Abstract
It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 256-271 |
| Number of pages | 16 |
| Journal | Controlled clinical trials |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jun 2003 |
| Externally published | Yes |
Keywords
- Clinical trials
- Ethics
- Good Clinical Practices
- Monitoring
- Protection
ASJC Scopus subject areas
- Pharmacology
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Toward protecting the safety of participants in clinical trials. / Califf, Robert M.; Morse, Michael A.; Wittes, Janet; Goodman, Steven N.; Nelson, Daniel K.; DeMets, David L.; Iafrate, R. Peter; Sugarman, Jeremy.
In: Controlled clinical trials, Vol. 24, No. 3, 06.2003, p. 256-271.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Toward protecting the safety of participants in clinical trials
AU - Califf, Robert M.
AU - Morse, Michael A.
AU - Wittes, Janet
AU - Goodman, Steven N.
AU - Nelson, Daniel K.
AU - DeMets, David L.
AU - Iafrate, R. Peter
AU - Sugarman, Jeremy
N1 - Funding Information: The Duke Clinical Research Institute provided financial support for the meeting that led to work on this paper, with unrestricted educational donations from AstraZeneca, Boehringer-Ingelheim Canada Ltd., Eli Lilly and Company, Key Pharmaceuticals, King Pharmaceuticals, Inc., Medco Research, Pfizer Central Research and Rhone-Poulenc Rorer. The opinions and recommendations in this article are those of the authors and may not necessarily reflect the views of members of the Duke Working Group on Monitoring Clinical Trials or their primary affiliations. Funding Information: Having described some of the limitations in the current system, we offer the following recommendations to enhance safety in clinical studies. To achieve a congruent and effective system with adequate protection of human research participants, the design of each study must be sound, the blueprint for it must be followed, and a system must be in place combining expertise and processes that can detect when deviations from the plan are needed. Neither thorough understanding of study design and data interpretation nor consistent process alone will accomplish this goal. Rather, content and process must be combined, effectively integrating all of the components previously discussed. In order to avoid duplication of efforts and assessments of AEs made without a complete knowledge of the agent under study, we agree with calls by the Office of the Inspector General and others to change how RERBs provide oversight for safety in clinical trials [10–12] . Local RERBs should focus on monitoring local research participants' safety by determining whether an adequate plan for monitoring their individual sites exists. The Institute of Medicine has recommended that all research involving human participants should take place under the direction of a Human Research Participant Protection Program [3] . Local programs, led by RERBs, can ensure that an adequate protection program exists for single-site, investigator-initiated studies, and initial and interval RERB approval for a study should be contingent on whether the protection program has carried out its mission. We agree with the recommendation of the National Bioethics Advisory Commission that “federal policy should permit central or lead Institutional Review Board review” for large multisite studies [32] . The Institute of Medicine recommends assigning a leadreview committee, and the European Directive requires “the adoption of a single opinion for the Member State” [3,7] . This would help avoid having multiple institutions reviewing the same protocol with the same level of scrutiny. Also, a central review board would have better access to experts in clinical research methods and in the particular medical condition being studied, which a local RERB might not. The U.S. National Cancer Institute has initiated a pilot project for the review of multicenter phase III trials that uses a central RERB and facilitated review [33] . Local RERBs then may use the results of this deliberation to permit them to focus on local issues regarding participant safety and the adequacy of consent procedures. Nevertheless, such a system will need to be refined as experience using it is garnered. We agree with the advisory commission that there should be a uniform, nationally created “system for reporting and evaluating adverse events” [32] . The AEs that occur in large, multicenter trials should be collected centrally, and based on review of this information by the DMC, a statement to local RERBs should be produced that indicates whether any undue safety hazards have been encountered and whether the study may proceed. Some RERBs may be unwilling to relinquish the ability to review individual serious and unexpected AEs, and they should be provided with summaries of the AEs and interpretations of their effect on the study. RERBs should expect that the study investigator, trial sponsor and the DMC (if any) will determine the relevance of AEs and give a recommendation on whether any changes in the trial design, trial continuation and consent process and document are required. An RERB cannot discharge its responsibilities properly without financial support for adequate staffing to handle the large paperwork burden and the commitment of the institutional leadership to make good research practices a priority [34] . We also agree with the advisory commission that funds should be available to support RERB duties, particularly federal funds for RERBs with oversight responsibilities for federally funded studies [32] . In addition, sponsors with a financial interest in the research should also supply some of the funding in the form of RERB review fees for their research. To ensure a minimum standard of expertise, an educational program for RERB members as recommended by the Office of the Inspector General and the advisory commission is vital [10,32] . We believe that such an educational program must include formal training in the core aspects of ethical research. In general, this would apply to junior IRB members with little prior experience in research safety monitoring or ethics. We believe that other credentials that demonstrate an understanding of these issues, such as prior experience as an IRB member or clinical trialist, might provide a reasonable substitute to such programs. We also encourage experienced clinical investigators to serve on RERBs, because their knowledge and experience likely would aid in appropriate review. Institutions that conduct clinical research have a responsibility to make it feasible for such individuals to play a meaningful role in RERB work. The Inspector General also has recommended that DMCs be required for some multisite trials [10] . The FDA has suggested that “DMCs should be established for controlled trials with mortality or major morbidity as a primary or secondary endpoint” and they “may also be helpful in settings where trial participants may be at elevated risk of such outcomes even if the study intervention addresses lesser outcomes such as relief of symptoms” [35] . We agree with these recommendations and believe that all multicenter trials for products or therapies (including behavioral therapies) intended to affect mortality or serious morbidity should have a DMC. Although DMCs typically are convened by sponsors, objectivity is best served if the DMC develops, on its own, clear procedures for its task (often described as a DMC charter) based on its firm understanding of its role in monitoring the trial [36] . We further recommend that the nonconfidential summaries of the committees' deliberations be reported to participating RERBs. These summaries are best limited to a statement that a meeting was held and that safety and efficacy data were reviewed, along with the committees' recommendations regarding trial continuation, modification or closure. In addition, the Inspector General previously pointed out that federal regulators had not yet established guidelines delineating the responsibilities of a DMC and the types of experience and training required of its members [37] . We welcome the draft guidance by the FDA “On the Establishment and Operation of Clinical Trial Data Monitoring Committees” issued for comment in November 2001 and believe guidelines should be established expeditiously [35] . The education and training of potential DMC members will necessarily be supplemented by on-the-job experience and that of veteran members. When DMC participation involves a substantial time commitment, members of the DMCs should be adequately compensated. Establishing guidelines for safety monitoring of single-center phase I and II trials should be made a priority. At a minimum, safety monitoring plans should require one or more knowledgeable persons not otherwise connected with the study to perform two major tasks: review the safety data periodically and generate monitoring updates. A knowledgeable investigator from the site who is not otherwise involved with the trial could serve in this role. The implementation of such a system, however, will require addressing several as-yet-unanswered questions: Who will prepare the data for this review? To whom will reports go? Would recommendations about additional safeguards be made to the investigator, the RERB or both? Although each investigative group may customize a monitoring plan to suit the special needs of the local participant population, the site environment and the specific clinical question posed by the study, the plan should conform to institutional standards set by the local RERB, ideally based on national standards. The standards should include detailed specifications about the level of training and experience required for those who will perform the monitoring, but flexibility should be allowed because requirements may vary substantially from trial to trial. They should describe the degree of independence that monitors will have from the study investigator(s) and industry sponsor (if any) and the process by which monitoring results will be reported and used to protect participants. Because local RERBs may not have adequate experience in assessing monitoring plans, guidance at the national level will be needed to enable RERBs to review such plans appropriately. To further enhance the safety of large-scale clinical research, we recommend a greater national investment in the development of collaborative information networks and databases, a resource that would allow more rapid and complete dissemination of participant safety data and data from animal and prior human studies for comparisons with current research. It is the ability to compare experiences of AEs on an ongoing study with what has been previously observed that would be the most helpful. Perhaps the availability of such data accrued over time also could avoid tragedies in smaller studies, such as the hexamethonium pulmonary toxicity. Again, we believe that a governmental regulatory agency such as the FDA will need to develop these databases, because the agency eventually will need to review much of the data about the safety and efficacy of medical products. Sponsors with INDs for medical products would be required to submit updated data to this database. Of course, the costs relative to the benefits would need to be evaluated in pilot projects first, because there is no current data about how effective such databases would be in protecting participant safety. This database need not replace the investigator brochure that may provide information in the context of a particular research study. However, when there are changes to the investigator brochure, sponsors should be required to identify the important changes so that RERBs can decide whether the changes should affect the informed-consent process and document. Sponsors can also do more to help investigators focus on the evaluation of AEs. For example, case report forms should be designed with the objective of capturing only data that will have relevance for clinical management or assessing the safety of the intervention. The time spent in completing them and collecting source documents to support them should not compromise attention to assessing and managing AEs. We recommend relaxing the requirement for collecting or copying source documents to place alongside the case report forms. We also recommend that audits and more specifically queries generated by audits focus on AEs and collection of data supporting major endpoints. Nevertheless, we believe that systematic audits with a statistical approach to assessing the quality of the data, comparing case report forms and source documents, still would be necessary to ensure the responsible conduct of research as well as the accuracy and completeness of the data [38] . We agree with the proposal of the Office of Inspector General, which requires educational programs for investigators about protection of human research participants [10] . The NIH rules that now require key personnel to have formal training in protection of human research participants likewise recognize the essential involvement of those besides investigators and RERB members [39] . We believe that formal training also should be provided to all staff members at an institution directly involved in clinical trials (such as study coordinators and research pharmacists), and we believe that it should be part of the culture of these institutions to encourage and make available basic training materials for all health care providers who may interact with patients participating in research. Although a curriculum of such training programs has not been specified at a national level, these programs should include basic issues in research ethics and the justification for current policies. In addition, to accomplish the desired goals, these programs should include the elements of GCP and practical aspects of clinical trial management, including record keeping and documentation. To make these programs realistic and relevant and to make their development efficient, efforts should be made to develop a national computer-based or Internet-based training program to supplement local educational efforts. To ensure consistency with federal regulations, it should be developed jointly by, or with input from, a federal agency, such as the Office for Human Research Protections or the FDA. With federal support for developing and maintaining these programs, they could be made available to institutions where clinical research is not prevalent and resources for developing in-house programs may be limited. The NIH's Internet-based elementary training in clinical trials for investigators and RERB members (accessible at << http://ohsr.od.nih.gov/ >>) is an important initial step in this regard. Some have asked whether a certification program for investigators and their associates would improve the quality of clinical research [40] . Although we are not advocating additional regulatory burdens, we concur that simple certification of completion of a training course would ensure that those performing clinical research have at least been exposed to its most fundamental aspects. We also agree that education alone is not the solution. Investigators and their staffs must be attentive to the day-to-day events at their sites. Protocols should be conducted in a way that requires active input from investigators. For example, we advocate that key safety issues such as review of AEs and a physical exam have investigator sign-off before proceeding. We suggest that clinical research sites develop and disseminate site-specific operating procedures for research, to help clinical investigators, their staffs, and nonresearch personnel comply with the complex regulations. Just as a nurse caring for a patient with tuberculosis might consult a hospital manual to ensure compliance with policies to reduce transmission of infection, those who interact with research participants might consult a manual to find out how to record an AE when confronted with one. We agree with the Institute of Medicine report that “research participants should understand their role in the study, the rationale of the study, and what is required of them to prevent unanticipated harm to themselves” [3] . As such, it is incumbent upon RERBs, investigators and their staffs to ensure that informed consent is meaningful. We call for a concerted and systematic effort, applied with academic rigor and led at the national level, to measure the efficacy of RERBs, DMCs and the regulatory bodies as protectors of research participants' and society's interests in research. Academic medical centers are in an important position to influence the national dialog about monitoring safety in clinical trials. Rigorous quantitative research should be applied to assessing the methods of clinical research and to developing and implementing optimal approaches to collecting and analyzing safety and efficacy data [41] . To date there has been little interest in or reward for learning, evaluating and improving the methods of clinical research, and little support exists for such efforts from funding agencies. Federal funding is needed to develop tools to evaluate the efficacy of safety monitoring. For example, such funding could help develop outcome measures for the safety of research participants. Methods of monitoring then could be tested to determine which yield the best participants' safety index. We recommend that the NIH and equivalent public funding agencies outside the United States increase their commitment to the training of clinical researchers through mentored training awards. Support for careers in clinical research should be emphasized, and a recently announced grant mechanism to support training of new researchers in research ethics is a laudable step in this direction [42] . We are aware that we cannot say for certain whether our recommendations would be effective enough to justify the cost. This again points to a flaw in the safety monitoring system, that it is not currently possible to assess quantitatively the effect of various modifications on safety of participants and it is also somewhat difficult to project the costs. Finally, we recommend continued clarification, on an international scale, about the requirements for monitoring participants' safety in clinical trials. We propose that the various regulatory agencies overseeing clinical research convene a meeting of their representatives and members of the research community to rewrite a harmonized set of standards. These standards should include recommendations that account for the new realities of clinical medicine and the changing role and capabilities of RERBs. We especially believe that clarity, harmony and logic of the requirements for AE reporting should be considered in this effort. We believe the current system is troubled because of gaps between the theoretical and actual practice of these groups as they oversee trials; they do not signify an irreparably broken system of safety monitoring.
PY - 2003/6
Y1 - 2003/6
N2 - It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.
AB - It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.
KW - Clinical trials
KW - Ethics
KW - Good Clinical Practices
KW - Monitoring
KW - Protection
UR - http://www.scopus.com/inward/record.url?scp=0038369246&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038369246&partnerID=8YFLogxK
U2 - 10.1016/S0197-2456(03)00005-9
DO - 10.1016/S0197-2456(03)00005-9
M3 - Article
C2 - 12757992
AN - SCOPUS:0038369246
VL - 24
SP - 256
EP - 271
JO - Controlled Clinical Trials
JF - Controlled Clinical Trials
SN - 0197-2456
IS - 3
ER -