By Mehmet S. Copur, MD, FACP
I greatly enjoyed the recent ASCO Connection article “Clinical Trial Research in the Genomic Age,” by ASCO Senior Writer Faith Hayden, especially the quote by ASCO Past President Dr. Michael Link—“The reason we got so much done in pediatric oncology over 30 years is because the regulatory environment was quite different and wasn’t quite as intrusive.” I would like to take this opportunity to elaborate more on the regulatory burden issue.
There is no doubt that compliance and regulatory oversight are essential for the conduct of any research activity. However, the recent changes in the regulatory environment that we all have been witnessing with great concern should make the research community think very seriously about this big threat. There is an urgent need for major changes in procedures for the initiation, conduct, monitoring, and safety reporting of clinical trials, so that they are more proportionate to the likely hazards. Innovative solutions to significantly reduce administrative burden while continuing to maintain accountability, integrity, and safety in the research arena are desperately needed. Inhibition of investigators, institutions, and agencies, I am afraid, will prevent us researchers from conducting trials at all, which may ultimately place our patients at much greater risk.
As bureaucracy increases, the efficiency of the trial process decreases. There is no evidence base to support the implementation of this current burden of extra bureaucracy, and I do not believe that we have to do a randomized trial to prove this point. As researchers, we should seek to adhere to the legal minimum required to carry out research rather than the bureaucratic maximum. We would like to see some ‘‘regulatory retreat’’ instead of ‘‘regulatory creep.’’ The magnitude of the problem is huge; below are some areas that urgently need to be addressed:
The approval process
The approval process is complex, costly, and time consuming. A single submission point for clinical trial authorization with defined timelines for approval is needed. Can the approval process be improved?
Risk-based approach
Currently a one-size-fits-all approach is not ideal. Regulation of low-risk trials of well-understood drugs may be different (less burdensome) than that of trials of completely new drugs, for which the risks are unknown. Can a risk-based approach be adopted with less burdensome rules and shorter approval time?
Central IRB for all
The HHS proposal would mandate that all domestic sites in a multisite trial name a single review board as the IRB of record, legally responsible for complying with federal regulations and ensuring that trial participants are properly informed of the risks and protected from dangerous protocols. The idea, known as a "central IRB," already is practiced widely in privately funded clinical trials and recently was implemented by the Veterans Health Administration and the National Cancer Institute. In this scenario, local IRBs would still have the ability to review protocols and consent forms and suggest changes but would play more of an advisory role. Do we still need local IRBs?
Revision of informed consent
Limit the acceptable length of informed-consent documents, prescribe how information is presented, allow certain types of information to be included in addenda-slash-legal boilerplate terms and make available standardized consent form templates. Can we come up with a universal and simple consent form with participants’ approval for future research (such as biospecimens research)?
Eliminating continuing IRB review
HHS requested feedback on a proposal to eliminate continuing IRB review for minimal-risk studies that involve surveys or focus on education or the social sciences. Can this be broadened to cover all studies?
Universal reporting of Adverse Events
HHS plans to create a single government website to allow electronic reporting of all clinical-trial adverse events and let investigators meet all federal reporting requirements. Can we come up with a universal web-based reporting system for all studies (government/nongovernment) with minimal forms and a unified reporting system?
Undue focus on individual case reports
Monitoring of drug safety involves undue focus on individual case reports without consideration of adverse-event rates in control groups. Greater emphasis on regular review of emerging safety data by independent data and safety monitoring committees in the context of the efficacy results, with appropriate sharing of this information with regulatory authorities may be more helpful. Can we come up with more sophisticated statistical methods such as a random check of adverse events?
Risk-based approach to monitoring
Monitoring of trial conduct involves disproportionate focus on retrospective data verification. Adoption of a risk-based approach to monitoring of clinical trials with increased use of centralized monitoring might be helpful. Can we adopt a risk-based centralized monitoring system?
The International Conference on Harmonization (ICH) version of Good Clinical Practice (GCP); other parts of the world could learn from the misguided trial regulations that have been created in Europe.
The International Conference on Harmonization (ICH) version of Good Clinical Practice (GCP) is inapplicable to most noncommercial research and is not usually legally binding (as conceded by the regulatory authorities in the United Kingdom). Other parts of the world should learn a lesson from the misguided trial regulations that have been created in Europe. There are serious concerns that the onerous procedural requirements for data management and documentation stipulated by ICH are deterring academic research where registration of a new pharmaceutical entity is not an objective. The ICH guideline on GCP provides extremely detailed instructions on data management and reporting of trials, as would be appropriate for drug companies seeking to license a new pharmaceutical entity with the relevant drug agencies. The true purpose of GCP, based upon foundations in the original Declaration of Helsinki, is to protect patients from unethical research, ensure that patients provide informed consent, and to conduct all trials to the highest possible standard. Few would dispute the need to incorporate the highest standards of GCP in all clinical trials, but does full application of ICH facilitate this goal? The largest independent cancer research network in Europe (EORTC) has reported that the number of new trials dropped from 38 in 2001, to 19 in 2004, to seven in 2005; trial costs have increased by 85% and trial initiation was five months slower.
Drug trials initiated in academia have similarities with conventional pharmaceutical company trials but also important differences. The primary aims of academic trials are to improve patient care rather than to develop new pharmacological entities. Surely, these objectives are of equivalent or of greater importance to society? In the conduct of both types of trial, GCP is important but the need for intrusive bureaucracy to ensure harmonization is much less relevant to academic studies usually carried out at a single site. There is no evidence that the intense bureaucracy of centralized politically driven procedures for ICH GCP has improved the care of trial participants in any way. There must be some room for maneuver in the legislation with regard to the interpretation of ‘‘good clinical practice’’ as opposed to accepting each new layer of bureaucracy. Can we develop authoritative and informed “good clinical trial practice” guidelines by experts in clinical trials, with input from regulators?
Research and the HIPAA Privacy Rule
An IOM report concluded that implementation of the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule has created significant obstacles for investigators conducting human subjects research, slowing the progress of science critical to developing treatments for illness and disease. By exempting research from the Privacy Rule, research could benefit while ensuring the protection of study participants and strengthening data security and privacy protections through the U.S. Department of Health and Human Services (HHS) “Common Rule.” If this is not possible the Privacy Rule must be modified to increase the number of data elements permitted in the limited data set to create a standard that is more closely aligned with the “Common Rule.” Can research be exempted from the HIPAA Privacy Rule or at least can it be modified?
Harmonized and simplified policies and practices for data sharing, privacy, security, and preservation
In the era of information technology, there is a need for policies related to data sharing, privacy, security, and preservation. ASCO’s recent effort in this topic with a letter to the Institute of Medicine on clinical trial data sharing is very timely. There may be an opportunity here to emphasize not creating more regulatory burden in the process of creating new policies. Can we prevent/minimize the possibility of creating additional regulatory burden in data sharing?
Coordination among federal agencies
There is a lack of coordination among federal agencies in the development and implementation of regulations, policies, and guidance documents. This lack of oversight and coordination results in duplicated efforts of investigators and their institutions as they strive to be in compliance with ever-changing regulations and guidelines. Can regulations policies guidelines be universalized?
There may be more but these are the most urgent ones I can think of. I am well aware how difficult this problem is and how unrealistic it may sound. If research community and all stake holders; such as NCI, FDA, ASCO, Academia, Industry join forces for the greater good we can accomplish a lot. I remain cautiously optimistic . . .
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References
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2. Department of Health and Human Services Office for Human Research Protections. Regulatory Changes in ANPRM: Comparison of Existing Rules with Some of the Changes Being Considered. http://www.hhs.gov/ohrp/humansubjects/anprmchangetable.html. Accessed May 5, 2009.
3. Steensma DP. J Clin Oncol. 2009; 27: 1737-9. PMID 19255310.
4. Dilts DM, Sandler AB. J Clin Oncol. 2006; 1: 4545-52. PMID: 17008693.
5. Federation of American Societies for Experimental Biology. FASEB Responds to the RFI on Reducing Investigator’s Administrative Workload for Federally Funded Research. http://www.faseb.org/Portals/2/PDFs/opa/6.7.13%20FASEB%20NSB%20RFI%20Response.pdf. Accessed June 7, 2013.
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