Non-clinical Assessment of New Drug Products
interspecies scaling of the animal doses to an equivalent human dose is usually based on normalisation to body surface area. For both small molecules and biopharmaceuticals, interspecies scaling based on body weight, area under the curve (AUC) or other exposure parameters might be appropriate.12
Summary
Over the past decade, scientists have learned much about the predictive value of a variety of testing strategies in evaluating drug and biologic products. In the future it is likely that approaches to non-clinical safety evaluation will continue to improve and provide the critical information necessary to enable the expeditious development and approval of safe and effective new therapies. Genomics, high-throughput screening technologies and molecular toxicology are all areas that are being explored more aggressively in terms of regulatory acceptance in supporting product development and approval. Careful design and the judicious use of animals should help provide for the early initiation of clinical studies and an uninterrupted clinical development programme.
The challenges facing regulatory agencies and industry sponsors allow for appropriate programmes to be implemented that will better anticipate safety concerns. It is especially important when using novel technologies and developing innovative in vitro and in vivo toxicity assays to design appropriate pre-clinical testing strategies to better characterise safety concerns. To ensure that new biologic products are both safe and effective, and that they are made available without
1.
www.ICH.org (accessed 27 October 2010). 2.
delay, regulatory agencies must actively participate in dialogues with industry and must maintain a regulatory environment that encourages innovation.
Industry must initiate interactions with regulatory authorities earlier in the development process (i.e. during the research and discovery phases). In addition, industry must not only understand the regulatory process, but must also prepare product development plans that are realistic, flexible and consistent with this process. For regulatory agencies and industry, it is critical that the process of product development be well managed. The ‘power of predictability’ of pre-clinical safety studies for clinical effects are only as good as the design of the programme. The same amount of careful consideration used in designing the clinical programme should be afforded to the pre-clinical programme. n
Michael R Hamrell is President of MORIAH Consultants, a regulatory affairs/clinical research consulting firm. He has worked in drug development, clinical research and regulatory affairs for over 25 years. He has also worked for pharmaceutical companies, contract research, government and biotech industries. Dr Hamrell is an Adjunct Professor of Molecular Pharmacology and Toxicology at the University of Southern California School of Pharmacy. He is also Adjunct Associate Professor at
the Massachusetts College of Pharmacy & Health Sciences, the School of Nursing at the University of North Carolina Wilmington and Adjunct Assistant Professor at George Washington University School of Medicine, Clinical Research Program.
ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals, July 2001.
3. Cavagnaro JA, Science-based approach to pre-clinical safety evaluation of biotechnology products, Pharm Eng, 1992;12(3):32–3.
4. Weissinger J, Nonclinical pharmacologic and toxicologic considerations for evaluating biologic products, Regul Toxicol Pharmacol, 1989;10:255–63.
5.
S6: Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, ICH Harmonised Tripartite Guidline, ICH, 16 July 1997. Available at:
www.ich.org/LOB/media /MEDIA503.pdf (accessed 27 October 2010).
6. Hamrell MR, Pre-clinical considerations for life-threatening illnesses, Clinical Research and Regulatory Affairs, 1992;9:225–32.
7. ICH S9 nonclinical evaluation for anticancer pharmaceuticals, Federal Register, 2010;75(44):10487.
8. 9.
ICH S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals, CPMP/ICH/423/02, EMEA, October 2005
FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, July 2009.
10. FDA Guidance for Industry: Nonclinical Safety Evaluation of
Pediatric Drug Products, US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, February 2006.
11. E7: Studies in Support of Special Populations: Geriatrics, ICH, July 1994. Available at:
www.ich.org/LOB/media /MEDIA483.pdf (accessed 27 October 2010).
12. FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, July 2005
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