 282 patients instead of the usual 2,000 to 3,000 patients.

Participating in a Clinical Trial

Most trials are comparisons of one drug versus no drugs, one drug ver­sus another drug, or different doses of one drug. Participants in a clini­cal trial usually have to meet a specified requirement—they must have a certain CD4 count, for instance, or a certain complication. These re­quirements are adhered to strictly. Though such strictness is frustrating to both the investigator and the potential participant, it is necessary for the trial to be a valid test of a drug and for the FDA to approve the drug.

Once in the trial, participants are assigned to groups called treat­ment arms. What the treatment arms are depends on what the trial is testing: one treatment arm might be high doses of a drug and another arm low doses; one arm might be one drug and the other arm another drug; one arm might be one drug and another arm no drug at all.

The purpose of a trial is to compare one treatment arm with another. Some trials, called placebo control trials, compare a drug with a placebo, a pill that has no effect on the body. Placebo trials are done because peo­ple taking any pill, including a placebo, feel better—not necessarily be­cause of the physiological effect of the drug, but because of the psycho­logical effect of taking a drug that might help. For example, 60 percent of the people treated with any drug, placebo or not, for arthritis claim that it improves their symptoms. The necessity for a placebo trial is less when the effects being evaluated are objective: weight, blood counts, tests for the virus, or frequency of medical complications. Some effects, however, are more subjective and cannot easily be measured by scientific yardsticks: the sense of well-being, the level of fatigue, the number of headaches. For these more subjective effects, a placebo control trial is more important. In most trials, the results of a trial are evaluated in terms of both subjective and objective effects.

It should be emphasized that the rule of clinical trials is that, if a drug is known to work, no treatment can be a placebo; in that case, the drug known to work becomes the standard for comparison. Further­more, once the trial shows a clear benefit, the trial must stop. Thus, in the AZT trials, when the analysis of data in September 1986 showed nineteen deaths in the placebo arm and only one death in the arm re­ceiving AZT, the trial was promptly stopped and everyone was given AZT. Assurance on this point is a matter of medical ethics.

The best way to make the comparison in any trial is to double-blind. Double-blinding means that neither investigator nor participant knows which drug or which dose the participant is receiving. Since both inves­tigator and participant are likely to have biases, double-blinding ensures that results will be evaluated objectively.

Although double-blinding is preferred, in some instances it is sim­ply not realistic. For example, when the trial is to find out which way to administer the drug, by pill or by vein, proper double-blinding would have one treatment arm receive the drug by vein and a placebo by pill, and the other treatment arm receive the drug by pill and placebo by vein. But receiving a drug intravenously is inconvenient and can be risky, and it might be inappropriate for participants to receive placebo by vein sim­ply to maintain the blind.

Not all trials are comparisons: some trials, called pilot trials (like pi­lot TV shows), simply gather enough background information to see if a larger trial would be justified. Other trials compare a new drug with an old drug tested previously—called a historical control. Many times, in an effort to gather additional information, the drug is just given with no second arm for comparison.

Advantages of Participating in a Clinical Trial

The advantages of participating in trials usually include the following:

1. New drugs: Usually, people have access to a new and unlicensed drug only by participating in a clinical trial. For people who have had sequential treatment failures and many resistance mutations, participation in a clinical trial is the only way to have access to drugs likely to be effective.

2. Good medical care: In clinical trials, the participant is monitored extensively in order to evaluate the drug’s effectiveness and toxicity. The advantage to the participant is the quality of medical care that accompanies monitoring. Moreover, the research groups that con­duct clinical trials are usually composed of health care providers who are devoted to controlling this disease and who are important sources of new information. Participants in clinical trials may find comfort in receiving care from health care providers who have such credentials and clear commitment, and who are working at the cut­ting edge of the field.

3. Free care: Most participants in clinical trials receive drugs and medical care related to the trial free of charge. The costs are usually covered by the research grant that supports the trial or by the man­ufacturer, who is interested either in FDA approval or in favorable publicity. However, the participant should not assume that all costs of medical care associated with HIV infection are likely to be in­cluded. Most trials provide the drug, the cost of monitoring for safety and effectiveness, and the cost of managing toxicity ascribed to the experimental drug. They do not provide the cost of care for any complications of HIV infection. Some trials are designed to pro­vide the drug and the cost of monitoring only if the participants are not covered by insurance.

4. Altruism: The advantages listed so far provide direct benefits to the person participating. Participating in a clinical trial also serves a greater need. Medical scientists, people with HIV infection, and people at risk for HIV infection all need more information about new drugs for treating HIV infection. Even the participant who does not benefit directly will nevertheless make a contribution to the wel­fare of others with or without HIV infection.

Disadvantages of Participating in a Clinical Trial

Several factors might dissuade a person from participating. The most fre­quent concerns are:

1. Inconvenience: Many trials require extensive testing and frequent visits to the clinic. These requirements should be clearly stated in the informed consent papers (see below, “Informed Consent for the Trial”). These tests and visits can be an enormous inconvenience to the participant.

2. Risk: Clinical trials are scientific experiments. They are carried out because medical scientists need information about the effective­ness and safety of a new drug, or about the safety and effectiveness of an old drug used in a new way. Some of these drugs are poten­tially toxic, and although trials never test drugs on humans that have not been first tested extensively in the laboratory and in animals, unanticipated side effects are always possible. The degree of risk ob­viously varies with different drugs and different conditions.

3. Assignment to the “wrong group”: For all controlled and double­blinded trials, there is always the risk that the participant will re­ceive the placebo, the less effective drug, the more toxic drug, or the less effective dose. Some participants attempt to break the blind and find out what drug or dose they are taking through a variety of mechanisms. The investigators understand participants’ reasons for doing this, but breaking the blind destroys the scientific credibility of the trials. If enough people break the blind, the trial might as well not be done.

4. Costs: Usually drugs and costs for monitoring are provided at no expense to the participant. Some drug trials, however, expect reim­bursement from the participants for the cost of medical care. You will need to establish what costs, if any, are involved before you agree to participate. In addition, if the drug is toxic, you will need to establish who pays the cost of care for any side effects.

5. Restrictions on other options for treatment: Most trials require that someone who is participating in one trial not participate at the same time in other trials. Some trials exclude people who have re­ceived other experimental drugs. Other trials prohibit the partici­pant from using certain drugs or from receiving certain treatments. You should carefully review any such restrictions before agreeing to participate in clinical trials. A reassurance: any participant in a trial can withdraw from participation at any time.

Supervision of Clinical Trials

To be sure that the potential benefits of a trial are larger than its poten­tial risk, the FDA requires that all trials be supervised by an independent review panel. This review panel, called the Institutional Review Board (IRB), must be composed of representatives from both the medical field and the nonmedical public. Most IRBs include representatives from law, nursing, medicine, and the clergy, as well as researchers who are expert in clinical trials. This group has the job of watching out for the partici­pants’ interests, seeing that scientific standards are upheld, and protect­ing medical ethics. At periodic intervals during the course of the trial, the IRB reviews the results. Any serious or unexpected toxicity must be reported immediately to both the IRB and the FDA. If the toxicity is se­rious and is thought to be related to the drug, all participants in the trial must be notified, and the informed consent form must be revised ac­cordingly.

Many trials, and especially those at multiple medical centers deal­ing with treatments of serious conditions such as HIV infection, are also supervised by a Data Safety Monitoring Board, which scrutinizes the data from the trials every six to twelve months. The Data Safety Moni­toring Board, made up of experts in the field who are not involved in the trial, is also privy to unblinded results. This board is different from the IRB because it has access to data from all centers participating in the trial, not just the local center. The board’s purpose is to stop the trial as soon as valid results combined from all centers emerge about the drug’s effectiveness or toxicity. Six months into the phase two trials of AZT, the Data Safety Monitoring Board’s review of the unblinded data con­vinced it to stop the trial and give all participants AZT. One year into the second big AZT trial, the data showed that the drug was beneficial when the CD4 count was below 500, and that it was less toxic at low doses; the trial was stopped and all participants with low CD4 counts were given low doses of AZT.

Informed Consent for the Trial

The most important safeguard in protecting the rights of participants in clinical trials is the informed consent process. All participants in clinical trials in the United States (and in most areas of the world) are required to sign an informed consent document. In the event that the participant is not competent to sign, this responsibility is assigned to the spouse, parent, an adult child, or a brother or sister (in that order). The informed consent document must also be signed by a witness and by the investigator.

Information in the consent form usually includes the following: Purpose of the trial. The informed consent document must include an explanation of the scientific question the trial is to answer. It must also include an explanation of why the participant qualifies for the trial.

Procedures. Informed consent must include an explanation of the trial’s design, that is, exactly how the trial will proceed. The explanation will in­clude the nature of the treatment arms; the method by which participants are assigned to a specific arm; the requirements for participation, includ­ing the number of clinic visits or the duration of hospitalization; the fre­quency and types of tests that will be done; the amount of blood that will be required; the duration of the trial; and the end point of the trial.

Risks. Informed consent must include an explanation of the drug’s side effects, including their anticipated frequency and severity. It is unrealis­tic to list every possible side effect, or even all of the side effects that have occurred in previous trials. But certainly the most severe and the most frequent side effects should be noted.

Benefits. Informed consent must include a statement of whether the participant has any realistic likelihood of benefiting from participation. Expenses for the drugs or for monitoring, and any payment to the par­ticipant, should also be explained.

Alternatives to participation. Informed consent must include the vari­ous options people have if they choose not to participate. This generally includes the statement that a decision not to participate will not affect your care. In other words, no one at the center offering the trial will bear a grudge if you choose not to participate.

Confidentiality of records. People with HIV infection are often con­cerned about the confidentiality of their trial records. Some trials are done without identifiers, that is without the names, addresses, hospital numbers, or Social Security numbers that would connect the data to a specific person. Trials done without identifiers essentially guarantee ano­nymity for the participant.

Unfortunately, it is often impractical and undesirable for clinical tri­als that collect clinically useful data over a prolonged period to be done without identifiers. The next best option to guarantee confidentiality is to keep the records in a locked file with limited access. The FDA and the drug company that sponsors the trial can require access to these locked files, but we are not aware that this access has ever resulted in a partic­ipant’s name being revealed to inappropriate persons.

In many instances, data obtained in the trial are also recorded in the participant’s medical record: such data can be relevant to medical treatment. Occasionally, participants object to what they view as an unnecessary dispersal of sensitive information. The best advice is to read the consent form carefully for an explanation of how data from the trial are handled and who has access to the record. If such an ex­planation is not included in the consent form, ask for further infor­mation.

Further information. No consent form can provide all the information desired by all the participants. And consent forms often include techni­cal information and medical terms that may be difficult to understand. It is expected that most participants will need to discuss any questions not answered or points not clarified with a member of the investigating team. If, either before or after signing the consent form, you have ques­tions about toxicity, alternatives to drugs, possible participation in other studies, or compensation for injury as a result of participation, they should be answered to your satisfaction. You should not sign the con­sent form until you are satisfied and have no further questions. One op­tion is to take the consent form home and list the questions you have af­ter you have reviewed the form and discussed it with others. In addition, most consent forms include the name and phone number of an appro­priate person to contact if the participant has any further questions af­ter participation begins.

Withdrawal of consent. Informed consent continues throughout the course of the trial, but withdrawal of consent at any time is the partici­pant’s right. Withdrawal must not have any repercussions for the par­ticipant. Withdrawal may not interfere with the availability of care.

Participation. To find the nearest clinical trial, call the hotline of the federally sponsored AIDS Clinical Trial Information Service: 1-800- TRIALS-A. The same information is available on its Web site: www.actis.org.