The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.
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TestSmart Pharmaceuticals
May 7-9, 2001
PIER 5 HOTEL
711 Eastern Avenue
Baltimore, Maryland
Sponsors: 3M, Bristol-Meyers Squibb Company, Huntingdon Life Sciences, Schering-Plough Research Institute, and Taconic Farms, Inc.
Abstract for TestSmart--Pharmaceuticals: An Efficient and Humane Approach to Predictors of Potential Toxic Effects of Drugs
ICH Approaches To Reducing Animal Use
Robert E. Osterberg
Center for Drug Education and Research, US Food and Drug Administration
The International Conference on Harmonization (ICH) began in April of 1990. Representatives from the government regulatory agencies and the pharmaceutical industries of Japan, Europe and the United States have composed guidelines for developing and registering new medicinal products including general directives for conducting animal studies. Each of these three regions has agreed to implement these harmonized guidelines as they are completed. An important goal of this process is to avoid duplication of the studies that must be performed before a new medicine is submitted for registration. Thus the adoption of ICH guidelines has significantly reduced the numbers of animals used for testing new medicinals because each regulatory region will accept data from studies conducted according to these guidelines. In addition, the ICH guidelines for carcinogenicity testing suggest that these assays may be refined by using transgenic animal models when appropriate. This would result in a large decrease in the duration of the assay and a reduction in the number of animals needed for the detection of potential carcinogenicity. The ICH Steering Committee has also recognized the need for a maintenance process to update the guidelines as scientific improvements are made and new knowledge is acquired. As our technical knowledge of the biological sciences increases, further refinements in the field of medicinal product development could also occur to further reduce our reliance on in vivo assays and further reduce the numbers of animals used in toxicity testing.
What is the ICH ?
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
ICH
EUROPE
- European Commission-European Union
- European Federation of Pharmaceutical Industries Association
ICH
JAPAN
- Ministry of Health, Labor and Welfare
- Japan Pharmaceutical Manufacturer's Association
ICH
UNITED STATES of AMERICA
- Food and Drug Administration
- Pharmaceutical Research and Manufacturers of America
International Conference on Harmonization
International Conferences
- ICH 1 - Brussels, November 1991
- ICH 2 - Orlando, October 1993
- ICH 3 - Yokohama, November 1995
- ICH 4 - Brussels, July 1997
- ICH 5 - San Diego, November 2000
Three Regions and Six Partners
ICH Targets of Harmonization
A-to improve the efficiency in development and registration of new drugs by:
- removing the need to duplicate animal tests
- this reduces animal usage thus making research more economical
- similar considerations for efficacy (clinical) and quality (chemistry)
Targets (continued)
B- Harmonize the application of requirements by:
- Definitions (MedDRA)
- Presentation of Documentation (CTD)
C- This results in: bringing new medicines to the market sooner
ICH Expert Working Groups
- Efficacy has 13 EWGs.
- Quality has 16 EWGs.
- Safety has 13 EWGs.
- Multidiscipline has 4 EWGs.
IFPMA: http://www.ifpma.org/ich5.html
FDA: http://www.fda.gov/cder/guidance/index.htm
Safety Expert Working Groups
- Carcinogenicity-When studies are needed
- Carcinogenicity-Use of 2 rodent species
- Carcinogenicity-Guidance for dose selection *
- Genetic Toxicology-Specific Aspects of regulatory tests
- Genetic Toxicology-Standard battery of regulatory tests
- Toxicokinetics
- Pharmacokinetics
Safety Expert Working Groups (CONTINUED)
- Single dose and repeat dose studies
- Reproduction toxicity
- Reprotox: Male fertility studies
- Safety Studies for biotechnology products
- Safety pharmacology
- Timing of preclinical studies in relation to clinical trials (M3)*
- Common technical document (M4)*
Quality Expert Working Groups
- Impurities in new drug substances
- Impurities in dosage forms
- Impurities-Residual Solvents*
These are EWGs that involve toxicology - Maintenance
ICH Maintenance
- Maintenance is intended to:
- provide results quickly
- use minimal resources
- be completed electronically
- make only minor changes
- Meetings are to be held only in exceptional situations.
S1A: The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals
When carcinogenicity studies may not be needed:
- pharmaceuticals for infrequent administration or for short duration, i.e., anesthetics, radiolabeled imaging agents, unless cause for concern.
- unequivocally genotoxic compounds
- pharmaceuticals for short life expectancy diseases
(reduction)
S1B: Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals
Normally-2-rodent 2-year bioassays.
- if findings of a short or long term carcinogenicity study and of genotoxicity tests and other data indicate that a pharmaceutical CLEARLY poses a carcinogenic hazard to humans, a second carcinogenicity study would not usually be useful.
- "weight of evidence" approach
(reduction)
S1B: Tests for carcinogenicity (continued)
- -to save resources, several potentially useful methods may be considered, if justified:
- initiator-promoter models in rodents
- several transgenic mouse assays such as p53 knockout, TgAc, TgHras-2, XPA deficient model
- neonatal rodent tumorigenicity model
(refinement)
S2A: Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
- discusses general concepts for mutagenicity and clastogenicity testing
- in vitro assays are discussed primarily
- in vivo bone marrow chromosome assays
- in vivo micronucleus assays
(replacement/reduction)
S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals
- gene mutation in bacteria
- in vitro mouse lymphoma or in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells
- in vivo test for chromosomal damage using rodent hematopoietic cells
Limitations of in vivo-if no systemic exposure use in vitro test (refinement)
S3A: Guideline on the Assessment of Systemic Exposure in Toxicity Studies
- guidance highlights the need to integrate PK into toxicity testing which should aid in the interpretation of the toxicity findings and promote rationale study design development. May use:
- "concomitant toxicokinetics" (refinement)
- satellite groups
- another similar study
S3B: Guidance for Repeat Dose Tissue Distribution Studies
- For most compounds, single dose tissue distribution studies will be adequate to show drug distribution and accumulation potential.
- Repeated dose tissue distribution studies should not be uniformly required for all compounds. (refinement)
- are appropriate for drugs with long half-lives, incomplete elimination or unanticipated organ toxicity.
S4A: Single Dose Acute Toxicity Testing for Pharmaceuticals
- use small #s of rodents and fewer non-rodents -- emphasis on "clinical" effects
- acceptable to use acute effects data from repeat dose range finding data from non-rodents instead
- "screening IND" could be used?
- "one dose for one dose"
- no classical LD50-53FR39650 (10/11/88)
- no testing very irritant/corrosive drugs
(reduction)
S4B: Duration of Chronic Toxicity Testing in Animals
FDA Proposal:
- for rodents-a study of 6 months duration is generally acceptable in all three regions.
- for non-rodents a study of 9 months duration is generally acceptable in all three regions
(refinement)
S5A: Detection of Toxicity to Reproduction for Medicinal Products
Segments 1, 2 and 3:
- These guidelines are a starting point.
- "If it can be shown-by means of kinetic, pharmacological and toxicological data-that the species selected is a relevant model for the human, a single species can be sufficient." (reduction)
- number of animals/sex/dose-should be sufficient to allow meaningful interpretation of the data
(refinement)
S5B: Detection of Toxicity etc.: Addendum on Toxicity to Male Fertility
- initially, the pre-mating drug treatment of male rats was 63 days.
- comparison of 63 and 28 days of pre-mating treatment found no differences in toxicity detection in testes.
- literature showed equal toxicity detection with pre-mating treatments of 14 and 28 days.
- Japanese study indicated a 2 week pre-mating exposure with appropriate dose-setting has equal potential in detecting toxicity on male reproductive organs.
(refinement)
S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
- Biopharmaceuticals that are structurally and pharmacologically comparable to a product for which there is wide experience in clinical practice may need less extensive toxicity testing. (refinement)
- Similar testing considerations apply as for non-biotech products.
S7A: Safety Pharmacology Studies for Human Pharmaceuticals
- Core battery:
- tests on Central Nervous, Cardiovascular and Respiratory systems
- animal models or ex vivo or in vitro preparations can be used such as isolated organs and tissues, cell cultures, ion channels, receptors, enzymes, etc.
- in some cases, safety pharmacology studies may not be needed, i.e., a new salt having similar PK and PD
(3-Rs)
Q3A and B: Impurities in New Drug Substances and Products
Qualification: process of acquiring and evaluating data that establishes the biological safety of an impurity or a given impurity profile at the level(s) specified.
- if an impurity(ies) have been adequately tested in safety or clinical studies, it is qualified.
- impurities that are significant metabolites present in animal/human studies are also qualified
(reduction)
Q3A and B: Impurities (continued)
- a level of a qualified impurity higher than that present in a new drug substance or product can also be justified based on analysis of the actual amount of impurity administered in previous safety studies.
(reduction)
Q3A and B (continued)
When a new impurity exceeds the threshold for substance or product:
- either decrease the impurity level below threshold or:
- consider its structure if known, survey literature, consider patient population/use,
- consider need for:
- genetic toxicology studies, repeat dose study(ies), specific end point studies, etc.