It took 20 years for the International Council for Harmonization’s (ICH’s) 1996 ICH E6(R1) Guideline for Good Clinical Practice (GCP) to reach the maturity needed for significant amendment. An earlier attempt by the U.S. Food and Drug Administration (FDA) in 1977 to institute similar provisions by regulation was basically unsuccessful, but lessons learned help develop the original ICH GCP document during the 1990s.
The ICH GCP E6(R2) update finalized in 2016 was prepared as an integrated addendum with insertions designed to keep the original structure intact. These changes incorporated recent methodologies focused on risk-based approaches to quality, improved language to accommodate the digital age, and additional clarifications for sponsor and investigator responsibilities.
With clinical research under increasing pressure for safety, quality, and cost improvements, ICH is proposing additional changes to GCP even as implementation of the new E6(R2) version is just getting under way.
So Long Ago—A [Not-So] Brief History
Nearly 20 years before the ICH published its original E6(R1) GCP guideline in 1996, the FDA had published a series of proposed regulations about clinical research. In retrospect, these would constitute much of what appeared later in ICH GCP. FDA’s objective was to assure the quality and integrity of the research activities subject to the agency’s jurisdiction, but the implications were more widespread; the FDA proposals included separate, but coordinated, regulations for sponsors and monitors, institutional review boards (IRBs), and clinical investigators.1-3
At the time, pharmaceutical industry representatives and many researchers voiced strong opposition to what FDA proposed. Citing the potential for enormous cost increases for compliance and a slowing of research progress, they lobbied successfully to halt implementation of most of the proposed regulations. Of the original proposals, only the IRB regulations were successfully rewritten and issued in final form in 1981.4
FDA still regulated drug trials and the approval process in the U.S., but even with incremental regulatory improvements over time, what were to be considered broadly acceptable practices for clinical trials remained unsettled. Study sponsors and their consultants were on their own to create internal, often proprietary, procedures. Worldwide, except for the ethical considerations for informed consent published following World War II,5,6 there were no competent health authorities using an agreed-upon set of guidelines for the conduct of clinical trials.
Pharmaceutical companies were keenly interested in using a commonly accepted framework to gain marketing approvals in various national markets. This was because it was often a requirement to conduct essentially the same clinical trial in multiple countries to gain local product approvals. Thus, when ICH was created in 1990 (it was known originally as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), it was a joint effort by regulators and trade associations in Europe, Japan, and the U.S. to create a commonly accepted set of guidelines—a “harmonized” voluntary consensus standard—for drug marketing approvals. By then, FDA had incorporated some of the earlier proposed regulations piecemeal into other rules and regulations, but the original cohesive arrangement had been lost.
Senior FDA regulators were an integral part of the ICH E6 development, and were well aware of the earlier proposed rules containing language about the responsibilities for sponsors, monitors, IRBs, and clinical investigators. Rather than attempt another comprehensive regulatory approach such as had been started 20 years earlier, FDA decided to adopt the ICH GCP E6(R1) guideline, which agency representatives helped write, as an official “guidance document” in 1997.7 The GCP guidance was not enforceable in the manner of other regulations in the U.S., but it provided the industry and regulators with a clearer picture of what constituted acceptable practices.
The E6(R1) GCP guideline from 1996 turned out to be one of the most durable of international voluntary consensus standards, absorbing 20 years of intensive use before resigning to a second edition. An entire industry of clinical investigators, sponsors, monitors, coordinators, nurses, IRB/institutional ethics committee members, trainers, consultants, auditors, government regulators, and other research staff members around the world interpreted and used the E6(R1) guideline, devised relevant procedures, built training programs (including the professional certification programs sponsored by the Association of Clinical Research Professionals, the Society of Clinical Research Associates, and others), received and documented their training, and managed thousands of clinical trials built largely around use of the ICH GCP guideline.
Regulatory authorities of many countries (ICH members in particular) adopted the original GCP guidelines in a formal manner without modification, while some others (e.g., India) adapted them significantly to align with local laws and subsequently published their own versions.8
With the experience of widespread use under evolving conditions, some misinterpretations of GCP were observed to have a negative impact on quality and trial costs. By 2014, ICH created an Expert Working Group (EWG) to update the GCP guideline. The clinical research world was evolving quickly, and revisions were needed due to globalization, increasing study complexities, and technological capabilities.9 The EWG gathered representatives from European Union (EU) regulatory authorities, the European Federation of Pharmaceutical Industries and Associations, FDA, the Pharmaceutical Research and Manufacturers of America, the Ministry of Health, Labor, and Welfare (MHLW) in Japan, the Japan Pharmaceutical Manufacturers Association, Health Canada, and Swissmedic, and benefitted from additional resources from other organizations.
The EWG made use of recent changes to clinical research procedures and quality practices (e.g., published position papers and studies, other consensus standards and guidance documents) to help prepare the GCP update.10–17 Goals included improved harmonization of practices with proactive quality management approaches and risk-based monitoring (RBM), and integration across other ICH documents. These harmonized practices were expected to relieve impediments to innovation while maintaining protection of trial participants and data quality.9
Consistency of approaches and clarification of earlier GCP misinterpretations were also expected to improve clinical drug development time and costs. The EWG used an “integrated addendum” approach to GCP document modifications, making changes to the original version as insertions while retaining the original E6(R1) outline structure.
The ICH EWG completed its first draft by June 2015, and the document was sent out for comments to ICH members and the public. The final text (called Step 4 in the approval process) of the E6(R2) update was approved by ICH and published on November 9, 2016.18
Here We Are
The implementation stage (Step 5) for the E6(R2) update is under way. Officially, the European Medicines Agency’s Committee for Medicinal Products for Human Use stepped up first and announced adoption of E6(R2) on December 15, 2016, with an effective date for the EU on June 14, 2017.19 Health Canada adopted the E6(R2) update next on May 25, 2017, announcing that full implementation would occur in April 2018.20 Japan’s MHLW/Pharmaceutical and Medical Devices Agency, Swissmedic, and the FDA have not yet announced official adoption or effective dates.
The ICH membership’s expansion beyond the original tripartite group (the EU, Japan, and the U.S.) brought in regulatory members from Canada, Switzerland, Brazil, China, and the Republic of Korea. An expanding list of 23 official ICH observers now includes authorities from India, Cuba, Mexico, Singapore, South Africa, Kazakhstan, Russia, Chinese Taipei, and Australia, plus several regional organizations (e.g., the Asia-Pacific Economic Cooperation forum, the Association of Southeast Asian Nations) and other international organizations (e.g., the World Health Organization, International Federation of Pharmaceutical Manufacturers, Council for International Organizations of Medical Sciences, United States Pharmacopeia, International Pharmaceutical Excipients Council). This means the E6(R2) update and related ICH harmonization documents will have a growing impact on an even larger part of the world’s healthcare industry as more stakeholders participate in developing and endorsing ICH guidelines.
The E6(R2) Impact on Study Quality and Operations—Focus on Changes
The E6(R2) GCP update is already creating a flurry of new interpretations and additional training curricula by consultants, institutions, sponsors, and contract research organizations (CROs). As the RBM adoption trend continues and sites and sponsors gain an increased understanding of the tenets of RBM,21 it should be noted that risk-based approaches to quality emphasized in the E6(R2) update are not new. These approaches have been established in other recognized quality standards, including the International Organization for Standardization’s ISO 9001:2015 (Quality management systems—Requirements) and ISO 31000:2009 (Risk management—Principles and guidelines), as well as regulatory positions in various countries.10,11,13 ICH also has indicated that use and interpretation of the E6(R2) guideline should not be made in isolation from other ICH documents.9,18
The following GCP changes in E6(R2) are likely to have the greatest impact on existing operations performed by sponsors, CROs, and clinical sites:
- Certified copies [Section 1.63]: The medium is no longer the message. In the world of electronic data, if you have a validated process to generate copies that make an accurate and complete copy, the copy you create can be considered certified. You have to take the non-trivial step to assure the process for making copies is validated, but when this is properly documented, a significant tool is at your disposal.
- Monitoring plans and monitoring [Sections 1.64 and 5.18.7]: Having a plan is not new, nor is centralized monitoring, but E6(R2) now mentions “centralized” monitoring frequently, so the emphasis is new. A focus on critical data and processes is specified, which relates to RBM methods.
- Monitoring reports [Section 5.18.6(e)]: Since centralized monitoring is emphasized, document that activity just as you would onsite visits.
- All trial information [Section 2.10]: Clarifies that “all” applies to paper and electronic records.
- Investigator responsibilities [Sections 4.2.5 and 4.2.6]: Delegation without supervision is not acceptable. This extends to any service provider, who must be qualified and have procedures to assure integrity of tasks and data.
- Investigator records [Section 4.9.0]: It is spelled out here, but you have the old ALCOA principle (saying data should be Attributable, Legible, Contemporaneous, Original, and Accurate) from the FDA with the added “C” for complete: ALCOAC. The term audit trail is added for non-paper records (but this was always a requirement in computerized clinical data systems).
- Sponsor responsibilities—Quality management [Section 5.0]: A clear statement is given here to let sponsors know they need to have a quality system in place, and that a risk-based approach is essential. One sentence should be memorized: “The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected.” From this statement, the basic ideas of risk-based approaches and RBM will follow. The subsections outline the importance of risk-based thinking throughout the clinical trial process—from inception and protocol development, where risk identification may begin, through the evaluation, control, communication, review, and reporting of risks and how they are addressed.
- Sponsor responsibilities—CRO oversight [Section 5.2.2]: Sponsors remain responsible for oversight and documenting tasks they delegate to others (parallel to investigator responsibilities under Section 4.2.6).
- Sponsor responsibilities—Monitoring [Section 5.18.3]: Risk-based approaches to RBM are emphasized and can be flexible; centralized (or remote) monitoring methods for data quality issues can be effective.12,16,17
- Sponsor responsibilities—Monitoring and noncompliance [Section 5.20.1]: Consider that “noncompliance” has to “significantly affect” or have “potential to significantly affect” human subject protections or data reliability to require an active response; noncompliance means sponsors should take appropriate action when needed.
- Essential documents [Section 8.1]: Sponsors and investigators must manage essential documents in a manner that permits search and retrieval regardless of storage format. It is possible that the essential documents list is incomplete for some trials, which may need supplemental materials included, or that some documents maybe less relevant for a given trial. This is another risk-based decision to consider. Documents generated by the investigator/institution must remain under their control, and not be subject to exclusive control by the sponsor.
The recent ICH GCP E6(R2) update is not the end of this story. While implementation and training for the E6(R2) GCP update is under way now, more changes are in the works down the road. ICH has planned the modernization of the 1997 ICH E8 guideline (General considerations for clinical trials) and simultaneously is proposing a subsequent “renovation” of E6(R2).22 These changes are expected to add flexibility for the range of clinical trial types that can be accommodated under GCP, including “real world” data from electronic health records, registries, and other sources not previously recognized as suitable for analysis in the manner of traditionally controlled clinical trials.
The preliminary plans for this work are set to begin late in 2017 or in 2018. The ICH effort may include developing a new ICH E6 “overarching principles” guideline, with a series of Annex documents focused on traditional interventional trials, nontraditional interventional trials, and other nontraditional trial designs. Like most consensus standards, significant revisions take time, but safety and quality standards remains paramount.
As the E6 renovation project gets under way, perhaps ICH will reconsider the guideline title as well. I have often observed that clinical investigators primarily responsible for the execution of a research protocol misunderstand the term or the responsibilities involved with “good clinical practice” as we use it.
Perhaps the GCP term is confused with the ordinary care investigators would deliver to their patients, since of course they trained for years to provide “good”—if not superior—care, the service they provide is “clinical,” and they are in medical “practice.” This may not be so surprising knowing that, on an annual basis, a high proportion of clinical investigators are research-naïve. Perhaps because of their initial research experience and training—or lack thereof—in leading a clinical research protocol, many first-time investigators never return to utilize or improve upon their new skills.
Regulatory inspections seem to support this idea, since year after year, the most common citations issued to investigators are for not following the protocol. To help everyone recognize the important difference between their clinical skills and the research activities they undertake, I’m hoping that the title “good clinical practice” (GCP) gets updated to “good clinical research practice” (GCRP), in recognition that this activity is clearly not at all like providing good patient care.
- S. Food and Drug Administration. 1977. Obligations of sponsors and monitors of clinical investigations (proposed rule). 42FR49612, September 27.
- S. Food and Drug Administration. 1978. Standards for institutional review boards for clinical investigations (proposed rule). 43FR35186, August 8.
- S. Food and Drug Administration. 1978. Obligations of clinical investigators (proposed rule). 43FR35210, August 8.
- S. Food and Drug Administration. 1981. Protection of human subjects; Standards for institutional review boards for clinical investigations (final rule). 46FR8958, January 27.
- The Nuremberg Code. 1949. In Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council Law, 10, Volume 2. Washington, D.C.: U.S. Government Printing Office, pp. 181–2.
- World Medical Association. 1964. Code of Ethics of the World Medical Association: Declaration of Helsinki. Helsinki, Finland.
- S. Food and Drug Administration. 1997. International conference on harmonization; good clinical practice: consolidated guideline (availability notice). 62FR25692, May 9.
- Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, Government of India. 2000. Good clinical practice guidelines.cdsco.nic.in/html/GCP1.html
- International Council for Harmonization. 2014. Final concept paper: Addendum for ICH E6: Guideline for good clinical practice (dated June 2). www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_Concept_Paper_July_2014.pdf
- S. Food and Drug Administration. 2012. Guidance for industry: Oversight of clinical investigations — a risk-based approach to monitoring. https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf
- European Medicines Agency. 2013. Reflection paper on risk based quality management in clinical trials. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500155491.pdf
- Lindblad AS, Manukyan Z, Purohit-Sheth T, Gensler G, Okwesili P, Meeker-O’Connell A, Ball L, Marler JR. 2014. Central site monitoring: results from a test of accuracy in identifying trials and sites failing Food and Drug Administration inspection. Clin Trials 11(2):205–17.
- Ministry of Health, Labor, and Welfare. 2013. Basic principles of risk-based monitoring [provisional translation]. www.pmda.go.jp/files/000215858.pdf
- International Council for Harmonization. 2005. ICH Harmonized Tripartite Guideline: Quality Risk Management, Q9. November 9. www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
- Meeker-O’Connell A, Glessner C, Behm M, Mulinde J, Roach N, Sweeney F, Tenaerts P, Landray MJ. 2016. Enhancing clinical evidence by proactively building quality into clinical trials. Clin Trials 13(4):439–44.
- Clinical Trials Transformation Initiative. 2011. CTTI recommendations: effective and efficient monitoring as a component of quality assurance in the conduct of clinical trials. https://www.ctti-clinicaltrials.org/files/monitoring-recommendations_1.pdf
- TransCelerate BioPharma. 2013. Position paper: risk-based monitoring methodology. www.transceleratebiopharmainc.com/wp-content/uploads/2013/10/TransCelerate-RBM-Position-Paper-FINAL-30MAY2013.pdfelines/Efficacy/E6/E6_R2__Step_4.pdf
- International Council for Harmonization. 2016. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf
- European Medicines Agency/Committee for Medicinal Products for Human Use. 2017. Guideline for good clinical practice E6(R2), Step 5. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf
- Health Canada. 2017. Guidance on Good clinical practice: integrated addendum to E6(R1) ICH topic E6(R2). www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e6r2-step4-eng.php
- Peterson JS, King D. 2016. Before RBM was in vogue: how NIH managed efficient monitoring. Presented at Association of Clinical Research Professionals Meeting & Expo in Atlanta, Ga., on April 17.
- International Council for Harmonization. 2017. ICH reflection on “GCP renovation”: modernization of ICH E8 and subsequent renovation of ICH E6. www.ich.org/fileadmin/Public_Web_Site/ICH_Products/GCP_Renovation/ICH_Reflection_paper_GCP_Renovation_Jan_2017_Final.pdf
Jan S. Peterson, MS, CCRA, RAC, MICR, ASQ CBA, (firstname.lastname@example.org) is senior regulatory affairs manager for the Emmes Corporation in Rockville, Md., and the 2017 vice chair of the ACRP Regulatory Affairs Committee.