The Value and Cost of Clinical Research Studies There is a lot in the lay literature these days about clinical studies – research studies in which people are the subjects and drugs, procedures, and disease course are examined. What is clinical research? Why would anyone participate? What do doctors and nurses, patients and families, and hospitals and universities get out of clinical research? Clinical and Translational Research Clinical Clinical research involves scientific and medical investigations in which people are the subjects being studied. Examples of clinical research include studies of which of two daily doses of a drug works best to decrease blood pressure; studies of what aspects of kidney function are abnormal in people with lupus; and studies of whether a new pacemaker is safe to use in people with heart rhythm disturbances. Translational Translational research also involves human subjects, but generally involves either taking information or material from the laboratory and implementing it in people or vice versa. Examples of translational research include studies that take blood from people with and without asthma and analyze it in a research laboratory to determine how chemicals released from blood cells differ between asthmatics and non-asthmatics; and studies that bring a new surgical technique developed in a computer simulation model to children with a specific kind of congenital heart disease. Randomized, Blinded, and Controlled Clinical Trials A clinical trial generally tests a new drug or device or technique. It is a way of assessing to what degree a new way of treating a disease or condition is safe and effective in a particular population. Drug trials are often conducted in phases, with determination in the laboratory of how much to give and how long the drug stays in the body first, human safety trials next, efficacy trials after that, and ongoing monitoring for safety and efficacy after it is approved for use. If a drug is being tried for a condition for which there is no standard therapy or a condition that is often just tolerated and not treated by patients, it is likely to be compared to what is called a “placebo”. A placebo is a treatment that looks like the drug being tested but that does not include the active ingredient. If a drug is being tried for a condition for which there is a standard therapy or a condition that cannot safely remain untreated, it is likely to be compared to standard therapy or added to the required treatment to see if it is better than standard therapy or if it improves the patient’s condition further relative to standard treatment alone. Sometimes a clinical trial compares two or more doses or dosing schedules or routes of administration (e.g., oral, by intravenous injection, or by nasal spray) to see whether one is either more efficacious or less toxic than the others. In this case, the drug itself is not experimental; the investigators are just trying to determine the best way to use it. A control is a standard comparator. That is, a controlled study uses a placebo or a known, standard therapy with which to compare the experimental treatment. If the patient or the person administering the therapy or the person making the measurements of efficacy or side effects knew which patient got the experimental drug and which patient got the control, they might be biased, even subconsciously, in reporting whether the treatment did or did not work or did or did not cause side effects. For this reason, such studies are usually blinded, with the identity of the treatment not known to patients and/or investigators. A double-blinded study is one in which neither the patients nor the investigators know which patient got what. In this case, the pharmacy might assign a code number to the container in which the treatment is provided and would maintain a record of which code numbers corresponded to control and experimental treatments, along with which patient got which number container. Finally, if the patient or the person administering the therapy could choose who got which treatment or if the scheme that decided this were not random (e.g., if the first five people enrolled got treatment A and the next five people got treatment B), this would both preclude blinding and increase the potential for bias. So most well-designed clinical trials include “randomization” (like pulling a number out of a hat) of which patient gets which treatment. All of this complex structure is aimed at minimizing the chances for biased perception of drug effects or interpretation of study results while ensuring that any patient enrolled in the study has an equal chance of reaping benefits from the study. Advantages for Participants Patients who participate in studies sometimes get some small remuneration for their participation. This has to be small and is often something like a specific gift certificate rather than cash because it cannot be large enough to be coercive to participation in the study. They usually will not incur monetary cost; that is, they most often have things like their transportation and/or parking costs covered by the study. Patients who participate in studies may or may not themselves benefit from the study. Given that it often takes 20 or 30 years for a drug to go from discovery in the laboratory to use in the clinic, it is actually unlikely that participating in a single study will result in direct personal benefit. In addition, because the investigators are doing the study because they truly do not know what the results will be, often participants take some risk in participating. Investigators do everything possible to minimize risk and their institutions and the agencies that fund the studies do their best to ensure that the potential benefits to society outweigh the risks. And, to be sure, there are many, many studies for which the risk is truly minimal. So Why do People Participate in Clinical Studies? Almost always, it is because they want to do everything possible to ensure that the next generation of people with the disease or condition they have has more and better possibilities for diagnosis, treatment and, prevention or cure than they do. They want to advance knowledge, improve prevention and treatment, and decrease suffering. They derive satisfaction from knowing that their participation has the potential to contribute to the betterment of the human condition. Advantages for Investigators Clinical research studies are often funded by government agencies, disease-focused foundations, or drug companies. The public often assumes this means that investigators make money doing clinical research. In fact, almost all clinical investigators are faculty members at universities that set their salaries. A clinical study funder may buy from the university some fraction of the faculty member’s time, making it available for the conduct of the study; or the funder may pay the university a certain dollar amount per patient enrolled, and everything, including the cost of supplies and equipment needed to perform the study, must come out of that lump sum. Usually, research costs the university money, as funding agencies do not fund all of the costs associated with doing the study. Why do Clinician-Investigators do Research? Mostly, it is for the same reason patients participate in it. Physicians are often frustrated by the limitations of what they can do for their patients in the here-and-now. They are curious as to whether even the very best of their treatments could be better – more efficacious with fewer side effects. They want to know that they contributed to ensuring that clinical care tomorrow will be better than anything we can do today. In addition, for those who are relatively new in a faculty position, doing an interesting study and publishing the results may help them “climb the academic ladder” and become a more senior-ranked professor. Also, achieving success in a study may open the door to being able to make participation in other studies available to one’s patients. Communicating the Risks and Benefits to Participants The initiation and conduct of clinical research is tightly regulated in the U.S. All proposals and associated patient consent forms for participation must be reviewed and approved by a group called an Institutional Review Board (IRB). The guidelines for IRB membership and for review and monitoring of clinical research are set by the Federal government. Funders of such research require prior approval by an IRB before monies are released and many include their own review of the ethical and safety aspects of a proposal in their assessment process as well. The education of potential participants in a study is done through the process of informed consent. Reading and signing a consent form is an important part of this process and a consent form should optimally provide, in writing understandable to an average layperson, all of the details of why the study is being done: Who is doing it? How will the results be reported? Where will the results be stored? What are the risks and benefits of the study to the participant and to the community? What is being done to minimize the risks? How can a participant withdraw from the study if they chose to? That said, a consent form alone is not informed consent. The ongoing dialogue between the investigators and the patient and the open opportunity to ask questions, re-examine participation, and fully understand the risks and benefits of the study – these in aggregate constitute informed consent. Openness on both sides of the equation is key to the process. A Debt of Gratitude The quality of life and the extraordinary likelihood of meaningful survival we enjoy today is the result of the collaboration of many groups who fuel the efforts to understand, to optimize, to prevent and cure illness. Clinical investigative teams who strive to make life and health better Patients and families who take risks, however small, knowing that the benefits may not accrue to them or their loved ones Funders – both outside and inside of academic and medical institutions – who fuel the efforts to understand, to optimize, to prevent and cure illness. We owe them all our thanks and admiration.