Supporting innovation through Scientific Advice - PEARRL Regulatory Science Symposium, 21st June 2017, University College Cork, Ireland.
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Supporting innovation through
Scientific Advice
PEARRL Regulatory Science Symposium,
21st June 2017, University College Cork, Ireland .
Sean Jones – Quality Assessor, MHRA
presented at the PEARRL Regulatory symposium 2017 – for personal use only
Why get Scientific Advice?
Regulatory Comfort Zone: Hard Law: Directives and Regulations
Soft Law: Guidelines and Q&As
3 Scientific Advice outside comfort zone
presented at the PEARRL Regulatory symposium 2017 – for personal use only
Why get Scientific Advice?
There is always more than one way to reach an objective.
Scientific Advice can help you choose the optimal route.
Making our regulation more supportive of safe innovation
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
Why Scientific Advice?
Enhance Probability of approval
Nature, (2015), 14, 302
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
Why Scientific Advice?
Enhance time to approval
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
Why Scientific Advice?
Well-Established (since about 2003)
MHRA: about 250/year
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
Scientific Advice: What?
EMA Legal Basis: Regulation 726/2004 Article 57-1 (n):
• Advising undertakings on the conduct of the various tests
and trials necessary to demonstrate the quality, safety and
efficacy of medicinal products.
NCA Legal Basis: No hard law
• Consists of questions, which are ordered to address
specific scientific issues (order: quality/biotech/pre-
clinical/clinical issues/significant benefit).
• Each question is followed by the company’s position and
justification(s).
• EMA and NCA: Final advice is non-binding to either party
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
Scientific advice - questions
Specific questions about issues with any aspect
of the development programme
Can discuss just one (e.g. non-clinical question)
or many issues that relate to different parts of a
submission (e.g. non-clinical, quality, clinical, statistical,
pharmacokinetics, risk management plan)
Vague questions
‘Is the programme adequate to obtain a licence’?
If the Company has received CHMP scientific advice,
asking the same questions to the NCA is not appropriate
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
What questions?
Questions may address specific scientific issues, such as:
• Quality: e.g. the chemical, pharmaceutical and
biological testing necessary to demonstrate the quality
of a medicinal product)
• Non-clinical: e.g. the toxicological and pharmacological
testing necessary to demonstrate the safety of a
medicinal product
• Clinical: e.g. endpoints, trial duration, target population,
choice of comparator
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presented at the PEARRL Regulatory symposium 2017 – for personal use only
What questions?
Also:
• Regulatory issues related to the product
• Proposed variation applications
• POM to P reclassifications
• Pharmacovigilance plans and post-authorisation safety
study protocols
• Changes to labelling of packaging leaflets for medicinal
products or a product range
• Advertising material for medicinal products
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyScientific Advice: What happens?
NCA: Generally Informal Face to Face meetings
• Company submits briefing - outlining product
development, results to date, and specific questions
• Regulatory Team put together (2 – 6 people) and review
the briefing and questions prior to meeting
• SA Meeting, usually about 90 minutes, within 6 weeks
• Company provides minutes of the meeting
• Draft SA Letter reviewed, and if necessary revised
• Formal SA Letter Issued
• EMA: Formal SA Letter only
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyQuality: A risk based, innovative approach to the
approval of "generic" topical products, without TE study
Current LALA Guideline:
Default: To demonstrate therapeutic equivalence clinical trials are in
principle necessary
Possible: PD studies, local availability studies, in vitro studies???
Current Bioequivalence Guideline:
Biowaiver for solutions, e.g. eye drops, nasal sprays or cutaneous
solutions
IF Test and reference same type of solution
AND Qualitatively and Quantitatively similar
AND Relevant pharmaceutical properties similar
AND Same method and means of administration
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyTwo Scientific Advice Meetings
Agreement that:
Demonstration of pharmaceutical
equivalence with respect to
qualitative, quantitative
and physicochemical properties
And
Series of in vivo and
in vitro studies, including PD studies,
Might be sufficient to predict therapeutic equivalence.
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyWhat happened?
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyScientific Advice: Taking Forward
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyMicroneedles: New Pharmaceutical Form
Drug delivery by physical breech of S.C.’s effective barrier
Promise of a new painless route of administration for large
MW biologicals and chemicals; Single dose presentation;
Avoids sharps injuries; Possible improved supply chain
Trigger of and access to dermal immunological system –
vaccines
BUT:
Need potent drugs and / or high loading
Challenges:
New technology; New formulations; New Manufacturing.
What else is being delivered?
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyBeyond the comfort zone
How to characterise the Pharmaceutical form?
Intradermal Injection Transdermal Patch
Aqueous solution for Inj. into dermis Flexible adhesive preparation applied to skin
Immediate release: local / systemic action Prolonged Release: systemic effect after passing skin
Preferable visual inspection before use barrier
Sterile Backing Layer and Release Liner defined
Particle Free Formulation Type: Matrix or reservoir
Container Integrity Apply to clean unbroken skin, gentle pressure
Uniformity of dosage units / content Non-Sterile
Mean content Normally: 95-105% Removal does not cause injury or detachment
Endotoxins Non irritant, non-sensitising
Requires small needle Uniformity of dosage units / content
Administration confirmed by inspection Mean content Normally: 95-105% (but 2.9.6: 90-110%).
Strength: Concentration In vitro testing Dissolution
Administration confirmed by inspection
Strength: Dose released per time
Total quantity of active in patch is declared.
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyMany different types
Great diversity different pros and cons
Materials: Metal; Silicon; Polymers;
Design: Needle length, shape, density
Dissolving / swelling MN – Polymers
accumulation?
Hollow MN – requires pumps
Immediate/Prolonged Release??
Administration Time?
Posology? Acute / chronic?
Heaf Test and Tine Test
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyMicrobiological risks
Currently used in cosmetic sectors
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlySome issues
• Patient focus:
• Site, period of administration, skin care.
• Usability, Minimised Administration Error, Robust. Disposal.
• Training, Clear Instructions qualified by studies.
• Cross contamination with re-use administration device?
• Quality with respect to safety
• Precautionary Principle: Sterile but
• Control of impurities, particles, foreign bodies
• Residues – what remains in the skin
• Excipients – safety profile
“The opportunity to discuss the regulatory hurdles with the
Competent Authority and to integrate the advice given into the
subsequent research programme was invaluable”
“The idea that discussions with the Competent Authority are for
industry alone and should be delayed until the latest possible
21 stage in a project are now seen as naïve and outdated.”
presented at the PEARRL Regulatory symposium 2017 – for personal use onlyScientific Advice Summary
• Well Established
• More probable and faster approval
• Expanding in scope and depth
• An important component to enhancing the pharmaceutical
regulatory environment for industry, enabling innovation and
faster access to medicines
• Stimulus to Notes for Guidance
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presented at the PEARRL Regulatory symposium 2017 – for personal use onlyWebsites:
MHRA:
https://www.gov.uk/medicines-get-scientific-advice-from-mhra
HPRA:
https://www.hpra.ie/homepage/medicines/regulatory-
information/national-scientific-and-regulatory-advice
Bfarm:
http://www.bfarm.de/EN/BfArM/Org/Advice_Procedures/_node.
html
EMA:
http://www.ema.europa.eu/docs/en_GB/document_library/Regul
atory_and_procedural_guideline/2009/10/WC500004089.pdf
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