Welcome back to trial management and advanced operations. My name is Sheriza Baksh, and I'm an Assistant Scientist at the Center for Clinical Trials and Evidence Synthesis at Johns Hopkins University. In this lecture, we will be discussing regulatory affairs in clinical trials and issues around avoiding trial misconduct. In our prior lecture, we discussed protocol events. Trial misconduct is handled in a different manner with regards to reporting and corrective actions. After this lecture, you should leave with a better understanding of the following key points. The first of these is that regulatory affairs of clinical trials in the United States is a result of federal statutes responding to concerns of patient safety and drug efficacy. Similarly, in other countries, trial investigators are held to federal and local standards in their study conduct. Institutional Review Boards, or IRBs, act like the policemen in charge of enforcing the federal and local regulations for clinical trials. IRBs conduct a both pre-planned milestone reviews as well as ad hoc reviews throughout the course of the clinical trial. In addition to these, there may or may not be a closeout report as well for the trial. In addition to IRBs, federal agencies may require that trial investigators report certain types of events to them. These reporting requirements may change depending on the nature of the investigational product. If a product has been approved, there may be less regulatory requirements for reporting these events. The ramifications for trial investigators engaging in fraud or trial misconduct can mean a potential loss of federal funding or even legal prosecution. In our previous lecture, we discussed reportable protocol events. Today, we are looking at a special subset of these events that involve breaches of ethical requirements. Please note that this is not referred to unintentional violations of ethical guidelines. These are intentional misconduct activities. The first line of defense in any ethical breach is the study investigators. They are responsible for ensuring that all study team members are educated on ethical principles and have the clinical expertise to complete study procedures. In the event that there is a breach, they are responsible for reporting said breach to the study sponsor, the DSMB, and the IRB. The study sponsor may be a federal or international funding body. The study sponsor may also be the same entity as a study investigator in the case of industry trials. The DSMB may provide recommendations on whether or not the study should be suspended. However, as these are recommendations, they do not necessarily have to be followed. The IRB, however, then determines the potential harm caused by the breach. They investigate the consequences of said breach and they work with the study investigators and sponsor to develop a risk mitigation procedure. The IRB may recommend study suspension if the breach poses substantial risks to study participants. Ethical breaches are generally considered reportable events to regulatory agencies and may result in the suspension of funding for study investigators and potentially the revocation of federal licenses to perform human subject research. These consequences cannot be underestimated. They can severely harm the potential professional development of young investigators and have the potential to bring down the overall public opinion of a particular entity. If the potential damage has extensive, study participants may be informed of the breach. Finally, if there are future ramifications for the study investigators, the general public may be informed through a variety of mechanisms, including mass medium and so-called research blacklists. Before we begin, let's go over the basics of ethical review. Investigators looking to submit clinical trial data for marketing approval for any medical product and investigators funded under a government agency are bound by ethical regulations. This is true for many countries around the globe, and you'll see as we go over these that there are commonalities between each of these agencies. These regulations can be at the institutional, local, or federal level, and oftentimes they do overlap. Conducting multi-center clinical trials in multiple countries further expands the regulatory oversight for a particular trial. In this section, we will review the guiding principles that oversight bodies may employ as well as the different levels of oversight and reporting responsibilities. The historical basis for the ethical oversight of clinical trial spans multiple nations and is the result of hard-learned lessons in the conduct of human subject research. On this slide, we have highlighted a few that have had tremendous impact on regulation within the United States as well as many other countries. After World War II, the Nuremberg trials prosecuted leaders of Nazi Germany for utilizing slave labor, invading multiple countries, and of course, the Holocaust. The Nazis inflicted terrible atrocities on civilians, including crimes against humanity. The Nazis were prosecuted for unethical medical research in the doctors' trial also referred to as United States of America versus Karl Brandt and colleagues. The accused were found guilty on conspiracy to commit war crimes and crimes against humanity. Crimes including non-consensual medical research on POWs and civilians, and planning and executing the murder of those with stigmatized or incurable medical conditions. Written into the verdict of the trial was a section entitled permissible medical experiments, which we now know as of Nuremberg Code. This 10-point document highlights the importance of consent, equipoise, and respect for human life. Two years later, the WHO and UNESCO established the Council for International Organizations of Medical Sciences. While much of their mission centers on medical product development and regulation, they also establish principles for the ethical conduct of medical research. They have a range of reports on various topics, including research in vulnerable populations and safety reporting in clinical trials. These guidelines form the basis for international reporting of adverse events in regulatory clinical trials internationally. Many international organizations have signed on to CIOMS, including those in Korea, South Africa, Belgium, and Italy. CIOMS also hold a database of adverse events for clinical trials globally for particular medical products. The Declaration of Helsinki was developed by the World Medical Association in 1964. This declaration is targeted to physician-scientists and prioritizes a research participant's health well-being, autonomy, and privacy in the conduct of research. This code along with the Nuremberg Code serve as a basis for the Code of Federal Regulations Title 45 in the United States. This is the basis for the ethical conduct of all federally funded research and the basis for IRB oversight. The Belmont Report was developed in 1978 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in the United States. This report outlines three guiding principles for the conduct of human subject research, namely respect for persons, beneficence, and justice. This report has been utilized in other countries as well and forms the basis of many other ethical guidelines internationally. A more extensive set of guidelines was developed in 1996-1997 by the International Conference on Harmonization known as Good Clinical Practice or GCP. While many countries sign on to the ICH as it is known, they have various degrees of enforcement for the ICH guidelines such as GCP. For instance, in Europe, GCP is fully enforceable. Whereas in the United States, FDA treats GCP as a guideline and NIH only requires training. In Canada, the Tri-Council Policy Statement, or TCPS, was developed by three funding agencies in the Canadian government: the Canadian Institutes of Health Research, the National Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council of Canada. The policy emphasizes respect for persons, concern for welfare and justice, mirroring the Belmont principles. Failure to comply with these ethical guidelines could lead to cessation of funding and other repercussions with each of these funding agencies. Finally, we have the common rule that was revised in 2018 in the United States and covers both biomedical and behavioral research. Twenty federal agencies have signed on to the Common Rule. It covers compliance consent, IRB requirements, and protections for vulnerable populations. Later in this lecture, we will discuss single IRBs in the context of multi-center clinical trials, which is also covered under this Common Rule. Together these guidelines, principles, and statements share many common elements that are collated and incorporated into federal and local regulatory requirements. For the purpose of this lecture, we will use a term IRB to refer to any independent ethical review body for a clinical trial. IRBs can be commercial or institutional, but they are held to the same oversight requirements. IRBs may serve as the only IRB for a particular clinical trial or is one of many IRBs for a trial. They may serve as a primary IRB or as a secondary IRB for a multi-center clinical trial, focusing on local requirements as needed. In essence, the IRBs serve as the first line of regulation enforcement in a clinical trial. They are charged with reviewing and monitoring both biomedical research involving humans and the data management surrounding that research. There are many types of review, including a full abbreviated and an exemption. The IRB purview starts before the research activities actually begin in the study planning phases. For instance, the site startup phase, the staff certification, and the recruitment phase of the study, and this can continue for as long as the data are being housed with the potential for analysis. The IRB oversight can end once any identifiable data are no longer collected and analyzed. Note that maintaining identifiable data without using or analyzing it is not considered human subject research and therefore does not require IRB oversight. IRBs also assess investigator's compliance with federal and local clinical research requirements, including ethical and clinical training. This may or may not include the full body of GCP, and it can include institutional requirements such as their Federalwide Assurances in the United States. IRBs also have the power to terminate a study from violations of federal or local regulations. Safety concerns also fall under this as GCP practice states that participants should not into undue suffering in the course of a clinical trial. During the initial review of a clinical trial application, the IRB has several elements that they would like to see addressed. The IRB generally wants to see evidence that there is uncertainty in the scientific community about which treatment group is clinically better than the other, and they want to see this through the course of the study. This may change with the introduction of external factors and evidence that may disrupt the equipoise for a particular study and impact the continuation of said study. IRBs also want to assess the overall risk-benefit for the study participants in all of the treatment groups. You can imagine situations where one treatment is known to be particularly beneficial for a particular study population. This could lead to some questions about the ethics of conducting a clinical trial in this context. Some IRBs may even question the diversity of the intended study population and might question strategies to increase diversity and inclusion of underrepresented populations. Part of the IRB review will also include an appraisal of data integrity, data management and security, and quality assurance throughout the trial. Training and certification of staff are also assessed during this time and they can include both ethical and technical training to ensure that all study procedures are conducted in a manner to maximize the participant's safety and their privacy. Additionally, staff are trained on how to prevent fraud and misconduct through their training. Finally, the IRB will check that all investigators are within the federal and local regulatory compliance for the conduct of the trial. The initial submission to the IRB contains a large amount of documents. The list on this slide is meant to be a snapshot of some of those documents that may be required, but please be sure to verify the list provided by your IRB. The first of these of course is the informed consent documents or assent documents, and these have to be translatable to the patient population at hand and they should also be pretty easy to understand and signed by all study participants. The second of these, of course, is the protocol. The protocol should completely and comprehensively address the study procedures for the clinical trial. Some IRBs may ask that any questionnaires, surveys, or interview scripts are also submitted for their review. They will assess the certifications of study staff. If this is an investigational product that is being used, they might ask for an investigator's brochure or some evidence for regulatory approval or the potential for regulatory approval such as with an IND, an Investigational New Drug application. They may even ask for an exemption if that is indeed the case for a particular product. The IRB could also look at the recruitment materials. Any patient-facing material is generally viewed and reviewed during this process. Finally, the IRB may also asked to see a data and safety monitoring plan for the course of the trial and for the data security beyond the end of the trial. Continuing review is for the continuation of the study. This review assesses the following; the overall risk to the participants and the balance with the potential benefits. Again, the goal here is to maintain equipoise throughout the study. The IRB wants to see equal recruitment and enrollment of study participants at this time as well. They want to see that the strategies you said you would employ at the beginning of the study are indeed continuing, and if they need to be changed, what changes are actually being implemented. The IRB would like to see adequate and complete informed consent, so this is where we assess whether or not all of the participants have indeed completed the informed consent process and that it's being communicated effectively. The IRB checks for a comprehensive data monitoring evidence. They want to make sure that the data monitoring plan you said you would implement is actually being implemented, and this can, of course, include a risk-based approach to study monitoring. The IRB also looks at the safeguarding of identifiable participant data. They want to ensure that your data security procedures are up-to-date and on par for the current technological advances. The IRB also looks at the absence of coercion or undue influence on study populations and also looks to see that vulnerable populations are protected through the course of the trial. The change in research or ad hoc submissions can include a multiple of materials. You could submit recruitment materials, any protocol amendments, or changes to the materials submitted in the initial submission. This often means an expedited review of protocol events as well. The change in research may or may not require a full IRB panel to adjudicate the particular change that is being implemented. Finally, the IRB may ask for a study closeout report and, at this point, this is when the IRB wants to assess any use of identifiable data to ensure that it is indeed complete. There are a few types of review situations that I wanted to highlight. Again, I will preface this by saying that this list is by no means exhaustive, but it gives you a sense of some of the scenarios you may encounter after submitting an application. While rare in clinical trials, there are rare situations where your study may be found to be exempt from IRB review. One example might be a clinical trial comparing a new flavor of a supplement compared to the existing flavor and their effect on daily adherence, per se. It is generally advisable that the decision on exemption be made by the IRB either through an assurance or an expedited review. Expedited reviews broad term that can apply to many situations. Generally, it refers to the review of an application by an IRB chair or another experienced reviewer. Some examples of when this might be used are the prospective collection of non-invasive specimens, collection of voice or image recordings for research, or continuing review of an application where no participants have been enrolled and no new risks have been identified. The continuing review is generally done annually for most trials, though it may be completed more frequently depending on the degree of risk to participants in the study. If you were studying an intervention in a population that is potentially high risk to a particular adverse event, you may be asked to do a continuing review more frequently than once a year. In the United States, the Office of Human Research Protection, OHRP, does allow for the continuing review to be conducted by another IRB, as long as the IRB is also federally registered. Continuing review may end once the collection of identifiable participant data has ended. This may or may not mean that the study has reached all of the criteria for study closeout and there may be analysis procedures to complete. Remember, the key here is the identifiable data. In the event of a lapse and continuing review, the OHRP advises that investigators and treating physicians make the initial determination of study continuation of enrolled participants. The IRB is then asked to make a similar determination as soon as possible. If it is not in the best interests of study participants, then all human research activities must be suspended until the IRB can complete the continuing review. We've spoken extensively on the Common Rule in this lecture. One of the provisions is a requirement for all multi-center clinical trials to use a single IRB, a so-called SIRB or an IRB of record. The use of a single IRB is intended to streamline study review activities by deduplicating efforts and reducing the back and forth negotiations of different IRB requirements for one study. The IRB of record bears the responsibilities for study oversight for another institution. This is usually documented through a written agreement between the two entities known as a reliance agreement. This may also be called a cooperative or authorization agreement. There may be a fee associated with the service, which is also documented and agreed to in the document. Some local IRBs may still require study investigators to submit additional documents for review or notification through the course of the trial. Despite there being an IRB of record, please consult with your IRB for details regarding your study. Participating sites are those sites that agree to use IRB of record as their primary ethical review body. Each participating site is required to complete an assessment of local contexts and institutional requirements. This questionnaire is meant to reflect the requirements in the local jurisdiction for the site and may translate to additional items for submission for participating site that may not be mirrored at other sites in the study. By employing a structure of a single IRBs serving participating sites, an individual site may also elect to submit locality and site-specific recruitment materials that best serves their source population. This might include site-specific, recruitment materials in another language, for instance. Because of the structure of the single IRB, the bureaucracy involved in the review of materials that may or may not be applicable to every site reduces the back-and-forth communication between IRBs for recruitment materials that may not be used at every site. When working on multi-center clinical trials in multiple countries, it is important to consider and incorporate local ethical requirements into your study design and conduct. Best practices would be to use the most restrictive jurisdiction as the basis for your decision-making around data collection and study monitoring. In terms of reporting, one can then tailor the collected information to the various regulatory agencies. In addition to different requirements, it is also important to be aware of the various timelines for IRB submission of changes in research or protocol events. The procedures study investigators developed for development or data collection of these items directly impact their ability to adhere to these timelines. For instance, if you have one IRB that requires a maximum of three days for reporting an unusual event leading to a potential ethical breach and one IRB that requires 24 hours, it would be best to set up a study reporting system that accommodates a 24-hour timeline. Some institutions or federal laws may require that an in-country IRB is the primary IRB for a particular site. In these situations, communication between the IRB of record and the international IRB becomes key. As any recommended changes to the study protocol or other study materials will need approval from both entities, this is incredibly important to ensure that the communication lines are clear. Study investigators should consider this when determining the order with which they submit materials to the IRB of record, the international IRB, and any local IRBs that may request review or notification. As with domestic trials, study investigators may choose to rely on the local IRBs either domestic or international for continuing review if they're federally registered. As with any newer process, there are strengths and drawbacks to using a single IRB. Some of them are outlined here and have been adapted from this paper listed below by Ervin and colleagues. In terms of benefits as we've covered, streamlining the review process is key here. That was the basis for actually implementing this process and has proved to be somewhat true over the last few years that it's been done. Single IRBs also save the timeline for most or all of the sites. There's also a simplification for any participant facing material in terms of their development and their review as they are only reviewed once and any issues that may arise can be dealt with almost immediately. Single IRBs also reduce the resources needed to actually complete an ethical review. As you can imagine, if there's central adjudication for these materials, you can rely on either a data coordinating center or one single site to actually submit and complete the necessary requirements for ethical review. Some of the barriers include the onboarding time for each of the sites. This can be particularly problematic at the beginning of the study. Depending on the existing relationships between institutions, this process may or may not be a barrier to completing that first-year milestone on time. Another barrier includes reconciling the local requirements between each of the sites. As you can imagine moving from one local site requirement to those that may be in a different country entirely, reconciling these local requirements can be quite challenging. There may be international discrepancies in the reporting timelines and the requirements for each of those reports. As well as definitions for what an event might actually be, so these also have to be reconciled in this process. Another barrier for single IRBs is the infrastructure for actually supporting the review of larger trials. Some SIRBs have been set up with the right resources, the right amount of people, with the right amount of training. Others, however, are working from the ground up in order to build this infrastructure. So the timelines that they're on may be different and may impact the overall progress of your study. The next barrier to single IRBs, of course, is the cost to each of the participating sites. They may or may not be charged for the use of a single IRB. Finally, it is unclear what the legal liability for the investigators and the institutions are when the relying IRB is different from the primary IRB, so it's another point of discussion that will be hashed out in the future.
