biomedicine the profession 27 september 2016

REGULATORY AFFAIRS

1 Regulatory Affairs, the role in pharma - BMC

Biomedicine the Profession – 27 September 2016

Anna Rytter, PhD

Regulatory Affairs & Quality Assurance Manager

Introduction

• Master program – molecular biology – Lund

• PhD – Experimental Brain Research, WNC -Lund

• Post doc – Apoptosis Laboratory, KB-Copenhagen

• LEO Pharma AB - originals, affiliate, national, Malmö

• LEO Pharma A/S originals, Head Office global -Ballerup

• EQL Pharma, - generics - Lund


Topics


• What is regulatory Affairs?

• Why regulate drug development

• Product Life Cycle - Regulatory Affairs Perspective

• Regulatory Affairs and its role in the Pharma company

• Regulatory documentation/tools

• A typical day in Regulatory Affairs

What is regulatory Affairs?

Definition according to Swedish Pharmaceutical Society:

Regulatory Affairs is the knowledge and application of strategic

and operational enforcement of the legal frame work concerning

pharmaceuticals and related products in a national and global

perspective.


Wiki:

Regulatory Affairs is a profession within regulated industries, such as pharmaceuticals, medical devices

(”…”).

Regulatory affairs (medical affairs) professionals (aka regulatory professionals) usually have responsibility

for the following general areas:

• Ensuring that their companies comply with all of the regulations and laws pertaining to their business.

• Working with federal, state, and local regulatory agencies and personnel on specific issues affecting

their business. i.e. working with such agencies as the Food and Drug Administrationor European

Medicines Agency

• Advising their companies on the regulatory aspects and climate that would affect proposed activities.

i.e. describing the "regulatory climate“…

https://en.wikipedia.org/wiki/Food_and_Drug_Administration

https://en.wikipedia.org/wiki/European_Medicines_Agency


Company perspective:

New medicinal products - and changes to marketed products – should be

approved asap and placed and kept on the market

Authority perspective:

To assess documentation submitted with the registration- or change

application and surveillance of the use of medicinal products

Why regulate?


• Drugs are not ordinary consumer products

– To ensure quality, safety and efficacy of drug products in order to

assure the continued protection of Public Health.

–Professional advice needed

– “Hidden quality”

Why regulate?

Benefit vs Risk

”All substances are poisons; there is none which is not a

poison. The right dose differentiates a poison and a remedy

(medicine)”

or

”The dose makes the poison”

Paracelsus (1493-1541)


Pharmaceutical regulation – A recent Development?


• Official books of drug quality standards – Italy 13th century

• First “modern” pharmacopoeias 16th century (e.g. Spanish

Pharmacopoeia)

• Pharmacopoeias define:

– the requirements for the qualitative and quantitative composition of medicines

– the tests to be carried out on medicines

– the tests to be carried out on substances and materials used in their

production

– But - no evaluation of safety or efficacy of medicines

Pharmaceutical regulation – driven by disasters

• Unfortunate events development of medicines regulation during

20th century

• 1937 – Sulfonamide - diethylene glycol poisoning, 100 people died

US Federal Food, Drug and Cosmetic Act and the birth of New

Drug application

• 1956 – thalidomide disaster, Neurosedyn. 10 000

newborn with deformities Major trigger for

development of the modern controls on the sale

and supply of pharmaceuticals

• EU Directive 65/65/EEC

10

Regulatory Affairs, the role in pharma - BMC

The modern era of drug regulation

11


There is a wealth of Regulations, Directives and Guidelines controlling

the sale, supply and study of medicines.

Agencies such as

• FDA (Food and Drug Administration) in US

• EMA (European Medicines Agency) in EU

• LV/MPA (National agencies (Läkemedelsverket)

in SE

set up to administer these rules and to approve medicines before they can

be sold.

The modern era of drug regulation

12


ICH

• Need for a wider harmonization led to the establishment of

International Conference on Harmonisation of the technical

requirements of pharmaceuticals for human use (ICH) 1990

• A network of the authorities in EU, US, Japan and industry

organisations

• Provide guideline on Quality, Safety, Efficacy and CTD

• No authority – recommendations which will have to be

regionally implemented

Why is Regulatory Affairs Needed?

• Drug development and commercialization is highly regulated.

• The path to drug registration (Marketing Authorization) is paved with

good intention but can be complicated

• Things change....constantly!


Regulatory Affairs in drug development

• Strategic

• Company decisions on new projects or in licencing.

• How should this product be documented?

• Risk assessments, time plans

• How quick can the product be on the market? Which is the best way?

• Operational

• Applications to authorities, structure and format

• Time plan

• Compliance

• Responsive

• Respond to questions

• Problem solving


Product Life Cycle - Regulatory Affairs Perspective


Post ApprovalPhase

• Life Cycle

Management/Compliance

• Post-approval Commitments

• Clinical Trial Applications

• New Indications

DevelopmentPhase

• Advice on development

• Scientific Advice

• Clinical Trial Applications

• Project management / Strategy

• Product Information - Claims

Application and ApprovalPhase

• Application Procedure

• Authority meetings/hearings

• Electronic submission

• Readability Testing / Labeling Support

The role of regulatory affairs – development phase

– Ensuring that the legislative requirements are met

• Regulatory strategy

• Cross-functional project teams

• Ensure application of guidelines

• Advice on studies to demonstrate safety, quality and efficacy

• Preparation of submission of application for clinical trials


Managing the preparation of the regulatory submission

including labelling

• Labelling/Product information

• Readability Testing

• Quality audits

• GMP of manufacturers

• GCP

• QP statements

• RMP

Product Information - SmPC and package leaflet

SmPC – Summary for the prescribers

Package leaflet – Information for the patient

• Indication and dosing

• Precautions and warnings

• Interactions with other drugs

• Undesirable effects

The claims in the Product Information needs to be supported by scientific data in the dossier.

Ensure input from different parties.

FASS18 Regulatory Affairs, the role in pharma - BMC

Prepare High-level documents


In all submission dossiers there will

overviews of the:

• non-clinical part

• quality part

• clinical part

– It is an introduction to the data

with a critical assessment of the

results.

– It justifies any deviations from

guidelines

– It justifies the development and

testing strategy.

The role of regulatory affairs – application and

approval phase

• Application Procedure

• Electronic submission

• Authority meetings/hearings

• Check progress of evaluation and anticipate questions (prepare

answers to expected questions)

• Clarify raised questions, plan response and strategies with

other departments

• Negotiate approval and Product Information with agencies


Approval!

Marketing authorisation (MA) granted

An agreement with the authorities

• Valid for a period of 5 years.

• After 5 years renewal required


The role of regulatory affairs – post approval phase

–Compliance - Submission of variations

–Renewals

–Pharmacovigilance

–Product information review

–New indications / New formulations

• Regulatory input to development plans!

–Regulatory Intelligence

• What does the future hold?


LIFE CYCLE

MANAGEMENT

The role of regulatory affairs - Summary

•GET THE PRODUCT ON THE MARKET QUICKLY

(Meet the legislative requirements and present the company position in the best

light to maximise competitiveness)

•KEEP THE PRODUCT ON THE MARKET FOR A LONG TIME


Regulatory documentation/tools

Regulatory documentation/tools

• In the past the regulatory documentation presented to the authorities

was printed on paper and organized in binders.

• Common Technical Document (CTD) is the standard format used for

Marketing Authorisation Applications (MAAs, EU) and New Drug

Applicatons (NDAs, US)

• Common agreed structure for the main sections (SAFETY, QUALITY, EFFICACY)

of a regulatory submission


The common technical document - CTD


• The Common Technical Document is divided into five modules:

–Module 1 Administrative and prescribing information

–Module 2 Overview and summary of modules 3 to 5

–Module 3 Quality (Pharmaceutical documentation)

–Module 4 Preclinical (Pharmacology/Toxicology)

–Module 5 Clinical - efficacy (Clinical Trials)

Tools - Electronic submission


26/Ut>/U1t

Routes to registration

3

Routes To Registration

Centralised

Procedure

Mutual

Recognition

procedure

Decentralised

ProcedureNational

Procedure

5

26-05-2016

Summary of MRP

• As soon as there is an existing MA, for same applicant and

same product, or pending application in Europe, MRP is

mandatory

• Submit national application in RMS

• National approval in RMS

• Applicant updates dossier in line with

assessment and re- submits to RMS

• Preparation of assessment report by RMS

• Submission of dossier to CMSs - validation

by CMSs

• MRP starts = 90 days

• Local artwork in CMSs (post 90 days)

• License grant in CMSs

Example of an MRP

• National Marketing Authorisation (MA) in lreland (IE) for a one strength cream.

Want to extend cover to the UK, PT, FR and NL.

• RMS (Reference Member State): IE

• CMS (Concerned Member State): UK, PT, FR and NL

• MRP Timeline

• 90-day procedure

• Followed by 30 day National Phase, Submit national translations of

PIL, SPC and Labelling

5

26-05-2016

Summary of CP

• Submit once to EMA plus Rapporteur/Co-

Rapporteur

• Full assessment done by two countries

• Majority decision

• 210 days to positive opinion, 250 days to

"decision".

• Only possible if originator was CP

• Only one MAH

• Only one product name

•National

Only possible if no existing MA in EU for same

applicant and same product, and only one

country targeted

•DCP

As soon as application is made, by same

applicant for same product, in more than one

Member State and no CP is chosen, DCP is

mandatory.

The various roles within Regulatory Affairs

• Project management

• Submission management

• Maintenance management - LCM

• CMC specialist (quality)

• Pre-clinical/Clinical specialist

• Labelling expert

• Regulatory intelligence

• Product responsible


Regulatory Intelligence

• Is a systematic process initiated by a defined need

• It is a collection of data and analysis of the data linked to a strategy

• It is legal and ethical (not espionage/hacking)

• So much information available on websites/databases

• Typical question – what other modified release

products with indications x and y exist in Europe? What clinical trials

supported the approval?


Global versus local Regulatory Affairs


• Global/Head office

– Strategies

– Specialized

– Contact with experts

– Compile common documents and variations and send to affiliates

– Contact with manufactre, sales and logistics

• Affiliate/local/market

– Specialist in local requirements – adapt the common documents

– Translations

– Contact with market, sales and logistics

– Customer complaints and questions

3

Generics

-

Originator

Production Often contract

manufacturing

Own facilities

Products Few high volume productsHigh number of

different products

and different types of

products

Original versus Generics

3

EQL Pharma AB:

• Small generic company in Lund

• Nordic market

• All manufacturing activities are outsourced to suppliers

• Final batch release in EU for a few products

,

30-05-2016

An average day at work



– planning, coordinating, summarizing

• Read, review, write

– Interpret legislations and, guidelines etc.

• Communication/collaboration – meetings/e-mails/TC

– Business Partners, CROs, manufacturers,

consultants and other experts

– Medicines Agencies

– Colleagues

• Small details versus bigger picture

• Fast but still precise…


• What is a Generic?

• Data Exclusivity

• Reference Product

• Differences in

Challenges


Generics

The term ‘generic medicinal product’ is described in article 10, paragraph 2 under b) of

Directive 2001/83/EG:

‘“generic medicinal product” shall mean a medicinal product that has the

same qualitative and quantitative composition in active substances and

the same pharmaceutical form as the reference medicinal product, and

whose bioequivalence with the reference medicinal product has been

demonstrated by appropriate bioavailability studies.’


Generic Product - Definition

• API has the same qualitative and quantitative composition

• Product has the same pharmaceutical form

• bioequivalence has been demonstrated

The ‘reference medicinal product’ is a medicinal product authorised

under Article 6, in accordance with the provisions of Article 8 of Directive

2001/83/EG’ (full dossier)

Article 10 of Directive 2001/83/EG not only governs the contents of the

generic medicinal product’s file, but also lays out rules for the

protection of data in the reference medicinal product’s dossier (data

exclusivity).


Reference Product - Definition

Lb/U!J/LU It

Patents, Data Exclusivity

• Patents

•Drug substance patents

• Product patents

• Process patents

•Drug Product patents

• Formulation

• Process

• Application (usage)

-

What is a Patent?

A patent is a grant made by a government that confers upon the

creator of an invention the sole right to make, use, and sell that

invention for a set period of time.

New

Have an inventive step Be sufficiently

described First to file

1t

Data exclusivity


26/05/201 f

Data Exclusivity

• 6/10 year rule states that the reference medicinal

drug products must be marketed in the community

for a period of at least 6/10 years before an

application for a generic drug product can be made.

• Example:

• 10 year countries: Belgium, Germany, ltaly. The

Netherlands, Sweden, UK, and Luxembourg.

• 6 year countries: Austria, Denmark, Finland,

lreland, Portugal, Spain, Greece, Norway and

lceland.

Data Exclusivity

• Data Exclusivity

•Directive 2004/27/EC amending Directive

2001/83/EC introduced 8 + 2 + 1 years

= 8 years approved before submission of

abridged application

= 10 years approved before marketing of

approved abridged application

= 11 years for extra innovative therapeutic

indication

Drug Product - Dissolution


Comparing dissolutionprofiles

• 12 units

• F2 factor

• If F2 >50, profiles considered similar

• If dissolution i 85% in 15 minutes, profiles considered similar

without mathematical justifications

Immediate releaseproduct

• Discriminatory power – not always required

• Specification: single point (80% in 15 minutes) – or

replaced by integration test

Prolonged releaseproduct

• Discriminatory power required- Critical

manufacturing variables that may affect

bioavailability

• Specification example:

1. 20-40% at 1 hr

2. 46-65% at 4 hrs

3. >85% at 10 hrs

1

Quality

&

GMP

(Good Manufacturing Practice)

3

•The GMP requirements are identical for manufacturing of

Generics and Originator products

•However the typical business structure is in general different

Generics

-

Originator

Production Often contract

manufacturing

Own facilities

Products Few high volume productsHigh number of

different products

and different types of

products

GMP - Generics vs. Originator

Challenges

Changes in the product or manufacturing process is often initiated by CMO due to

their needs or in some cases needs of other costumers. We must prepare and

submit the variations to implement the change.

Since we are one step away from the production it can be difficult to evaluate if

a changes is needed or just convenient for the CM

Challenges with this can be that we as contract giver is notified with short

deadline to prepare and submit the variation to the authorities The variation

documentation may be in-complete long timeline for approval at the

Authorities challenges in relation to the coordination of timing of the

implementation in relation to new orders

Variations to the manufacturer of the product after

approval

Challenges

Addition of a new API manufacturer :

The variation should include a QP Declaration

An audit of the API manufacturer and intermediate site if relevant is required.

Has often been performed by the CM since they use the same API for

several customers

QP must approve the quality of the audit and audit report and agree with

the auditor about the conclusion .

- Sometimes there are different interpretation of the audit requirement

within EU (regarding frequency and content).

- Transport conditions

- Control af the product and artwork

- CoA (Certificate af Analysis)

- CoC (Certificate af Conformance)

- Audit status

- Deviations (from manufacturing)

- Change controls (variations)

- Batch record review

- CoA from EU testing (for products manufactured outside EU/EEA/MRA}

30-05-2016

Release of products

•Audit of API and contract manufacturer (at least every 3rd year)

•Variations and implement approvals

•Product Quality Review (PQR)

•The objective is to verify the consistency of the existing process, the appropriateness of current

specificat ions for both starting materials and finished product to highlight any trends and to

identify product and process improvements.

•PQR also includes a review of

- All batch related data and test results including stability test results

- Starting materials

- Commitments and variations related to module 3

- Changes to equipment, process and analytical methods

- Technical agreement

- Deviations, Complaints and Recalls

Pharmacovigilance

Life Cycle management

Pharmacovigilance for Generic Products

(Almost) Same obligations for generics and originator

medicinal products.

However there are differences:

9

30-05-2016

Pharmacovigilance

Pharmacovigilance is an important part ot the lite cycle management for generic

products together with RA and QA

Generic companies have the same obligations as originator companies to secure

that the products is sate to use for the patients.

The authorities, originator and generic companies must cooperate to secure that the

benetit ot the product outweighs the risks and that the satety profile is up-to-date

with the latest knowledge and publicly available.

The implementation ot pharmacovigilance legislation will be on-going for several

years to find the appropriate leve! ot surveillance for originator and generic

products.

Originator Medicinal Product

• For a new product on the market, the:

• surveillance must be intense,

• the safety profile for type of adverse reactions and frequency,

contraindications, interactions etc. must be updated frequently.

• One single serious adverse reaction can require immediate action:

• Urgent changes in the SPC;

• Withdrawal of the product from the market

• temporary or permanent.

• Each report for adverse reactions must be evaluated throughout by specialists

(doctors, pharmacists etc.)

30-05-2016

• Several departments involved in safety and pharmacovigilance:

- Clinical Research Operations

- Drug Safety Department

- Medical Information

- Medical Advisors

Risk Management Plans (RMP)

A risk management plan should describe the activities of a MAH to minimise the risks

associated with a product after it is marketed.

Extra monitoring of specific issues, PASS, educational material.

Originator product - more unknowns at first launch Generic products - well-known risk

The risk management plan for the generic product can/should be based on the risk

management plan for the reference product. However, when there is no RMP for

originator a new RMP should be prepared from scratch for the generic product!

Surveillance of adverse events

Receipt and evaluation of reports from the market

Literature surveillance

Implementation of EU initiatives

For example recommendations on labelling

Pharmacovigilance tasks



– planning, coordinating, summarizing

• Read, review, write

– Interpret legislations and, guidelines etc.

• Communication/collaboration – meetings/e-mails/TC

– Business Partners, CROs, manufacturers,

consultants and other experts

– Medicines Agencies

– Colleagues

• Small details versus bigger picture

• Fast but still precise…


Regulatory Affairs – what I like

• Collaborations and contacts

• Diversity of tasks and challenges

• Finding solutions

• Learn new things

• Defining needs, planning


Thank you!


biomedicine the profession 27 september 2016

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