application of non-animal approaches for decision- making .... jones, david#5.pdf · the mhra...
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NC3Rs December 2018
Application of Non-animal Approaches for Decision-making in Chemical Safety Assessment – A
Regulatory Viewpoint
David R JonesExpert Pharmaco-Toxicologist
MHRAwww.mhra.gov.uk
NC3Rs December 2018
ANY OPINIONS EXPRESSED IN THIS PRESENTATION
ARE MY OWN,
ARE NOT NECESSARILY SHARED BY OTHER
ASSESSORS AT THE MHRA,
AND CAN NOT BE CONSIDERED TO BE UK POLICY
NC3Rs December 2018
ANY OPINIONS EXPRESSED IN THIS PRESENTATION
ARE ALSO NOT NECESSARILY SHARED BY OTHER
ASSESSORS FROM THE SWP,
AND CAN NOT BE CONSIDERED TO BE EU POLICY
NC3Rs December 2018
CROWN COPYRIGHT 2018
The materials featured within this MHRA presentation are subject to Crown copyright protection for this event. Any other copy or use of Crown copyright materials features in this presentation, in any form or medium, is subject to prior approval of the MHRA which has Delegated Authority from Her Majesty’s Stationery Office (HMSO) to administer Crown copyright for MHRA originated material. Applications should be in writing, clearly stating the proposed use / reuse of the information, and should be sent to the MHRA at the following address: Conference and Education Function, MHRA, 10 South Colonnade, Canary Wharf, London, E14 4PU or e-mail [email protected]. You may not sell or resell any information reproduced to any third party without prior agreement. The permission to reproduce Crown copyright material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyholders concerned.
NC3Rs December 2018
Medicines and Healthcare products Regulatory Agency (MHRA)
An executive agency of the Department of Health
NC3Rs December 2018
Medicines and Healthcare products Regulatory Agency (MHRA)An executive agency of the UK Department of Health
The agency has 3 centres:•the Clinical Practice Research Datalink (CPRD), a data research service that aims to improve public health by using anonymised NHS clinical data•the National Institute for Biological Standards and Control (NIBSC), a global leader in the standardisation and control of biological medicines•the Medicines and Healthcare products Regulatory Agency (MHRA)
NC3Rs December 2018
The MHRA:
Regulates the safety, quality, effectiveness & performance of medicines and medical devices for the UK.
Employs over 1200 people.
Is largely funded by fee income from provision of services to industry.
Runs scientific committees which advise Ministers on safety of devices and medicines.
Is mainly based in Central London.
NC3Rs December 2018
The MHRA is responsible for:Ensuring that medicines, medical devices and blood components for transfusion meet applicable standards of safety, quality and efficacy.
Ensuring that the supply chain for medicines, medical devices and blood components is safe and secure.
Promoting international standardisation and harmonisation to assure the effectiveness and safety of biological medicines.
Helping to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices and blood components, leading to safer and more effective use.
Supporting innovation and research and development that’s beneficial to public health.
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• The MHRA Toxicologists evaluate non-clinical data submitted in support of applications for product licenses or clinical trials
• The UK Good Laboratory Practice monitoring unit is part of the MHRA and is involved in the inspection of GLP compliance
The Role of Toxicologists at the MHRA
NC3Rs December 2018
• The MHRA has the protection of humans and their environment as its Primary Duty
• The MHRA believes that some animal use will remain necessary for Safety Evaluation purposes for the foreseeable future.
• The MHRA is committed to the principles in line with the Animals (Scientific Procedures) Act of 1986
The Role of Toxicologists at the MHRA
NC3Rs December 2018
NC3Rs December 2018
The MHRA fully supports the NC3Rs. MHRA staff attend the workshops and contribute to many projects.
The MHRA has direct and indirect links with other organisations working in the field of predictive toxicology.
The MHRA welcomes discussions with parties seeking to improve drug development/drug safety procedures.
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Regulatory Guidelines
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MHRA
EMA (Now)
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MHRA
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Regulatory guidelines are like the modern map of the London Underground.
They don’t completely represent the “real” world.
There’s almost always more than one way to reach an objective and the recommended route might not be the one you should follow!
NC3Rs December 2018
Samuel Johnson said “Patriotism is the last refuge of the scoundrel.”
I say “Rigorously following Regulatory Guidelines is the last refuge of those who don’t know how to develop medicines!!.”
NEVER FOLLOW A REGULATORY GUIDELINE IF THERE IS A GOOD SCIENTIFIC RATIONALE NOT TO!!!
NC3Rs December 2018
The development of a pharmaceutical is a stepwise process involving an evaluation of both animal and human efficacy and safety information.
As a general matter, nonclinical studies are a necessary part of drug development for both rare and common diseases.
Nonclinical studies can contribute to a better understanding of the drug’s mechanism of action.
NC3Rs December 2018
The data generated from nonclinical studies are important,particularly to the design of the early stage clinical trials with respect to selecting the starting clinical dose level, dose escalation plan, dosing regimen, and route of administration.
The nonclinical data may help guide patient eligibility criteria and will often determine some important safety monitoring procedures.
BUT Nonclinical Does Not Necessarily mean Animal.
Non-animal approaches in drug development are not just possible, but are recommended in many cases.
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The value of non-animal models in nonclinical proof of concept studies is well established for all types of Medicinal Products, especially ATMPs.
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In accordance with Directive 2010/63/EU, the principle of the 3Rs (Replacement, Reduction and Refinement) needs to be considered when selecting testing approaches to be used for regulatory testing of human and veterinary medicinal products.
This guideline aims to encourage stakeholders and authorities to initiate, support and accept development and use of 3Rs testing approaches.
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NC3Rs December 2018
This report summarises the discussions at the Scientific Conference on “Non-Animal Approaches – The Way Forward” held in Brussels, Belgium on 6-7 December, 2016.
The European Commission organised the Scientific Conference to engage the scientific community and relevant stakeholders in a debate on how to exploit cutting edge advances in biomedical and other research in the development of scientifically valid non-animal approaches (alternatives to animal testing).
NC3Rs December 2018
There is a clear need for better, more predictive and better validated non-clinical models of disease and efficacy.
Alternatives are integral part of drug Discovery and Development.
Replacement HAS TO BE SCIENCE and technology driven.
Legislation cannot make it happen. Political deadlines do not make sense if the SCIENCE solutions are lacking. We must avoid actions which might simply drive work abroad to countries where lower standards or less stringent testing guidelines apply.
NC3Rs December 2018
However, it will make the task much easier if Regulatory Authorities are involved as early as possible in any validation exercises.
The MHRA and other Regulatory Authorities are content to allow companies to develop assays under a “safe harbour” approach.
The MHRA and other EU Regulatory Authorities are willing to participate in SCIENCE driven projects with defined aims. We, as Regulators, do not want these projects to take years. We want alternatives as soon as possible!!
NC3Rs December 2018
The challenge to academia, industry and regulatory scientists is to remain focused on designing nonclinical studies in relevant models, including non-animal models, to answer specific questions in time to support clinical decision making and communication of potential risks.
Maintaining effective dialogue among scientists in academia, industry and Regulatory Agencies during model development, qualification and validation will be essential to address this challenge.
NC3Rs December 2018
We have recently written to a number of pharmaceutical companies openly criticising their un-warranted use of animal studies that do not add any appreciable value to the determination of the potential safety of an IMP.
Animal studies should only be conducted to evaluate safety concerns that cannot be adequately addressed in other nonclinical studies.
Conducting animal studies to provide “a comfort factor” before exposing humans is totally unacceptable.
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Problem Areas and How to Resolve Them
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Scientific Advice!!
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Risk comes from not knowing what you’re doing!
Warren Buffett
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The MHRA has, for many years, provided scientific and regulatory advice to sponsors.
Scientific advice can be requested during any stage of the initial development of the medicinal product (before submission of a marketing authorisation application), and also during the pre-submission period for a variation to an existing marketing authorisation.
NC3Rs December 2018
The MHRA prefers to meet face-to-face with companies but in exceptional circumstances, video-conferencing may be arranged.
Telephone and tele-conference meetings are generally not considered satisfactory to discuss complex scientific and regulatory issues.
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The MHRA Licensing Division held about 450 Scientific Advice meetings with Companies in 2017.
The MHRA Clinical Trials Unit has held almost 130 meetings with companies, academic institutes or hospital groups over the last 12 months!
The CTU’s email helpline fields about 250 queries a month.
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Scientific advice can also be obtained from the CHMP.
The Scientific Advice Working Party (SAWP) has been established as a standing working party with the sole remit of providing Scientific Advice and Protocol Assistance to applicants.
It is the SAWP/CHMP responsibility to give Scientific Advice to industry by answering to questions based on the documentation provided by the company in the light of the current scientific knowledge.
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Take Home Message
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Gerhard Zbinden (a toxicologist even older than me!!) once said:Don’t do something just because you can.Don’t do something just because that’s the way you’ve always done it.Don’t do something because others do it.Don’t do something just because you think you’re expected to.Don’t do something to generate results you can’t interpret.
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AVOIDS THE DELUSION
THEY WANT TO LISTEN
TO YOU!
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Any Questions ?
Don’t be shy!
There’s no such thing as a silly question to a Regulator!
And I promise I won’t take note of your names!!
NC3Rs December 2018
Any Further Questions ?
Please Feel Free to Contact the MHRA If You Have Any Further Queries:
Telephone: 020 3080 6000Address: 10 South Colonnade, Canary Wharf
London E14 4PUHome Page: www.mhra.gov.uk