Regulatory Affairs Journal (RAJ) Pharma February 5 2009

Are Humans the Best Model for Human Medicines?

Doctors and scientists from the Safer Medicines Campaign believe that human biology-based tests can predict the safety of human medicines more accurately than conventional animal tests. Neena Brizmohun talks to the UK-based group about plans to put this belief to the test.

Draft UK legislation introduced in the House of Commons on 26 January is calling for a definitive answer on whether traditional animal tests for evaluating drug safety should be replaced by human biology-based tests.

The Safety of Medicines (Evaluation) Bill 2009 proposes for the first time that animal tests be directly compared with currently available human biology-based tests, which include in vitro and in silico (ie computer simulation) techniques and early clinical tests, involving minuscule levels of exposure to the new drug. The chief architects of the bill are the Safer Medicines Campaign (a patient safety organisation focused on evidence-based analysis of animal experimentation to assess the balance of help or harm to human health) and the Safer Medicines Trust, the campaign's charitable wing.

The law in all major markets requires that drugs are tested in animals before they can enter human clinical trials. The Safer Medicines campaigners believe, however, that there exists a battery of scientifically reliable human biology-based tests that can predict the safety of new drugs more accurately than animal tests. The group, which is comprised of doctors and scientists, also believes that a human biology-based test approach would help speed up the drug development process. Should the bill be passed, and the comparison show that human biology-based methods outperform animal tests, the campaigners plan to lobby for the newer methods to replace animal trials as a means of screening new drugs for safety prior to clinical trials and marketing.

The Safer Medicines Trust in late 2008 hosted the Speed and Safety in Drug Discovery conference at the Royal Society in London, where delegates were told of state-of-the-art developments in human biology-based tests. At the meeting were the organisation's science consultant, Dr Margaret Clotworthy, and science advisor, Dr Bob Coleman, both of whom told RAJ Pharma about the new tests and about the need to drop animal trials from the drug development process.

Dr Margaret Clotworthy Science consultant to the Safer Medicines Trust	Dr Bob Coleman Science advisor to the Safer Medicines Trust

NB: In terms of drug safety, why does the Safer Medicines Campaign believe that animal tests should be replaced?

MC: There is substantial evidence of the shortcomings of animal-based tests in predicting safety in humans. For example, the arthritis painkiller Vioxx (rofecoxib), withdrawn in 2004, killed up to 140,000 people after being "proved safe" in animals, including monkeys. More recently in March 2006, Phase I clinical trials in the UK of TeGenero's drug CD28-SuperMAB (TGN1412) left in intensive care six young men who had received the drug. TGN1412 had been previously tested at 500 times the dose in monkeys. More than 10,000 people die every year in the UK because of side effects of prescription medicines? - now the fourth biggest killer in the western world. The corresponding figure in the US is over 100,000.


NB: Apart from improving safety, how else might replacing animal tests with human in vitro analysis enhance the drug development process?

MC: A report by the US Food and Drug Administration in 2004 revealed that an astonishing 92% of new drugs fail in clinical trials following success in animal tests. Although these failures are not all due to safety concerns, we believe that this rate of attrition could be improved by relying more on human biology-focused assays. In addition, substances that could save many lives are not approved because they are harmful to animals. Also, many of our most popular drugs can be quite detrimental to animals. For example, ibuprofen is toxic to dogs and the chronic myelogenous leukaemia drug Glivec (imatinib) was almost lost because it caused severe liver toxicity in dogs. Fortunately, as the drug seemed so very promising in human cell culture tests, its manufacturer persisted with its development.


NB: Can you name some of the currently available human biology-based tests that you believe are likely to assess drug safety more accurately than animal tests?

MC and BC: The non-animal tests that might better predict drug safety include tissue-culture tests, tests based on human tissues, DNA chips, computer modelling, microdialysis and microdosing.


NB: What are your views on the 3Rs principle of reducing, refining and replacing animal experiments, which a number of regulators and key groups representing the pharmaceutical industry have pledged to adopt?

MC: The 3Rs as a concept has been around for decades. Its principle has merit in theory from an animal welfare perspective, but makes little scientific sense. We believe that if it is not scientifically valid to use a lot of animals, then it is not scientifically valid to use fewer of them. If a practice does not work, there is little point in reducing or refining it.


NB: Can you describe some of the major steps taken by regulators aiming to see animal testing replaced by in vitro human tests

MC: The European Union, under Directive 86/609, mandates the replacement of animal tests with in vitro alternatives where they are available. Europe, through the actions of the European Centre for the Validation of Alternative Methods has been much swifter to validate and adopt non-animal methods than the centre's counterpart in the US, the Interagency Coordination Committee on the Validation of Alternative Methods.

However, there now appears to be a very positive shift in attitude in the US, as evidenced by the publication in 2007 of a report commissioned by the US Environmental Protection Agency and conducted by the National Research Council Committee on Toxicity Testing and Assessment of Environmental Agents. The Toxicity Testing in the 21st Century: A Vision and a Strategy report concluded that animal testing could and should largely be replaced by in vitro and in silico methods alongside epidemiology (in the field of environmental toxicity testing) within a decade. It pointed to the progress being made in developing technologies for medical toxicity testing and suggested that these technologies ought to be adopted for environmental toxicity testing purposes. With the backlog of thousands of chemicals in need of testing in the EU under the REACH regulation, and in the US under the High Production Volume programme, current animal-based tests are simply too costly, too time-consuming and of dubious relevance. Three US federal agencies have now embarked on a major collaboration to bring about the use of the newer technologies for environmental toxicity testing purposes.

Also in the US, doctors and scientists have been brought together via the Mandatory Alternatives Petition to urge the FDA to mandate the replacement of animal tests with scientifically proven human biology-based methods in line with EU Directive 86/609.

In what might also signal a move towards the elimination of animal testing for drugs, the US and EU in 2007 agreed to collaborate more closely on validating non-animal methods for cosmetic testing.


NB: Considering the apparent wealth of evidence that calls into question the reliability of animal tests, why does the practice continue?

MC: Firstly, animal trials are a legal requirement, a situation we are trying to address. As was pointed out by a speaker at our conference at the Royal Society, they are deemed to have value because they are required by law and not because they are of great scientific value.

Secondly, there is a "conservative nature" regarding toxicity testing. Authors of the Toxicity Testing in the 21st Century: A Vision and a Strategy report said that they expect the "paradigm shift" away from animal tests towards human biology-based methods to encounter resistance, as toxicological testing practices are "deeply ingrained". They stated that in order to succeed, the implementation of "policies designed to overcome tendencies to resist novel approaches and maintain the status quo will be important". Another very pertinent comment on the issue comes from a presentation at a Safety Pharmacology Society workshop held in 2007 at Pfizer, in Kent, in the UK. Here, Icilio Cavero, a pharma/biotech industry consultant on cardiovascular safety issues, said that novelty does not easily penetrate into the pharmaceutical environment. In particular, he said, novelty does not easily penetrate the very conservative world of safety sciences, which all too readily responds with the often heard boring refrain of "the regulators won't accept these new approaches". The safety science community should be reminded that regulators expect them to take the initiative to improve their sometimes catastrophic record in predicting clinical drug safety as a result of their investigational efforts. 

Technological lock-in is another reason for the continuation of animal trials. The reason why animal testing remains so pervasive despite doubts over its efficacy was discussed in a paper published in the journal Structural Change and Economic Dynamics in December 2004. Equipment, expertise, careers, facilities have been built on/and are devoted to the use of animals in this field, and it is a field in which there is a great deal of experience, comfort and familiarity as a result - none of which means it is actually superior to the newer methods now available. Of course, the view that animal tests are useful is also reinforced by the fact that, naturally, they do not always get it wrong; the question is whether we do not now have much more predictive methods at our disposal.   

Finally, animal testing persists because of liability protection issues: an important consideration for manufacturers, who would need Government support during any transitional period/for a new system. 


NB: Can you comment on the argument by the US FDA that current in vitro tests, regardless of the species of origin, cannot reliably predict in vivo responses?

MC: This argument ignores the fact that the currently available animal in vivo test methods are themselves fundamentally unreliable. Given that metabolic processes differ greatly between species, information garnered in animal experiments has no predictive value and is wholly unscientific when applied to humans.

BC: The chief problem associated with a human in vitro approach is in modelling complex integrated systems as they exist in vivo; it will be difficult to model such processes as control of blood pressure and brain function. However, both of these lend themselves to in silico modelling approaches, and failing that, should some animal experimentation be required, the use of in vitro techniques to compare the relevant pharmacology and physiology of the relevant cells/tissues may prove invaluable in identifying the most relevant animal species.


NB: How might your proposal in the Safety of Medicines (Evaluation) Bill 2009 lead to a shift from animal trials to human biology-based testing?

BC: While there is much scientifically and ethically based opposition to the use of experimental animals in the drug industry, it is unlikely that drug companies will truly minimise, let alone abandon, their use until they are convinced that there exist more reliable, accessible alternatives. The challenge, therefore, is to convince them that valid alternative methods exist, that they are economically viable, and that they are more reliable than those currently in use. The evaluation proposed in the bill will be the first to evaluate whether the human biology-based tests are better than animal tests by pitting the two approaches head-to-head.


NB: What will the evaluation proposed in the bill involve?

MC: The bill calls for the appointment of a Medicines Safety Evaluation Panel to conduct a review of drug safety testing methods, the results of which it must report back to the Secretary of State within two years of the date of its appointment. It proposes taking a wide range of drugs that have already been widely used in patients - so we know the problems they can cause - and running them through a suite of the latest tests. Comparing those results with the results we already have from animal tests will reveal which methods are most predictive for humans.


NB: Which drugs do you propose testing?

BC: No final decision has been made on the matter, but probably no more than ten drugs will be selected. These will comprise a selection from a list of small molecules and biologicals that have either been withdrawn or received black box warnings. Non-approved drugs linked with adverse drug reactions might also be considered. Drugs that may be considered include: Lotronex (alosetron); Trasylol (aprotinin); Baycol Crestor (cerivastatin rosuvastatin); Redux Pondimin (dexfenfluramine fenfluramine); Ritalin (methylphenidate); Vioxx Celebrex (rofecoxib celecoxib); and CD28-SuperMAB (TGN1412). Biologicals with warnings that might be considered include: MabCampath (alemtuzumab); Kineret (anakinra); Regranex (beclapermin); Avastin (bevacuzimab), Exubera (insulin human inhalation powder); Remicade (infliximab); Herceptin (trastuzumab); and Pegasys (peginterferon alfa-2a).


NB: When do you expect a final vote to be taken on the bill?

MC: We expect to know if the bill has been successfully passed during 2009.


NB:How definitive do you expect the findings from your comparison initiative to be in terms of calling for change to existing regulations?

MC: We believe that an outcome in favour of human biology-based techniques should be sufficient to prompt a major reassessment of drug safety testing requirements. Although the initiative would cover a relatively small number of drugs, it would cover a range of drug types and look at a cross-section of adverse drug reactions. However, larger follow-up studies may well be desirable. It is possible that there may be submissions for generating further appropriate data to the Innovative Medicines?? Initiative [the public-private partnership on research issues between the European Commission and European pharmaceutical industry federation Efpia - Ed].


NB: What are the financial and economic implications of replacing animal studies with human in vitro tests for pharmaceutical companies?

BC: The financial/economic implications are impossible to quantify at this stage. There will be considerable savings achieved in the reduction in costs associated with animal husbandry, but these will be offset by the costs related to acquisition of human tissues.

Human tissue-related costs are also impossible to quantify at this stage, as the necessary infrastructure essential to enable its acquisition in sufficient quantity has not been put in place. As far as the UK is concerned, I believe that if the National Health Service and industry work together to establish a system that will facilitate the acquisition of human organs and tissues for both transplant and research, the costs to industry would not exceed the animal-based savings. Even if the overall costs remain at a similar level, the anticipated reduction in failure rate and associated increase in productivity will represent a real and very welcome economic advantage. Anything that reduces the current cost of getting a drug to market (currently around US$1 billion per drug) is going to be welcomed by the industry.


NB: Can you comment on the need to harmonise on an international basis regulations that might call for the elimination of animal tests for pharmaceutical development?

BC: Harmonisation must be on a global basis. The UK and Europe are undoubtedly ahead in their concerns about animal welfare, and will probably prove the most willing to consider a more ethical approach to drug safety evaluation. However, the US FDA is very much aware of the shortcomings of the current approaches, and would undoubtedly be very interested in results that indicate a more effective - and more ethical - way.

Acceptance in the UK, the EU and the US would undoubtedly have a profound influence on other regulators. However, regulators that have a cultural reluctance towards the acquisition and use of human tissues for any purpose, such as those in Japan, may find a move in this direction problematic in the immediate term. But it is important to appreciate that things are changing in Japan, as while there is probably still much culturally based resistance, there have recently been changes to the law in Japan to make such acquisition and use legal; Western influences are having a great impact.


NB: Finally, how long do you think it might be before we see animal testing laws in the major markets replaced by human biology-based tests?

MC and BC: Realistically, even if the Safer Medicines Trust initiative gets the go-ahead and appropriate funding is forthcoming, and the results prove positive, it is going to take some years to get the results and evaluate the outcome, and put in place any changes necessary to facilitate operation of the human-based approach. In view of The Toxicity Testing in the 21st Century: A Vision and a Strategy report which urged animal tests to be largely replaced within ten years, this does not seem an unrealistic expectation - providing the results of the comparison show that the latest human biology based methods confer advantages over the animal-based system.