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Panel Discussion: Effectiveness and reliability of alternative methods used for regulatory purposes

On December 1 of last year the European Partnership for Alternative Approaches to Animal Testing (EPAA) celebrated its tenth anniversary with a conference in the European Parliament. As part of the conference Julie Girling, Member of the European Parliament and EPAA stakeholder, chaired a roundtable to discuss challenges in developing alternative methods seeking to replace, reduce and refine animal procedures. Around the table were Maurice Whelan from the European Commission Directorate General Joint Research Centre, Erwin Roggen from Novozymes, Sonja Beken from the European Medicines Agency (EMA) and Joop de Knecht from the Organisation for Economic Co-operation and Development (OECD).

How can alternative methods be translated into reliable regulatory methods?

The first step is to engage researchers into the conversation, according to Prof Whelan: we need the output of research programmes to help develop policies and regulations in science. He also recognised the role of risk assessors in early stages of the R&D process to accurately formulate the problem to orientate the research. Dr Beken added that only research can determine the drivers for better safety and efficacy. In her view, regulators should act as an external advisory panel to help identify needs. However, Dr Roggen rightly pointed out that the focus of researchers is not the method itself, which is merely used as a tool to prove or refute a hypothesis. He warned that this can make it difficult to engage scientists in this conversation.

Dr Knecht highlighted EPAA’s work in developing Adverse Outcome Pathways (AOP).

AOPs are used for the risk assessment of chemicals to describe the existing knowledge of the causal links between a molecular initiating event, intermediate events and adverse outcomes at the individual or population level. The AOP developed for skin sensitization is currently used as part of an integrated approach for testing and assessment. Dr Knecht noted that we first have to know for each group of chemicals what events they trigger, sequentially link these events and finally test the pathway. The knowledge regarding each of these events comes from different research laboratories; hence a mutual strategy for developing such pathways is required.

How can we ensure that alternative methods are reliable?

The speakers agreed that for alternative methods to be reliable, the validation process would require well described and detailed methods that could confirm or reject the usefulness of a new method.

According to Prof Whelan, validation should be a confirmatory process rather than an investigative one. He noted that unfortunately this is often the bottleneck due to the current pressure scientists experience to secure funding and to publish their work. Since the method is only the tool scientists use in their research, often little attention is paid to the Material and Methods part of the scientific article.

Dr Beken mentioned that the European Medicines Agency (EMA) has developed validation criteria based on the intended use of alternative methods to ensure reliability. The EMA decides which method is worth validating for which field after an open discussion with stakeholders.

Dr Roggen added that in some cases an alternative method can be reliable when combined with other methods. However, the limitation of this approach lies in a potential incompatibility of a particular chemical with a given method or in the incompatibility of the combination of methods with the current regulatory guidelines. In the latter case, he noted that stakeholders are often reluctant to re-submit a validation application to the regulatory authorities and end up not pursuing the development of the method.

The overall consensus was that implementation of validated alternative methods would benefit from having a consistent global approach. In this sense, EPAA has also been fundamental in fostering international dialogue and convergence seeking to homogenise the validation criteria.

What can be done when an alternative method still has a degree of uncertainty?

Dr Knecht explained that a certain level of uncertainty is also present in in vitro methods and that regulatory authorities should establish which degree of uncertainty will be accepted. One of the main challenges when developing an alternative method is to describe its limitations, added Dr Roggen. Regulatory authorities, he said, should put forward a framework to allow for the description of limitations and uncertainties of new methods. This could enable flexibility in the current guidelines to allow for various levels of risk assessment depending on the target. Such a framework will aid the development of alternative methods, their incorporation into guidelines and their downstream implementation in the industry.

Dr Beken added that even when a method is validated that does not imply it is accepted by the regulatory authorities and incorporated into the guidelines. She explained that for a validated method to be accepted by the regulatory authorities it must be tested in parallel with conventional methods to produce data that will confirm the usefulness of the method. The EMA and the European Union Reference Laboratory for alternatives to animal testing (EURL-ECVAM) should work closer together to foster incorporation of alternative methods into guidelines, she added.

Prof Whelan invited everyone to identify opportunities for sharing information on R&D and validation of alternative methods. He emphasised that the process is as important as the final result and that sharing case studies will help to get a common understanding of the process.

The panel discussion revealed a shared interest in developing a clear risk assessment framework for alternative methods. Such a framework should aim to include guidelines on the development, predictability, validation and regulatory acceptance of these methods. To achieve this objective it is required to bring together basic research, industry and regulators: the EPAA initiative could be the way forward.

Despite the advances in the field made to date, scientists’ engagement with regulatory authorities, together with an accurate description of scientific methods and more flexibility in the regulatory guidelines, would allow for a faster and more efficient development and uptake of alternative methods.


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