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Petition to the Food and Drug Administration (FDA) for Mandatory Use of Non-Animal Methods


I. Purpose, Rationale and Scope

This petition seeks a change in US Food and Drug Administration (FDA) policy that would require, and not merely permit or recommend, that pharmaceutical companies, device manufacturers, and other entities regulated by the FDA submit data only from scientifically satisfactory non-animal alternatives, and in lieu of corresponding animal test methods, whenever such scientifically satisfactory alternatives are available.

Although there are sound scientific, economic and ethical reasons why the use of scientifically satisfactory non-animal methods should be mandatory, there is little effective incentive or support for researchers, businesses, regulatory agencies and educators to adopt them, or to develop new ones.

In contrast to the US, Europe has moved ahead in this area following European Union (EU) Directive 86/609 in 1986. In particular, Article 7.2 states, “An experiment shall not be performed (on an animal), if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practically available.” This requirement is legally binding on all member states of the European Union. Adoption of a similar regulation in the US would go far towards harmonizing policy and practice on both sides of the Atlantic.

Absent similar legislation in the US, it is understood that the FDA currently takes the position that it does not have the authority to mandate the use of specific non-animal alternatives or to restrict the use of animal test methods. It is further understood that the FDA takes the position that it is required to review and incorporate all documentation submitted in applications, including animal test data even when such data are not required.

Nevertheless, there are effective steps the FDA can take toward this goal under its current authority, while additional efforts proceed to produce the requested mandate. These are reflected in the specific actions requested in Section VI of this Executive Summary. The purpose of this petition is to seek the mandate outlined in the first paragraph of this section, by whatever combination of regulatory, rule-making, and legislative measures may be required.

II. Current Practice – Advantages, Validation and Regulatory Approval of Alternative Methods

Non-animal methods spare significant numbers of animals from pain and distress, are often less costly and time-consuming, and may require lower investment in personnel and other resources. Most importantly, they have more predictive value and specificity to the human condition.

Examples of the superior predictive value of non-animal tests include the Multicenter Evaluation of In-Vitro Cytotoxicity (MEIC), Evaluation-guided Development of In-vitro Test batteries (EDIT) and ACuteTox projects in Sweden, in vitro tests for cancer causation and drug efficacy/toxicity at the US National Cancer Institute (NCI), and microdosing technologies. In fact, some 30 empirical studies have so far been published showing equal or greater efficacy for non-animal methods.

Animal tests, many of which have been in use for decades, have never been formally validated. Despite this, a bias persists towards them and, with no true gold standard available, they have typically been used as the default standard against which non-animal tests are judged. In vitro data therefore show only a 70 to 80% correlation with animal data due to the latter’s natural variance, and so may appear inferior to animal tests due to the biological variability in the animal paradigm.

Twenty alternatives have been successfully validated by the European Centre for the Validation of Alternative Methods (ECVAM), 10 of which have gained regulatory acceptance. In the US, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) has validated fewer methods (six, at the time of writing), clearly suggesting a need for greater harmonization. This need is further illustrated by the favorable impact harmonization has had on reducing animal use in drug development and safety testing worldwide, via the International Conference on Harmonization (ICH) and the Test Guidelines Program of the Organisation for Economic Cooperation and Development (OECD).

III. Costs and Problems Associated with Animal Use

Extrapolating across species is a tenuous enterprise. Animal test data are undermined by species differences in anatomy, organ structure and function, toxin metabolism, chemical absorption, and mechanisms of DNA repair, and compounded by additional variables introduced by demographics and husbandry.

These problems manifest repeatedly when attempting to apply animal data to human clinical conditions: examples include Hormone Replacement Therapy (HRT); development of HIV protease inhibitors; Vioxx and other COX-2 inhibitors; teratology studies; harmful effects of smoking; significant clinical problems with drugs including non-steroidal anti-inflammatories (NSAIDs), antibiotics, anti-virals, antidepressants, and cardiovascular medications among others. Many safe human drugs would not survive animal testing today because of severe or lethal toxicity in some species, such as penicillin, acetaminophen and aspirin. More than 80 AIDS vaccines have failed in human trials, and over 4,000 studies have been reported demonstrating the efficacy of more than 700 drugs in animal models of stroke – none of the approximately 150 of these tested in humans has shown human benefit.

Ninety-two percent of drugs that enter clinical trials following extensive animal testing fail to progress and gain approval for marketing. Of the 8% that do not fail, over half are recalled or relabeled post-marketing due to unforeseen, or worse than expected, adverse events. Levels of discordance between results from animals and humans run at between 67 and 96%.

Recent examinations of animal trials have shown they often run concurrently with human studies, and the results are often conflicting; that there is a poor correlation of cancer risk between assessments carried out by the US EPA and the International Agency for Cancer Research (IARC); and that transgenic animal models frequently fail to duplicate human symptoms characteristic of many conditions, let alone to enable scientists to elucidate the molecular processes underlying those diseases.

There are also economic advantages to replacement methods. For example, the DakDak test (used to measure the efficacy of sunscreens in preventing skin damage) can provide data for five or six products at less than half the cost of testing one product in animals. The current “gold standard” for testing a chemical to determine if it is carcinogenic is the rodent bioassay, which takes around five years from planning to evaluation and review, at a cost of up to $4 million or more per substance. In the EU the “REACH” (Registration, Evaluation and Authorization of CHemicals) program is projected to consume up to 13 million animals at a cost of $11 billion US dollars. In vitro screening allows companies to identify promising test materials in a cost- and time-efficient manner before progressing to expensive human trials. Additionally, non-animal methods save on various hidden costs associated with animal methods including animal procurement, maintenance and husbandry, and hazardous waste disposal. Finally, costly legal claims against companies that rely heavily on animal data may become more commonplace. For example, the pharmaceutical company Merck is currently facing litigation for improperly relying on animal tests to show that its painkiller Vioxx was safe for humans.

Other factors resulting in the inherent suffering of animals used in testing include the manner in which animals are housed, transported and supplied. Common laboratory routines have been shown to cause pronounced stress, and links between such stress and the development of behavioral stereotypies (which are believed to reflect animal suffering) are well established.

IV. The Law in the US and the EU

The potential for animals to suffer pain and distress in experiments was implicitly acknowledged with the passage of the Animal Welfare Act in 1966. Since that time, multiple amendments to the AWA, along with other policies and guidelines designed to improve the legal protection of animals in laboratories, have all sought to reduce animal suffering in research and testing, and have led to policies and guidelines that promote the development and use of animal replacement methods.

Of particular note is the 1993 NIH Revitalization Act, which mandates the need for eliminating and reducing the use of animals in research. The law calls for the National Institutes of Health to “conduct or support research into methods of biomedical research and experimentation that do not require the use of animals,” as well as for reducing the number of animals used in research.

Directive 86/609 by the Council of Europe is widely acknowledged as a primary factor responsible for Europe’s preeminence in the field of non-animal methods, asserting that it is scientifically and morally insupportable to harm animals when valid alternatives may be used instead. The EU Directive mandates the use of non-animal methods, places their development and utilization into the political agenda of all EU countries, and has helped to spawn further legislation. Today, the concept of non-animal methods is accepted as standard practice by EU-based researchers and industry. The US, however, has yet to embrace these methods on a comparable level.

V. Scientific and Public Support

It has been shown repeatedly that the American public is uncomfortable with animal testing, particularly when it involves animal pain and distress, and/or the testing of non-essential products. As a publicly funded organization, the FDA has a duty to use public monies in a cost-effective manner, and is obliged to address the concerns of the American population.

According to polls, 75% of Americans disapprove of all animal research and testing that causes severe pain and distress, and one-third object to all animal experimentation. Testing procedures account for the vast majority of animals reported in the highest categories of pain and distress, underscoring the importance of replacing animal use in regulatory toxicity testing. These prevailing sentiments suggest widespread public support for the aim of this petition: that replacement methods be required when they are available and proven effective.

Broad scientific support for non-animal methods is evident in the sort of language being drafted for relevant legislation, in their growth and diversification, and in the number of scientists and scientific organizations supporting them.

VI. Conclusion and Action Requested

The time is optimal for regulatory and legislative changes in the use of animals for preclinical drug and device testing. As long as US laws and FDA regulations do not provide a mandate to move forward in this area, there is little incentive for improvement from the current suboptimal preclinical testing methods. There are many sound humane, scientific and economic reasons for replacing animal methods with scientifically satisfactory alternatives, and there are legislative precedents for doing so in Europe and in the US at the state level. Requiring the use of such alternatives is vital if the US is to improve the accuracy of preclinical testing, minimize the approval and marketing of hazardous drugs and devices, and keep pace with Europe in advancing the goal of replacing animal test methods with more reliable and humane methods.

We request the FDA to promulgate a regulation to mandate that:

“An animal experiment should not be performed if another scientifically proven (by any reputable authority, such as ECVAM) method of obtaining the results, not involving the use of animals, exists. Exceptions to the use of scientifically satisfactory* methods instead of the animal tests they replace will require submission of adequate justification to the appropriate regulatory body in each ICH member constituency (the USA, the EU, and Japan). Exceptions should only be granted for reasons of extraordinary hardship regarding performance measures or economic impact, and should otherwise be denied.”

We specifically request that the FDA include in its reply to this petition any legal or regulatory reasons why this request cannot be achieved, and the appropriate steps necessary to provide any necessary authority to the FDA.

Pending resolution of any such legal or regulatory constraints, we request that the FDA promote the intent of the regulation proposed in this petition as permitted under its current authorizations, as follows:

A.   The FDA should develop and implement standardized procedures requiring that its drug and device application reviewers accept as valid and sufficient any and all data submitted using scientifically validated alternatives to animal test methods. Individual reviewers must not require additional animal test data in such instances, or applicants will unnecessarily include such data in initial applications so as to avoid approval delays.

B.   The FDA should use the strongest possible language in its industry guidelines regarding the acceptability and sufficiency of scientifically satisfactory non-animal alternatives, clearly indicating that the FDA requires only the non-animal data and does not require (and will not request) any corresponding animal test data. If the agency believes that the term required is proscribed under current authorizations, then terms such as strongly recommended or strongly preferred should be used rather than terms such as acceptable or permissible.

C.   The FDA should institute a policy that designates as “scientifically satisfactory” any and all non-animal alternatives meeting the definition in this section, above.

D.   The FDA should support and participate in efforts to obtain any additional legal or regulatory authorizations required to permit the FDA to mandate the specific use of scientifically satisfactory non-animal alternatives, and to exclude the submission of animal test data when such alternatives are available.

E.   The FDA should support and participate in efforts to obtain adequate funding targeted specifically at the development and utilization of its extensive human drug database as a particularly effective method for improving preclinical and clinical drug testing and public safety, informing FDA decisions regarding content of new drug or device applications, and replacing animal test methods with scientifically satisfactory non-animal alternative methods.

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