Question

Drug testing of low wage workers or high school students Essay 4-5 pages with 8-10 sources includes

Answer 1

What Is a Clinical Trial?

Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials.

Although "new" may imply "better," it is not known whether the potential medical treatment offers benefit to patients until clinical research on that treatment is complete. Clinical trials are an integral part of new product discovery and development and are required by the Food and Drug Administration before a new product can be brought to the market.

The FDA is committed to protecting the participants of clinical trials, as well as providing reliable information to those interested in participating. Recently, unethical behavior on the part of some researchers has shaken the public trust and prompted the federal government to establish regulations and guidelines for clinical research to protect participants from unreasonable risks.

Although efforts are made to control risks to clinical trial participants, some risk may be unavoidable because of the uncertainty inherent in clinical research involving new medical products. It's important, therefore, that people make their decision to participate in a clinical trial only after they have a full understanding of the entire process and the risks that may be involved.

Why Participate in a Clinical Trial?

People volunteer to participate in clinical trials for different reasons. Some volunteer because they want to help advance medical knowledge. Others have tried all available treatments for their condition without success.

In a 2000 Harris Poll of cancer clinical trial participants, 76 percent of the respondents said they participated because they believed that the trial offered the best quality of care for their disease. Helping other people and receiving more and better attention for their own specific disease were other reasons cited.
People should not, however, be tempted to enroll in a clinical trial simply because a potential treatment is being offered free during a study, or because of the promise of money, says David Banks, an FDA pharmacist.

"People lured by compensation may overlook the known risks," Banks says. "Or [they may fail] to adequately appreciate the potential for discovery of serious new side effects during clinical testing of a new treatment." Banks also says that clinical trials "are generally not a means for patients to receive long-term treatment for their chronic disease." Still, he adds, "clinical trials often represent an option to seriously consider."

Who Can Participate?

It's important to test medical products in the people they are meant to help. In the past, most new drug testing had been done on white men. Groups such as women, blacks, and Hispanics often were not adequately represented. It's important to test medical products in a wide variety of people because drugs can work differently in people of various ages, races, ethnicity, and gender. The FDA seeks to ensure that people from many different groups are included in clinical trials.

Trial guidelines, or eligibility requirements, are developed by the researchers and usually include criteria for age, sex, type and stage of disease, previous treatment history, and other medical conditions. Some trials involve people with a particular illness or condition to be studied, while others seek healthy volunteers. Inclusion or exclusion criteria--medical or social standards used to determine whether a person may or may not be allowed to enter a clinical trial--help identify appropriate participants and help to exclude those who may be put at risk by participating in a trial.

Volunteering for a clinical trial is no guarantee of acceptance. Similarly, there's no guarantee that an individual in a clinical trial will receive the drug or medical product being studied.

What Happens in a Clinical Trial?

Every clinical trial is carefully designed to answer certain research questions. A trial plan called a protocol maps out what study procedures will be done, by whom, and why. Products are often tested to see how they compare to standard treatments or to no treatment. The FDA often provides extensive technical assistance to researchers conducting clinical trials, helping them design better trials that can characterize effects of a new product more efficiently, while reducing risks to those participating in the trials.

The clinical trial team includes doctors and nurses, as well as other health care professionals. This team checks the health of the participant at the beginning of the trial and assesses whether that person is eligible to participate. Those found to be eligible--and who agree to participate--are given specific instructions, and then monitored and carefully assessed during the trial and after it is completed.

Done at hospitals and research centers around the country, clinical trials are conducted in phases. Phase 1 trials try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects. Usually, a small number of healthy volunteers (between 20 and 80) are used in Phase 1 trials.

Phase 2 trials include more participants (about 100-300) who have the disease or condition that the product potentially could treat. In Phase 2 trials, researchers seek to gather further safety data and preliminary evidence of the drug's beneficial effects (efficacy), and they develop and refine research methods for future trials with this drug. If the Phase 2 trials indicate that the drug may be effective--and the risks are considered acceptable, given the observed efficacy and the severity of the disease--the drug moves to Phase 3.

In Phase 3 trials, the drug is studied in a larger number of people with the disease (approximately 1,000-3,000). This phase further tests the product's effectiveness, monitors side effects and, in some cases, compares the product's effects to a standard treatment, if one is already available. As more and more participants are tested over longer periods of time, the less common side effects are more likely to be revealed.

Sometimes, Phase 4 trials are conducted after a product is already approved and on the market to find out more about the treatment's long-term risks, benefits, and optimal use, or to test the product in different populations of people, such as children.

Phase 2 and Phase 3 clinical trials generally involve a "control" standard. In many studies, one group of volunteers will be given an experimental or "test" drug or treatment, while the control group is given either a standard treatment for the illness or an inactive pill, liquid, or powder that has no treatment value (placebo). This control group provides a basis for comparison for assessing effects of the test treatment. In some studies, the control group will receive a placebo instead of an active drug or treatment. In other cases, it is considered unethical to use placebos, particularly if an effective treatment is available. Withholding treatment (even for a short time) would subject research participants to unreasonable risks.

The treatment each trial participant receives is often decided by a process called randomization. This process can be compared to a coin toss that is done by computer. During clinical trials, no one likely knows which therapy is better, and randomization assures that treatment selection will be free of any preference a physician may have. Randomization increases the likelihood that the groups of people receiving the test drug or control are comparable at the start of the trial, enabling comparisons in health status between groups of patients who participated in the trial.

In conjunction with randomization, a feature known as blinding helps ensure that bias doesn't distort the conduct of a trial or the interpretation of its results. Single-blinding means the participant does not know whether he or she is receiving the experimental drug, an established treatment for that disease, or a placebo. In a single-blinded trial, the research team does know what the participant is receiving.

A double-blinded trial means that neither the participant nor the research team knows during the trial which participants receive the experimental drug. The patient will usually find out what he or she received at a pre-specified time in the trial.

What Are the Risks?

Some treatments being studied can have unpleasant, or even serious, side effects. Often these are temporary and end when the treatment is stopped. Others, however, can be permanent. Some side effects appear during treatment, and others may not show up until after the study is over. The risks depend on the treatment being studied and the health of the people participating in the trial. All known risks must be fully explained by the researchers before the trial begins. If new risk information becomes available during the trial, participants must be informed.

Unnecessary Drugs Mean Unnecessary Experiments

A widespread ethical problem, although one that has not yet received much attention, is raised by the development of new pharmaceuticals. All new drugs are tested on human volunteers. There is, of course, no way subjects can be fully apprised of the risks in advance, as that is what the tests purport to determine. This situation is generally considered acceptable, provided volunteers give “informed” consent. Many of the drugs under development today, however, offer little clinical benefit beyond those available from existing treatments. Many are developed simply to create a patentable variation on an existing drug. It is easy to justify asking informed, consenting individuals to risk limited harm in order to develop new drug therapies for a condition from which they are suffering or for which existing treatments are inadequate. The same may not apply when the drug being tested offers no new benefits to the subjects because they are healthy volunteers, or when the drug offers no significant benefits to anyone because it is essentially a copy of an existing drug.

Manufacturers, of course, hope that animal tests will give an indication of how a given drug will affect humans. However, a full 70 to 75 percent of drugs approved by the Food and Drug Administration for clinical trials based on promising results in animal tests, ultimately prove unsafe or ineffective for humans.2 Even limited clinical trials cannot reveal the full range of drug risks. A U.S. General Accounting Office (GAO) study reports that of the 198 new drugs which entered the market between 1976 and 1985, 102 (52 percent) caused adverse reactions that premarket tests failed to predict.3 Even in the brief period between January and August 1997, at least 53 drugs currently on the market were relabeled due to unexpected adverse effects.4

In the GAO study, no fewer than eight of the drugs in question were benzodiazepines, similar to Valium, Librium, and numerous other sedatives of this class. Two were heterocyclic antidepressants, adding little or nothing to the numerous existing drugs of this type. Several others were variations of cephalosporin antibiotics, antihypertensives, and fertility drugs. These are not needed drugs. The risks taken to develop these drugs by trial participants, and to a certain extent by consumers, were not in the name of science, but in the name of market share.

As physicians, we necessarily have a relationship with the pharmaceutical companies that produce, develop, and market drugs involved in medical treatment. A reflective, perhaps critical posture towards some of the standard practices of these companies—such as the routine development of unnecessary drugs—may help to ensure higher ethical standards in research.

Unnecessary Experimentation on Children

Unnecessary and questionable human experimentation is not limited to pharmaceutical development. In experiments at the National Institutes of Health (NIH), a genetically engineered human growth hormone (hGH) is injected into healthy short children. Consent is obtained from parents and affirmed by the children themselves. The children receive 156 injections each year in the hope of becoming taller.

Growth hormone is clearly indicated for hormone-deficient children who would otherwise remain extremely short. Until the early 1980s, they were the only ones eligible to receive it; because it was harvested from human cadavers, supplies were limited. But genetic engineering changed that, and the hormone can now be manufactured in mass quantities. This has led pharmaceutical houses to eye a huge potential market: healthy children who are simply shorter than average.

Short stature, of course, is not a disease. The problems short children face relate only to how others react to their height and their own feelings about it. The hGH injection, on the other hand, poses significant risks, both physical and psychological.

These injections are linked in some studies to a potential for increased cancer risk,5-8 are painful, and may aggravate, rather than reduce, the stigma of short stature.9,10 Moreover, while growth rate is increased in the short term, it is unclear that the final net height of the child is significantly increased by the treatment.

The Physicians Committee for Responsible Medicine worked to halt these experiments and recommended that the biological and psychological effects of hGH treatment be studied in hormone-deficient children who already receive hGH, and that non-pharmacologic interventions to counteract the stigma of short stature also be investigated. Unfortunately, the hGH studies have continued without modification, putting healthy short children at risk.

Use of Placebo in Clinical Research

Whooping cough, also known as pertussis, is a serious threat to infants, with dangerous and sometimes fatal complications. Vaccination has nearly wiped out pertussis in the U.S. Uncertainties remain, however, over the relative merits and safety of traditional whole-cell vaccines versus newer, acellular versions, prompting the NIH to propose an experiment testing various vaccines on children.

The controversial part of the 1993 experiment was the inclusion of a placebo group of more than 500 infants who get no protection at all, an estimated 5 percent of whom were expected to develop whooping cough, compared to the 1.4 percent estimated risk for the study group as a whole. Because of these risks, this study would not be permissible in the U.S. The NIH, however, insisted on the inclusion of a placebo control and therefore initiated the study in Italy where there are fewer restrictions on human research trials. Originally, Italian health officials recoiled from these studies on ethical as well as practical grounds, but persistent pressure from the NIH ensured that the study was conducted with the placebo group.

The use of double-blind placebo-controlled studies is the “gold standard” in the research community, usually for good reason. However, when a well-accepted treatment is available, the use of a placebo control group is not always acceptable and is sometimes unethical.11 In such cases, it is often appropriate to conduct research using the standard treatment as an active control. The pertussis experiments on Italian children were an example of dogmatic adherence to a research protocol which trumped ethical concerns.

Placebos, Ethics, and Poorer Nations

The ethical problems that placebo-controlled trials raise are especially complicated in research conducted in economically disadvantaged countries. Recently, attention has been brought to studies conducted in Africa on preventing the transmission of HIV from mothers to newborns. Standard treatment for HIV-infected pregnant women in the U.S. is a costly regimen of AZT. This treatment can save the life of one in seven infants born to women with AIDS.12 Sadly, the cost of AZT treatment is well beyond the means of most of the world’s population. This troubling situation has motivated studies to find a cost-effective treatment that can confer at least some benefit in poorer countries where the current standard of care is no treatment at all. A variety of these studies is now underway in which a control group of HIV-positive pregnant women receives no antiretroviral treatment.

Such studies would clearly be unethical in the U.S. where AZT treatment is the standard of care for all HIV-positive mothers. Peter Lurie, M.D., M.P.H., and Sidney Wolfe, M.D., in an editorial in the New England Journal of Medicine, hold that such use of placebo controls in research trials in poor nations is unethical as well. They contend that, by using placebo control groups, researchers adopt a double standard leading to “an incentive to use as research subjects those with the least access to health care.”13Lurie and Wolfe argue that an active control receiving the standard regimen of AZT can and should be compared with promising alternative therapies (such as a reduced dosage of AZT) to develop an effective, affordable treatment for poor countries.

Control Groups and Nutrition

Similar ethical problems are also emerging in nutrition research. In the past, it was ethical for prevention trials in heart disease or other serious conditions to include a control group which received weak nutritional guidelines or no dietary intervention at all. However, that was before diet and lifestyle changes—particularly those using very low fat, vegetarian diets—were shown to reverse existing heart disease, push adult-onset diabetes into remission, significantly lower blood pressure, and reduce the risk of some forms of cancer. Perhaps in the not-too-distant future, such comparison groups will no longer be permissible.

The Ethical Landscape

Ethical issues in human research generally arise in relation to population groups that are vulnerable to abuse. For example, much of the ethically dubious research conducted in poor countries would not occur were the level of medical care not so limited. Similarly, the cruelty of the Tuskegee experiments clearly reflected racial prejudice. The NIH experiments on short children were motivated to counter a fundamentally social problem, the stigma of short stature, with a profitable pharmacologic solution. The unethical military experiments during the Cold War would have been impossible if GIs had had the right to abort assignments or raise complaints. As we address the ethical issues of human experimentation, we often find ourselves traversing complex ethical terrain. Vigilance is most essential when vulnerable populations are involved.

Sources:

1. Flieger K. Testing drugs in people. U.S. Food and Drug Administration. September 10, 1997.
2. U.S. General Accounting Office. FDA Drug Review: Postapproval Risks 1976-85. U.S. General Accounting Office, Washington, D.C., 1990.
3. MedWatch, U.S. Food and Drug Administration. Labeling changes related to drug safety. U.S. Food and Drug Administration Home Page; http://www.fda.gov/medwatch/safety.htm. September 10, 1997.
4. Arteaga CL, Osborne CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res. 1989;49:6237-6241.
5. Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen on serum insulin-like growth factor I levels in stage I breast cancer patients. J Natl Cancer Inst. 1990;82:1693-1697.
6. Stoll BA. Growth hormone and breast cancer. Clin Oncol. 1992;4:4-5.
7. Stoll BA. Does extra height justify a higher risk of breast cancer? Ann Oncol. 1992;3:29-30.
8. Kusalic M, Fortin C. Growth hormone treatment in hypopituitary dwarfs: longitudinal psychological effects. Canad Psychiatric Asso J. 1975;20:325-331.
9. Grew RS, Stabler B, Williams RW, Underwood LE. Facilitating patient understanding in the treatment of growth delay. Clin Pediatr. 1983;22:685-90.
10. For a more extensive discussion of the ethical status of placebo-controlled trials see especially: Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research II: ethical, legal and regulatory myths. J Law Med Ethics. 1996;24:252-259.