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07/02/2021

Registration of the Medicinal Component

Jason Collins, Director, ESPL Regulatory Consulting

The Organisation for Professionals in Regulatory Affairs

Learning Outcomes

 Understand the types of regulatory procedures available  Understand the different types of application  Overview of information included in regulatory submissions  Transferability of documentation for different markets

The Organisation for Professionals in Regulatory Affairs

07/02/2021

WHAT ARE THE MEDICINES REGULATIONS

 Basis for regulation of medicines in the EU • 2001/83/EC (as amended)  Definition of a medicine from 2001/83/EC: ● Medicinal product: ● (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; ● or ● (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

The Organisation for Professionals in Regulatory Affairs

Jargon Buster

 The medicinal substance is often referred to by a number of different terms:  Active ingredient  API – Active Pharmaceutical Ingredient

 Active Substance  Drug Substance

 NCE - New Chemical Entity  NME – New Molecular Entity

The Organisation for Professionals in Regulatory Affairs

07/02/2021

DRUG DEVICE COMBINATIONS

How do these medicinal substances fit with combination products: • Integral • Pre-filled syringe • Inhaler Registration as a medicine, but device must conform to device standards (CE Mark)

• Separate • Vial of drug sold with empty syringe Each is subject to registration by their respective system

• Ancillary Drug • Anticoagulant coated catheter Registration as a device, but drug must conform to medicines standards

The Organisation for Professionals in Regulatory Affairs

Development of a Medicine

Establishment of Quality, Safety and Efficacy • Pharmaceutical quality • Consistently produce the same product with the same characteristics and performance • Non-Clinical Safety • Animal studies to understand how the product behaves and establish safe levels of dose and impurities • Clinical Efficacy and Safety • Human studies, Phase 1-3; first in healthy volunteers (usually) to confirm safety, then dose establishment in patients, and then efficacy and safety in patients

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Development of a Medicine

From discovery of a potential new candidate substance to obtaining a license to sell the medicine: • 12.5 years • £1.15 billion • 1 medicine (from 5,000-10,000 initial candidate molecules)

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Registration Procedures

Legal Basis:  Depends on… ● The type of data you are submitting ● Whether your drug substance is – New – Well established  Is this… ● A totally new chemical entity? ● A biologic? ● A new formulation? ● A generic?

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Article 8(3) applications

EITHER ● A FULL SET OF SUPPORTING DATA … a whole CTD – Quality, Safety, Efficacy

OR ● A MIXED APPLICATION – Some of the information is replaced with published information

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Article 10(1)

 GENERIC PRODUCTS  BIOSIMILAR PRODUCTS

● Cross-refers to a REFERENCE PRODUCT with respect to SAFETY and EFFICACY

● Related to the EXCLUSIVITY PERIOD of the reference product…

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The 8 + 2 + 1 rule

 New products – 10 years exclusivity

 A generic application cannot be submitted until 8 years of the exclusivity period have elapsed

 A generic product cannot be SOLD or SUPPLIED until the exclusivity period has expired.

 In some instances an extra year of exclusivity can be granted to the reference product ● For example, if a paediatric indication is added.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Two important principles with generics / biosimilars…

 The reference product does not have to be approved in the MSs that are the subject of the application ● The single market principle applies  If the MA for the reference product is WITHDRAWN after approval of the generic… ● The generic licence does not have to be withdrawn

The Organisation for Professionals in Regulatory Affairs

Article 10 applications

 10 (2) (b) ● GENERIC APPLICATION ● WHEN IS A PRODUCT A GENERIC? – SAME qualitative and quantitative COMPOSITION as the reference product – SAME pharmaceutical form – BIOEQUIVALENCE with the reference product – Demonstrated using bioavailability studies ● Different sales, esters, isomers, mixtures of isomers, derivatives – ARE CONSIDERED TO BE THE SAME DRUG SUBSTANCE – Unless their properties are different with respect to SAFETY and /or EFFICACY

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Articles 10(3) and 10(4)

 Where: ● the strict definition of a generic cannot be met

● bioavailability studies cannot be used to demonstrate bioequivalence ● There are changes to the drug substance, indications, strength, pharmaceutical form or route of administration compared to the reference product

 Nonclinical / Clinical data may be needed.

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Article 10a

 WELL ESTABLISHED USE (WEU) ● Entirely bibliographic support for Nonclinical / Clinical

● Well-established? – Drug substance has been on the market for at least 10 years AND has recognised safety and efficacy.

● WEU – relies on the same therapeutic use!

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Article 10b

 FIXED COMBINATION

● Only acceptable if – Each individual drug substance has been authorised in the EU – …and the twist:

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Article 10c

 INFORMED CONSENT

● Requires that the MA holder of the reference product gives permission to cross reference to the data in their MA – Cross reference is applicable to Modules 3, 4 and 5 – It will always be linked to the reference product – permanent access to the reference product documents – This route is usually a method for companies to obtain a duplicate license for an existing product which they can use for licencee agreements/alternative branding, for example.

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07/02/2021

CONDITIONAL MARKETING AUTHORISATIONS  Special authorisation: ● Designed to speed up access to medicines for patients with unmet needs. ● Renewed annually ● Authorised prior to completion of Phase III studies  Since 2006 ● Over 40 products approved on this basis – Including for HIV infection, breast cancer, severe epilepsy in infants

and multi-drug resistant tuberculosis – Almost half were orphan medicines

The Organisation for Professionals in Regulatory Affairs

What is the Marketing Authorisation?

 A COMMITMENT to manufacture, sell and supply a drug product in accordance with evidence provided on its: ● QUALITY ● SAFETY ● EFFICACY

The Organisation for Professionals in Regulatory Affairs

07/02/2021

The requirement

 Directive 2001/83/EC requires that applications for authorisation to place a medicinal product on the market have to be accompanied by a dossier containing particulars and documents relating in particular to the results of physico-chemical, biological or microbiological tests as well as pharmacological and toxicological tests and clinical trials carried out on the product and thus proving its quality, safety and efficacy.

The Organisation for Professionals in Regulatory Affairs

GMP and Quality…

 Directive 2003/94/EC “ The manufacturer shall ensure that all manufacturing operations subject to an authorisation for marketing are carried out in accordance with the information given in the application”

The Organisation for Professionals in Regulatory Affairs

07/02/2021

The Marketing Authorisation…

 The result of significant investment in money, time, resource ● For industry

● … and also for the regulatory assessors

The Organisation for Professionals in Regulatory Affairs

What’s written in your Marketing Authorisation….

 Determines the extent to which you have flexibility to release the product

 It’s therefore crucial to understand the content of the MA and the commitments that this brings.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Authorisation Procedures - EU

The Organisation for Professionals in Regulatory Affairs

Centralised Procedure

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Centralised Procedure

• No previous licenses exist in the EU for the product • Application is submitted to, and the procedure coordinated by, the European Medicines Agency (EMA) • Defined timelines for review of the application • Outcome is a single license that is valid in all EU Member states • Fee for application for a single strength, one pharmaceutical form, one presentation is €296,500 (currently)

The Organisation for Professionals in Regulatory Affairs

Decentralised Procedure

• No previous licenses exist in the EU for the product • Select a Reference Member State who will conduct the main review of the application • Select 1 or more Concerned Member States who will base their decision on granting a licence on the review conducted by the RMS (CMS should only disagree with a positive opinion of the RMS on the basis of a serious safety issue, however, in reality, other reasons are often observed) • Outcome is a NATIONAL licence in each of the Member states who agree/approve the product

• Defined timelines for review of the application • Fees are paid nationally and can vary considerably.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Mutual Recognition Procedure

Similar to Decentralised procedure with one key difference: • The product is already approved in the Reference Member State • CMSs should only disagree with approving the product on the basis of a serious safety risk (although in practice, other grounds for non-approval are often observed) • Outcome is a NATIONAL licence in each of the Member states who agree/approve the product • Defined timelines for review of the application • Fees are paid nationally and can vary considerably.

The Organisation for Professionals in Regulatory Affairs

National Procedure

• Application made to a single EU member state • No defined timelines for review • Cannot make a parallel national application in another EU member state

The Organisation for Professionals in Regulatory Affairs

07/02/2021

STRUCTURE of the Application: 5 Discrete Modules…

 Very Important Principle…

 The NATIONAL / REGIONAL requirements for data supporting new drug product applications are unchanged.

 JUST the FORMAT and LAYOUT of the data have been standardised.

The Organisation for Professionals in Regulatory Affairs

Information in the CTD

 Consider the Reviewer ● Who is the expert on the product?…YOU ● Reviewer/Assessor is not necessarily an expert in YOUR product

● Documents will need to clearly explain the key information and the rationale ● Lead the reviewer through the data so they can follow the story of development and quality ● Good critique-style Module 2 summaries and overviews provide the reviewer with confidence of the underlying detail/data; – Vague or unexplained information - the more the reviewer will need to look at the detail in Modules 3, 4 and 5

The Organisation for Professionals in Regulatory Affairs

07/02/2021

The level of information will depend on the Product  High ● A new chemical/biological product with limited experience, or a new delivery system/pharmaceutical form How much information to include in the CTD

 What about ● A basic solution for injection of a well established active substance?

The Organisation for Professionals in Regulatory Affairs

Drug Substance information

3 options for presenting drug substance information in the CTD Module 3.2.S. 1. Full information ● Populating all sections with relevant data 2. Active Substance Master File (ASMF)

● Applicants Part ● Restricted Part 3. European Pharmacopoeia Certificate of Suitability (CEP) ● Minimises information needed in the Module 3.2.S

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Descriptions – e.g. containers and analytical methods

• Describe the container clearly and in detail, but don’t need technical drawings or lots of details • Pictures/photos are helpful for a reviewer • Avoid minor details that may change regularly (eg. …in a bottle with a red plastic cap) • Avoid providing the SOP, or internal method description. • Needs to be a summary of the method • Validation description should also be a summary, not a copy of the validation report. Could use a table format.

The Organisation for Professionals in Regulatory Affairs

Quick note on Module 3.2.P.2

• Pharmaceutical Development

• NOT part of the “registered” information • Describes how the product was designed and assessed • The formulation • The manufacturing process • Other key attributes that led to selection of the critical features (formulation/processes/controls) ● DESIGN DECISIONS – Investigations that worked and those that did not – Learnings from the data generated – Innovative approaches – Identification of critical parameters

“If you haven’t written it down, you haven’t done it”

The Organisation for Professionals in Regulatory Affairs

07/02/2021

HOW TO MANAGE THIS FOR..

DRUG DEVICE COMBINATIONS?

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Drug device combination products

Minimal requirements: Medicinal Products Directive 2001/83/EEC as amended , Annex I (3.2) 12. Where applicable and if needed, a CE marking which is required by Community legislation on medical devices shall be provided.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

The CTD .. Where would you put the device information?

The Organisation for Professionals in Regulatory Affairs

Information on device component Module 3, European Community Additional Information — Medical Device — Certificate(s) of Suitability

Where applicable and if needed, a CE marking which is required by Community legislation on medical devices shall be provided. “… supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be delivered with the medicinal produc t ”

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Increasing complexity of device components

Credit: Mark Chipperfield, Corvus Device: MedTech and Pharma Platform Zurich 2014

The Organisation for Professionals in Regulatory Affairs

EEA: Device content of an MAA

 (discussed in principle in the new draft Quality guideline) • 3.2.P should contain information on the product-specific quality aspects related to the device relevant to the quality, safety and efficacy of the medicinal product. • 3.2.R should include relevant information related to the demonstration of compliance of the device(s) with MDR Annex 1 (the GSPRs) e.g. NBOp, NB Certificate of Conformity and/or device manufacturer’s EU Declaration of Conformity. • Module 3 should include appropriate information on the manufacture, control and usability of the DDC as defined for the intended patient population. • Usability and human factor studies are multidisciplinary in nature and could be included in section 5.3.5.4, ‘ Other Clinical Study Reports’ of the CTD, with appropriate reference to Module 3 as these may be reviewed by both pharmaceutical and clinical assessors, each with different focus. • For ATMPs , the content of the MAA may be adapted, provided that this is justified under a risk-based approach.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

The Organisation for Professionals in Regulatory Affairs

EEA: Device content of a DDC …who will assess?

 (specified in the new draft guideline) • “The core precept of this guideline is that the

Competent Authority for the regulation of medicines (CA) will evaluate the device specific aspects of safety and performance relevant to the quality, safety and efficacy of the medicinal product, and that, as applicable, the NB will assess the relevant GSPRs. “

The Organisation for Professionals in Regulatory Affairs

07/02/2021

EMA Draft Quality Guideline

 If the device is self-certifiable: ● The applicant should submit the results of the assessment of the conformity of the device part with the relevant GSPRs  If the device (when used alone) would require NB assessment: ● the applicant is required to provide an opinion on the conformity of the device with the relevant GSPRs issued by a suitably accredited NB.  Note that “to enable both the assessor and applicant to determine how the NB opinion was formed, avoid duplication of assessment and identify aspects to be considered during the MAA, it is recommended that the NB Opinion is presented as a technical summary report.  A template for this is provided in the EMA Guideline on the quality requirements for drug-device combinations (EMA/CHMP/QWP/BWP/259165/2019)

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Meanwhile… which guidances are relevant for DDCs and where do they come from?

● ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

● ISO: International Organisation for Standardisation

● IMDRF : International Medical Device Regulators’ Forum

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Meanwhile… which guidances are relevant for DDCs and where do they come from? ● EU: shortage of guidances e.g. DRAFT Quality requirements for DDCs

● FDA: Multiple Guidances for Combination Products https://www.fda.gov/combination-products/guidance- regulatory-information/combination-products-guidance- documents :

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Global Transferability

Different Systems for Classification/Application of Devices

Japan • Pre-Market Submission (Notification) • Pre-Market Certification • Pre-Market Approval

USA

• Pre-Market Notification 510K • PMA (Pre-Market Approval)

• Class I Self-Certification • Notified Body Certification

The Organisation for Professionals in Regulatory Affairs

07/02/2021

WHAT ABOUT THE USA

NDA • This is a “full” application where the applicant provides clinical and/or literature support.

ANDA • This is an “Abbreviated” application, similar to a “generic” application in the EU

OTC (monograph) •

This is a different system whereby there are requirements listed in the CFR, where, provided the product meets these requirements, it can be marketed, without a prior review/approval by FDA

BLA • This is the acronym for an application for a biological product

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WHAT ABOUT THE USA

• CTD format is applicable

• Some differences in the content but the majority will be similar

• Module 1 – Administrative information • This Module is region specific and will be different to an EU Module 1

• Different Approach to review • Bottom up vs top down

The Organisation for Professionals in Regulatory Affairs

07/02/2021

USA Combination product - definition 21 CFR § 3.2 (e) (1) A product comprised of two or more regulated components i.e., drug/device, biological/device, drug/biological, or drug/device/biological …combined as a single entity

(2) Two or more separate products packed together in a single package or as a unit…

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labelling is intended for use only with an approved individually specified drug, device, or biological product… (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labelling is for use only with another individually specified investigational drug, device, or biological product…

The Organisation for Professionals in Regulatory Affairs

US FDA : Office of Combination Products (OCP)

• Established in 2002 • Important contact point

• Determine - CDER, CDRH or CBER lead review process • Facilitates interaction between different review centers internally • Website – Combination products https://www.fda.gov/combination-products

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Primary Mode of Action (PMOA)

Defined in 21 CFR Part 3

“the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action that is expected to make the greatest contribution to the overall intended therapeutic effects of the combination product”

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Lead center review

• The Lead Center is the FDA centre that has been assigned the review responsibility.

• May be reviewed in consultation with another centre

• May also be reviewed in collaboration with another centre.

The Organisation for Professionals in Regulatory Affairs

07/02/2021

Approval process

• A combination product will most likely require – a PMA application if classified as device, – an NDA if classified as drug, or – a BLA if classified as a biological product.

Some CDRH assigned combination products may use 510k if there is a predicate device available.

• Early and close interaction with the FDA review Center is always encouraged to facilitate the process and the increase the likelihood of a successful application.

The Organisation for Professionals in Regulatory Affairs

USA: Device content within NDA/BLA

Module 3

Cross References

3.2.R Device Constituent Part • Administrative • Description & Design Features • Manufacturing • Labelling • Device Life • Biocompatibility • Software • Safety • Functionality & Performance • Attachments

P1 Description & Composition

P2 Pharmaceutical Development

P5 Control of Drug Product

P7 Container Closure

P3 Manufacture

P8 Stability

P2.4 – Container Closure

Product Description

P3.1 - Facilities

P5.1 - Specifications

P7 - Descriptions

P8.1 – Stability Summary

P3.3- Manufacturing Process

P2.5 – Microbiology

P5.2 - Procedures

P7 - Specifications

P8.2 – Stability Commitments

P2.6 – Compatibility

P5.3 - Validation

P7 – Test Methods

P8.3 – Stability Data

Applicant Supplier

Links to Master Files

List of subsections is indicative and not exhaustive

Device MAF

Type III DMF

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07/02/2021

Learning Outcomes Recap

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