These are dramatic cases that captured public attention and led to the development of regulations designed to protect research participants.

Transcription

1 Clinical Trials Every year hundreds of thousands of people in the United States and Canada are enrolled in clinical trials -- in studies designed to find better ways to treat illnesses. Many trials involve people who are very ill, often near death with diseases such as cancer. Other trials involve problems that are not immediately life threatening, for example, trials designed to determine the effectiveness of drugs for psychological problems such as depression or trials involving the common cold. There are tens of thousands of clinical trials going on around the world at any given time, perhaps over 40,000. Trials may involve thousands of people, or fewer than a dozen. They are used to test almost every form of medical practice, from detection and screening techniques designed to discover diseases earlier to chemotherapy designed to save lives or increase life expectancy. Trials even may be used to test the effectiveness of informed consent documents. The number and variety of clinical trials alone makes them confusing to prospective participants, including patients facing serious diseases. Question. I heard that clinical trials are big business, with lots of people making money. I even heard that participants are sometimes paid. Is that true? Answer. Trials sometimes are big business, with billions of dollars spent on them by drug companies in the United States alone. Some studies do pay participants and physician recruiters. This alone does not make trials a bad thing, but it can lead to abuses. Researchers might face conflicts of interest. For example, they might slant results in favor of sponsors, even if only slightly. Prospective participants in trials should be especially concerned if their personal physician is leading a study, because then their physician might not be able to give objective advice about whether it is beneficial to participate in the trial. Historically, medical studies have involved serious abuses of participants. After World War II, it became apparent that Nazi prisoners were mutilated and killed in medical experiments. In reaction to this, the Nuremberg Code was developed in 1946 as a guide to clinical researchers. The Code emphasizes that the research participant must be a voluntary participant who may leave the experiment at any time, that the study must have scientific merit, that participant suffering and injury be minimized, and that typically no study should involve likely participant death. Significant, even shocking, research participant abuse has occurred in the United States. One of the most infamous cases is the Tuskegee syphilis study. Four hundred black men with syphilis were misinformed about the purpose of the study, and where not effectively treated when such treatments became available 1

2 in the I940s. Another well know case involves the I961 New York City Jewish Chronic Disease Hospital study in which chronically ill patients were injected with live cancer cells. Patients were not informed about the nature of the study. The researchers were subsequently found guilty of deceit and unprofessional conduct. The New York State Willowbrook study, begun in I961, deliberately infecting institutionalized children with infectious hepatitis. Although parents consented to the study, they were coerced into doing so because without giving consent, their children would not be accepted into the institution. These are dramatic cases that captured public attention and led to the development of regulations designed to protect research participants. Question. These abuses are incredible. I can't imagine that they could occur today. Answer. Even today, with many safeguards in place, abuses still occur. One case recently hit the news. An 18-year-old boy, Jesse Gelsinger, suffered from a rare life-threatening disease. In 1999, he decided to join a phase one trial testing an innovative gene therapy treatment. He died almost as soon as he began the treatments. The claim is that he was not adequately informed about possible risks. Afterwards, the National Institute of Health found that many researchers around the United States failed to report serious adverse events. Although perhaps not as flagrant as the historical abuses, the study that Jesse participated in is considered by many people to be a clear abuse of proper practice. In response to increasing clinical research funding by the federal government and to public awareness of abusive studies, the United States Congress appointed a commission to identify ethical principles for appropriately conducting research on humans. This inquiry resulted in the I979 Belmont Report, which presents basic principles to guide the ethical conduct of medical research involving humans. The Belmont Report lists three principles, which remain essential ethical ingredients in current United States regulations of research on humans. The principles are: 1. Respect for persons 2. Beneficence 3. Justice Respect for persons rejects the idea that people should be simply used for the purposes of others. People are capable of making decisions and living by those 2

3 decisions. This makes humans autonomous, that is, self-ruling, and thereby deserving of respect. Humans should be treated as ends and not merely as means. In the research context, respect essentially involves an informed consent process that includes appropriately complete and truthful information about a research project. Based upon this information, people should decide whether or not to participate. Respect means that consent to participate is free of any pressure or coercion. It should be voluntary and informed. Some people are unable to give consent. This is true, for example, of young children and those mentally incapacitated by disease. Such people should be given an opportunity to choose in so far as they are able; when they are not able to choose, a substitute decision maker may be called upon to make the selection for them. The decision maker is often a spouse or a child's parent. Beneficence as a moral principle holds that there is a moral obligation not to harm people and to do good for them. In the research context, beneficence requires that the study be worth the risks involved. Research is needed precisely because there are unanswered questions. For example, there may be uncertainty about a new drug. A drug thought to be effective, might prove ineffective or even very harmful. Research subjects often undergo risks due to uncertainly. In deciding whether a research project is morally acceptable, risks and potential benefits to society or the individuals involved must be carefully balanced in order to determine that the expected benefits from the trial, in terms of knowledge gained, exceed the risks. While society in general benefits from clinical trials, research should not put participants at a greater risk of harm than is necessary. Furthermore, individuals must not be intentionally harmed. Justice involves fair treatment of people. When people are treated unequally, we typically require reasons for doing so. When groups of people, such as women or African-Americans, are treated differently we often have reason to suspect injustice. In the research context, justice means that risks and benefits involved in trials be assigned fairly. If one group of people suffers greater risks in trials than another group, this may be reason to believe that a study is unjust. If one group benefits more than another group from a study, this is another reason for believing that a study is unjust. For example, if only men are included in a particular study, this might be unfair to women provided that women are medically appropriate for the study. Some people are selected for studies simply because they are more available. 3

4 This might involve an injustice. The selection process must be fair, ideally including people from all groups whenever medically appropriate. Another document designed to protect research subjects is the World Medical Association's Declaration of Helsinki. Although first adopted in I964, the Declaration has been rewritten several times, including an important revision in The Declaration insists on well-conducted and beneficial experiments that protect the well being of participants. It also underscores the importance of informed consent. The Declaration is importantly different from other documents because it covers details about the conduct of clinical trials. Clinical trials do not simply test a new treatment, comparing it with known cure rates. Rather many trials are designed so that one treatment is compared with another treatment or with the absence of treatment. A trial may contain two, or more, different groups of people. Each group is called an arm of the trial. One group will get the new experimental treatment. Another group may get the best current treatment. Or another group may receive a placebo. A placebo may resemble the actual treatment, but actually has no medically effective components. For example, a participant may be given a sugar pill, but one that appears similar to the actual pill. Many trials contain a placebo arm. That means that some participants do not receive active treatment. Question. Why is a placebo arm used in many clinical trials? Answer. It is surprisingly difficult to get good information about the effectiveness of drugs. Many people get better from illnesses without any medical treatment at all, or from treatments that do not contain active ingredients, such as placebos. So if someone gets treatment and then gets better, it is difficult to know whether the person got better because of the treatment or whether they would have recovered without treatment, or perhaps would have improved by taking a sugar pill. By comparing a treatment against a placebo, one gets better information about the extent to which the treatment provided benefit and the extent to which the patient would have improved without the treatment. For example, if significantly more people in the experimental arm get better than in the placebo arm, at least part of the difference may be attributed to the drug. Comparing an active treatment with a placebo is considered the best way to find out the actual benefit derived from the treatment. If we simply gave the treatment in a trial without comparing it to something else, we would not know the extent of the treatment's benefit. It is well known that many patients do tend to feel better after receiving a placebo. So a treatment might be no better than a placebo, yet might appear to have some good results. 4

5 Since a placebo has no medical benefit in itself, its use is controversial. If a placebo arm is used, it means that some people in a clinical trial would not receive actual medical treatment. Nevertheless, many people do respond to a placebo. For example, in a study of psychological depression, over 30% of the people in the placebo arm may respond favorably to a placebo. This is why a new depression medication may need to be tested against a placebo. In this case, a new drug may seem effective if it helps 30% of the people who receive it. However, in a placebo arm, a higher percentage of those who receive the placebo might show benefit, indicating that the new drug is probably ineffective, medically speaking. In the study, It does no better than a placebo. However, a placebo may be known to be less effective than the current best treatment. Under these circumstances it may seem morally inappropriate to use a placebo. If a placebo is used, then a treatment known to be superior would be deliberately withheld from participants. Instead it might be that the new drug should be tested to see whether it is better than the current best treatment. For this reason the Declaration of Helsinki contains the following statement: "The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. (Paragraph 29)" Paragraph 29 of the Declaration of Helsinki seems to prohibit the use of placebos unless there is no known current affective therapy. However, the paragraph has been clarified by approving the use of a placebo arm even when there is a current effective therapy, provided there are scientifically sound reasons to include the placebo arm. Also a placebo may be used if a minor condition is studied where the use of a placebo would not subject a participant to additional risks or irreversible harm. For example, a placebo may be used in a study of the common cold. For many diseases, placebo arms are not employed. For example, large cancer trials involving chemotherapy do not typically contain placebo arms. Other studies routinely use placebo arms, such as clinical depression studies. In deciding whether or not to participate in a clinical trial, a prospective participant should clearly understand whether a placebo arm is being employed. If it is, it is likely that half or a third of the participants will be randomly assigned to that arm. The prospective participant should know that those in the placebo arm will not receive medically effective treatment. The only benefit they will receive, if any, will come by the placebo effect. This is the effect people receive when they believe they are being medically treated even though they are not being treated by active therapies. We mentioned already that clinical trials are complex. There are many types of trials. Some trials have various arms, such as a placebo arm. Some trials involve people who are extremely ill, while others involve people without serious medical 5

6 problems. One of the most important distinctions is the phase that a trial is in. Typically trials are divided into three phases simply called: phase I, phase II and phase III. A phase I clinical trial is not about determining the effectiveness of a treatment, but rather to find out how a new treatment should be administered. For example, suppose a new cancer treatment involves a previously untried chemotherapy. The therapy may already have been studied in the lab but not previously tested on humans. Since the therapy is new, questions arise over its safety as well as how much should be given and at what intervals. In order to answer these questions, physicians begin by administering the therapy in low doses, carefully monitoring side effects and toxic reactions. The dosage will be increased, until the proper level is determined. While many drugs are determined to be safe enough to use as therapies, some drugs do not pass the phase I trial test, either because they are judged unsafe or perhaps because it is discovered that they are not effectively absorbed by the body. Usually a phase I clinical trial involves relatively few people; in a cancer phase I trials, typically fewer than 100 people will be involved. Sometimes phase I trials use healthy people, and sometimes people who are very ill. Cancer phase I trials often rely upon patients who face death and for whom no effective therapy has been found. Patients should fully understand that phase I trials are not designed to cure patients or to extend life. Instead, they are designed to determine proper dosage. As a matter of fact, sometimes phase I trials do produce good results, but this is relatively rare. In cancer trials, the number of people helped in phase I trials may be less than 5%, and the gain for many is relatively minor. Often very ill people go into phase I trials as a last hope, slim as it might be, or to help others by participating in the research process. Unfortunately, many people may be going into these trials believing that the chance of a significant benefit is high. The mistaken hope that a trial is likely to produce a cure or increased life expectancy is called the therapeutic misconception. It means that people mistake a trial for actual therapy when that is neither its goal nor its expected outcome. The therapeutic misconception applies to other phases as well. For example, when a trial contains a placebo arm, some trial subjects will not receive an active therapy. Participants may not understand this, believing that a physician or nurse would not recruit them unless they would receive the best possible treatment. To believe this is to be subject to the therapeutic misconception. 6

7 Patients who decide to enter phase I trials, especially cancer trials, should be certain that they understand what the trial is attempting to do. Special efforts should be taken to ensure that such patients are given full information in a way that they can clearly understand the trial. These patients should not be coerced into entering the trial, even in subtle ways. The motivation for an extremely ill person to accept participation in a phase I trial that makes the greatest sense is the desire to be involved in the research effort so that the patient may be part of the process that eventually leads to an increased life expectancy for others suffering from a similar disease. Question. I understand that about 5% of the people who participate in phase I cancer trials do experience some improvement in their medical condition. For example, tumor size might be decreased. If it is true that people are facing death and other treatments have not worked, why shouldn't they try a phase I trial hoping it will lead to extra months or years of life? Answer. Your question centers on a very serious problem. It is true that often in phase I trials a small number of people benefit, but this is a small number. Also, some people might have seen some improvement even without the trial. Furthermore, the trial may involve serious side effects. The improvement might be short-lived, bringing only weeks or months of additional life at a low quality. Those hoping for a cure should carefully consider the small potential benefit and the serious risks involved. By and large, the best reason for participating in these trials is the hope for a medical progress that will help future patients. For the overwhelming number of participants in phase I cancer trials, the hope for a cure is unrealistic. After determining that a drug is safe for therapeutic purposes, its effectiveness may be studied. To do this, a relatively small trial might be initiated. This trial might use a control group, those who receive standard therapy or a placebo. The other group will receive the experimental therapy. It is likely that participants will be randomly assigned to these groups. That means that the assignment will be done by chance, by a process similar to drawing the patient's name out of a hat. This is called a randomized clinical trial. In this way it is thought that the two groups will have similar traits. If all the older patients, for example, were put into one group, then the results might simply mean that older people respond well or poorly. By randomizing, one expects to get an equal number of older and younger people into each group. So any response should not be due to age, but to the underlining disease process. Another feature is important: trials are often blind. This means that the patient does not know which group he or she is assigned to. A patient will not know, for example, whether a placebo or active therapy will be used. Trials are double blind when neither the patient nor the health care providers know which group 7

8 the patient is in. Double blind randomized studies are considered the best way to gain reliable treatment information. During a phase II clinical trial, researchers should continue to monitor the drug's safety. Although the number of participants in the trial - up to around 200 people - might be too small to determine the general effectiveness of the drug, it can indicate that a drug deserves further study with more participants involved. So in a phase II trial, physicians and other health care professionals will watch for the effectiveness of the treatment. If a treatment is safe and appears to be effective, it will pass the phase II trial test and may go on to a phase III study. Participation in a phase II study has at least two significant drawbacks. First of all, a patient may be assigned to a placebo arm, if such an arm is used. Secondly, the drug has yet to be tested for effectiveness on human beings, except for minor indications based on a phase I study. Participants in phase II trials face the risk that the experimental therapy will prove ineffective. Nevertheless, safety has been demonstrated, and effectiveness is expected, perhaps based on laboratory studies, animal studies, or on the use of similar treatments. Some trials use variations on already effective therapies. For example, these trials may alter the timing and dosage of the administration of the therapy. Or the trial may use a different combination of drugs believed to be effective. Such trials are much more likely to be successful in the sense of leading to therapeutic benefits. Trials should be carefully explained, and patients are free to ask questions about whatever they do not understand. Patients should carefully determine whether they believe a phase II trial is in their best interest. A patient might be motivated by the desire to help other patients in the future. But if motivated by the desire to find a cure, patients should understand the drawbacks to phase II trials. This is especially true if the therapy involved has not yet been used in the treatment of diseases. On the other hand, patients should keep in mind that the trial is being conducted because there are reasons, albeit not fully tested, to believe that the therapy in question will have success. This expectation may become especially important if the patient's current best therapy has failed. A phase III clinical trial is very much like a phase II trial, with two important differences. First of all, the therapy studied in a phase III trial has shown some success in a phase II trial. Secondly, a phase III trial is much larger with a greater number of people participating, sometimes several thousand, although perhaps much fewer. This means that the results of the trial might more conclusively show whether the treatment is effective. 8

9 Phase III trials are likely to be randomized and double blind. Many phase III trials involve a placebo arm, while others do not. Some will study new drugs not currently in use, while others will use new combinations of drugs or variations on treatments that are already approved for therapeutic purposes. Sometimes a trial will compare two drugs each thought to be effective in order to determine which is more cost effective, or perhaps which has longer lasting benefits. It is crucially important to understand exactly the potential risks and benefits of participating in a trial. These should be carefully explained to prospective participants. Clinical trials, to be good science, need to follow strict protocols. A protocol is a set of instructions that are used to conduct the entire trial. It specifies everything from who should be allowed to participate to the level and timing of treatments. It should indicate what should be done when patients experience setbacks and how long the trial will last. A good protocol is very carefully constructed. Often, trials are conducted at leading medical institutions, with some of the best physicians in the nation determining the exact protocol. Everyone in the study will be treated similarly, based upon the eventualities covered in the protocol. For example, the protocol in a cancer trial may have contingencies built in for what will be done when a patient's white blood count becomes too low. If that happens, the patient may be treated differently than other patients not facing such circumstances, but nevertheless the intention is to follow the protocol. Since a protocol is very well designed, or at least should be, some people believe that in many circumstances treatment under a protocol will be more effective for patients. Physicians and nurses treating without the guidance of a thorough protocol may, for example, overreact to certain circumstances a patient faces. Too little of the treatment may be given in response to a low white blood count. A protocol may be designed in a better way to deal with such problems. Based upon the expertise of the physicians involved, clinical trials might provide better therapy than standard treatment. Other people object that protocols are overly rigid and do not allow for individualized treatment. The patient becomes, in this view, just a number in a study. Even if a physician believes that the protocol should not be followed, he or she may follow the protocol for the sake of the study. For the time that a patient is a member of the trial, the protocol should be followed; if the protocol is not followed, the patient should not be allowed to continue in the study. In short, this objection amounts to the claim that patients have a right to the best judgment of their physicians, and that in a trial this will not happen. 9

10 Some types of clinical trials have been very successful in treating patients. This is especially true with pediatric cancer patients. The majority of such children are treated in trials; those trials tend to provide known effective treatments, with some alterations hoped to produce better results. Some experimental treatments are not as successful as the current therapy. Keep in mind that the reason for a trial is that something is unknown. There are risks in all clinical trials. Safety and effectiveness are typically not fully known. Patients should understand exactly what it means to be in a clinical trial and accordingly make their choice to participate or not. Question. Given the facts that a patient may be randomly placed into a placebo arm, a current therapy arm, or an experimental arm, and the fact that a protocol rigidly determines what will be done, what sense does it make for a person to consent to participation in a clinical trial? Answer. Sometimes the best reason for participating in a clinical trial is the fact that it may help advance medical science. But many trials do provide good therapy. Some patients have not responded well to current therapies, and their best hope may be the possibility of being given an experimental therapy in a phase III trial. Phase III trials are often designed by extremely good physicians and sometimes the overall results are significantly better than the results of standard therapy. Given the different kinds of trials, patients should make very careful decisions about whether they should participate in a clinical trial. A therapeutic relationship exists between a patient and his or her health care provider as long as the provider is treating that patient's medical problems. In this relationship, health care professionals have a moral obligation to provide treatment according to the standards of their profession and to treat a patient with dignity and respect. The priority of the needs of the patient may create problems when health care providers are engaged in clinical trials. For example, suppose a patient is suffering from severe depression. A physician might suggest that the patient enlist in a clinical trial. But the trial may have a placebo arm and the patient may have a chance of being given a medically ineffective treatment instead of the experimental therapy. A physician or nurse may believe that suggesting participation in the trial is contrary to his or her therapeutic obligation to the patient because by taking part in the trial the patient might not receive needed therapy. Although many clinical trials offer excellent therapy, many also limit therapy for scientific reasons. This is true when a placebo is one arm of a trial. Even when patients are told that they might be in a placebo arm, they sometimes 10

11 continue to believe that this will not happen. For example, they might believe that their physician would not do this to them. Or they might not understand what they were told. They might not have listened carefully when use of a placebo was explained. In such cases, the therapeutic misconception applies. The patient believes that research is equivalent to therapy while receiving a placebo is not medical therapy. Also, patients may believe that the therapy he or she is receiving has been designed for them individually. As we have seen, this is not the case in trials. In cancer trials, placebo arms are typically not used, at least for serious cases. Nevertheless, in certain trials, the aim is not therapy but to determine the proper dose of a drug. This is called a phase I trial. Therapy is not intended, yet many patients may see it as their last hope. Even though there is a small chance a patient will be helped in a phase I trial, believing such a trial provides therapy is considered a therapeutic misconception. Clinical equipoise is the moral requirement that all arms of a clinical trial involving people with serious illness have similar expected outcomes. One arm of a trial might be a placebo, another a proven therapy, and a third might be the experimental agent. When one arm is thought to be superior to another, many believe that it is immoral to place ill people in an inferior arm. Randomly placing ill people in different arms of a trial may be morally proper when all arms are considered likely to produce equivalent results. Under such conditions the arms of a trial are in clinical equipoise. Some bioethicists believe that clinical equipoise hardly ever exists because researchers will usually believe that one or the other arm is superior. Thus, they reject clinical equipoise as unhelpful requirement that does not facilitate gaining knowledge. Other bioethicists believe that clinical equipoise is a needed moral safeguard and should be required in all trials. Keep in mind that judgments about the effectiveness of arms of trials are often incorrect. After all, experimentation is designed to determine whether or not, or to what extent, a therapy is effective. Thus, uncertainty about the relative effectiveness of different trial arms should be expected. Many researchers believe that their experimental procedures will be superior to standard therapies. However, this may be mistaken and is, before a trial, scientifically unproven. Because the researcher might believe that the experimental therapy is superior, he or she might not think the trial exhibits clinical equipoise. However, the researcher might believe that standard practitioner would not agree because the experimental therapy is unproven. Thus, clinical equipoise may be best determined from the point of view of accepted medical practice and not that of an individual researcher. 11

12 Now that we know more about clinical trials -- some of the history of abuse of trials, and some of the risks and benefits of clinical trials -- we turn to regulations that have been put into place by the United States federal government designed to protect human research participants. These regulations are also in place to help ensure that research involving human subjects is effectively carried out and socially beneficial. Federal laws regulate only those institutions which receive, or may receive, federal funding. The federal government spends an enormous amount of money on research involving human participants, so these laws affect many institutions including almost all major universities and teaching hospitals. Federal regulations expect researchers to design safe and scientifically sound research studies, conducted by qualified investigators. An appropriate Institutional Review Board, generally called an IRB, must approve studies. Informed consent must be obtained. Participants should be monitored throughout the trial to ensure that their rights are not violated. Researches are required to report unexpected occurrences that harm participants. Recruitment of participants should be designed to produce fair participation. In particular, women and minorities should be included in order to ensure that research benefits all people who might suffer from a disease or disorder. If inclusion of women or minorities is not appropriate, for example, due to a disease that only affects men or difficulties in recruitment, then a rationale must be provided for exclusion. It is considered unfair to include patients who may feel pressured to participate in a trial. Special efforts must be taken to ensure that such coercion does not exist. Special protections are in place when research involves vulnerable populations, such as children, those unable to consent, prisoners, fetuses, pregnant women, the terminally ill, students, and employees. Children may be involved in a trial that involves "more than minimal risk," but also holds the prospect of benefiting that child. In such trials, the risk must be justified in relation to those expected benefits. That is, the expected benefits must be 12

13 great enough to make the risk worthwhile. The expected benefits in relation to the risks must be at least as great as that of the best available alternative. Even though a child is not old enough to give consent, when appropriate, the approval, or assent of the child must be sought if the child is old enough to appreciate the circumstances involved. In many cases, assent of an older child is required by federal regulations. If the research involved does not provide direct benefit to children, participation in the study must involve only a minor increase over minimal risk. This risk must be within the child's life experiences, including medical experience. The scientific value of the project must relate to the disorder that the child faces. Special permission might be granted by the U. S. Department of Health and Human Services if, among other things, the research is ethically conducted and holds the promise of preventing diseases that affect the welfare of children. Prisoners, as with children, are considered a vulnerable population. Additional safeguards must be taken to ensure that research done with the participation of prisoners is genuinely voluntary. For example, the advantages of participation for the prisoner should not be large in comparison with ordinary conditions for prisoners such that their ability to appropriately weigh risks and benefits would be clouded. For example, offering a prisoner freedom in exchange for participation would be considered wrong. In general, it is not inappropriate to pay research participants. Yet payment is worrisome when it leads to coercive participation or undue influence on the informed consent process. This may be especially true when a less wealthy population is involved. Federal regulations also require that proposals for research on human beings be reviewed -- prior to initiating the project -- by an Institutional Review Board (IRB). The IRB is intended to protect the safety, welfare, and rights of human research participants. At least one IRB must be set up by all institutions that may receive federal funding for research. A large research hospital or university may have many IRBs. IRBs must have at least five members, and those members should be from diverse ethnic, gender, and cultural backgrounds. At least one member should have a science background, and at least one member must not be affiliated with the institution. An IRB is assigned a variety of responsibilities. It should examine protocols to assure that risks are minimized and are reasonable in relation to any expected benefits to the participants. It should determine that important information would result from the trial. The IRB should ensure that participants are selected in an 13

14 equitable manner. It should determine whether or not informed consent, if required, would be properly obtained and documented. It should check for additional safeguards when children or vulnerable subjects are involved. It should determine that risks to participants are justified in relation to the expected benefits of the research. An IRB has the responsibility of monitoring research in an ongoing way. This is an especially important duty when research involves high risk to participants. Researchers are required, in many trials, to submit a plan to monitor the safety of their trial. A trial might be stopped if it involves serious unexpected consequences to research participants. A trial might also be stopped if the experimental therapy proves highly beneficial. In many trials, participants in other arms may then be offered the experimental therapy. We have briefly presented some of the responsibilities of IRBs. Their job is to protect research participants. This should give some assurance that clinical trials are designed to safeguard participants by, for example, minimizing risk. However, an IRB review is no guarantee that this is true. The IRBs may be overworked, and thereby unable to give adequate attention to a particular research proposal. Secondly, IRBs may be unaware of some of the risks due to the technicalities of a complex research proposal. Even though an IRB reviews a trial, a patient considering participation should learn as much as possible about the trial. A patient should come to his or her own independent judgment about the risks and expected benefits of participation. Question. Exactly how good is the protection provided by IRBs? Answer. It is very difficult to know just how effective IRBs are. Some undoubtedly are very good, and some are just plain overworked and therefore cannot provide effective protection. This may be especially true in large institutions conducting hundreds of trials. IRBs are undoubtedly a crucial part of patient protection, but they are not foolproof. Patients cannot simply rely on IRBs to protect them. Patients have a right to reject participation in a trial. Researchers have a moral and legal obligation to obtain informed consent from competent prospective trial participants. All relevant information about the trial should be disclosed. Efforts must be made to ensure that the prospective participant understands the information that was provided. Informed consent must be given voluntarily without coercion. 14

15 Participants may withdraw their consent at any time, and this should be permitted without penalty. If a person is considering participation in a clinical trial, he or she should make sure that disclosure about the trial is complete and understandable. Make sure that no coercion is involved. A prospective participant should understand that some trials might be medically beneficial. This is especially true for trials involving cancer therapy for children. But even in that case, parents should be diligent in considering whether the trial is in the best interest of their child. All trials have risks. Many trials have potential benefits for participants. Expected benefits and risks should be carefully weighed. Patients should keep in mind that assignment to a placebo arm, if used in a trial, will be random. This means that a patient is might not receive medically effective treatment if the patient is enrolled in a trial with a placebo arm. If the patient wants the experimental therapy, that patient should understand the odds might be against being assigned to the experimental arm. Furthermore, it should be kept in mind that trials are designed to resolve uncertainties. No matter how confident a researcher is about an experimental therapy, that researcher may be wrong. There is always risk that an experimental therapy may be inferior or harmful. Patients faced with a choice of whether or not to participate in a clinical trial should do the following: Carefully consider all of the risks and expected benefits that may be involved. Speak with the physicians or nurses who are conducting the trial. Know all the main facts about the trial, including how participants will be divided into trial arms. Find out whether selection for arms will be random. Fully understand whether or not participants stand a chance of being placed in a placebo group; one that does not receive active therapy Understand the attempts that will be made to keep patient information private. Explore alternatives to treatment in a trial. Determine how much flexibility is allowed by the protocol. Insist upon adequate informed consent. 15