Since 1990, experts from regulatory authorities and pharmaceutical industry trade associations of the US, Europe, and Japan have been working to harmonize the technical requirements (safety, quality, and efficacy testing procedures) for human drug product registration through the activities of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (ICH, n.d.).
The purpose for internationally harmonizing technical requirements is "to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines" (ICH, n.d.). Such efforts would reduce costs (by reducing the need for humans, animals, and materials) and drug development time, while maintaining product quality, safety, and regulatory obligations.
The members of ICH consist of the six founding organizations – one regulatory authority and one industry trade association from the US, the EU, and Japan. These organizations are:
Pharmaceutical Research and Manufacturers of America (PhRMA)
Three additional members, "observers" from non-ICH countries or regions, are: the World Health Organization (WHO); the European Free Trade Association (EFTA); and Canada.
The ICH Steering Committee is composed of representatives from a regulatory authority and industry organization from each of the three regions. "The Steering Committee...determines the policies and procedures for ICH, selects topics for harmonization, and monitors the progress of harmonization initiatives" (ICH, n.d.). The ICH addresses four topic areas: Safety, Quality, Efficacy, and Multidisciplinary, and has four associated Expert Working Groups (EWG). The ICH is administered by the ICH Secretariat at the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) in Geneva, Switzerland (ICH, n.d.).
The ICH has achieved harmonization of technical guidelines and developed a harmonized format for registration applications known as the Common Technical Document (CTD) and Electronic Common Technical Document (eCTD) (ICH, n.d.). They have also formed the ICH Global Cooperation Group (GCG) to work with the ICH Observers in providing information on ICH activities and guidelines to non-ICH countries and companies. Regional harmonization initiatives have been encouraged to designate GCG representatives. The ICH also "acknowledges the important role of WHO in disseminating information and providing input beyond the ICH regions" (ICH, n.d.).
New ICH harmonization activities can be proposed by organizations outside the ICH, but must be channeled through one of the ICH member organizations. A Concept Paper is required to initiate new activities. The Concept Paper is a short document that describes the type of harmonization action proposed, a statement of the perceived problem, a summary of the main technical and scientific issues to be harmonized, background information, and a recommendation for the type of EWG needed. When the IHC Steering Committee endorses a Concept Paper, they establish an EWG and publish the Concept Paper on the ICH website.
Test Guidelines
"The ICH guidelines represent agreed-upon scientific guidance for meeting technical requirements for registration within the three ICH regions - EU, US and Japan. Each regulatory co-sponsor implements the guidelines according to its national/regional requirements.... [The guidelines] are intended to be used in combination with any regional requirements, [and] can be used by industry as a means of reducing testing duplication" (ICH, n.d.).
The ICH Guidelines are grouped into four categories: Quality, Safety, Efficacy, and Multidisciplinary. Information on the ICH Guidelines can be found on the ICH's website under tabs Q, S, E, M, respectively.
The ICH Safety Guidelines include:
- carcinogenicity studies
- genotoxicity tests3
- toxicokinetics for systemic exposure
- pharmacokinetics repeated dose studies
- single dose toxicity tests (to replace the eliminated LD50 test)
- chronic toxicity testing (repeat dose)
- reproduction toxicity
- pre-clinical safety evaluation of biotechnology-derived pharmaceuticals
- safety pharmacology studies
- non-clinical evaluation for delayed ventricular repolarization
- immunotoxicology studies
- non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals
Alternatives Policies & Actions
At one of the earliest ICH meetings, the members indicated that their international harmonization activities "are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness" (ICH, n.d.).
The revised ICH Terms of Reference (1997) includes the following statement on animal use: "To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal and material resources, without compromising safety."
The following specific ICH efforts have the potential to contribute to the 3R's for animal use in toxicological tests:
The ICH Safety EWG addresses issues related to drug safety and the toxicological tests used to evaluate drug safety. The ICH has revised a number of toxicity testing guidelines to eliminate duplicate or obsolete standards. This has resulted in a reduction in animals used for drug safety evaluations by the elimination of requirements for the acute oral LD50 test and for the 12-month rodent toxicity study (ICCVAM, 1997). Harmonization of toxicity testing guidelines also has the potential to refine or replace an animal test.
The ICH does not appear to have a formal policy on animal testing or to consider reducing or replacing animals as part of their mission, except as stated above. The inclusion of representatives of the international animal welfare community in the activities of the ICH could further benefit their complementary objective to identify and implement alternative toxicological tests that may provide faster, more cost effective, and/or more human-relevant results.
An important activity of the ICH to the worldwide reduction of animals used in drug safety testing is their revising and harmonizing of specific toxicity test guidelines. It was reported at the October 2006 Steering Committee that EWGs were working to revise the requirements in the Genotoxicity and the Non-clinical Safety Studies for the Conduct of Human Clinical Trials. The Final Concept Paper for revision of the Non-clinical Safety Studies for the Conduct of Human Clinical Trials guideline (September 20, 2006) claims that new data and new approaches for non-clinical and clinical research, compared to those in the current guideline, will accelerate the drug development process and provide an overall reduction in animals use and suffering. The issues to be resolved by revising the guideline include regional differences in the protocols used for certain toxicity studies, and the use of emerging approaches (exploratory investigational new drug (IND) and microdose studies) for the toxicity package for entry into phase I clinical trials.
References
Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). (1997). Validation and regulatory acceptance of toxicological test methods.
International Conference on Harmonization (ICH). (n.d.). Welcome to the official website for ICH.
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