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Clinical Trials

Clinical trials

Definition

A clinical trial is a research study designed to answer specific medical questions regarding cancer care.

Description

The clinical trial is a scientific study that follows a written guideline (protocol) or recipe for treatment. It is the only scientific mechanism designed to test the effectiveness of new and promising therapies. The clinical trial provides intensive testing of new or updated treatment regimens. Almost all standard treatments in the field of oncology (cancer) originated from clinical trials. These trials are conducted by medical, surgical and radiation oncologists (cancer specialists).

Cancer clinical trials are the key to preventing, diagnosing and treating all types of cancer. It is estimated that 60% of all cancer patients in the United States are being cured. Yet, fewer than 3% of adult cancer patients participate in clinical trials. In contrast, about 71% of children enter clinical trials. This has led to major advancements in treatment and high cure rates for many childhood cancers such as Wilms' tumor (malignant neoplasm of the kidney), osteosarcoma (tumor of the bone), and childhood leukemia (cancer of the blood).

Types of clinical trials

Clinical trials that involve new drugs or devices for humans must first be tested in animals. When a new or investigational drug has been discovered that shows anti-tumor activity in laboratory animals, it is tested on a small number of patients with different types of cancer, usually in a university setting. These are called Phase I trials and are designed to test the maximum tolerated dose (MTD) and side effects or toxicities of a new drug. This phase also helps determine how a new drug should be given (by mouth or by injection). The patients being tested are those with advanced cancer who have exhausted other treatment options. These patients may not personally benefit from participation in the trial.

If the investigational agent or drug continues to show anti-tumor activity and if the side effects are tolerable and not life-threatening, the drug is moved into a Phase II trial for further testing. In a Phase II trial, the drug is offered to a specific group of patients having the same tumor type. The drug is being tested to determine if it regresses tumor growth. Additional information on side effects of the treatment is also evaluated in this phase.

If the drug continues to show response to the patient's cancer, it is moved into a Phase III trial. At this phase, the investigational treatment is compared to the standard cancer therapy. This is to ensure that no one in a study is left without any treatment when standard treatment is available. If there is no standard therapy, a placebo (a pill that looks like the drug being studied but contains no active medication) may be used for comparison. However, researchers must inform potential patients of this possibility before patients decide whether to participate. Patients are usually assigned their treatment by a process called randomization, which is similar to the toss of a coin. Comparison or randomized trials help researchers find the most effective treatment for a specific type of cancer.

The objectives of Phase III trials include tumor response to treatment, survival, and quality of life during therapy. This phase can involve 400-1000 patients. Anti-tumor response by a significant proportion of the involved patients indicates that the investigational drug or treatment is ready to be submitted to the Food and Drug Administration (FDA) for approval. If approved, the drug is released from investigational status and made available for commercial use in patients with the specifically tested type of cancer.

What to expect as part of a clinical trial

Taking part in a clinical trial does not mean that patients are seen as or treated like "guinea pigs, " or that they will receive substandard care. Cancer patients who enroll in clinical trials may be the first to receive a new technique or drug that becomes the standard of care. Clinical trials, however, have risks, as well. The treatment or drug being tested is new, and the side effects may be unknown. The cancer patient, his or her loved ones, and the patient's physician must weigh the risks and benefits when deciding whether or not to enroll in a clinical trial.

When patients participate in a clinical trial, they receive treatment in a cancer center, hospital, clinic, and/or doctor's office. Doctors, nurses, social workers, and other health professionals may be part of the treatment team, and will closely monitor progress. Cancer clinical trial patients:

  • are, as stated above, under close scrutiny
  • are seen frequently by the members of the treatment team
  • are tested often
  • follow the treatment plan their doctor prescribes and as according to the study's protocol
  • and may also have other responsibilities, such as keeping a log or filling out health forms.

Some studies continue to check on patients after their treatment is completed.

Resources

BOOKS

Klimaszewski, Angela D., Jennifer L. Aikin, Monica A. Bacon, Susan A. DiStasio, Heidi E. Ehrenberger, Bertie A. Ford, Ed. Manual for Clinical Trials Nursing. Pittsburgh: Oncology Nursing Press, Inc., 2000.

Murphy, Gerald P., Walter Lawrence, Jr., and Raymond E.Lenhard, Jr., Ed. American Cancer Society Textbook of Clinical Oncology. Atlanta: American Cancer Society, 1995.

Varricchio, Claudette, Ed. A Cancer Source Book for Nurses. Atlanta: Jones and Barlett Publishers, 1997: pp. 69-79.

OTHER

National Cancer Institute. An Introduction to Clinical Trials. January 2000 National Cancer Institute. 8 July 2001. <http://cancertrials.nci.nih.gov>.

National Cancer Institute. Cancer Trials. 8 July 2001. <http://cancertrials.nci.nih.gov/>

Phyllis M. Stein, B.S., CCRP

KEY TERMS

Leukemia

Cancer of the blood and bone marrow.

Maximum tolerated dose (MTD)

The highest dose of an investigational drug that patients can tolerate without life-threatening or fatal side effects.

Oncology

The study of cancer.

Osteosarcoma

A tumor of the bone. The most common childhood cancer.

Placebo

A preparation without medication.

Protocol

A written, scientific guideline used for treatment planning in clinical trials.

Wilms' tumor

A malignant tumor of the kidney; occurs most frequently in children.

QUESTIONS TO ASK THE DOCTOR

  • Am I eligible for a clinical trial?
  • Where can I get more information?

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Clinical Trials

Clinical trials

Definition

A clinical trial is a carefully designed research study that is carried out with human volunteers. The trial is designed to answer specific questions concerning the effectiveness of a drug, treatment, or diagnostic method, or to improve patients' quality of life.

Description

Qualification for a clinical trial involves the selection of various desirable criteria (inclusion criteria), as well as criteria by which volunteers are rejected (exclusion criteria). Typical criteria include age, gender, the type and severity of the disease, prior treatment, and other medical conditions.

Depending on the clinical trial, the volunteers that are recruited could be healthy or ill with the disease under study. There are a number of different types of clinical trials that utilize differing types of study plans (protocols). A treatment trial evaluates a new treatment, new drug combinations, new surgical strategies, or innovative radiation therapy. A prevention trial seeks to find better ways to prevent disease from occurring or prevent disease from returning. Medicines, vaccines, vitamins, and lifestyle changes can all be candidates for a prevention trial. A diagnostic trial is designed to find better means of diagnosis for a particular disease or medical condition. A screening trial is designed to determine the best way to detect a particular disease or medical condition. Finally, a quality of life trial (supportive care trial) seeks to improve the comfort and daily life of people with a chronic illness.

Clinical trials, particularly treatment and prevention trials, often have several components, or phases. The following phases (I-IV) relate to the scope of the trial:

  • Phase I trial evaluates the new drug or treatment in a small group of people (less than 100). Humans do not necessarily need to participate in such a trial. Experiments in the lab using microbiological cultures or tissue cells may suffice. The trial's purpose is to provide early indications of a drug or treatment's safety, safe dosage range, and reveal any side effects.
  • Phase II trial follows a phase I trial. A promising drug or treatment is tested on a larger group of people (100300) to better determine the effectiveness and to monitor safety more critically. Use of a larger population can help reveal side effects that could be hidden by the use of only a few volunteers.
  • Phase III trial evaluates a drug or treatment that has proven effective in the phase I and II trials and is tested on a large population (1,0003,000) to confirm its effectiveness, reveal any rarer side effects, and gather information that will allow the drug or treatment to be safely marketed.
  • Phase IV trial occurs after a product has been released in the marketplace. Monitoring of a drug or treatment in very large numbers of people provides further information on benefits and risks.

A typical clinical trial involves medical doctors and nurses, although social workers and other health care workers may also contribute. The members of the clinical team monitor the health of each volunteer at the outset and during the trial, give instructions, and often provide follow-up after the trial is completed. For a clinical trial volunteer, this means more visits to the health care facility than would normally occur, although compensation such as transportation expense is sometimes provided.

A critical part of a clinical trial is obtaining the consent of volunteers for their participation. It is mandatory that a trial's risks (i.e., side effects, little or no effect of treatment) and benefits (i.e., more proactive role in health care, access to new therapies, advance medical care) be clearly explained to participants. Once this is done, volunteers provide their informed consent by signing a document. This document is not legally binding, so volunteers are not obligated to complete the trial. An ethical clinical trial will never reveal the identities of the volunteers.

In addition to the drug being studied, clinical trials of new drugs will typically use a pill, liquid, or powder that looks the same as the active compound, but that has no medicinal value. This inactive compound, known as a placebo, is usually given to the control group of volunteers, who are compared to the test group that receives the active drug. Usually the volunteers do not know whether they receive a placebo or the active drug. A clinical trial can be designed so that the researchers are also unaware of which people receive the active drug. When volunteers and researchers are both unaware, the trial is described as being double blind. Volunteers are often assigned to the control or test groups at random. This action is designed to minimize any bias due to age, gender, race, or other factors.

Resources

OTHER

"An Introduction to Clinical Trials." ClinicalTrials.gov. January 21, 2004 (March 30, 2004). <http://www.clinicaltrials.gov/ct/info/whatis)>.

ORGANIZATIONS

National Institutes of Health, Clinical Center. 6100 Executive Blvd., Suite 3C01MSC 7511, Bethesda, MD 20892-7511. (301) 496-2563 or (800) 411-1222; Fax: (301) 402-2984. [email protected] <http://www.cc.nih.gov/home.cgi>.

Brian Douglas Hoyle, PhD

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Clinical Trials

Clinical Trials

A clinical trial is a prospective study of the effectiveness of a new treatment, such as a drug, surgical technique, or medical device. The term prospective indicates that there is a well-defined starting point from which the subjects are tracked for some definite period of time. Before a clinical trial is conducted, laboratory experimentation and animal trials on the proposed treatment is performed.

Clinical trials must meet strict government guidelines established by the U. S. Food and Drug Administration (FDA) to assure the safety of subjects and the scientific validity of the trial. Prior to admission to a clinical trial, subjects must meet the study requirements and be sufficiently informed regarding the purpose of the trial. A new treatment may have major benefits but may also have significant side effects for the type of patient that it could help. Careful screening and examination help select persons who meet the trial's design and intent. Informed consent, required of all participants, will alert the subjects not only to the purpose and design of trial with its potential benefits but to any known or suspected side effects or complications.

A phase I trial is a small-scale test in healthy volunteers to determine the general safety of the treatment with human subjects. Phase II tests the safety and effectiveness of the new treatment in a small group of patients who might benefit. A phase III trial is a large-scale study to scientifically document the value of the proposed drug, technique, or device. Phase IV studies allow the long-term follow-up of patients to determine side effects and continued effectiveness after a treatment reaches the market.

The expense involved in clinical trials is due to the extensive development and research costs, initial laboratory testing, and their large-scale nature. Conducted at multiple sites around the country, clinical trials have significant infrastructure for record-keeping, follow-up, dissemination, and safety.

Craig Clifford

Bibliography

Friedman, L. M., C. D. Furberg, and D. L. DeMets. Fundamentals of Clinical Trials, 3rd ed. New York: Springer-Verlag, 1998.

Whitehead, John. The Design and Analysis of Sequential Clinical Trials, 2nd ed. New York: John Wiley & Sons, 1997.

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Clinical Trials Network

CLINICAL TRIALS NETWORK

In an effort to find the most effective treatments for drug addiction, the National Institute on Drug Abuse (NIDA) has established a clinical trials research network to test new pharmacological and behavioral treatments in diverse patient populations. Clinical trials have been used for diseases such as cancer and AIDS as a fast, effective, and safe way to test new treatments. Also, as with other diseases, there are a number of effective treatments for addiction. However, the efficacy of these new treatments has been demonstrated primarily in specialized treatment research settings, with somewhat restricted patient populations. As a consequence, few of these new drug-abuse treatments are being applied on a wide-scale basis in real-life practice settings

In response, NIDA has established the National Drug Abuse Treatment Clinical Trials Network (CTN). The CTN is based on a model used successfully by other NIH institutes, including the National Cancer Institute, the National Heart Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases. The CTN provides a research infrastructure to test whether new and improved treatment components are effective in real-life settings with diverse patient populations.

THE CTN STRUCTURE

NIDA has established the first six nodes of the CTN in various regions of the country. Each node or functional unit of the CTN is affiliated with a research-based organization and a number of drug-abuse treatment programs in the community. The CTN brings together researchers and practitioners as partners to conduct full-scale testing of promising new medications and behavioral treatments in a wide range of community drug-abuse treatment settings with patients from a variety of ethnic and social back-grounds. (The nodes to date include nodes in New England, the Delaware Valley, the Mid-Atlantic, the Northwest, the Pacific region, and New York.) Each of these centers is linked with at least five community treatment programs in its region. CTN research is carried out in the community-based treatment setting. Each node works with the other nodes and with NIDA to conduct multisite and cross-regional clinical trials research.

THE MISSION OF THE CTN

The overall goal of the CTN is to improve the quality of drug-abuse and addiction treatment throughout the nation using science as the vehicle. Toward this end, the mission of the CTN is threefold:

  1. Conduct studies of behavioral, pharmacological, and integrated behavioral and pharmacological treatment interventions in multisite clinical trials to determine effectiveness across a broad range of community-based treatment settings and diversified patient populations.
  2. Transfer the research results to physicians, providers, and their patients to improve the quality of drug abuse treatment throughout the country using science as the vehicle.
  3. Provide advice on changing policies to ensure the delivery of effective therapies in community-based treatment programs.

CURRENT AND FUTURE DIRECTIONS

Three science-based treatment research protocols will start in 2000, including two behavioral therapies developed to enhance treatment outcomes, and one that will test a new medication for use in opiate detoxification. Several other protocols are currently being developed. All treatment components to be tested have been shown to be effective in controlled research environments.

When complete, it is expected that the network will consist of twenty to thirty nodes consisting of regional research treatment centers linked to ten to fifteen community-based treatment programs that represent the variety of settings and patient populations prevalent in that particular region of the country. The CTN will help ensure that treatment research in drug abuse and addiction meets the needs of the wider community, including minorities, women, children, adolescents, and underserved populations. The CTN will also be useful to other aspects of NIDA's research portfolio. For example, multi-site clinical trials with diverse patient populations will provide a valuable resource to researchers interested in elucidating genetic and environmental determinants of vulnerability. Ultimately, increased understanding of the roles played by genetics, environment, and their interaction in shaping an individual's susceptibility to drug addiction will lead to a variety of more targeted drug abuse prevention and treatment approaches. For more information, visit NIDA's website at www.nida.nih.gov.

For more information about NIDA's National Drug Abuse Treatment Clinical Trials Network, visit the NIDA website at www.drugabuse.gov.

Alan I. Leshner

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Clinical Trials

Clinical Trials

Definition

Description

Considerations before entering a clinical trial as a subject

Resources

Definition

A clinical trial is a controlled scientific experiment designed to determine the effectiveness of a treatment in curing or lessening the symptoms of a disease or disorder.

Description

Clinical trials typically are used to assess the effectiveness of a new treatment in comparison with the current standard of care or an existing treatment for a disease or disorder. For example, before a new drug is approved by the U.S. Food and Drug Administration (FDA) for release and use in the United States, the drug must first undergo rigorous testing to determine (a) whether or not it is effective in treating the disorder, and (b) what side effects may result from the drug use that make it inadvisable or dangerous to some or all potential patients.

Clinical trials are research studies designed according to professional standards using scientific methods. In clinical trials, as many variables as possible are controlled to determine the effects of the drug or treatment option. For example, a simple experiment to test the effectiveness of a new drug for epilepsy might include the following steps. First, researchers typically randomly divide the research subjects into two groups: one group that receives the new drug and the other group that receives the conventional drug or treatment. The group receiving the new drug is called the experimental group and the group receiving no treatment or conventional treatment is called the control group. Researchers then collect baseline data on the symptoms of the subjects prior to treatment, such as number and frequency of seizures . This phase of the experiment is called the pretest. After the pretest data are collected, the researchers give the new drug (the independent variable) to the experimental group while not changing the treatment of the control group. After an appropriate amount of time for the drug to take effect, the subjects are tested again using the same criteria as were used for the pretest to determine any difference between the two groups as a result of the drug (dependent variable). When all the data are collected, they are statistically analyzed to determine if there is a reasonable basis to say that the effects of the new drug are significantly different from the effects of the old treatment (or no treatment) and not due to chance variations. This basic research design can be made more complicated to simultaneously answer multiple research questions, such as what dose of the new medication is most effective, whether increasing dosage levels of the medication results in more side effects, whether the drug is effective for some demographic groups but not others (e.g., only works well on adult females but not on adult males), or to compare several treatments at once.

KEY TERMS

Control group —A group in a research study that does not receive the experimental treatment. For example, in an experiment testing the effectiveness of a new drug, the control group might receive the current drug of choice while the experimental group receives the new drug under investigation.

Dependent variable —The outcome variable in an experiment. For example, in a test of the effects of a new drug for the treatment of a disease, the effects of the drug on the disease (i.e., the change in symptoms after taking the drug) would be the dependent variable.

Double-blind study —A research study in which neither the participants nor the professional administering the drug or treatment know whether they are receiving the experimental treatment or a placebo or control treatment.

Experimental group —The group of participants in a research study who receive the experimental treatment or drug under investigation.

Independent variable —The variable in an experiment that is manipulated by researchers in order to determine its effects. For example, in a test of the effects of a new drug on the treatment of a disease, whether or not the subjects received the new drug would be the independent variable.

Informed consent —A legal document prepared as an agreement for treatment or nontreatment that requires physicians to disclose the benefits, risks, and alternatives of the treatment. Informed consent allows fully informed, rational patients to be involved in the choices about their health.

Placebo —A preparation without pharmacological effect that is given in place of a drug in clinical trials to determine the effectiveness of the drug under study; a “sugar pill.”

Randomization —The process of randomly assigning participants in an experiment to the various conditions (i.e., experimental and control groups) so that each individual has an equal chance of being assigned to any of the groups. Randomization helps ensure that each of the groups is roughly the same and that the results are due to the treatment, not to the makeup of the groups.

Research subject —A participant in a research experiment or clinical trial.

There are several general types of clinical trials:

  • treatment trials that test the relative effectiveness of new drugs or treatments or combinations of drugs and/or treatments
  • prevention trials that investigate ways to prevent a disease in individuals who have not previously had it or to prevent its return in individuals who have previously had the condition
  • diagnostic trials that seek to find better ways for diagnosing a disorder or illness
  • screening trials to determine the best way to detect a disease or disorder
  • quality-of-life trials that investigate how to make life easier or more normal for those with a chronic illness

Clinical trials typically have four phases. In Phase I, the experimental drug or treatment is tested on a small group of people to investigate its safety, determine a recommended dosage or range, and identify potential side effects. In Phase II, the experimental drug or treatment is tested on a larger group of people to further determine its effectiveness and safety. Phase III clinical trials examine the drug or treatment from an even wider perspective. The experimental drug or treatment is given to large groups of people to confirm the findings of the previous studies on a larger population. Phase III clinical trials are also often used to compare the relative effectiveness of treatments and gather safety information. Finally, Phase IV clinical trials are run after a drug has been marketed. At this time a drug may undergo further studies to examine its risks, benefits, and optimal use.

Considerations before entering a clinical trial as a subject

Clinical trials are necessary to help ensure the safety and effectiveness of a drug or treatment before it is put into general use. In addition, joining a clinical trial as a research subject may be of potential benefit to patients who have exhausted available treatment options without success. Clinical trials give patients the opportunity to try a new drug or treatment that may help their condition when conventional methods have failed. However, certain things must be considered before joining a clinical trial as a subject.

First, there is no guarantee that subjects in clinical trials will receive the new drug or treatment. They may

be randomly placed in the control group where they receive a placebo or conventional treatment rather than the new drug or treatment. There is no way to tell whether or not one will be in the experimental group or the control group. Frequently,even researchers or people administrating the treatment do not know which group the subject is in (this is called a double-blind study) so that their expectations will not unintentionally bias the results. Therefore,all other available treatment options should typically be tried before joining a clinical trial as a subject.

In addition, there is always the possibility of encountering unknown negative side effects from the new drug or treatment. For this reason, subjects in clinical trials are required to read, understand, and sign informed consent documents. The decision to join a clinical trial as a subject should always be made in conjunction with one’s health care provider in order to reduce the risk of negative side effects from the treatment.

Resources

BOOKS

VandenBos, Gary R.,ed.APA Dictionary of Psychology. Washington,D.C.: American Psychological Association, 2007.

ORGANIZATIONS

National Institutes of Health.<http://www.clinicaltrials.gov>.

Pharmaceutical Research and Manufacturers of America (PhRMA). <http://www.phrma.org>.

Ruth A. Wienclaw,Phd

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Clinical Trials

CLINICAL TRIALS

Clinical trials are systematic investigations on human subjects testing the safety and efficacy of novel medical interventions, including drug, surgical, or behavioral treatments. Conventionally clinical trials are divided into four types or phases. In a phase I clinical trial, typically involving tens of subjects, a novel procedure is tested for the first time in human beings and data is collected on safety. In a phase II trial, which may involve hundreds of patients, evidence is sought that a novel intervention has a therapeutic effect on the disease of interest. In a phase III clinical trial, often involving thousands of patients, the novel intervention is compared to a standard intervention or placebo. In a phase IV trial, called a post-marketing study, information is collected on the long-term safety and efficacy of the intervention from patients receiving the intervention in clinical practice and measured against a control treatment. The rigorous evaluation of novel medical interventions in clinical trials is a foundation of evidence-based medicine.



Historical Development

The randomized clinical trial is one of the most important advances in medicine in the twentieth century. Prior to its development, treatments were adopted on the basis of the publication of a series of cases in which their use had proved helpful. Due to numerous sources of potential bias, including variation in expertise from one clinician to the next, and the selection of patients more likely to recover for inclusion in the study, case series often led to misleading results. Clinicians were faced with numerous treatments from which to choose, and little evidentiary basis upon which to ground a choice. For example, Richard Doll, a well-known British clinical trialist, described how at the start of his research into the treatment of peptic ulcer in 1948, he was able to list purported treatments beginning with each letter of the alphabet.

In clinical trials until mid-twentieth century, two treatments for comparison were allocated to alternating patients. This method was flawed by the fact that physicians could anticipate the treatment assignment, and thereby select which treatment a particular patient would receive by changing the patient's position in the queue. It was not until mid-century that R.A. Fisher's allocation strategy using random numbers, developed in 1926 for agricultural experiments, was used in clinical trials. Allocation using random numbers countered bias in selection and provided statisticians with an estimate of random error, a key component of modern statistical analysis. The first clinical trial to randomly allocate treatments to patients using random numbers was the United Kingdom Medical Research Council (MRC) whooping cough immunization trial initiated in 1946. The better-known MRC streptomycin trial in tuberculosis started a few months later, but published its results before the whooping cough trial in 1948.

Since the mid-twentieth century, the clinical trial has undergone a dramatic increase in use for the evaluation of the safety and efficacy of novel medical interventions. A variety of social and political factors supported this trend. The period following the Second World War witnessed an unprecedented public investment in health research. In 1945, the United States National Institutes of Health budgetary appropriation was $700,000; in 1970 its appropriation was $1.5 billion. Drugs regulation underwent significant changes in this period as well. From 1938 to 1962, the U.S. Food and Drug Administration (FDA) was only empowered to require that new drugs be tested for safety. Following on the heels of the thalidomide tragedy, in which hundreds of infants were born with congenital malformations after exposure to thalidomide in utero, legislative reform dramatically increased the FDA's power. The 1962 Kefauver-Harris Act expanded the FDA's mandate to test new drugs for both safety and efficacy.

The testing of new drugs for safety and efficacy in clinical trials occurs in an increasingly international environment. Cooperation among drugs regulators and manufacturers seeks to standardize the conduct of clinical trials and their review by drugs regulators. The International Conference on Harmonization Good Clinical Practice guidelines are a key instantiation of this effort. The protection of human subjects in research is similarly seen as a matter of global concern. Perhaps the most influential ethics document in the international forum is the World Medical Association's Declaration of Helsinki. The declaration requires that clinical trials be reviewed by appropriately constituted research ethics committees; research be free of misconduct; the consent of human subjects be obtained; study participation pose a favorable balance of benefits to harms; and subjects be selected equitably.


Ethical Issues

Some of the most important ethical challenges of clinical trials stem from conflicting duties of the physician-researcher. Physicians have fiduciary obligations to patients, including a duty to provide competent personal care. Researchers, by contrast, have obligations to science and society, including duties to provide treatment as prescribed in the trial protocol, ensure that patients comply with treatment, and encourage them to stay in the study. Given that these duties may conflict, the central moral question of the clinical trial is: When may physicians legitimately offer patients enrollment in a clinical trial? While a variety of answers have been provided to this question, the most widely accepted is that of clinical equipoise. According to clinical equipoise, physicians may legitimately offer patients enrollment in a clinical trial only if the medical interventions within the study are consistent with competent medical care. More formally, it requires that at the start of the study there exists a state of honest, professional disagreement as to the preferred treatment. The consequences of clinical equipoise for the design of clinical trials are far reaching.

Two issues in respect to the design of clinical trials have dominated research ethics literature since the 1990s. The first is the proper role of placebo controls in the new drug approval process in developed countries. Drug regulatory agencies in developed countries, such as the FDA, have long required that new drugs prove superior to placebos in at least two clinical trials before licensure. The practice in the United States is rooted in legislation that requires the FDA to ensure new drugs are efficacious, that is, that they have some effect in treating the condition of interest, but generally restricts its ability to demand evidence of comparative effectiveness. According to clinical equipoise, placebo-controlled clinical trials are unproblematic when there is no proven treatment for the condition of interest.

Criticism has focused on the use of placebo controls in clinical trials testing novel interventions for treatable medical conditions, such as severe depression and schizophrenia. The use of placebos in these cases is impermissible, because no competent physician would fail to offer a patient treatment and, accordingly, clinical equipoise is violated.

The 2002 revision of the Declaration of Helsinki sets aside this fundamental moral requirement, and for the first time permits the use of a placebo control when "compelling and scientifically sound methodological reasons" exist. This change seems to violate a core provision of the declaration requiring that "[i]n medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society." Whether there are in fact scientifically sound methodological reasons to prefer a placebo control over a standard treatment control remains an open question.

The second clinical trial design issue to receive considerable attention in the literature is the choice of control treatment in clinical trials of new and affordable treatments for developing countries. Disagreement was originally sparked by clinical trials testing the efficacy of short-course zidovudine against placebos for the prevention of transmission of HIV from mother to child. Critics of the clinical trials pointed to the existence of an effective prevention regimen called ACTG 076 used in developed countries. Denying subjects in the clinical trials conducted in developing countries access to this prevention regimen, they claimed, constitutes an ethical double standard between developed and developing countries.

Proponents of the clinical trials countered that the ACTG 076 regimen is not suited to administration in many developing countries and the cost is prohibitive. Changes in international regulation have tended to entrench rather than resolve the dispute. The Declaration of Helsinki proscribes placebo controlled trials in developing countries when effective treatment exists in developed countries saying that "[t]he benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." Yet the "International Ethical Guidelines for Biomedical Research Involving Human Subjects" permit placebo controlled trials under these circumstances provided the clinical trial is "responsive to the health needs of the population from which the research subjects are recruited and there [is] assurance that, if it proves to be safe and effective, it will be made reasonably available to that population."

OPEN QUESTIONS. The interface between the ethics and science of clinical trials is replete with challenging questions yet to be addressed adequately. What ought the role be for adaptive designs, for instance, clinical trials in which the probability of being assigned to one treatment or another is dynamic in an attempt to minimize the number of subjects who receive the treatment that turns out to be inferior? Can alternative medical treatments be evaluated rigorously in clinical trials? Alternative practitioners may claim that alternative treatments cannot be removed from a holistic treatment context, a substantial obstacle to the rigorous assessment of the treatment's efficacy. How will pharmacogenetic testing impact the conduct of clinical trials? Proponents of pharmacogenetics suggest that identification by genetic testing of those likely to respond to treatments and those likely to suffer adverse events would increase the efficiency and safety of clinical trials. Critics wonder if the gains from such testing will be as large as promised and what impact it will have on the generalizability of clinical trial results.

While ethical issues in the design of clinical trials are the subject of ongoing scholarship, ethical aspects of the conduct and reporting of clinical trials are relatively ignored. As clinical trials accumulate data on outcomes, disparities may emerge between the treatments in the clinical trial raising questions as to whether the trial ought to be stopped early. It is generally agreed that when clinical trials use outcome measures of mortality or serious morbidity an independent data monitoring committee should be established to periodically review accumulating data. A satisfactory moral framework to guide the decisions of data monitoring committees has yet to be developed.

Ethical issues in the reporting of clinical trial results also deserve attention. If researchers fail to report the results of a negative clinical trial, subjects in the trial were exposed to risk for naught and the problem of publication bias is compounded. While this seems problematic intuitively, a moral basis for an obligation to publicize clinical trial results has yet to be articulated.


CHARLES WEIJER

SEE ALSO Complementary and Alternative Medicine; Drugs; Human Subjects Research.

BIBLIOGRAPHY

Angell, Marcia. (1997). "The Ethics of Clinical Research in the Third World." New England Journal of Medicine 337: 847–849. A stinging critique of placebo controlled clinical trials testing the efficacy of short course zidovudine in the prevention of perinatal transmission of HIV in developing countries.

Crouch, Robert, and John Arras. (1998). "AZT Trials and Tribulations." Hastings Center Report 28(6): 26–34. A sober response to Marcia Angell's critique.

Doll, Richard. (1998). "Controlled trials: The 1948 Watershed." British Medical Journal 317: 1217-1220. A historical review of changes to clinical trials at mid-century by one of the central figures in its development.

Emanuel, Ezekiel; Robert Crouch; John Arras; et al., eds. (2003). Ethical and Regulatory Aspects of Clinical Research: Readings and Commentary. Baltimore, MD: Johns Hopkins University Press. The definitive collection of readings in the ethics of human experimentation.

Miller, Paul, and Charles Weijer. (2003). "Rehabilitating Equipoise." Kennedy Institute of Ethics Journal 13: 93–118. A philosophical piece examining the conflicting duties of physician and researcher, and how these conflicts might be resolved.

Piantadosi, Steve. (1997). Clinical Trials: A Methodologic Perspective. New York: John Wiley & Sons. An authoritative methodological resource for the design of clinical trials.


INTERNET RESOURCES

Council for International Organizations of Medical Sciences. "International Ethical Guidelines for Biomedical Research Involving Human Subjects." Available from http://www.cioms.ch/frame_guidelines_nov_2002.htm. Guidelines for the conduct of research in resource-poor nations.

National Placebo Working Committee. "National Placebo Initiative: Draft Report of the National Placebo Working Committee." Canadian Institutes of Health Research. Available from http://www.cihr-irsc.gc.ca/e/services/pdf_19320.htm. A thorough document setting out the scientific, ethical, legal, and policy case for and against the widespread use of placebo controls in clinical trials.

World Medical Association. "Declaration of Helsinki." Available from http://www.wma.net/e/policy/b3.htm. The most influential international statement of moral standards for the conduct of clinical research.

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