What You Need To Know About Clinical Trials (Before You Need One)

A research technologist prepares a Tessa Therapeutics Pte. virus specific t-cells (VST) infusion for cancer patients as part of a clinical trial inside a good manufacturing practice (GMP) room at Singapore’s National Cancer Center (NCCS) in Singapore, on Feb 23, 2017. Tessa is developing novel anti-cancer therapies that rely on turbo-charging the body’s cancer-killing immune system. The Singapore-based biotechnology firm has two treatments in patient studies, including one in the final of three stages of trials usually needed for regulatory approval. Photographer: Nicky Loh/Bloomberg

No matter how good a treatment is, sometimes it fails a patient. Maybe the patient’s illness was so advanced by the time treatment began that the therapy could not work effectively. Maybe the patient has a genetic mutation or some other factor that prevented a drug that works on many other patients from being effective for this individual. Maybe the treatment initially worked but the illness recurred. Whatever the reason, there may come a time when a patient will need to think about what happens when the standard therapies fail to help.

In this circumstance, patients will need to decide whether to pursue non-standard treatment options. Some patients will find the right decision for them is to not continue with treatment. All patients, so long as they are competent and can understand the implications of their choices, are able to make this choice. These patients will not be abandoned by their medical team, but the goals of care will shift to symptom management, including pain relief and, when needed, end-of-life care.

Other patients, however, will choose to press on. Sometimes they choose to try something non-scientific, based on faith, anecdote, hope or advice found on the internet. Other patients will try drugs approved to treat other conditions, in hopes that, for example, a drug prescribed for allergies may help multiple sclerosis. This is called off-label treatment (because the drug is being used in a manner not listed on its label) and is legal; however, insurers may not reimburse the cost of drugs used off-label. Some patients will look to clinical trials, tests of investigational treatments for treating the condition or illness in question. And sometimes patients will choose to try these different approaches at the same time: for example, entering a clinical trial while altering diet or trying supplements. (In this case, patients should always discuss their activities with the researchers, both to prevent avoidable harm to the patient and to ensure that the researchers understand that any change in the patient’s condition may be due to something other than the experimental treatment they are providing.)

Clinical Trials 101

For those patients who choose to participate in clinical trials, it is important to understand that much is unknown about the treatment being tested: whether or how well it works, if it is safe, and what side effects may result, in the short or the long term.

Because of these unknowns, there are potential risks to enrolling in clinical trials, along with potential benefits. The new treatment may work for you, or it may not work for you; furthermore, it may cause you to get even worse, develop other problems or even die. Of course, to some extent these risks exist not only for drugs in development but also for FDA-approved drugs: While they have been proven safe and effective in a population, there is no guarantee that they are safe and effective for every individual. Indeed, given the fact that drugs are tested only on a relatively small number of patients in clinical trials — and that patient-subjects with additional medical problems or problematic medical histories are generally excluded from these trials — sometimes it is not until after a drug has been approved and is being used in a more diverse patient population that relatively rare or long-term side effects may come to light.

But if the standard treatments for your disease are not helping, then un-approved medicines may interest you: the new drugs that are in the process of being tested. There are three stages of clinical trials: Phases I, II and III, each one involving an increased number of research subjects. In Phase I trials, researchers are trying to determine how the body processes the drug and how much of it they can use in a person before it causes intolerable side effects. Phase I studies help determine an acceptable initial dose for further study. In Phase II trials, the new drug is being evaluated both for how it impacts the disease/condition (efficacy) and what side effects it may cause. Phase III trials also look for efficacy and safety, often in comparison with another drug or a placebo. (Trials can span two phases, as in, for example, a Phase I/II study.) As a new drug progresses through the clinical trial process and is used on an increasing number of research subjects, more and more information is accumulated.

In most diseases, Phase I clinical trials are not anticipated to be of much, or even any, therapeutic benefit to the patient. Indeed, Phase I trials are usually conducted on healthy volunteers rather than patients; however, drugs like chemotherapy, which cannot ethically be used on healthy people, are tested on patient-subjects. These individuals should be informed that they are not likely to benefit from this experience; rather, the patient is allowing scientists to test a new drug in his or her body to see if it is worthy of continued study. Normally patients would be offered the opportunity to participate in a Phase I trial only after all possible curative treatments have been tried, though sometimes a patient whose disease is stable may be invited to participate in a Phase I trial.

Every so often, a patient will medically benefit from a Phase 1 drug. This is an exceptional outcome, although in certain areas of study — such as with targeted cancer therapies — it is becoming more common. Generally, though, if Phase I participants benefit from being in the clinical trial, it is from the additional care and monitoring that comes with being a part of the study. For example, the extra monitoring that accompanies may result in your healthcare providers more quickly identifying an infection that needs treating.

However, this extra monitoring comes at a cost. Patient-subjects typically have to make additional trips to the doctor, incurring costs from the trip, the babysitter they had to hire, or their time away from work. They can spend hours sitting in traffic or waiting rooms or being infused with the new drug — time that they could be spending with their families, working, or doing other things that are important to them. And occasionally patients find that their insurance may not pay for things affiliated with their research participation, such as the additional scans or the cost of anti-nausea medicine. (Often, however, these costs are covered by the study.) Furthermore, the United States has no law providing compensation for research injuries, so if a patient is injured or killed during a clinical trial, there is often little that can be done to help her or her heirs.

So participating in a clinical trial is a gamble: it may help, it may not help, or it may hurt. To determine which outcome is most likely for them, patients should be informed about certain things when considering a clinical trial. What phase is the trial in? How many people has the drug been tested on? How safe does the drug appear to be? Is there efficacy data, and if so, what does it show? If the researchers are not providing this information, patients (or their companions) should ask these questions. However, the reason the trial is being conducted is that there are still unknowns. So even if the drug has looked promising so far, it may not work for a particular patient or, even worse, it may cause harm to that person. However, again, the clinical trial could also benefit the person. By learning what is known and unknown about the therapies being used and how they have worked on others, a potential patient-subject is better able to make an informed decision about joining the proposed clinical trial.

There are other questions to ask in advance of agreeing to participate in a clinical trial. How many visits to the trial site will be required? Can visits be scheduled outside of work hours? Is there money available to assist with travel expenses, loss of work, or childcare? What treatment costs, if any, will the patient will be responsible for paying? If the drug helps, will the patient be able to still get it after the trial ends? If a patient participates in a trial, does that preclude her or him from being able to try other treatments? What outcome is being studied in the trial, and what impact might that outcome (say, tumor shrinkage) have on the patient’s life expectancy and/or the quality of life? Some of these questions will be answered in the paperwork (informed consent document) that researchers give patients prior to their joining a clinical trial: thus, it is important to read this paperwork and to ask any questions that were not addressed.

Shutterstock

Concerns About Therapeutic Misconception And Exploitation

While many people choose to participate in clinical research to help advance treatments for their disease, most research volunteers also hope to benefit from the investigational treatment. This hope can cross the line into “therapeutic misconception,” in which the patient believes the new therapy will be personally beneficial, even though efficacy and safety have not been established. Research teams are ethically obligated to ensure that patients understand that the investigational therapy being tested is in no way guaranteed to work and that its effects may be worse than the disease itself. Researchers should strive to balance reality with hope: They should not deprive patients of optimism, but they also should not take advantage of a patient’s unrealistic expectations. Avoiding therapeutic misconception, not only in patients but in researchers, is difficult as we, as a culture, often perceive new therapies as better therapies.

As such, another ethical requirement for clinical trials is that there be equipoise between the various treatments being offered. This means that researchers do not know, on the basis of data, that one treatment being tested is superior to the other. For example, if a clinical trial has two “arms,” in which patients in one arm get the standard treatment for the condition being studied and patients in the second arm get the drug being tested, researchers cannot know which treatment is better — if they do, it would be unethical to conduct the trial and knowingly treating some patient-subjects with a subpar therapy. Researchers may have hunches about which drug will be better, but hunches are not data, and treatment recommendations should not be based on unfounded hunches. Indeed, many hunches have been proven wrong by the clinical data generated by clinical trials. Likewise, while a researcher may know that drug X works better than drug Y in, say, older people, this does not automatically mean that the same will be true in children. So, when moving from one population to another, there can still be equipoise, allowing a trial to be conducted ethically.

Where there is no alternative to the treatment being studied, equipoise requires that researchers not know whether the treatment is better or worse than nothing; hence, it is ethical to conduct trials where the new treatment is compared to a placebo. It would be unethical to conduct a trial comparing a new drug to a placebo when there is an existing, available treatment. In that case, rather than the new drug being compared to a placebo, it would be compared to the other, available drug, unless there is already data that destroys equipoise— in which case a trial is not necessary anyway. In some cases, researchers argue that a placebo is necessary even though there is reason to believe the drug being tested in better than placebo. In order to be ethical, these trials often involve a “cross-over” design, in which every patient-subject, at some point during the trial, receives both the placebo and the active drug.

Clinical trials must stop if the data is compelling enough to break equipoise, i.e., if it becomes clear that one treatment is superior to the other. As such, while a clinical trial is ongoing, the data from it goes before something called a Data Safety Monitoring Board (DSMB). If the results of the various treatments are more different than could be expected from chance, the DSMB informs the researchers that the trial must stop as there is no longer equipoise.

Therapeutic misconception not only affects patients: it affects clinicians and researchers. If the hypothesis behind a drug makes sense, or if another patient who took a drug did well on it, it is only natural for a clinician to believe that the drug works. This underlying belief may color what the healthcare provider says and does not say about the investigational drug, possibly to the point of influencing the patient’s decision about whether to try the drug. Furthermore, a researcher’s belief in the drug could surreptitiously color the data collected from the trial. For example, if tumor growth is being measured in millimeters, and the results of a scan are not crystal clear, then whether a tumor has grown can be a judgment call.

For this reason, clinical trials sometimes employ methods to ensure that the patient, the researcher, or both are unaware of what treatment is being used; this is called “blinding.” And, because the results of a research study that tested a new drug on patients that are somehow different from those patients receiving the other treatment would produce biased data, patients are randomly allocated to get either the drug being tested or an approved drug (or placebo, when there is no other treatment). What is often called the “gold standard” of clinical trials is a randomized, double blind trial in which patient-subjects are assigned treatments randomly and in which neither the patient-subject nor the research team knows which treatment a particular patient-subject is receiving. While these trials can still have problems (for example, not enrolling a sufficient number of patients to ensure that the results are statistically significant), this design cuts down on the number of ways that the resulting data can be biased in favor of one or the other treatment — and decreasing bias increases the likelihood that a trial finds meaningful data that will add to our knowledge base.

Regardless of how a clinical trial is structured, it is important that patients understand what they are agreeing to do (or have done to them). Even though it important to enroll patients in clinical trials in order to gain knowledge about new therapies, patients should never unknowingly or unwillingly participate in a study. There are several safeguards to protect patients from being exploited as research subjects. One is that all research projects (“protocols”) must first be reviewed by a body called an institutional review board (IRB). One of the primary responsibilities of an IRB is ensuring that patients considering participating in a clinical trial understand the points covered in this article: that research does not necessarily help, that it can harm, and that it can have financial and other implications for the patient. The IRB reviews proposed trials to make sure that all potential participants would be thoroughly informed about the potential risks and benefits of enrolling and the IRB maintains oversight of ongoing trials to ensure that, as new information about the experimental treatment is learned, the informed consent document listing these potential risks and benefits is updated accordingly. The IRB also ensures that, while some clinical trials provide nominal compensation to participants for their time and/or inconvenience, researchers do not offer potential participants money, gifts, or other items desirable enough to sway a person’s decision to participate.

Shutterstock

Social issues relevant to clinical trials

One reason patients, and people in general, sometimes have unrealistic expectations about clinical research is because of the current epidemic of medical hype. From popular TV shows to magazine stories to social media to press releases to advertisements, the narrative that medicine can cure anything is omnipresent. Likewise, the use of such terms as “breakthroughs” and “game-changers” makes cures seem much closer to reality than, sadly, they often are. When cures fail to materialize, institutions like the FDA are sometimes scapegoated or conspiracy theories arise — like the idea that pharmaceutical companies can cure diseases but choose not to because it is more profitable to treat patients with ineffective drugs than to restore them to a state of health. Worse, patients can be led to believe that they just didn’t want to be cured badly enough, or that they sabotaged their recovery by thinking negative thoughts, by not eating a specific diet, or by not choosing a more extreme untested treatment. These are harmful myths that unfairly blame patients for their diseases and outcomes. Human biology is hard to understand, and figuring out how to manipulate that biology in a way that helps rather than hurts patients is harder. The path to a successful approved drug is littered with potential treatments that turned out to be ineffective or were too toxic.

Clinical research is conceived of and conducted by people. As such, it is subject, as all human endeavors are, to bias or poor study design. An IRB can review the ethics of a study, but it is typically not equipped to evaluate the scientific accuracy and validity of the study design (such as whether the trial needs more participants to produce statistically significant results). Other bodies sometimes evaluate trial designs for their usefulness and to ensure that they’re as free from bias as possible, but this is not done universally. And even with excellent study designs, there can be human error in collecting data, which will make the results less valuable.

Not all trial results are published, which limits the number of people who will know what the trial found. Even in cases where results are published, researchers do not always make the raw data available, which limits the ability of other researchers to understand what happened in the trial. So, there is much work to be done to make sure clinical trials are being run as well as possible, and various groups both domestic and global are tackling these issues. While no one patient is able to impact these larger issues, potential trials participants should at least be aware of them. When considering enrolling in a clinical trial, patients can ask if they will be informed of the trial’s findings; if they will continue to receive the new experimental medicine post-trial if they were benefitting from it; and if the trial data will be made available to other researchers (and, if so, how their privacy will be guaranteed).

There is a saying that a good drug proves itself early. Indeed, in exceptional cases, a drug can demonstrate whether it will help patients as early as Phase I testing, even though this first use of the drug is not intended to look for or to prove efficacy. But sometimes a drug does not appear to be effective until after a trial has ended, when researchers reviewing data discover that the drug may, in fact, have worked but only in a certain subgroup of people (for example, those with a certain disease subtype or a certain genetic mutation). After-the-fact subgroup analysis is controversial and should ideally be used only to generate ideas for another clinical trial, not as proof of efficacy.

In some cases, trials cannot recruit enough patient-subjects to participate in them because the requirements are too onerous: too many in-patient stays, too many scans, too many blood draws. In these cases, the researchers need to compromise between the ideal trial design and what is possible, given the desires and concerns of the possible trial participants.

Clinical research is a community activity. Although we hear stories of the intrepid patient, or parent, who single-handedly discovers a cure, such instances are almost unimaginably rare. Finding treatments normally involves numerous patients willing to participate in trials, even when it is unlikely that they will personally benefit. Informing these patients that clinical trials are an option requires an educated healthcare workforce that knows how to refer patients to research centers and how to explain clinical research. All clinicians, even those who do not conduct research, must be able to do this. Meanwhile, patients should feel free to ask their doctor if clinical trials are an option for their disease or condition – especially, but not only if, the standard treatment options are not working. If the doctor does not know, the patient may wish to consider a second opinion from a healthcare provider who is more familiar with clinical research. Alternatively, patients can contact advocacy groups for their disease/condition and ask about participating in research. Patients can look on ClinicalTrials.gov or other trial finder services for studies that they might want to join. Not all trial finders are equal, however, so patients should ask questions — including if there is a charge for the service and if their personal data will be protected — before using one of these.

Clinical trials are the necessary process by which new treatments are tested for safety and efficacy. Participating in a clinical trial can possibly help patient-subjects while improving the treatment of a disease or condition. But the time for patients to learn about clinical research is now, while they are healthy or while their medical situation is under control. When a patient is in dire straits is not the time for him to be learning the ins and outs of clinical trials or to be grappling with the ethical and logistical questions they raise. Furthermore, while many patients may not wish to participate in a clinical trial when there standard treatments available, receiving one or more of these treatments may render you ineligible to participate in some trials. So ask questions about clinical trials; learn how to find open trials; and consider enrolling in them before you are out of treatment options. Your knowledge may someday save a life – your own, or that of somebody you love.

Thanks to Lisa Kearns, Richard Klein, and Jane Reese-Coulbourne for their comments on drafts of this article.

Source