Clinical Trials—A Very Human Enterprise
 Introduction
You or someone you know may be facing a severe and life-threatening illness. You may be dealing with an illness that isn’t severe, but is unpleasant and debilitating. You may now be considering a variety of treatments – each of them offering different benefits and risks. Some treatments may only be available through clinical trials.
For every conceivable health condition, somebody is probably doing a research study on it somewhere. Most trials test either a new drug or new uses for or forms of an existing drug, such as a painkiller given through a skin patch rather than by mouth. Other research studies simply measure the benefits of one drug over another. Many thousands of clinical trials focus on preventing, or more efficiently treating, chronic health conditions like osteoporosis, Parkinson’s disease, depression and diabetes. Even for cosmetic conditions like male pattern baldness and acne, research scientists across the country are busily testing what could be next year’s medical breakthroughs.
In 2002, the National Institutes of Health (NIH) and pharmaceutical and biotechnology companies will spend more than $50 billion on research and development – from the discovery phase to FDA approval – of thousands of potential medical treatments and interventions. Many of the largest pharmaceutical companies, for example, have hundreds of new drugs in development, and many of these drugs are being actively studied among participants in clinical trials.
Here is just a sampling of the many types of clinical trials that have actively sought volunteers in recent years:
- Experimental vaccine for urinary tract infection
- Oral insulin for controlling blood sugar in diabetics
- Treatments to prevent restenosis following cardiac surgery
- Topical cream for early-stage skin cancer
- Oral drugs to improve sexual performance
- Cancer screening tests for smokers and people with emphysema and bronchitis
- Non-stimulant drugs for treating attention deficit hyperactivity disorder
- Drugs to prevent joint deterioration in people with rheumatoid arthritis
- Comparisons of treatment options for heart failure patients
- New medications to treat age-related memory loss
Regardless of the disease condition under investigation, no medical therapy is tested in a clinical trial without the approval of the U.S. Food and Drug Administration (FDA) – the chief agency overseeing the pharmaceutical and medical device research industries. And no new medical therapy is allowed by the FDA to be sold unless it is properly tested according to strict guidelines designed to ensure that the drug works and does no unexpected harm. One of the FDA’s top concerns is the safety and ethical treatment of human subjects, or volunteers in clinical trials.
In the United States, pharmaceutical and biotechnology companies sponsor most clinical trials of medical treatments. In total, these companies will spend more than $10 billion on clinical research in 2002. This money is used to pay for the research professionals managing the projects, for equipment and facilities and study grants to research centers conducting the projects. In 2002, more than $4 billion – of that $10 billion – will be paid as grants to investigators within these research centers. Investigators are primarily physicians who agree to carry out clinical trials according to a very detailed plan known as the study protocol. The protocol safeguards human subject protection and provides direction for research professionals to follow in order to ensure that the study is conducted properly.
The study protocol builds on what is already known about an investigational drug based on results from lab and animal testing and from what is later learned in studies on humans. The protocol establishes the purpose and goals of the clinical trial; who will be included in the trial and who will be excluded from enrolling in it; and what variables will be measured and analyzed. It also spells out other important details, such as when a different dose of the study drug might be tried and how patients will be followed while on study.
When developing a protocol, a company or government agency has to consider dozens of questions. What is to be learned from the study? What outcomes will be measured? How long should the trial last? Who will participate? Should some or all of the volunteers receive the study drug? Is there an existing treatment to compare to the new one? What, currently, is the best standard of treatment? Should some subjects be given a placebo? What procedures will be done during research visits? How can the study optimize the potential benefits of a novel treatment while minimizing the potential harm? Under what conditions will the protocol be changed or the study stopped?
The results of clinical trials will not be taken seriously by the FDA unless the protocol follows accepted principles of scientific research. When comparing drug treatments, for example, patient groups must be alike in all important aspects, such as stage and character of disease and age range, and must only differ by the drug that each group receives. Clinical trials must also study different ethnic groups who will eventually be taking a new drug or medical treatment.
The protocol must make sense for the type of trial and condition under study. If the standard medication for an illness is usually ineffective, for example, early clinical trials may involve only the new investigational drug. Worldwide, there are an estimated 10,000 investigational drugs being studied from the discovery phase through the clinical phase.
The number of people allowed to participate in a trial will depend on a host of factors including: how many people have the condition in question; the availability of other treatments; the number of people willing to volunteer; and how much is known about the therapy being studied. This sample size is also arrived at by doing statistical calculations that ensure there are enough participants in studies to answer the research question.
The age, health and gender of participants to be recruited also have a big effect on how the study protocol is written. Pediatric clinical trials, for instance, need to consider changing body size and drug absorption rates as children age – and even whether it is appropriate to use healthy youngsters as volunteers. Trials designed for women have to take into account gender differences in behavior and aging and the possibility of pregnancy. Trials designed specifically for pregnant women – and there aren’t many – must give careful thought to how patients’ vital signs are taken and how medications are given. They must also include a thorough check of the baby after delivery to look for any unintended effects, good or bad. Trials for life-threatening diseases require special stopping rules so that a particularly promising product can quickly be made available to the desperately ill, even before any real clinical benefit has been confirmed. These criteria also serve to identify serious toxicities that would cause the trial to be terminated early.
A clinical trial is sometimes called a clinical research study or a research protocol. But a clinical trial primarily refers to the location where a study protocol is being tested. In other words, a single protocol involves multiple locations across a variety of cities, states and even countries where clinical trials are conducted. Government and industry sponsor more than 80,000 trials in the United States each year, representing as many as 5,000 to 6,000 protocols.
Clinical trials are a human enterprise. Each year, 200,000 research professionals manage and conduct clinical trials; more than 1 million volunteers will complete them.
Many people come together to make a clinical trial happen long before the first person even volunteers to participate. The collective brain power of eminent scientists and statisticians is used to produce drug development plans and study protocols. Often, nurses and doctors will be involved in clinical trial planning and design. Teams of physicians and scientists at the FDA review the protocol to ensure it is safe and ethical for human subject participation. (The official term for a person participating in a clinical trial is human subject, although the term participant is also used and will be used more and more.) Local and national review committees – called Institutional or Ethical Review Boards (IRBs) – must also review and approve study protocols. IRBs are made up of doctors, nurses, and other community members who are responsible for determining if a study is safe, sensible and in keeping with the local standards of healthcare quality.
Once a clinical trial is underway, many more people get involved. Sponsor companies dispatch study monitors to assure that research sites are collecting data correctly and treating study volunteers according to the protocol that was submitted to them. The IRB makes sure that advertisements for study subjects aren’t misleading and then follows the study’s progress, intervening on the subject’s behalf if questions or problems arise. The FDA inspects research sites to be sure its rules about trial conduct are followed. It immediately handles any serious safety concerns involving the investigational drug or the conduct of researchers.
FDA rules and regulations help eliminate the temptation of pharmaceutical companies to cut corners in their zeal to get a product to market. They also help ensure that physician researchers, for whom clinical trials can mean prestige as well as income, follow sound scientific practices. Pharmaceutical companies and physician researchers tend to vigorously defend the FDA’s watchdog role, even if they feel the agency can sometimes be overly cautious. Some doctors and patient advocates argue that, in this age of genetic research, even more human subject protections are needed.
With every new drug, the mission of the pharmaceutical company is to determine if a product’s promising performance in the lab and during animal testing can be replicated in people. The challenge then becomes determining the best ways to administer a new treatment – by pill, liquid, injection, inhaler or patch – and at precisely what dose. Any unintended reactions to the drug during testing must be recorded. If unintended reactions are severe and frequent enough, these serious adverse events (SAEs) could immediately end a clinical trial. But if the adverse events (AEs) are minor (in relation to the drug’s benefits) and the FDA later approves the drug for sale in the market, the information will appear on the drug’s label and package insert as possible side effects.
You have probably seen these package inserts in many of the medications that you buy from the retail pharmacy. The wording contained in the package insert – including product warnings and a description of side effects – are reported results from numerous clinical trials that have been conducted.
Building a Support Network
Another important part of the human side of clinical trials is the support network that you create. Study volunteers are not alone in their clinical trial participation. Your decision to participate in a clinical trial is best made with input from the people you know and trust. Your network should include your family physician or specialist who has previously been treating your disease or condition. Your primary care and specialty nurses may be very helpful in sorting out your identification of a clinical trial and the risks and benefits of participating in one.
Perhaps no one has a greater interest in your well-being as a potential study subject than your family and friends. They will want to be actively involved in the decision-making process. Young children rely on their parents or guardians for support and guidance. Parents in their later years may well depend on their adult children. Whatever your support network, you need to draw comfort, assistance and resolve from your family, friends and advocates in order to determine if a clinical trial is right for you. And once you’ve enrolled in a trial, you need to tap that support network for ongoing encouragement, advice and maybe even transportation to and from visits to the research center.
Many medical conditions have special support groups and communities that can help assist in evaluating clinical trials as treatment options. In the appendix of this book, we have provided information about helpful national health associations and patient advocacy groups. You can also find information about local support groups in the Yellow Pages, your primary care centers, hospitals, the Internet and even your public library. There are also a growing number of online self-help groups that provide up-to-the-minute information on new drugs and treatments, as well as electronic bulletin boards and chat rooms where patients can share their personal stories and experiences with both standard and investigational therapies.
The Clinical Trial Process
For many patients, a clinical trial is an opportunity to gain access to a drug – albeit, generally short-term – as much as five or six years before it becomes commercially available through retail, mail-order or health system pharmacies. Clinical trials are nearly the final leg of a new medical treatment’s journey from the laboratory to your medicine cabinet. In all, it may take as much as twenty years and an estimated $800 million to bring a single new drug treatment from its initial discovery through to the market. The chance of a promising drug candidate even reaching the clinical trial stage is very low.
A drug making its debut in a clinical trial begins as a molecule discovered by scientists in the research laboratory. It takes approximately 10 years of study in test tubes and laboratory mice to reach the point where a treatment might be tested for its safety and effectiveness in humans.
During the discovery phase, scientists find new molecular entities (NMEs) that can be tested for their usefulness as drugs. NMEs are typically extracted from plants or are created by modifying known molecules. Researchers conduct extensive test-tube experiments on NMEs to learn about their effects on human cells. These tests help scientists determine the molecule’s role in altering biological processes and may also reveal whether a molecule, when administered as a drug, will be toxic. Scientists at pharmaceutical companies evaluate hundreds of thousands of molecules in order to find a few that have the potential to become a safe and effective treatment. Those few NMEs then advance to testing in animal models.
Testing in animals marks the beginning of pre-clinical testing and is a critical step in the process. Animal testing reveals important information about how a drug will behave in a living organism. During pre-clinical studies, researchers will be able to observe how a drug affects the animal’s organs (such as the brain, liver, kidneys and reproductive organs) and how it is absorbed and excreted from the animal’s body. Scientists set out to answer two fundamental questions during animal studies: (1) Is the drug likely to be safe when administered in humans?; (2) Is the drug likely to have a desirable therapeutic effect? For example, does the drug lower the animals’ blood pressure or does it fight infection? If the answer to both questions is yes, then researchers may decide to begin the process of testing a new drug in humans.
Approximately one in 50 drugs that enter pre-clinical testing prove safe enough and effective enough to be tested in people. And animal studies can only help researchers approximate a drug’s safety and effectiveness in humans. But before researchers can begin testing a drug in people, they must submit an application to the FDA that provides the results of the laboratory and animal studies along with a detailed plan for the proposed clinical trials. This request for FDA permission to begin human testing is called an Investigational New Drug or IND application. If the IND application is not rejected by the FDA, clinical trials can begin.
Clinical trials are designed to answer five basic questions about an investigational new drug or device:
- Is it safe?
- Is it effective?
- What side effects does it produce?
- What dosage is most effective?
- Is it more effective than or equally as effective as other treatments already on the market?
Only one in five drugs that enter clinical trials will prove safe and effective enough to receive FDA approval. And some of these drugs end up being most effective for patients with different diseases than those that they were originally created to treat.
It is this long, costly and exhaustive process of clinical research that has brought so many scientific advances and has ultimately saved immeasurable numbers of human lives. Clinical research brought the world vaccines for polio and diphtheria, antibiotics for tuberculosis and pneumonia and medicines to lower cholesterol and control asthma attacks. Today, new drugs continue to be discovered and developed at an ever more frantic pace. More than 120 new remedies get the FDA’s stamp of approval every year, including a handful of “breakthrough” drugs that provide the first effective treatment ever for a variety of medical conditions.
Clinical trials led to the introduction, in the late 1990s, of the first approved drug for preventing the progression of joint damage in rheumatoid arthritis. They also brought to market an antibody engineered to target and kill cancer cells in patients all but given up for dead. More recently, clinical trials have provided diabetics with a once-a-day glucose-lowering drug and victims of Alzheimer’s disease with a pill – derived from the bulbs of daffodils – to keep their memory longer. Clinical trials have also given us another new cancer drug that literally “turns off” the signal of a protein that causes certain types of leukemia. Virtually no disease category has escaped progress as a result of clinical trials.
Even relatively small improvements to existing drugs, which represent over 40% of new drugs approved by the FDA each year, provide important health benefits to patients. Newer drugs often have fewer side effects, are safer and more effective, and are taken more easily and conveniently. Not surprisingly, these top the list of drugs physicians mostly commonly prescribe. A new drug form – tablets instead of liquids or a pill taken once-a-day versus two- or four-times-a-day – can be a major benefit to individuals who have trouble chewing, swallowing or remembering to take their medications. If you or someone you care about is taking a relatively safe and effective – yet inconvenient or invasive – treatment, there is a good chance that better treatments are being tested.
Clinical Trial Phases
There are four clinical trial phases, each with a different set of objectives and requirements – from simple outpatient studies requiring only a couple of hours a month to situations requiring overnight or extended stays at medical facilities.
During phase I studies, a drug is tested for the first time in small numbers (20 to 100) of healthy volunteers – often college students. Phase I trials typically last from several months up to one year. The goal of these trials is to learn about safe dosage ranges in which a drug can be administered, the method of absorption and distribution in the body and the possible toxicity of a new treatment. Researchers start by giving volunteers a single dose of the drug. Then they gradually increase the dosage level until minor side effects like nausea or headaches start to occur. That’s how researchers learn about the more common side effects that limit the treatment dosage levels. Payment to participants in this phase of the process is also common because it’s often the only way to get enough volunteers.
Only certain new, very toxic treatments for cancer and infectious diseases are tested on actual patients in phase I trials. And only in terminally ill cancer patients – where there are often no other options available – is the dosage amount increased until it is literally intolerable. For these cancer patients, the greatest hope of survival lies in destroying the highest possible number of cancer cells in the body just short of death. Researchers are usually leading experts in their field.
Until 1993, mostly males were enrolled as study subjects in phase I clinical trials because it was considered unethical to allow women to do so. Researchers were concerned that women might become pregnant during a clinical trial and put both the subject and her child at risk. Today, however, more women are allowed to make that decision for themselves. But they must not get pregnant while participating in a clinical trial. During the trial, female study subjects are typically expected to use some form of birth control – contraception or abstinence.
Phase I studies are conducted in numerous locations – frequently in academic settings or in private, specialty centers. Participants are often confined for 24-hour periods to a special inpatient unit – complete with kitchen and recreational facilities – where they may undergo frequent blood and urine tests. These tests help researchers understand how the investigational drug is absorbed, distributed, metabolized and excreted by the human body. This will assist researchers in determining if a new drug will have to be given one, two, three or more times a day. But how safe the drug truly is remains a mystery because so few people have taken it. Due to safety and toxicity problems, many investigational drugs are abandoned during phase I testing. According to the FDA, approximately 70% of new medical treatments pass this testing stage.
In phase II studies, researchers begin to understand how safe and effective an investigational drug will be for patients for whom the drug is intended. Similar to phase I, safety is still the primary goal. Phase II studies are conducted on a relatively small number of volunteers – usually 100 to 300 patients who have the disease or condition targeted by the new medical therapy. Clinical trials in this phase take between one and three years to complete. Phase II studies look to answer such basic questions as “Do patients improve?” and “What are the usual side effects?” Researchers also learn if the treatment dosage needs to be lowered or raised.
Eligibility requirements tend to be strict in phase II trials. These scientifically demanding studies are usually “randomized,” meaning that volunteers are assigned to different groups – of which only a subset will receive the investigational drug. The control group will get another standard treatment or a placebo for part of, or perhaps throughout, the entire study. This method helps take the bias out of study results due to human choices or other factors unrelated to the treatments being tested. Typically, the study is double-blinded, meaning that neither the patient nor the researcher knows who is getting the investigational drug and who is getting the placebo or standard treatment.
A phase II study may measure something that isn’t the drug’s ultimate clinical value, such as improving survival after a heart attack. It would instead look at how well the drug opens blood vessels after a heart attack. Overall, it’s shorter than the final (phase III) test and involves a smaller population of people. Phase II trials are also the period when researchers look at the body’s response to different doses of a drug.
Only about one-third of drugs that enter clinical testing ever successfully complete phase II and progress to larger-scale phase III studies. This stage provides hard, statistical facts about a drug. Phase III clinical trials involve extensive testing to assess safety, efficacy and dosage levels in a large group of patients facing a specific illness. The study drug is tested on as many as several thousand people over a period of two to five years. Often, “real world” results – such as how long a person can sit at a basketball game, write a letter, or hike up and down stairs – are seen as equally important as clinical findings (lower blood pressure or higher white cell count, for example) in measuring a drug’s usefulness. Phase III trials are most often conducted in a doctor’s office.
The goal in this research phase is often to have an investigational treatment evaluated by practicing physicians who might one day prescribe it. These trials often involve a more diverse patient group for whom the treatment is initially intended. The number of volunteers needed for a phase III study depends on how many people have the targeted disease. Compared to studies of medications designed to prevent heart attacks, those for asthma would be smaller because researchers can learn something from every single participant, and every enrollee will actually have the disease.
Phase III studies almost always involve a relatively large number of participants with similar demographic characteristics. At this stage, researchers may also look to compare the drug’s safety and effectiveness in different subsets of patients – men versus women, blacks versus whites, elderly versus young – and how well the treatment works in mild, moderate and severe forms of the same disease. Researchers are also able to test different dosage levels of the drug so that they know, quite precisely, how much of it most people need to get the good effects with as few bad effects as possible.
Drugs tested in phase III clinical trials may include remedies already approved by the FDA to treat a different medical condition – such as a study of a multipurpose antimicrobial to treat a specific opportunistic infection in AIDS patients. Phase III studies usually test a new drug in comparison with a placebo or an existing treatment.
Therapies that have reached phase III have already passed toxicity testing and have proved to be at least somewhat effective. But subjects in phase III trials still usually have no better than a 50% chance of getting the investigational treatment versus a placebo or standard therapy. About 80% of drugs that enter phase III will successfully complete this stage.
Once clinical trials are completed and the results are analyzed, the company sponsoring the research may submit a New Drug Application (NDA) to the Food and Drug Administration if there is enough positive information about the safety and effectiveness of the treatment. The NDA is given to one of two groups within the FDA: (1) The Center for Drug Evaluation and Research (CDER) and (2) The Center for Biologics Evaluation and Research (CBER). The former review group is responsible for evaluating prescription and over-the-counter drugs. The latter group is responsible for evaluating blood and blood products, vaccines, allergenics and medical treatments made from living organisms. The FDA will also look to advisory committees made up of medical experts to assist in determining whether a treatment should be approved for sale on the market. Applications for new medical devices are submitted to the Center for Devices and Radiological Health.
The FDA review period usually lasts about one year for most NDAs. The FDA also has an expedited review process for priority drugs – usually lasting under six months. Priority drugs are those that represent a notable treatment benefit for critical and severe illnesses. FDA review and approval doesn’t always happen as quickly as pharmaceutical and biotechnology companies would like. The FDA recently withheld its approval for an effective nasal flu vaccine aimed at toddlers, for example. The agency asked the company to conduct more studies looking at how well the new treatment combines with other vaccines and whether there’s a rare risk of pneumonia or asthma among certain children.
The FDA would also be skeptical, for example, if a high blood pressure medication caused a higher-than-expected rate of facial swelling among a minority population. It wouldn’t matter if researchers believed they could fix the problem by changing the dose. To prove it to the FDA, the pharmaceutical company would have to conduct a large-scale study of the drug specifically targeting that population. Approximately 60% of all NDAs are approved by the Food and Drug Administration.
After pharmaceutical companies receive FDA approval to market a drug, they will sometimes conduct phase IV studies. These clinical trials are performed – often at the FDA’s urging – to uncover additional information about a new treatment. What is the long-term safety and effectiveness of a drug? What impact does it have on improving patients’ day-to-day lives? When do physicians decide to prescribe the new treatment relative to others in the market? How does the new treatment compare with other similar treatments available to patients? Phase IV clinical trials typically involve large numbers of patients who are routinely taking the medical treatment under investigation. In some cases, phase IV studies are conducted to see if a drug causes unique problems for a certain patient subgroup. The results of these studies may be used to revise product labeling or to further support claims and comparisons that pharmaceutical companies make in package inserts and product advertisements. The offices of community-based physicians are particularly well suited for phase IV studies because they provide routine care for patients and they administer prescriptions regularly.
If you or a loved one is looking to gain access to a novel, investigational treatment not yet available on the market, then you should primarily consider phase II and III studies; however, your participation in any clinical trial is dependent upon your meeting stringent inclusion and exclusion criteria, as described in the protocol. Not only are you looking for trials that are right for you, but you must also be the right subject for the trial.
Outside of clinical trials, there are unique situations where desperately ill patients may gain access to medical therapies yet to be approved by the FDA. A treatment IND may be issued if an investigational drug has provided enough data to suggest that the drug may be effective without posing unreasonable risk. Under a treatment IND, seriously ill patients – not participating in clinical trials – can begin to receive a drug from their physician before the drug receives FDA approval. Investigational drugs can also be administered in an urgent situation in which there isn’t enough time for the sponsor company to submit an IND. In these instances, the FDA may authorize shipment of the drug to health providers for a specific emergency use.
There are occasions when clinical trials have ended and patients are allowed to continue taking the investigational medication while awaiting FDA approval. The FDA may grant Compassionate Use when a study drug is already being marketed in another country and when the drug is the only reasonable treatment available.
Importance of Diversity in Clinical Trials
Fifteen to twenty years ago, research used to be limited primarily to white males, 30 to 40 years old. These days, virtually everyone – men, women, children, the elderly and minorities – has an opportunity to participate in clinical trials. This is largely a result of regulatory pressure from the FDA to spread the benefits and burdens of research participation equitably. It has also become clear that drugs behave differently in people, depending on their gender, age and ethnic group.
The National Institutes of Health – one of the government’s largest sponsors of clinical research – specifically requires that its clinical studies include women and minorities. The FDA, through regulation and regulatory guidelines, expects the same.
The FDA also requires that children participate in all clinical trials for new medications that will be or could be used to treat conditions or diseases in children. And the FDA provides incentives for drug companies to conduct similar studies on certain marketed drugs now used to treat pediatric conditions. Medicare has recently eliminated a key barrier to participation by the elderly. Medicare will now cover care required during clinical trials. This includes payment for all services normally covered in conventional care settings and for services provided during clinical trials that wouldn’t otherwise be provided free of charge. The chief requirement is that the clinical trials involve a study drug that intends to treat a specific condition such as high blood pressure or migraine.
Women in Clinical Trials
Whereas gender mix in clinical trials appears to be relatively balanced, there is no question that protocol designs have historically addressed disease as it manifests in adult males. During the past decade, public pressures have fueled stricter government requirements for gender-specific studies in both NIH- and industry-sponsored research projects. Pharmaceutical and biotechnology companies have also sought ways to increase the market potential for new and existing drugs by gathering clinical data to make specific claims about drug safety and effectiveness among women. As a result, clinical trials are increasingly being designed to assess gender-specific medical treatment safety and efficacy.
Many diseases behave differently in women than in men. Risk factors, symptoms, clinical course and response to treatment can all be gender-specific. Among a long list of differences, men and women vary by:
- body size, composition and metabolism
- the ways their bodies change during the aging process, e.g., puberty and midlife
- endogenous hormones
- exogenous hormones
Due to these differences and other factors researchers have discovered over the years that:
- Lung cancer kills more women than other cancers do.
- Alzheimer’s disease is twice as prevalent in women.
- Men and women experience pain differently.
- Women are two to three times more likely to experience depression – due to less serotonin uptake in the brain.
- About 75% of autoimmune diseases occur in women – most frequently during childbearing years
- Cardiovascular disease kills approximately 250,000 more women each year than all forms of cancer combined, accounting for 58% of all deaths. Within a year of the first myocardial infarction, 44% of women die, compared to 27% of men.
Although the FDA recommended in 1993 that clinical studies include enough women to understand the unique ways in which their bodies respond to drugs, nearly a decade later, women are still underrepresented in small, phase I safety trials. And when eligibility is restricted by age, older women are disproportionately excluded from studies of diseases that are more common in women at older ages. The possibility of becoming pregnant also excludes most women in their childbearing years.
Generally, a woman capable of conceiving a child won’t be considered for a clinical trial unless she’s not pregnant and agrees to use birth control. Many studies require that women of childbearing age use two forms of contraception during participation. Pharma-ceutical companies don’t want their drugs tested among women who are – or might get – pregnant, mostly because the risk of a lawsuit by the mother is too high. Even in normal pregnancies, 1% to 2% end with an abnormal birth. Many parents are quick to blame poor birth outcomes on drugs. Some doctors erroneously believe that certain drugs cause fetal abnormalities. But genes and chromosomes are the primary culprits, according to Marilynn C. Frederiksen, M.D., associate professor of obstetrics and gynecology at Northwestern University Medical School.
All of this presents a major barrier to clinical trial participation by women who don’t want, can’t afford or are religiously opposed to contraception. Things aren’t bound to change unless the National Institutes of Health (NIH) comes up with the funds to conduct special dosing studies in pregnant women, said Frederiksen. And that probably won’t happen quickly or easily. The NIH doesn’t have any institutes that devote research dollars specifically to female health issues.
As a direct result of the 1993 NIH Revitalization Act, NIH-sponsored clinical research now routinely includes sufficient numbers of non-pregnant women. Pharmaceutical companies following FDA guidelines, however, pay for most clinical trials. The FDA recommended back in 1977 that premenopausal women capable of becoming pregnant be excluded from early drug trials. In practice, the participation of women in all phases was affected. The FDA’s current stance – that a “reasonable” number of women be included in all clinical trials – hasn’t fully addressed participation inequities.
In trials where women are included, the Government Accounting Office recently reported that about one-third of pharmaceutical companies fail to present gender-specific safety and efficacy data in their new drug application (NDA) summaries, as required by the FDA. NDAs also frequently arrive at the FDA without any recommended dose adjustments based on sex. Similarly, investigational new drug annual reports routinely leave out the number of study participants by gender.
The participation of women in clinical trials is essential. Real-world experience has proven that some drugs that work well in men may be ineffective or more dangerous to the opposite sex regardless of body size. Women respond in varying ways to drugs during different stages of their menstrual cycle. Hormonal contraceptives and hormone replacement therapy in menopause may even have their own effects. Women also experience pain differently than men and are far more likely to die within a year of a heart attack.
The exclusion of women from early-phase studies, in particular, delays the discovery of sex-specific dosing requirements and side effects, and may limit the identification of drugs that are useful just for women. The problem is compounded by the fact that animal studies, when scientists learn about many of a drug’s potential adverse reactions, also tend to exclude females. Limiting studies to a single gender requires fewer study subjects (animal or human) and, thus, shorter and less costly studies.
Many diseases disproportionately affect women, among them: breast cancer, Alzheimer’s disease, rheumatoid arthritis, multiple sclerosis, osteoporosis, diabetes and depression. And there are a multitude of unanswered questions. Why, for example, does heart disease kill more women over 50 years old than men of the same age? And why are eating disorders so prevalent in young women and nearly impossible to cure in some of them?
There are hopeful signs of change. Pharmaceutical companies are devoting a tremendous amount of money to trials focusing on diseases and conditions that only affect women. They’re also pushing for more representative patient populations in their non-sex-specific studies. But women can be tough to attract to trials because the protocols written for them tend to involve a lot of time-consuming tests.
There are many ethical issues to consider – especially when a woman is pregnant. Does a mother have the right to expose her unborn child to investigational substances whose side effects are not yet fully understood? And what, if anything, does the father have to say about it? What if the couple is no longer married, or the father of the baby is not her husband? Will babies born to these women later sue their mothers for allowing them to be exposed to a drug while in the womb?
Many of the same types of questions have been raised when children are enrolled in studies by the consent of a parent. Children, like pregnant women, are considered a “vulnerable population” and have therefore been given special protections by research regulators. (See “Vulnerable Populations”.)
“In a very real sense, what is good for mom is good for her unborn child,” said Frederiksen. Treating pregnant women with investigational AIDS drugs, for instance, helps prevent prenatal transmission of the virus. Pregnant women who take antibiotics for sinusitis also lower the odds their baby will develop nasal allergies and asthma and, by heading off fever, reduce the likelihood of a pre-term birth. Some conditions are pregnancy-related and can only be treated during pregnancy. “If we don’t test drugs then, we’ll never know if they’re effective.”
Minorities in Clinical Trials
Certain minority populations are more likely to suffer from specific diseases, such as diabetes and hypertension, and respond to medications differently. In response, the government has made minority inclusion mandatory for trials that it sponsors. Pharmaceutical and biotechnology companies are following suit. They realize that it is in their best interest to study drugs in the specific populations that will use them most frequently.
The government directly funds many clinical trials. The NIH Revitalization Act of 1993 requires that all studies funded by the National Institutes of Health have representation from different minority groups unless there’s a good reason to exclude them. The NIH believes data from these groups ought to be analyzed separately in case gender, race or ethnic origin has some bearing on the research results.
As the overall number and size of clinical trials continue to grow, government agencies and pharmaceutical and biotechnology companies are making greater efforts to ensure that clinical trials see higher levels of participation from racial and ethnic minority groups.
A review of drugs approved between 1995 and 1999, published by the FDA in October 2001, shows that blacks participate in clinical trials to a greater extent than other racial and ethnic groups, but overall participation among all minority groups remains low. Far more data are available on minority participation in trials specifically for cancer. Blacks, for instance, are represented in small (less than 3%) but roughly proportional numbers with whites on clinical trials sponsored by the National Cancer Institute (NCI), according to epidemiologist Otis Brawley, M.D., associate director of the Winship Cancer Institute in Atlanta. But, said Brawley, they’re clearly underrepresented on prevention studies needing people free of the disease.
Participation of a representative group of volunteers helps researchers understand the different ways that people respond to medical treatments. For a variety of reasons, some illnesses occur much more frequently and progress at different rates in certain populations. Among blacks, for example, there is a higher incidence of hypertension, diabetes and HIV infection. There are documented racial differences in the way people respond to a long list of drugs from ACE-inhibitors to antidepressants. Different levels of certain enzymes in Asians, for example, combined with cultural and dietary disparities, can either diminish or prolong their response to a drug. Drug responses depend on a wide variety of factors – many of them related to an individual’s racial and ethnic background. The National Pharmaceutical Council is updating a 42-page monograph it published in 1993 that documents some of these important differences.
Clinical researchers typically conduct “Subset Analyses” of clinical trial data in order to draw conclusions about specific racial and ethnic responses to investigational drugs. Under the NIH Revitalization Act of 1993, no phase III study will receive government funding without the inclusion of minorities such that a “a valid subset analysis” of potential racial differences can be conducted. Subset analysis requires statisticians to collect data on as many non-white patients as are needed to draw meaningful conclusions.
The FDA recently received a new set of guidelines that emphasize the need for new drug applications (NDAs) to describe the number of people of various racial/ethnic groups that were given the study drug during clinical trials and how well the data were analyzed for differences between them. Terry Toigo, associate commissioner of the FDA’s Office of Special Health Issues said that her office has also started reviewing information on drug approvals between 1998 and 2001 for diseases that disproportionately affect black patients, such as hypertension, diabetes, AIDS, asthma and breast and prostate cancers. The FDA hopes that this review will provide additional guidance to industry when they design their clinical trials.
The involvement of minority physicians has been shown to have a positive impact on minority involvement in clinical trials. At this time, only about 7% of all physicians in the United States belong to a minority group and a very small percentage are actively involved in clinical research. Several medical societies and associations are now looking for ways to encourage minority physician involvement in clinical trials.
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