All U.S. clinical trials must include mechanisms to ensure the ethical treatment of human subjects. Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug), the regulatory agency for the country where the drug will be sold. Before a clinical trial gets underway, its protocol must be extensively reviewed to see that its benefits outweigh its risks. Reviewers include FDA officials and Institutional Review Boards (IRBs), committees at each research institution comprised of physicians, other health-care professionals, statisticians, ethicists, local community members, patient advocates, and people with the disease under study. IRBs not only approve studies before they begin, but also monitor their progress until completion. In addition to federal requirements, some states also have their own regulations governing human research. Finally, international agreements such as the Nuremberg Code, the Declaration of Helsinki, and the International Code of Medical Ethics put forth principles for conducting ethical research. To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB’s main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient’s legally authorized representative (See IRB QA information sheet). In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPPA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the “rights, safety and well being of trial subjects are protected”. The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary. Informed consent is clearly a ‘necessary’ condition for ethical conduct but does not ‘ensure’ ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments, and then quantified methods may play an important role.
Local site investigators and their IRB: A physician’s first duty is to his/her patients, and if a physician investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and cannot act unethically to obtain and maintain their participation (also see Sunshine Act established in 2013 for physician’s financial transparency reports). The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study; in other words, they (or their legally authorized representatives) must give truly informed consent. Are in compliance with HIPAA rules. They are responsible for reviewing all adverse event reports sent by the sponsor. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred, and the sponsor, regarding the relationship of the adverse event to the study treatments). They also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events. When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.
The interrelationship and interaction between the research sponsor, the clinical investigator and the IRB may be very complex. The regulations do not prohibit direct sponsor-IRB contacts, although, the sponsor-IRB interaction customarily occurs through the investigator who conducts the clinical study as agreed when they sign the FDA-1572, for drug and biologic studies.
FDA regulations [21 CFR 312.23(a)(1)(iv)] require that a sponsor assure the FDA that a study will be conducted in compliance with the informed consent and IRB regulations [21 CFR part 50 and 21 CFR part 56]. Sponsors should rely on the clinical investigator, who assures the sponsor on form FDA-1572 that the study will be reviewed by an IRB who is functioning in compliance with the regulations.
An IRB must notify an investigator in writing of its decision to approve, disapprove or request modifications in a proposed research activity [21 CFR 56.109(e)]. This correspondence should be made available to the sponsor by the clinical investigator. In the Agency’s view, this required documentation provides the sponsor with reasonable assurance that an IRB complies with 21 CFR part 56 and that it will be responsible for initial and continuing review of the study. Also, the sponsor and, in fact, anyone who is interested, may obtain an Establishment Inspection Report from an FDA inspection of an IRB. These reports summarize the conditions observed during the IRB inspection. FDA, however, does not certify IRBs.
Required Care at Outside Institutions: Several issues are raised when a subject who is participating in a research study at one institution is admitted to another facility. In the scenario when a subject’s treatment/hospitalization at an outside site is not related to the research, the investigator at the study site is responsible for test drug administration and follow-up and therefore, should be aware of the hospitalization and must report the event as an unexpected adverse incident, if it is possibly related to use of the test article. For the scenario that on study care is at an outside site must be first permitted by the sponsor and the study site’s IRB, however the study site remains responsible for the test drug administration and collects research data when the subject returns. In another scenario that the study site shares the responsibility of monitoring subject status with an outside site, the outside site is to be identified as a sub-investigator of the protocol and that site’s IRB should review and approve the protocol as the study site has which would involve signing a second Informed consent form detailing only the specific procedures involved while at that facility.
Scientific Review: Experts review clinical trial protocols before studies are launched to make sure that they are based on sound science. All clinical trials that are funded by the federal government must go through this type of review. Many other clinical trial sponsors, such as drug companies, also seek expert advice on the scientific merit of their trial protocols.
Institutional Review Boards (IRBs): These boards also review clinical trial protocols before studies can begin. The board members make sure that the risk of harms in a trial is low and that any harms are reasonable when compared to the possible benefits. They also closely watch the ongoing progress of the trial from beginning to end, and must review ongoing trials at least yearly. IRBs can require changes to the protocol—or even stop the trial—if necessary to ensure patient safety. Federal rules require that each IRB include at least five people, including: one scientist, one person who is not a scientist, one person who is not associated with the institution where the trial is taking place and who is not an immediate family member of someone who is associated with that institution, IRBs can also include doctors, nurses, social workers, chaplains, patient advocates, and other health care or community professionals. All members of an IRB are required to be educated about the IRB’s purpose, functions, and responsibilities, as outlined in federal regulations. In most cases IRBs are located where the trial is to take place. Many institutions that carry out clinical trials have their own IRBs. A clinical trial that is taking place at more than one institution often undergoes review by each institution’s IRB. Approval by an IRB, or ethics board, is necessary before all but the most informal medical research can begin. The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly “continuing review” report from the investigator updates the IRB on the progress of the study and any new safety information related to the study. Also see the IRB FAQ Information Sheet.
Data and Safety Monitoring Boards (DSMBs): Some clinical trials – especially phase III clinical trials, which often involve many institutions – use a Data and Safety Monitoring Board (DSMB). Similar to IRBs, DSMBs review the progress of a clinical trial and monitor participant safety. They also review data on the effectiveness of the trial interventions. Each trial has only one DSMB. A DSMB is a group of doctors, statisticians, and others who are independent of the people, organizations, and institutions that are sponsoring, organizing, and conducting the clinical trial. DSMB members are experts in clinical research and clinical trials. They ensure that trial data are complete, and they can stop a trial early if safety concerns arise or if an answer to the main research question is obtained earlier than expected. Stopping a trial early because the main research question has been answered may make it possible for people who are not in the trial to get access to an effective intervention sooner. DSMBs have scheduled meetings to review clinical data, and their meeting minutes or recommendations are forwarded to the IRBs. Scientific oversight informs decisions about a trial while it’s under way. For example, some trials are stopped early if benefits from a strategy or treatment are obvious. That way, wider access to the new strategy can occur sooner. Sponsors also may stop a trial, or part of a trial, early if the strategy or treatment is having harmful effects.
Office of Human Research Protections (OHRP): The U.S. Department of Health and Human Services’ (HHS’) Office for Human Research Protections (OHRP) oversees all research done or supported by HHS. The OHRP helps protect the rights, welfare, and well-being of research participants. They provide guidance and oversight to the IRBs, develop educational programs and materials, and offer advice on research-related issues. OHRP enforces important regulations for patient protection in clinical trials, called the Common Rule. These regulations set standards regarding: The informed consent process, IRB formation and function, The involvement of prisoners, children, and other vulnerable groups in research.
Food and Drug Administration (FDA): FDA also plays a role in protecting people taking part in research and ensuring the integrity of data from trials. The FDA can remove researchers from conducting clinical trials when the researcher has repeatedly or purposely not followed the rules intended to protect patients. Or when the researcher has not ensured data integrity. FDA approves new drugs before they can be sold. This helps: Prevent quackery, Ensure that drugs work as they should, Make sure the drug’s health benefits outweigh their risks. In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. Inspections of both clinical and non-clinical studies are performed by the FDA’s bioresearch monitoring program (BIMO), as supported by the Office of Good Clinical Practice (OGCP) and Office of Regulatory Affairs (ORA). This audit may be random, or for cause (because the investigator is suspected of fraudulent data). (Also see public information and FDA records.) Avoiding an audit is an incentive for investigators to follow study procedures. They check to make sure that the proposed studies have proper informed consent and protection for human subjects. The FDA also provides oversight and guidance at various stages throughout the studies. For example, before large-scale phase III trials begin, the FDA provides input on how these studies should be done.
ClinicalTrials.gov: ClinicalTrials.gov is a Web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions. The Web site is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH). Information on ClinicalTrials.gov is provided and updated by the sponsor or principal investigator of the clinical study.