spacer
home > epc > spring 2010 > responsible research
PUBLICATIONS
European Pharmaceutical Contractor

Responsible Research

Kathryn Chapman and Vicky Robinson at the National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) discuss the need to transform drug development by reducing reliance on animals

The rate of new drug approvals has remained largely unchanged for 60 years, despite a huge increase in investment (currently at $50 billion per year (1)). It has been documented on a regular basis that the drug development model has become unaffordable, is limited in its current form, and is in urgent need of reform. A wide range of factors contribute to the problem, including low approval and high attrition rates (2), safety issues and insufficient flexibility to deal with the additional complexities of developing novel therapies such as biotechnologybased products. Many of these factors, however, expose a common concern – the traditional use of animal models is not appropriate for the challenges faced by the pharmaceutical industry in the 21st century and a new approach to preclinical drug development is necessary.

Traditional research methods, including in vivo models, have provided insight into many disease processes and have undoubtedly contributed to improvements in human health and medicine. However, the existing models are not sophisticated enough to meet current research demands; change is essential. Scientific knowledge is expanding at an unprecedented rate, with more advanced medicinal chemistry providing increasing numbers of new chemical entities, and genomics and proteomics determining all feasible drug targets. Add to this the complexities of personalised medicine, untangling the contribution of genetic and environmental factors and the wide spectrum of clinical symptoms for many disease phenotypes, and it is apparent that an approach which integrates the latest technologies, studies in humans and human tissues, and more predictive animal models, is crucial.

The US FDA’s Critical Path Initiative and the European Innovative Medicines Initiative have cited animal models as major bottlenecks in the drug pipeline in terms of their predictivity, reliability and translation to the clinic (3,4). The cost of in vivo research continues to rise, and there is a vast array of new technologies (such as tissue engineering and stem cells) that have yet to be fully exploited to minimise animal use in drug development. In 2008, 21 per cent of procedures on animals in Great Britain were for pharmaceutical research and development, including fundamental, applied and toxicology research (5).

A research agenda, with reduced reliance on animals, will be integral to the successful transformation of the drug development process to support innovation, develop affordable, novel treatments and address public concern about in vivo research. Recently, in The Lancet, Barker described a flexible blueprint for the future of drug development (6). Much of this focuses on clinical research, but a similar blueprint can be envisaged for preclinical studies. Central to this model is increased collaboration among industry scientists on pre-competitive issues, which the industry has started to embrace in recent years through various initiatives.

The NC3Rs, a UK Government-sponsored organisation, is working to integrate the three Rs as a central component of efforts to revolutionise the drug development process (see The Three Rs, page 43). Experience working with scientists from industry, academia and regulatory bodies has demonstrated that this approach has the potential to improve drug development from a scientific and business perspective. Over the last five years, this model of providing a neutral environment for data-sharing, fostering the use of new technologies and facilitating crossdisciplinary, cross-company and crosssector collaboration has led to new opportunities to address the challenges of animal research facing the pharmaceutical industry. This article outlines some of the successes to date.

TACKLING CONTROVERSIAL AREAS

The use of non-human primates (NHPs) in research has been high on the agenda recently, with the revision of the European Directive 86/609 (7) and an opinion from the European Commission’s Scientific Committee on Health and Environmental Risks (SCHER) on the need for NHPs in research (8). Approximately, 92 per cent of the NHPs used in the UK are in pharmaceutical development. The number of NHPs used worldwide is increasing, largely as a result of the focus on the development of biologicals – mainly monoclonal antibodies (mAbs). It is estimated that over the next few years, the number of biologics in the drug pipeline could outstrip new chemical entities. The development of mAbs brings new opportunities to the pharmaceutical and biotechnology industries as their properties, for example, being highly target-specific, make them ideal drugs with few off-target effects. However, these properties can cause difficulties in selecting appropriate animal models for safety testing, as mAbs are also highly species specific, and in some cases there is no relevant animal model for preclinical studies. Often, the NHP is the only relevant species and the challenge, from both a business and ethical perspective, is to minimise their use.

Open discussion with scientists and regulators about the challenges of NHP use commenced with a workshop to develop a contingency plan for the development of mAbs in the event that NHPs were no longer available, for example, due to logistical problems such as supply or disease outbreak (9). The ideas emerging from the workshop have been explored further in a collaboration involving 24 pharmaceutical and biotechnology companies and regulatory authorities from the UK, elsewhere in Europe, the US and Japan. By sharing data on 120 unique mAbs, including study designs, the use of surrogate molecules and antibody potency, opportunities have been identified to reduce NHP use by up to 50 per cent per mAb by decreasing the number of recovery animals, dose groups and chronic studies performed (10,11).

Regulatory flexibility which allows for decisions on preclinical studies to be based entirely on scientific rationale rather than a ‘tick box’ approach is central to a safer, more cost-effective and efficient mAb development process. The current addendum to ICH S6 goes some way towards this; however, further work on the interpretation and implementation of the Guidance will be necessary for this potential to be realised in practice. To support this, work is continuing with the pharmaceutical and biotechnology industries to improve data access and sharing. The impact of the rising cost of new drugs is demonstrated by mAbs, with healthcare providers, national health services and insurers unwilling to make some mAbs routinely available for patients. The opportunities that have been identified to minimise NHP use have the potential to reduce the number and length of preclinical studies, minimise costs and allow mAbs to enter clinical trials earlier.

TRANSLATING NEW TECHNOLOGIES

One emerging area with the potential to revolutionise drug development and reduce animal use is tissue engineering. The ability to engineer and manipulate a range of human tissues in vitro holds great promise in providing new therapies in areas of unmet medical need. The properties that make the clinical prospect of tissue engineering so exciting can also be exploited to provide novel disease models, screening tools and safety testing paradigms that are more relevant to human biology than can be afforded by some animal models. The potential of tissue engineering to replace animal use has recently been demonstrated by the regulatory acceptance of the human epidermis models for skin irritation testing within the EU (12). To integrate tissue engineering models into the drug development pathway, it is essential that those involved in developing the models understand the specific requirements of industry and are able to tailor their products accordingly. Collaboration between industry and academia is therefore essential.

WHOLE ANIMAL BIOLOGY

Many preclinical studies, such as those for systemic toxicity, are dependent on the integrated whole animal system. Nevertheless, there are opportunities for applying the three Rs and considering how the use of animals could be minimised; nausea and emesis have been used as a test case. Nausea and emesis are complex reactions mediated through neural and endocrine pathways involving multiple target organs and tissues. They are some of the most common side effects encountered in medicine, either as symptoms of disease or as side effects of treatment. Assessing the emetic liability of new compounds in all therapeutic areas is an important aspect of the drug development process; nausea and emesis are second only to abuse potential in their impact on the preclinical development of new drugs, with the observation of these side effects potentially triggering additional in vivo studies to investigate safety. Being highly aversive, nausea and vomiting can also compromise patient compliance.

It is hard to envisage how any multisystem reflex could be studied without in vivo models. However, the use of animals for nausea and emesis is complex; rodents, which are commonly used in the drug development process, do not have an emetic reflex and therefore emetic liability has to be inferred through surrogate tests such as taste aversion and the ingestion of non-nutritive material (termed pica); different animals have different sensitivities to known emetogens in humans making preclinical species selection difficult; and assessing the subjective sensation of nausea in animals is inherently problematic.

A new hypothetical paradigm for assessing emetic liability has been developed which increases the use of in silico predictive modelling, cell and tissue culture systems, and lower organisms such as caenorhabditis elegans and dictyostelium (see Figure 1) (15). This approach integrates structure activity relationships, activation of pathways known to mediate nausea and emesis and the aversion behaviour of lower species with molecular parallels to emesis in mammals. A range of research programmes are currently being supported to explore the feasibility of this approach in practice. This has the potential to reduce attrition due to nausea and emesis in the most costly, late stages of drug development and the use of animals.

REDUNDANCY IN THE DRUG DEVELOPMENT PROCESS

Approaches which exploit new science and technology will underpin a revolution in the drug development process providing better model systems. Nevertheless, progress can also be made by reviewing and re-evaluating the scientific objective of studies that have historically been part of the preclinical package and determining whether the information provided continues to be of value in the assessment of human safety.

A collaboration involving 18 European pharmaceutical companies and CROs has challenged the value of single dose acute toxicity studies in drug development – the only test in pharmaceutical development where the death of the animal is an endpoint. Based on a retrospective analysis of over 70 compounds, it has been demonstrated that single dose acute toxicity studies have little value in assessing risk to humans and informing future preclinical studies (16-17). As a direct consequence of this analysis, the requirement for these studies prior to first-in-man clinical trials was removed from the regulatory guidance, ICH M3, in 2009. This work has implications for other sectors, including the chemical industry, where opportunities to waive acute toxicity tests have also been identified (18).

THE THREE Rs AS A BLUEPRINT FOR PRECLINICAL DEVELOPMENT

The examples described in this paper provide a snapshot of the role that the three Rs can play in providing a framework for the challenges facing the pharmaceutical industry. Increasingly, innovators in industry are embracing the challenge to accelerate the development of improved non-animal models and refined animal models, increasing the breadth and usefulness of the drug development toolbox. Further work is necessary to ensure that a modernised drug development pathway is flexible enough to incorporate all the novel ideas and approaches and that their potential for enhanced drug development and the three Rs is realised.

The 3 Rs - Replacement, Reduction, Refinement

Replacement refers to methods that avoid or replace the use of animals defined as ‘protected’ under the Animals (Scientific Procedures) Act 1986.

Reduction refers to methods that minimise animal use and enable researchers to obtain comparable levels of information from fewer animals, or to obtain more information from the same number of animals, thereby reducing future use of animals.

Refinement refers to improvements to husbandry and procedures that minimise pain, suffering, distress or lasting harm, or improve animal welfare.

A blueprint for preclinical research that reduces the reliance on animal use is dependent on:

  • An open environment where there is a willingness to review the value of the current models
  • Increased data access and sharing to identify and evaluate further opportunities, particularly in contentious areas
  • Imaginative approaches for incorporation of novel methods in preclinical development
  • New benchmarking strategies to assess whether alternative approaches are suitable to address current research needs
  • Engagement of academic scientists from a range of disciplines with a better understanding of the challenges facing industry
  • Active involvement of regulators with awareness of the latest technologies
  • Commitment of industry and regulators to science-based decisions on the necessity and interpretation of in vivo experiments

Implementation of such a blueprint will require continued commitment from the industry, but there are compelling incentives to embrace the challenge. Here exists an opportunity to streamline drug development that we cannot afford to overlook.

References

  1. Munos B, Lessons from 60 years of pharmaceutical innovation, Nature Reviews Drug Discovery 8: pp959- 968, 2009
  2. Kola I and Landis J, Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 3: pp711-716, 2004
  3. US Food and Drug Administration, The Critical Path Initiative, www.fda.gov/ScienceResearch/Special Topics/CriticalPathInitiative/default.htm
  4. The Innovative Medicines Initiative Research Agenda, www.imi.europa.eu/ sra_en.html
  5. UK Home Office. Statistics of Scientific Procedures on Living Animals Great Britain, 2008 www.homeoffice.gov.uk/rds/pdfs09/s panimals08.pdf
  6. Barker R, A flexible blueprint for the future of drug development, The Lancet 375: pp357-359, 2010
  7. Revision of Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes (ec.europa.eu/ environment/chemicals/lab_animals/ revision_en.htm
  8. The need for non-human primates in biomedical research, production and testing of products and devices, Scientific Committee on Health and Environmental Risks (2009) www.ec.europa.eu/environment/chemi cals/lab_animals/pdf/scher_o_110.pdf
  9. Chapman K, Pullen N, Graham M and Ragan I, Preclinical safety testing of monoclonal antibodies: the significance of species relevance, Nature Reviews Drug Discovery 6: pp120-126, 2007
  10. Chapman K, Pullen N, Coney L, Dempster M, Andrews L, Bajramovic J, Baldrick P, Buckley L, Jacobs A, Hale G, Green C, Ragan I and Robinson V, Preclinical development of monoclonal antibodies: considerations for the use of non-human primates, mAbs 1: pp500-511, 2009
  11. Chapman K, Pullen N, Andrews L and Ragan I, The future of non-human primate use in mAb development, Drug Discovery Today (in press, 2010)
  12. EC (2009) Commission Regulation (EC) No 761/2009 of 23 July 2009 amending, for the purpose of its adaptation to technical progress, Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
  13. Holmes AM, Judd JA, Tattersall FD, Aziz Q and Andrews P, Opportunities for the replacement of animals in the study of nausea and vomiting, British Journal of Pharmacology 157: pp865-880, 2009
  14. Robinson S, Delongeas J, Donald E, Dreher D, Festag M, Kervyn S, Lampo A, Nahas K, Nogues V, Ockert D, Quinn K, Old S, Pickersgill N, Somers K, Stark C, Stei P, Waterson L and Chapman K, European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development, Regulatory Toxicology and Pharmacology 50: pp345-352, 2007
  15. Robinson S and Chapman K, Are acute toxicity studies required to support overdose for new medicines? Regulatory Toxicology and Pharmacology 55: pp110, 2009
  16. Creton S, Dewhurst IC, Earl LK, Grehen SC, Guest R, Hotchkiss JA, Indans I, Woolhiser M and Billington R, Acute toxicity of chemicals: opportunities to avoid redundant testing and use alternative approaches, Critical Reviews in Toxicology 40: pp50-83, 2010

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer

Kathryn Chapman is responsible for the NC3Rs programmes of work that engage with the pharmaceutical and regulatory communities, she also leads the NC3Rs Innovation and Translation Group. Kathryn holds a PhD in molecular biology from the University of Manchester. Before joining the NC3Rs, Kathryn carried out research at Harvard Medical School, the Wellcome Trust Sanger Centre, GlaxoSmithKline.

Vicky Robinson is Chief Executive of the NC3Rs. She holds a PhD in Developmental Biology from the Imperial Cancer Research Fund, London. Vicky was a post-doctoral researcher at the Medical Research Council’s (MRC) National Institute for Medical Research before taking up a position as a Senior Scientific Officer in the Research Animals Department at the RSPCA. Prior to the establishment of the NC3Rs, Vicky was head of the MRC’s Centre for Best Practice for Animals in Research.

spacer
Kathryn Chapman
spacer
spacer
spacer
Vicky Robinson
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

Introducing Signant Health [Formerly CRF Bracket] and the Industry’s Most Comprehensive Patient-Centric Suite for Clinical Research

Philadelphia and London – June 10, 2019: CRF Bracket, formed by the 2018 merger of CRF Health and Bracket, today launched as Signant Health (signanthealth.com). Uniting eCOA, eConsent, Patient Engagement, IRT, Clinical Supplies and Endpoint Quality into the industry’s most comprehensive patient-centric suite, Signant makes it easier to participate in – and sites and study teams to run – clinical trials. This intense focus on the patient experience, deep therapeutic area expertise and global operational scale enable sponsors and CROs to extend the reach of drug development, expand patient opportunities and improve data quality.
More info >>

White Papers

Key to Outsourcing Method Development and Validation A Pragmatic Approach

RSSL

In an industry that is seeing an increasing level of work being outsourced, the Contract Research Organisation (CRO) of choice needs to have proven experience in both the pragmatism and flexibility of the method developer’s mind set and a regulatory background in validation.
More info >>

 
Industry Events

SAPHEX 2019

23-24 October 2019, GALLAGHER CONVENTION CENTRE, 10 RICHARDS DRIVE, HALFWAY HOUSE, MIDRAND, 1685, SOUTH AFRICA

SAPHEX 2019 will be held on the 23rd-24th October at the Gallagher Convention Centre, Johannesburg, South Africa.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement