Clinical Trials

Every drug that makes it to the pharmacy shelf must leap over numerous hurdles, starting with experimentation in the lab, followed by clinical trials in humans and culminating with the scrutiny of the U.S. Food and Drug Administration (FDA), which must review and approve all proposed new medications for safety and effectiveness before they can be sold to consumers. The process can take upwards of 10 years, and clinical testing is the trial by fire that makes or breaks any prospective new drug. Pharmaceutical companies also test drugs that have already been approved, to monitor long-term safety and effectiveness. Additional labeling claims or proposed new uses of drugs previously approved for commercial sale must be evaluated in subsequent clinical trials. Though you may not be as familiar with clinical trials as with ordinary health care, such studies are not limited to a few isolated clinics. Trials are conducted throughout the U.S., in both major cities and small towns, in university facilities, hospitals and individual doctor's offices. Currently, more than 13,000 studies of drugs and biologics (treatments, such as vaccines and biotechnology drugs, derived from living organisms) are in active clinical trials. Each year, more than 100,000 patients participate in clinical trials sponsored by the National Institutes of Health (NIH) and many more participate in privately sponsored trials, usually conducted by pharmaceutical or biotechnology companies. New medical devices and even new procedures and approaches to diagnosing or treating diseases must undergo clinical testing to prove their merit. A study might ask whether using a particular drug in addition to surgery is better than surgery alone, or whether earlier, more aggressive treatment of a condition produces a better outcome. Any question health care professionals might have about how best to diagnose and treat a medical condition may be addressed scientifically by a clinical trial. Clinical trial results themselves must pass a test as well. Results of safety and/or efficacy must be "statistically significant". That means a mathematical analysis of the results must show that the results obtained are highly likely to be "true" and not the result of chance. Risks and benefits of taking part in a clinical trial Why do people participate in clinical trials? Some people who are very ill or who are not responding to standard treatments join clinical trials in order to receive new, investigational treatment. They are hoping that this treatment, possibly a new drug, medical device or procedure, will work better for them than standard therapy. Others participate in clinical trials to contribute to medical science, while others take part for the chance to try the newest treatment that they hope will work better than the current standard. Participation in a clinical trial brings a host of potential benefits and possible risks for the consumer. The benefits include access to new treatments otherwise unavailable as well as an opportunity to help others by contributing to medical research. Sometimes, it also means access to top medical care, although the majority of FDA approved clinical trails, are conducted in community practices. If a treatment proves effective, you, as the participant in the clinical trial, may be offered the treatment, even if you have been in the control group. When you enroll in a clinical trial, however, you should be aware of the potential risks associated with the study. You may also be signing up for some inconveniences. The treatment may have side effects or produce adverse reactions with other medications or foods. You may receive a placebo (although they are not used in cancer trials), or you may receive the experimental treatment but not derive any benefit. If there is an existing effective therapy, weigh your options carefully in light of the fact that you may get only a placebo treatment. Another factor to keep in mind is that the design of the trial may require frequent trips to the study site, hospital stays, or difficult or uncomfortable procedures. Clinical trials, at least late-stage trials, may not be as risky as most health care professionals and participants believe. An initial 1999 review of 25 studies found that outcomes were better overall for participants in Phase III clinical trials than in those who did not join a clinical trial. The surprising results suggest the need for a broader analysis; if confirmed, additional studies could address the reasons for the so-called "inclusion benefit." It could be, for example, that volunteers for trials tend to be more conscientious about their health, or that the more attentive care provided in trials makes a significant difference. Clinical trial sponsors may include government agencies, such as the National Institutes of Health (NIH); pharmaceutical or medical device companies; individual physicians; or health care institutions. Trials may be conducted in a variety of locations: hospitals, universities, doctors' offices or community clinics. If you participate in a clinical trial, you may have more clinic visits and tests than you would if you were not taking part in a study. That's because the research team needs to gather detailed data on the progress of your treatment. They may need frequent blood tests, for example, to measure the amount of a medication in your bloodstream or to measure markers of disease severity (glucose, for example, in diabetics) or disease progression. You may have specific duties as well that you do on your own, such as keeping a diary or filling out forms about your health. Some studies may follow your progress even after the treatment ends. In addition to doctors, the clinical trial team may include nurses, social workers, data entry technicians and other health care professionals. If you participate in a trial, they will review your health history and current medication with you at the beginning of the trial, give you instructions for participating in the trial, monitor you during the trial and they may contact you after the study is completed. Clinical trial lingo A clinical trial's design is called a protocol; before the trial can begin, a research ethical review board or an institutional review board (IRB) for each study must approve the protocol. These independent groups serve as volunteer advocates. If the trial involves a new drug, the FDA also must approve the study protocol. The protocol specifies such details as the number and type of volunteer necessary to prove statistical validity of the hypothesis, or the investigators initial thesis that the study was designed to test. Statistical validity is the degree to which an observed result, such as a difference between two measurements, can be relied upon and not attributed to random error in sampling and measurement. The FDA evaluates the data to be collected and the dosages of any medications to insure they are appropriate. Many trials include multiple "arms," or groups of participants given different treatments for the purposes of comparison. One arm (or group of volunteers) might receive an experimental drug, while another arm receives a standard treatment or placebo. Additionally, the IRB oversees patient safety throughout the course of the trial. Words used to describe clinical trials include: Open-label-A drug trial in which both the researchers and the volunteers know what drug is being administered and at what dose. A non-blinded or non-randomized trial. Sometimes such studies are conducted while a drug is awaiting review; during that period, participants or insurers may be required to pay the wholesale cost of the medication. Placebo-controlled-A trial in which some participants are given the drug that's being tested and others are given a placebo, or inactive compound. A placebo can have many forms, in addition to the familiar pills; a placebo, for example, may be an injected saline (inactive) solution in the case of an injected or infused drug, or an inactive cream or nasal spray. The placebo will look exactly like the experimental medication. Double-blinded or double-masked-Usually participants don't know if they're receiving the treatment being tested or not. Such studies are termed single-blinded. But in some cases, health care providers also don't know which group is receiving the drug and which a placebo. These studies are called "double-blinded." Randomized-A randomized trial is one in which participants are randomly selected for either the experimental group or the control group. Often, researchers use a computer program to determine who goes into which group. Neither the researcher nor the volunteer has any input or control into which group you enter. Phases of Clinical Trials Clinical trials are differentiated between several different phases. The initial trials, usually small (10 to 30 volunteers), are called Phase I trials. Some Phase I trials use the same dose of a drug throughout the trial, but others may increase the dose, in order to determine the maximum safe dosage and to discover what, if any, side effects result as the dose is increased. Additionally, researchers sometimes take note of effectiveness data gathered during Phase I trials - did participants stabilize or get better? - the primary purpose of these studies is to measure the drug's safety. In Phase II trials, researchers again look at safety, but also gather data on efficacy. This is the first time the treatment or procedure is tested in patients with the medical condition. Some Phase II trials compare the drug to existing treatments, others to a placebo. Phase II trials generally target volunteers with a specific disease to evaluate the potential benefits of the new drug in this population. Phase II trials are usually larger than Phase I studies and may include up to several hundred participants. Phase III trials are the make-or-break tests of efficacy and effectiveness and the first time the drug is used in a broad population. While in a Phase II trial a cancer drug may be tested against many different cancers, a Phase III trial will focus on the one or two cancers in which the drug shows the most promise. At least two phase III trials of new drugs are required before the FDA will consider a drug for marketing. A successful Phase III trial for a previously approved drug or a new procedure, however, could change physician practices. These studies may recruit from several hundred to upwards of 10,000 participants and are designed to evaluate efficacy, compare the experimental treatment to other treatments (if any) or placebo and monitor safety. Because Phase III trials are so much larger than other studies, they provide the best data on overall effectiveness and safety of the treatment in the general population. Phase IV trials are conducted after the FDA grants marketing approval. These studies can provide valuable insight on the effects of long-term use of a drug in the general population. They are designed to accomplish a wide range of objectives. Some are ongoing safety trials, some are registry trials examining the long-term impact of the drug on a disease process, others are pharmacoeconomic studies to determine the cost/benefit analysis. An observational study is not a clinical trial in the traditional sense, although it still requires IRB/HIPAA (Health Insurance Portability and Accountability Act) compliance. It is a study that tracks, but does not interfere with, health-related behaviors. For example, an observational study may compare ovarian cancer rates in women who take oral birth control pills to those who don't. Or an observational study might ask a series of questions to women diagnosed with cancer at an early age and compare the responses to those of women not diagnosed with cancer. Results from observational studies might point the way toward a clinical trial. For example, if oral contraceptives appear to reduce ovarian cancer rates in observational studies, a clinical trial may be designed to verify that observation. But why not just accept the conclusion of the observational study and avoid the added expense of a trial? Observational studies tend to be inconclusive because it is exceedingly difficult to exclude all other factors that may play a role in different outcomes. For example, women who use birth control pills might be more likely to follow a healthy diet or less likely to smoke, or have other behaviors that influence cancer rates. A clinical trial is a formal structured process that seeks to exclude variables and answer specific questions by randomly placing participants in treated or untreated groups, helps control for such factors. Participation in an observational study is often less demanding than a clinical trial (although some studies require elaborate diaries of food choices, exercise tracking, etc.) and usually carries very little or no risk. How to join a clinical trial If you are interested in participating in a clinical trial, you may have to do some of the legwork yourself. Some trials are advertised, but most are not. Physicians may be reluctant to refer patients to a trial if there is an existing treatment or if they are concerned about loosing a patient to another physician. Additionally, insurance companies may refuse to pay for care provided as part of clinical trials. Indeed, recruitment of participants is a major hurdle for researchers. Currently, only 3 to 5 percent of eligible cancer patients take part in clinical trials. A former director of the National Cancer Institute (NCI) said that if only 10 percent of cancer patients participated in trials, the time it takes to complete most efficacy trials (Phase II) could be slashed from the current three to five years to just one year. Until a few years ago, it was difficult for patients to find out about clinical trials, but now there are resources you can use to find out about trials for a particular condition. Cancer patients can contact 1-800-4-CANCER, an information service sponsored by NCI that provides information on the more than 1,500 clinical trials that are NCI-funded. The information is available online at http://www.cancer.gov/clinicaltrials For information on the more than 5,000 federally funded trials that are currently recruiting participants, go to http://www.clinicaltrials.gov. (The site plans to begin listing industry-sponsored trials soon.) Patient advocacy organizations are another good resource. CenterWatch Clinical Trials Listing ServiceT (http://www.centerwatch.com/), a Boston-based publishing and information services company, and ClinicalTrials.com (http://www.clinicaltrials.com), a privately owned Website, also contain trial listings. Additionally, there are many other websites available; not all will have credible information, however. Obviously the main criterion for most clinical trials is that you fit the indication, i.e., have the condition the researchers want to treat. All trials define specific participant-selection criteria. A study may look at participants of a particular age range, or those with a certain level of disease severity. Many trials, such as those designed to evaluate the value of preventive care, seek healthy volunteers. Women's increasing participation In recent years, researchers have stepped up efforts to include women, minorities, the elderly and children in clinical trials. In the past, Caucasian men were disproportionately represented in clinical trials. One factor that limited women's participation was an FDA ban from 1977 to 1993 on early-stage testing of most medications in women of childbearing age, for fear of causing birth defects. Women's health advocates worked for years to change this and other policies that stifled research involving women's health, noting that many women of childbearing age use contraception, are not sexually active, or have chosen not to have children. The issue was important, because if gender affects the way a drug works in the body, and these differences are identified in early phases of research, then subsequent studies can be tailored to explore these differences and figure out how best to use the drug in both men and women. Moreover, the advocates argued, women should be allowed to weigh the risks and benefits and make their own choices about their bodies. One result of this political pressure was the creation in 1990 of the NIH's Office on Women's Health, charged with setting an agenda for research and ensuring adequate representation of women and minorities in NIH-funded trials. Today, women are recruited for trials, even if they are of childbearing age, however they are also informed of the potential risks to the fetus of untested medication. Researchers reduce the risk of fetal exposure by counseling women about the potential risk (if any) to the fetus, and giving the drug during or immediately following the menstrual period or only after a negative pregnancy test. Even aside from the fertility issue, women have often been underrepresented in clinical trials, most notably in cardiovascular clinical trials, in which women account for 49 percent of the cases of the diseases. According to a 2000 study of federally funded research from 1965 to 1998, the percentage of women enrolled in studies that enrolled both genders was 38 percent. In the mid-1980s, researchers began more actively recruiting women for such trials, partly due to political pressure and partly due to new discoveries that showed significant clinical differences in the diseases as manifested in men and women. The advent of two massive clinical trials enrolling only women - the Women's Health Study, with 40,000 participants, and the Women's Health Initiative, with 70,000 - are making up for some of the discrepancies in the past. However, even in the 1990s women remained under-represented in mixed-gender cardiovascular trials (with the exception of those examining high blood pressure). A 1993 federal law requires that women be included in every clinical trial involving a disease that affects them and that the NIH make sure studies are designed to collect and analyze data on gender differences. Drugs often work differently in men and women due to differences in such factors as body size, body fat distribution and hormones. Many drugs, for example, linger in the body for longer periods of time in women than in men. Unfortunately, gathering enough data to detect meaningful gender differences often means substantially increasing the size and cost of a trial. Rather than starting with mammoth trials, some experts suggest gathering data in smaller trials that may suggest trends that could be further examined in subsequent, more targeted trials. In late 2003, Congress passed the Pediatric Research Equity Act, which enables the FDA to require testing of drugs for pediatric use when drug firms do not test them voluntarily. In the past, more than half of new drugs targeted for use in children were not adequately studied in children. As for risks, the American Academy of Pediatrics has stated that using medications in controlled clinical trials poses less of a risk than releasing those medications for widespread use in children without adequate data. Oversight and informed consent Every U.S. site that conducts human clinical research trials must submit the protocol to an Institutional Review Board (IRB). An IRB reviews trial protocols for safety and other issues and monitors ongoing trials conducted by the site or institution. Such committees include physicians and other health care professionals, statisticians and laypersons who work together to ensure trials adhere to ethical standards and respect for participant rights. The IRB is charged with ensuring that: participant risk is kept to a minimum informed consent is obtained from every participant or a legal guardian or representative of the participant; the IRB also makes sure participants who are incompetent or otherwise vulnerable (prisoners, for example) are protected participant selection is fair the potential value of the knowledge or participant benefit gained from the trial outweighs the risks participant privacy is protected The FDA inspects IRB records and operations from time to time to make sure the proper procedures are being followed, and may impose penalties if problems are uncovered. Many trials also have Data and Safety Monitoring Committees, which review studies in progress. During a study, if the committee finds that the treatment is harmful or of no benefit, it will stop the study; the committee may also stop the study if there is clear-cut evidence the treatment is superior. All participants then receive the better treatment. The system for providing oversight has its critics, who contend IRBs in particular need revamping. According to a 1998 report in the Journal of the American Medical Association, the groups are often overburdened and end up spending the bulk of their time dealing with paperwork, and rarely make direct observations of the way researchers are interacting with participants. Moreover, they are generally not very well equipped to handle the special needs of mentally or physically handicapped participants, to monitor financial conflicts of interest among researchers, or to monitor protocols for multi-site trials. Informed consent Before joining a clinical trial, you, or a person legally responsible for you, will have to provide informed consent. (An exception is made for certain emergency treatments.) In most cases, the information will be written and you will be asked to sign a document stating you have been given information and understand it. The FDA requires that researchers share the following information with clinical trial participants: that the study involves research of an unproven drug, device or procedure the purpose of the research how long the study is expected to take what will go on in the study and which parts of the study are experimental possible risks or discomforts possible benefits other procedures or treatments that you might want to consider instead of the proposed treatment that the FDA, the sponsor, the IRB, or their designees may inspect study records, but the records will be kept confidential whether any medical treatments are available if an injury occurs, what those treatments are, where they can be found, and who will pay for the treatment the person to contact with questions about the study, your rights, and injuries related to research participating in the study is voluntary and you can quit any time without losing the rights or benefits to which you would normally be entitled. During the informed consent process, ask any questions that may affect your decision to participate. Consider writing down your questions in advance, asking a friend or relative to join you during the risks/benefits discussion with a health care professional, or bringing a tape recorder so you can replay the discussion later. Before you sign informed consent documents and join the trial, make sure you've taken enough time to think through the issues and discuss them with family and friends. Once you join a trial, remember that informed consent is a process that continues for the duration of the study, and you may ask questions even after signing the informed consent forms. It is important that you know that you can drop out of a trial at any time. It is also important that you talk with your research team to tell them why you want to drop out. Sometimes, problems such as lack of transportation or childcare can be resolved or side effects better managed. If you decide to drop out of a trial, tell the research team why; the information can be helpful, especially if it pertains to side effects, but even if the cause seems less serious-for example, a dosing regimen so complicated it doesn't seem worth the bother-be sure to let them know. Sometimes such input prompts tweaking to make products or procedures more patient-friendly. Will you pay to participate? Determining who pays for participant care in a clinical trial can be a delicate matter. The costs associated with participating in a clinical trial fall into two categories: Usual or standard of care costs, such as doctor visits, hospital stays, clinical laboratory tests, x-rays and so on, which occur whether you are part of a trial or receiving standard treatment. These costs are normally covered by insurance, if you have it, or by you, if you don't. Extra care or study-related costs associated with trial participation, such as additional tests that may not be fully covered by the trial sponsor or research institution. The sponsor of the clinical trial usually covers research costs, such as data collection and management, research physician and nurse time, analysis of results and tests performed purely for research purposes. Some studies provide free services and medications and even pay volunteers for participating and/or reimburse them for expenses associated with trial preparation, such as travel costs, meals and accommodations. In studies of a new medication, the drug may be provided free from the manufacturer, but you or your insurance company will be charged for other costs, such as physician appointments and other services. Other trials will require you or your health insurance provider to pay as usual, even for the experimental service. Make sure you know what charges you will be responsible for before participating, and check with your insurer before joining a trial in which the health plan will be billed. If you want to participate in a trial, you should: Find out about the costs associated with the trial and determine which are covered by the sponsor or institution or physician practice. Find out about your health plan's policy on experimental or investigational treatments. Read your policy closely; if the answers are not clear, call the customer service line, check the Web site or write to them asking for specific information about clinical trials coverage. Work with your health care professional to ensure the health care team meets its own obligations in terms of paying for certain parts of the treatment as provided for under your benefit plan. You may want to ask your health care professional or hospital to send an information package to the plan that includes the following: the results of previous studies, especially any data published in a peer-reviewed medical journal a letter that cites the insurance contract's language to explain why the service should be covered letters from researchers explaining the trial support letters from patient advocacy groups Work closely with your company's benefits manager. Often, they serve as your advocate should disagreements arise. Give your health plan a deadline to make a coverage decision. Most insurance companies are reluctant to pay for experimental (also called investigational) services or medications. Once your insurer learns you are in a clinical trial, you may experience payment denials even for services or medications that would ordinarily be covered. However, coverage has improved so you should check carefully with your insurance company. Health plans usually cover only established services and medications-those for which there are sufficient data to demonstrate safety and effectiveness. (Note: Even if you are not participating in a clinical trial, your insurer may deem some services investigational or experimental if administrators judge there is inadequate data to support the advantage of the treatment over standard care.) Insurers usually look at several factors in determining whether participant costs will be covered: Sponsorship-Some plans set standards of scientific rigor and oversight that a trial sponsor must meet in order to qualify for coverage. Trial phase and type-Some plans cover participant costs only for experimental treatment deemed "medically necessary," for the individual participant. They may also consider the phase of the trial; some plans cover Phase III trials, because the treatments that reach that stage of testing have a track record of efficacy. Some plans may allow participation in a Phase I or II trial with documentation of effectiveness. Cost -- Some plans may provide coverage if trial care is not significantly more expensive than standard treatment. Availability of effective treatment -- Coverage may be provided only for conditions for which no standard therapy is available. Qualifications -- A plan requires that the medical staff and facility meet guidelines that show they are qualified to perform unique or unusual services associated with the trial. If your claim is denied, review your insurance to find out about the appeals process. In the battle to win coverage, you and your doctor may have to demonstrate: The therapy is not just part of a research study, but also a valid procedure that benefits participants. Your situation is similar to that of other participants participating in clinical trials as part of a covered benefit. Possible complications have been anticipated and can be managed. Your state likely has an insurance customers' hotline or advocacy office that may be able to provide help. The insurance commissioner's office is another option. Keep copies of all materials you and your doctor send to the health plan, as well as all information the plan sends you. Depending on where you live, you may have a legal right to clinical trial coverage. Rhode Island, for example, mandates coverage of costs for Phase II and III trials, and Maryland requires coverage for all phases of clinical trials for life-threatening diseases. But most states have yet to require such coverage. If Medicare is your primary health plan, there is good news. In 2000, Medicare began covering beneficiaries' participant care costs in clinical trials. Medicare will pay any charges normally covered, including tests, procedures and doctor visits. The plan will also pay normally covered charges associated with the experimental treatment (for example, Medicare would pay for anti-vomiting medication administered in conjunction with an experimental cancer chemotherapy drug). If an experimental drug or procedures causes a side effect whose treatment is covered by Medicare, the plan will pay those charges as well. Like other insurers, however, Medicare still does not cover: the medications or devices that are being evaluated in the trial research costs materials provided free by the trial sponsor