Supporting innovation through Scientific AdvicePEARRL 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

3

Why get Scientific Advice?

Regulatory Comfort Zone: Hard Law: Directives and Regulations

Soft Law: Guidelines and Q&As

Scientific Advice outside comfort zonepresented at the PEARRL Regulatory symposium 2017 – for personal use only

4

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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

5

Why Scientific Advice?Enhance Probability of approval

Nature, (2015), 14, 302

presented at the PEARRL Regulatory symposium 2017 – for personal use only

6

Why Scientific Advice?Enhance time to approval

presented at the PEARRL Regulatory symposium 2017 – for personal use only

7

Why Scientific Advice?Well-Established (since about 2003)

MHRA: about 250/year

presented at the PEARRL Regulatory symposium 2017 – for personal use only

8

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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

9

Scientific advice - questions

Specific questions about issues with any aspect of the development programmeCan 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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

10

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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

11

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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

12

Scientific 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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

13

Quality: A risk based, innovative approach to the approval of "generic" topical products, without TE studyCurrent 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 solutionAND Qualitatively and Quantitatively similarAND Relevant pharmaceutical properties similarAND Same method and means of administration

presented at the PEARRL Regulatory symposium 2017 – for personal use only

14

Two Scientific Advice MeetingsAgreement that:Demonstration of pharmaceuticalequivalence with respect toqualitative, quantitativeand physicochemical properties

And

Series of in vivo andin vitro studies, including PD studies, Might be sufficient to predict therapeutic equivalence.

presented at the PEARRL Regulatory symposium 2017 – for personal use only

15

What happened?

presented at the PEARRL Regulatory symposium 2017 – for personal use only

16

Scientific Advice: Taking Forward

presented at the PEARRL Regulatory symposium 2017 – for personal use only

17

Microneedles: New Pharmaceutical FormDrug delivery by physical breech of S.C.’s effective barrierPromise of a new painless route of administration for large MW biologicals and chemicals; Single dose presentation;Avoids sharps injuries; Possible improved supply chainTrigger of and access to dermal immunological system –vaccinesBUT: Need potent drugs and / or high loading Challenges:New technology; New formulations; New Manufacturing.What else is being delivered?

presented at the PEARRL Regulatory symposium 2017 – for personal use only

18

How to characterise the Pharmaceutical form?Intradermal Injection

Aqueous solution for Inj. into dermisImmediate release: local / systemic actionPreferable visual inspection before useSterileParticle FreeContainer IntegrityUniformity of dosage units / contentMean content Normally: 95-105%EndotoxinsRequires small needleAdministration confirmed by inspectionStrength: Concentration

Transdermal Patch

Flexible adhesive preparation applied to skinProlonged Release: systemic effect after passing skin barrierBacking Layer and Release Liner definedFormulation Type: Matrix or reservoir Apply to clean unbroken skin, gentle pressureNon-SterileRemoval does not cause injury or detachmentNon irritant, non-sensitisingUniformity of dosage units / content Mean content Normally: 95-105% (but 2.9.6: 90-110%).In vitro testing DissolutionAdministration confirmed by inspectionStrength: Dose released per timeTotal quantity of active in patch is declared.

Beyond the comfort zone

presented at the PEARRL Regulatory symposium 2017 – for personal use only

19

Many different typesGreat 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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

20

Microbiological risks

Currently used in cosmetic sectors

presented at the PEARRL Regulatory symposium 2017 – for personal use only

21

Some 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

stage in a project are now seen as naïve and outdated.”presented at the PEARRL Regulatory symposium 2017 – for personal use only

22

Scientific 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

presented at the PEARRL Regulatory symposium 2017 – for personal use only

23

Websites:

MHRA: https://www.gov.uk/medicines-get-scientific-advice-from-mhraHPRA:https://www.hpra.ie/homepage/medicines/regulatory-information/national-scientific-and-regulatory-adviceBfarm:http://www.bfarm.de/EN/BfArM/Org/Advice_Procedures/_node.htmlEMA:http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004089.pdf

23

presented at the PEARRL Regulatory symposium 2017 – for personal use only