master class regulatory affairs

Master class Regulatory Affairs

22-April-2021

Alex Zwiers

Intro to Zwiers

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Founded in 2011 – now 30 employees - >40 clients

Pharma – medical devices - biocides – cosmetics- borderline products

Pharma, regulatory affairs – from patent to submission to end of life cycle

Medical devices - from ISO 13485 to complete technical file

Other activities

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PublishingSubmissions of electronic dossiers (e-IND, e-CTDs)

(pharmaco)vigilanceQPPV/ PV systems/ audits

Training: Several training modules

Spin-off regulatory science

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A Decade of Marketing Authorization Applications of Anticancer Drugs in the European Union: An Analysis of Procedural Timelines Marjolein Garsen, Maaike Steenhof & Alex Zwiers

Therapeutic Innovation & Regulatory Science (2021)

Implementation of Quality by Design (QbD) Principles in Regulatory Dossiers of Medicinal Products in the European Union (EU) Between 2014 and 2019. Ter Horst JP1, Turimella SL1, Metsers F1, Zwiers A1 Therapeutic Innovation & Regulatory Science, 13 Jan 2021, 55(3):583-590

What can you expect?

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Medicinal products: to merge the basic concepts with typical examples and supplemented by our regulatory science projectsIn order to prevent

What can you not expect

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Today no information on medical devices, becauseHowever, should you have questions: contact us at: alex.zwiers@az-regulatory.com

Agenda:

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3 important questions Two examples

Important questions

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When we start to work on a project we want to know:

What is your product?What is the legal basis?Which regulatory procedure?

Why should you also know the answers to these questions very early?

Question 1: What is your product?

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• Legal definitions : Medicinal product vs medical device vs cosmetic/ food or borderline / combination product

• Claims & dosage Medicinal product vs food

Medicinal substanceAny substance or combination of substancespresented as having properties for treating orpreventing diseases in human beings;orAny substance or combination of substanceswhich may be used in or administered tohuman beings either with a view to restoring,correcting or modifying physiologicalfunctions by exerting a pharmacological,immunological or metabolic action, or tomaking a medicinal diagnosis.

MPD 2001/83/EC

Medicinal substance

• Pharmacological,• Immunological or• metabolic action

Question 1: What is your product?

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• Legal classificationsSome products are classified per law

• Pharmaceutical classificationATC – which group?

How well do you know your own product?

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Product for neuropathic pain: what is the indication?post-herpetic neuralgia painful diabetic neuropathyBack painTreatment of neuropathic painTreatment and prevention of neuropathic pain?

How well do you know your own product

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Important tool to know your product

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Very useful documentNot mandatory, can be included in the pre-INDOther formats are OKForces you to think about the end (labeling)

What if you still do not know it?

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Seek scientific advice:EMA – interesting with SME statusIndividual health authorities: CBG, MPA, BfArM, MHRA E.g. CBG – ‘advies op maat’ (repurposing)Take care that you have generated essential data!

Our regulatory science: Garsen et al., 2021

Scientific advice links

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CBG:https://www.cbg-meb.nl/onderwerpen/hv-wetenschappelijk-en-regulatoir-adviesEMA:https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-advice-protocol-assistance

The application form for scientific advice of the CBG

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What is the legal basis? (which article applies?)

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Art. 8.3 Stand-alone / full dossier Art. 10.1 Generic Art. 10.3 Hybrid Art. 10.4 Similar biological Art. 10 (a) Well-established use Art. 10 (b) Fixed combination

What are the regulatory procedures?

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Why is it important to know which regulatory procedure you could or should follow?

FeesTimelinesStrategyDifferent parties to interact

Centralised Procedure - CP

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CP

Single submission to EMA

Approval by European Commision

Valid in the entire EU territory

Optional: New Active SubstanceMandatory: Biotech products, ATMPs,

certain therapeutics classes (oncology), and orphan products

210 days (+ clockstops)All EU Member

StatesAccelerated to 150 days

Regulatory toolbox

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Early market access

less data

fastermore input

Conditional approvalExceptional circumstancesAccelerated assessmentPRIME

Regulatory toolboxConditional approval: Medicines that fulfil an unmet medical need;The benefit of immediate availability for patients is greater than the risk of less comprehensive data than normally required;The authorization is valid for1 year and will be renewed every year.

Exceptional circumstances: The company is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the condition to be treated is rare or because collection of full information is not possible or is unethical

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Regulatory toolboxAccelerated assessment:Applications may be eligible for accelerated assessment if the CHMP decides the product is of major interest for public health and therapeutic innovation.

PRIME (PRIority MEdicnes):This voluntary scheme is based on enhanced interaction and early dialogue with developers of promising medicines, to optimise development plans and speed up evaluation so these medicines can reach patients earlier.The scheme focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. These medicines are considered priority medicines by EMA.

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COVID-19 vaccines, regulatory tools

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Scientific advice (free)COVID-19 pandemic task forceAdditional resourcesQuicker manufacturing site approval Rolling reviewAccelerated assessment (<150d)Conditional approvalLarge scale safety monitoring

Source: EMA website: covid-19-vaccines-development-evaluation-approval-monitoring

CHMP opinion between January 2010 and December 2019 , n= 96

EMA orphan designation/ expedited program %

Accelerated assessment (AA) 14 (15%)

Conditional marketing authorization (CMA) 23 (24%)

Orphan designation (OD) 40 (42%)

Priority medicine (PRIME) 3 (3%)

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CHMP opinion between January 2010 and December 2019 , n= 96

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EMA orphan designation/ expedited program %

AA & CMA 3 (3%)

AA & PRIME 0 (0%)

CMA & PRIME 1 (1%)

Expedited program (AA, CMA & PRIME) 34 (35%)

No expedited program (AA, CMA & PRIME) 62 (65%)

OD/ no expedited program (AA, CMA & PRIME) 27 (28%)

No OD/ no expedited program (AA, CMA & PRIME) 38 (40%)

Figures for Centralised procedure

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Source: https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines/medicine-evaluation-figures#annual-medicines-highlights-(2015-2020)-section

Mutual Recognition Procedure – MRP Decentralised Procedure - DCP

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One or more EU Member States

MRP

Sequential approach: national procedure →Reference MS followed by Concerned MS

Where the medicinal product has already received in a MS a MA at the time of

application

90 days + 30 days (national phase)

DCP

Parallel submission to RMS and CMS

210 days + 30 days (national phase)

MRP or DCP - Statistics of finalised MRP/DCP

MRP188 Generic42 Hybrid

DCP744 Generic133 Hybrid

How can this old drug be approved via the CP?

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Via the CP = ??Nationally approved = generic

We talked about:

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Accelerated approvalConditional approvalRepurposing(bio) genericsHybridsPRIME

TPPOrphan drugsCP/ DCP/ MRP/nationalLegal basisScientific adviceExceptional circumstances

Let’s not forget the content!

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Common Technical Document:An agreed-upon common format for the “modular” presentation of summaries, reports and dataIncorporates relevant ICH guidelinesElectronic CTD

Two examples:

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Old drug new formulationOncology product

Oncology product

Impact of regulatory status on time to approvalEffect of company size on outcome

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Impact of orphan / conditional or accelerated review on approval?

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Effect of company size on succes?

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Old drug with new formulation

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Which legal basis: hybrid or full application (based on own studies and literature)?Do we need to do a clinical study ? Maybe one only?Toxicology studies for a product of more than 30 years old?

Which legal basis?

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Has impact on:Data requirementPediatric studiesData exclusivityYes/no reference required....

Legal basis

Article 8(3) Full(-mixed) application

Article 10(1) Generic application

Article 10(3) Hybrid application

Article 10(4) Biosimilar application

Article 10a Well-established use application

Article 10b Fixed combination application

Article 10c Informed consent application

Which legal basis?

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Full mixed application: combination of your own studies + literature. Hybrid application – you refer to another product, but no need to be bioequivalent (is not a generic). Strategy is to bridge and do studies and try to cover the difference.

Do we need to do a clinical study ?

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Regulatory science project

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40 MAAs for repurposed drugs using article 8(3) full-mixed dossier• 28 new formulation • 7 new indication • 5 both new formulation and new indication

Period covered: 2000-2017

New formulation, clinical (33 MAA)

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% applicants performing own clinical studies

# own studies # pivotal studies

Pharmacokinetics 79% 1-15 NA

Pharmacodynamics 21% 1-8 NA

Safety/efficacy 100% 1-7 (average 1-3) 1-2

93% of the applicants used data from the literatureAll applicants performed at least one clinical study

Toxicology studies needed?

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Toxicology studies needed?

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Required Normally not

necessary

Pharmacology

X

Pharmacokinetics

X

Single/repeat dose toxicity (including local tolerance)

X

Reproductive toxicity X1

Genotoxicity X

Carcinogenicity

X

New formulation, preclinical (33 MAA)

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All applicants used data from the literature

91% of applicants performed at least one preclinical study

% applicants performing own preclinical studies

Guideline non-clinical studies full-mixed MAA

Pharmacology 42% Normally not necessary

Pharmacokinetics 53% Normally not necessary

Single/repeat dose toxicity (including local tolerance)

82% Normally not necessary

Reproductive toxicity 23% Required

Genotoxicity 39% Required

Carcinogenicity 10% Normally not necessary

Links to guidelines

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ICH E1: https://database.ich.org/sites/default/files/E1_Guideline.pdf

ICH S6: https://www.ema.europa.eu/en/ich-s6-r1-preclinical-safety-evaluation-biotechnology-derived-pharmaceuticals

ICH S9: https://www.ema.europa.eu/en/ich-s9-non-clinical-evaluation-anticancer-pharmaceuticalshttps://www.ema.europa.eu/en/non-clinical-documentation-mixed-marketing-authorisation-applications

Publication Garsen et al: A Decade of Marketing Authorization Applications of Anticancer Drugs in the European Union: An Analysis of Procedural Timelines: https://pubmed.ncbi.nlm.nih.gov/33543409/

Thank you for your attention!

www.az-regulatory.com

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