GCP Challenges for 2008 and Beyond

COMMENTARY

Matthew Whalen, Brian Edwards, John Mather

INTRODUCTION Here, Good Clinical Practice(s) (GCPs) are viewed in both their current and potential state as central to the social enterprise called clinical research. In that light, this piece reflects the seminal definition from EU Directive 2001/20/EC, article 1, clause 2:

“Good clinical practice is a set of internationally recognized ethical and scientific quality requirements which must be observed for designing, conducting, recording, and reporting clinical trials that involve the participation of human subjects.”

Featuring “ethical and scientific quality requirements” and the phrasing of “designing, conducting…” is significant. Together, they emphasize the essential need to understand the nature of quality and processes - in the most far-reaching sense of each - in order to make clinical research viable. Addressing the challenges facing GCPs is closely aligned with refram- ing and reforming the entire system of research and development of biomedical therapeutics. As such, it is critical to view GCPs in a larger con- text, inclusive of, but not limited to, regulatory reform.

CURRENT CHALLENGES Professionals working in the GCP environment are facing important challenges - equally familiar to our other GXP colleagues, including development of appropriately educated and trained GCP professionals themselves to support GCP development. However, there does appear to be intensified urgency due to the im- mediate relevancy of GCPs for the world's patients and research volun- teers, reinforced by on-going media and political attention as well as pressure on development pipelines. Four such challenges are among the most far-reaching in terms of im- plications for reform: • Globalization - embracing both developing and re-developing countries opening up a wealth of new opportunities as the marketplace determines where research can be performed to achieve the best value while maintaining acceptable local and international ethical standards.

8 Journal of GXP Compliance Matthew Whalen, Brian Edwards, John Mather

• Innovation - the on-going and dramatic ones, corporations to small healthcare centers and pri- such as pharmacogenetics, and the uncertainties vate practices based on best evidence derived of novel biotechnology, such as stem cells and from safety practices in other safety-conscious nanotechnology, and their ethical and social sectors of society and ideally converted into ramifications. Guiding Principles • Resource Investments - significant scrutiny from • Information and knowledge management - in both within the life sciences sector and outside; particular, the inter-connectivity across the as well as pressures on reimbursement with a whole research endeavor and project stakehold- failing ROI (Return on Investment) once bio- ers and extrapolation into the marketplace medical therapies are marketed; and • Organizational learning and memory so that the • Trust - what may be unprecedented shakiness of system of the entire research enterprise learns confidence and increasing skepticism of the from mistakes world's publics in organizations and corporate • Internal and external management and monitor- infrastructure, in general, and the pharmaceuti- ing of audits of research sites and inter-organiza- cal sector, in particular. tional committees responsible for important as- As a result, not only international regulatory au- pects of trials, such as the IRBs/ERCs and thorities, but also the full-range of R&D stakehold- DMCs/DSMBs ers is under operational, public, and political pres- • Developmental structures supporting profes- sure to reform the system that delivers the lifecycle sionalization of the clinical research team in- of biomedical therapies while still maintaining ac- cluding formal education and certification stan- ceptable safety and ethical standards. dards, and When these big picture challenges are translated in • Better international implementation of the Insti- terms of GCPs, they may be reduced, if grossly, to a tutional Official, GMP Qualified Person, Quali- focus on “overseers,” such as regulators and monitors, fied Person for Pharmacovigilance, and Chief and “oversight-related structures of the clinical re- Safety Officer roles as key organizational over- search process,” such as regulatory and accreditation seers of research and marketing of therapies agencies. What are the roles, responsibilities, and who have been allocated legal accountabilities processes to improve the adequacy and related orga- for overlapping parts of the system nizational and individual accountabilities? Renovation on this scale requires a certain funda- mental perspective: Seeing research systemically as There is a spectrum of reform potential: opposed to functional fragments and silos - both • Internationally harmonized regulations and within organizations and in the network of relations- guidance under-girding human subject protec- linking organizations. Diagrammatically, the empha- tions, that is, rational and culturally-appropriate sis is on the flow between and among the pieces, for implementation of the Declaration of Helsinki, example: World Health Organization (WHO) guidelines, • From a dynamic job description where respon- and other benchmark ethical statements sibilities include not only to and for whom, but • Widely-accessible and 'user-friendly' public com- with whom munications - ranging from public registries and • Through depiction of the human research pro- databases to media presentations popularizing re- tection program of an organization and the vari- search education - that support transparency and ety of supporting functions as well as outreaches public confidence, in the broadest sense, while • To a 'global' mapping of a project or program also keeping patients and subjects properly in- that, literally, reaches across the full-range of formed to maintain their interest and compliance stakeholders with treatment and research protocols This does not, however, lessen the importance of • Organizational safety culture, spanning nation individual accountability within the larger system. state and multi-lateral agencies through large Indeed, accountability is most effective and efficient

January 2008 Volume 12 Number 2 9 COMMENTARY when maintained by each individual functioning grees of implementation of the spectrum of possible within collaborating teams founded on mutual inter- reforms. dependence with each looking out for the other. The While there is not a crisis in the traditional, full- environment is cross-disciplinary - and disciplined - blown sense, there is a slow burning brush fire ac- making it far more likely that any deliberate and celerating because the root causes of recurrent crises malevolent violations stand out in such a way that continue not to be fully investigated. Further, what inappropriate behavior is exposed promptly. Equally solutions have been suggested, have neither been important to strengthening accountability is the systematic in nature nor applied systemically. Sadly, blame-free dimension of this kind of environment there are those who complacently believe the drug when the actions are not deliberate nor malevolent - safety crises have been fully investigated, further ag- focusing on the insufficiency of process rather than gravating the situation. victimizing the individual. As a result, the root causes, including those of drug safety, have largely been ignored so that the BASIS FOR URGENCY threshold for declaring yet another new crisis is now What is generating the intensity of urgency for re- depressingly low. This further erodes long-term pub- form now is greater than that solely associated with lic confidence and is exacerbated by the inadequacy the safety of therapeutics products. Rather, it is one of societies to meet three challenges urgently requir- embracing processes, teams, and system of GXPs. ing a much more mature and robust system: The urgency, not surprisingly, is a cumulative effect • The presence of epidemics and pandemics, such of the aforementioned challenges and varying de- as avian influenza and multi-resistant bacteria

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10 Journal of GXP Compliance Matthew Whalen, Brian Edwards, John Mather

which demand a flexible and fast-track ap- The good news is that at least part of the direction proach to vaccination and antibiotic develop- needing to be pursued is laid out in the related dis- ment with excellent surveillance mechanisms to ciplines of organizational science and operational re- enable early use of novel medicines search as well as learning from the experience of • The global criminal trade in counterfeit medi- other industries and social structures. The processes cines and adulteration of medicines which re- have been tested and the evidence exists, waiting to quire united international action akin to re- be applied. sponses to terrorism, and Now is the time to treat aggressively the illness • The conduct of clinical trials, especially in de- within the current system if rebuilding and main- veloping and redeveloping countries, where the taining the trust of society in the safety and effective- meaning of informed consent and risk need to ness of therapeutic products and their development be better understood so as not to infringe on the is to be achieved. GXP Declaration of Helsinki and other seminal, international ethical guidance ARTICLE ACRONYM LISTING DMC Data Monitoring Committee THE ULTIMATE CHALLENGE DSMB Data Safety Monitoring Board Against this backdrop, what is the significance of GCPs in this era? ERC Ethics Review Committee To state the complex as simply as possible: The 'P' EU European Union is inclusive of the processes at work behind and be- GCP Good Clinical Practice tween the practices - a confluence of best practices, GXP Good Clinical, Laboratory, small gcps, and capital (or codified) GCPs as they Manufacturing Practice are operationalized in the intricate system of stake- IRB Institutional Review Board holders defined as clinical research to ensure patients' and subjects' interests are protected. ROI Return on Investment So, the penultimate challenge is to place GCPs in WHO World Health Organization a larger reality of oversight responsibilities and inter- actions as appreciated more dynamically and sys- ABOUT THE AUTHORS temically. Matthew Whalen, Ph.D., is a member of the Board of Directors of There are, and have been, advocates of broaden- the non-profit Pharmaceutical Safety Institute and the Institute's ing the 'x' of GXPs to include Good Regulatory Prac- Vice President. The Institute is based in Philadelphia, PA, USA. tices, Good Recruitment Practices, Good Safety Prac- tices, and doubtless more. If the penultimate Brian Edwards, M.D. works with NDA Regulatory Science Ltd, Leatherhead U.K. challenge for GCPs is to function as just suggested, these other 'x's' along with the more traditional John Mather, M.D. is President, UNI-CORN LLC, Washington, DC. Good Laboratory and Manufacturing Practices face a similar situation. If so, how can this interaction and All the authors are members of the Editorial Board of the Journal integration best be achieved? This is the ultimate of GXP Compliance, among their other professional obligations. Dr. Whalen, the corresponding author, can be reached at challenge - a truly integrated system that insures [email protected]. benefit over risk, rights and welfare over abuse and exploitation, and safety over arrogance and greed.

January 2008 Volume 12 Number 2 11