all about regulatory affairs - granzer · all about regulatory affairs forum – heidelberg –...

All About Regulatory Affairs

Forum – Heidelberg – August 2010

Dr. Ulrich Granzer

www.granzer.biz

Choice of procedure

When do we have a choice of procedure for a generic medicinal product?– When the originator product was approved centrally

• New pharmaceutical forms with new features are no generics

– When it is a classical small molecule• Independent of indication!

– When it fulfils the eligibility criteria for the centralized procedure

• Innovation

• Novel (new) technology

3

MRP and DCP

Scope

4

Scope of MRP/DCP:

New active substances (if not mandatory for the centralised procedure)

Generic medicinal products to authorised reference medicinal products

Informed consent

Well established use (WEU; bibliographic applications)

line extensions to national authorisations

known substances in new combination

New indications/new pharmaceutical forms for known substances

5

Article 17 of Directive 2001/83/EC

“1. ...

Applications for marketing authorizations in two or more Member States in respect of the same medicinal product shall be submitted in accordance with Articles 27 to 39.

2. Where a Member State notes that another marketing authorization application for the same medicinal product is being examined in another Member State, the Member State concerned shall decline to assess the application and shall advise the applicant that Articles 27 to 39 apply.”

6

Article 18 of Directive 2001/83/EC

“Where a Member State is informed in accordance with Article 8(3)(1) that another Member State has authorized a medicinal product which is the subject of a marketing authorization application in the Member State concerned, it shall reject the application unless it was submitted in compliance with Articles 27 to 39.”

Factors influencing the selection of procedure

Marketing agreements– Co-marketing:

• No of independent marketing authorizations

• No of Trade Names

– Co-promotion• Only one Trade Name

– No of partners in the EU

– Markets, where the product shall be launched

MRP still a choice?

Single (national) approval first

Followed by MR round(s)

9

Application to first member state

Assessment reportincluding SPC, PIL

First Authorization: RMS

210 days

Applicant request on mutual recognition of first(reference) authorisation

Mutual Recognition Process

Objections from CMSsBy day 50

clarification and dialogue / point ofview of applicant (orally or writing)

resolution of issues

Additional National Authorization(s)

35 days

National evaluation and licencing process

Mutual Recognition Procedure

90 days

5 days

MR – advantages and issues

No slots necessary

Freedom to chose the national authority

Timelines can be negotiated on a national level

Option to be faster than in DCP due to immediate start

But: one single country first, loss of marketing opportunity for multinational companies

DCP - Slots

The Problem

No of procedures finished in 2008

MRP: Split by Member State

DCP: Split by Member State

15

EEA – distribution of RMS roles

Why bother with the Centralized Procedure?

Decentralised Procedure

17

18

Application to all member statesRMS to start review

CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days)

PAR to CMSs and Applicant

70 days

Day 105: Clock stop orpositive close of procedure

RMS updates PrAR to prepare draft AR (DAR)

Day 106: Submission of the response

RMS evaluation of the dossier: Preliminary Assessment Report(PAR)

Decentralized Procedure

30 days

Preparation of response document by applicant3 – 6 months

Day 120: Consensus?End of procedure

Day 120: No consensus?Follow on process

19

Day 120: Follow on process

CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days)

Day 145: CMSs send (final) comments on draft AR

25 days

Day 150: Consensus?:

Procedure is forwarded to the Coordination group for the Mutual Recogntionand the Decentralized Procedure (CMD)

Day 180: CMD becomes involved

CMSs prepare response to Draft Assessment Report


30 days

RMS prepares report on outstanding issues by Day 18030 days

Day 195: Discussion at CMD/Break out session

End of procedureYes?

NO?


Day 210: Mutual Approval?

Referral to CMD


End of procedureGrant of national licenses within 30 days

Yes?NO?

Publication ofAssessment report on the internet


Day 210: Mutual Approval?

Referral to CMD


End of procedureGrant of national licenses within 30 days

Yes?

NO?: life becomes difficult!

Publication ofAssessment report on the internet

22

CMD(h)-Referral in DCP and MRP

CMD-Referral - Trigger:

Disagreement between MS concerned by the application at the end of MRP (Day 90) or DCP (Day 210) based on potential serious risk to public health

What does this mean?– If all are positive: Case closed

– If all are negative but the applicant: CASE CLOSED

One MS, the RMS, has to be positive to trigger a referral

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Day 0 RMS starts procedure: Draft LoQ to MSs for comments

Day 10 final LoQ to the Applicant

Day~20 1st CMD-Meeting: Discussion of case

Day 25 Response from Applicant on LoQ

10 days for preparation of response (day 11 – day 20)– No new information

– Usually no new arguments

– Improvement of statements if possible

– Cooperation with RMS, if RMS is positive

– Cooperation with CMS, if at least one CMS is positive

60 Days CMD-Procedure (CMD-SOP)

Day 35 Updated AR of the RMS to CMD

Day 45 MSs position on response to LoQ

Day~50 Discussions at 2nd CMD-Meeting; Hearing of written comments

Day 60 close of procedure with two options:

consensus or referral to CHMP

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Withdrawal of Applications

The applicant has the right to withdraw the application until the last day of the MRP or DCP.

However, if the applicant has withdrawn the application from a MS because a potential serious risk to public health was raised by this MS, the application will be automatically forewarded for discussion to the CMD(h)

A withdrawal will not help the applicant!

27

Referrals to CHMP in 2007 (21 Procedures)

Product Reason for Referral to CHMP CHMPVantas Safety & Efficacy positive

Fentastad (5) Bioequivalence, SPC, Quality, Non-clinical Negative-RE

Simvastatin Krka Bioequivalence negative

Eformax Quality, Safety & Efficacy negative

Bicaluplex 150 mg Safety & Efficacy of an indication positive

Xeomin Safety & Efficacy positive

Menitorix Safety & Efficacy positive

Coxtral Efficacy negative

Pulairmax Quality, Safety & Efficacy negative

Oracea Safety & Efficacy positive

Rapinyl Safety & Efficacy positive

Alvesco Efficacy positive

Atorvastatin (4) Bioequivalence withdrawn

Slots – current situation

UK: depends on indication, no clear guidance, ask

S: “slot days” where requests for certain times are being accepted

D: Slots in 2012 and 2013

NL: Working on system, but no “quick” slots

DK: Already in 2012

Makes CP attractive????

The centralized procedure

Eligibility

For all New Molecular Entities

For all Biotech-Products

For all Advanced Therapies

For innovative products

For all products, which originally were authorized using the centralized procedure

Generics

For all products, where the originator has used the CP generics have the choice to go either route:– National and then MR

– DCP

– Central

Biosimilars– Must go centrally, although programs right now are being

adapted towards a generic approach, e.g. G-CSF, where a pD testing is being accepted

The CP: Pro’s and Con’s

Pro’s One authorization for the

entire EEA

Approval costs

Con’s Loss in flexibility

– Co-Marketing

– Name (one name only)

Parallel importation

Increased complexity in contracts

Rapporteur nominated by CHMP

Intention to file 7 months prior to MAA

The Centralized Procedure

Example:– The European Medicines Agency (EMA) today adopted a

positive opinion recommending for the first time the granting of a marketing authorisation for a generic of a centrally authorised medicine for human use. The recommendation was made by the Agency’s Committee for Medicinal Products for Human Use (CHMP) at its 16-19 July 2007 meeting.

– This first positive opinion is for Zalasta (olanzapine), from Krka, d.d., Novo Mesto, which is intended for the treatment of schizophrenia and moderate to severe manic episode. The reference product for Zalasta is ZYPREXA from Eli Lilly Nederland BV, which has been authorised in the European Union since 1996.

Appointment of Rapporteurs:

Rapporteurships shall be open to all CHMP delegations. The scope of these Rapporteurships shall relate to the pre-authorisation phase and the introduction of quality changes in the post-authorisation maintenance.

In the case that several different generic companies apply for applications based on the same bioequivalence study, the same Rapporteur shall be appointed to ensure consistency in the scientific evaluation/post authorisation maintenance of the medicinal products concerned.

Optimally, these cases shall be identified at EMA pre-submission meetings with generic companies.

The Centralised ProcedureArticles 6 – 14 of Regulation 726/2004

List of Questions

CHMP Meeting

CHMP OpinionDay 210

CHMP Meeting(Hearing)

Additonal questions/issues:

Dossier Submission

Nominationof Rapporteur and Co-Rapporteur by

CHMP Preparation of Assessment Report

CHMP Opinion

Negative Positive

120 + Days

Appeal

Final Opinion

Commission

Commission

BindingCommission

Decision(Approval)

Draft Decision

MarketingAuthorisation

Holder

Member StatesStanding

Committee

Application to EMA

Applicant; Requestfor re-examination

210 days

Deatiled grounds

Abbreviation:MS = Member State

Final CHMP Opinion

Final steps in CP & Commissions Decision Procedure

45 days

60 days

Important new questions of ascientific or technical nature

Applicant: No requestfor re-examination

CHMP Opinion

Draft of Commission Decision

15 days

Transmission of the opinion with Annexesto Commission, MS and applicant

15 days

Standing Committee Applicant

15 days

Referral to Agency new Rapporteur

YES

Final Commission Decision = Approval

NO

Communication to the Council: Commission may defer the decision for 1 month

Council may take adivergent decision

22 days

15 days

15 days

Summary

The CP is an alternative to the DCP/MR if:– The product should be marketed in the majority of the EEA

countries

– If one trade name is being used

– If co-promotion is the only option for partnership• If co-marketing: more than one license, approval of additional

licenses by EU commission

– If one central pharmacovigilance repository is being kept

Scientific Advice: Beispiel USAStructure and content of key FDA Meetings – and its EU counterparts

Meeting with the FDA

Nothing required

Highly recommended

Three different types: A; B; C

Timelines for the different meetings

Type A

Immediate need - stalled drug development program (i.e., a critical path)

Generally reserved for dispute resolution, to discuss clinical holds, and special protocol assessment

Scheduled with 30 days of FDA receipt of a written request

Company may not want to have such a meeting!!!!!!!!!!!!!!!

Type B

Pre-IND Certain end of Phase 1 End of Phase 2/pre-Phase 3 Pre-NDA/BLA FDA generally grants ‘one’ each of the Type B for

each potential application (i.e., NDA, BLA). Scheduled within 60 days of the FDA receipt of the

written request

Type C

Do not pertain to the development/review of NDA

Policy meeting, meetign on a special item of “global” importance, like discussion on surrogate endpoints

Not related to advertising/promotional labeling launch activities and materials

Scheduled within 75 days of request

Pre-IND meeting

Primary focus on pre-clinical and clinical data to support proposed initial IND trial

Preliminary overview of proposed drug development program

May be equivalent to EOP1 or EOP2 meeting for drugs already studied in foreign countries or under other INDs

Goal: Avoid clinical hold on initial IND

End of phase II meeting

Most important meeting between FDA and sponsor during drug development

Review of pre-clinical, clinical, and CMC data from Phase 1 and 2 studies

Review proposed “pivotal” trials and overall drug development program

Focus on proposed claims for labeling Goal: FDA agreement to Phase 3 program

Pre-NDA (pre-Submission) meeting

Ideally 6 to 12 months before planned NDA submission– Uncover major, unresolved problems– Preliminary review of data from Phase 3 studies– Primary focus on format and content of NDA– Discussion of plan for electronic submission

Goals: Avoid refusal to file and prepare for efficient review of NDA

Special Protocol Assessment

Reauthorization of PDUFA 1997 (PDUFA II)

-Provision for ‘special protocol assessment’ & agreement

Evaluate within 45 days certain protocols / issues to assess adequacy per scientific / regulatory requirements

Procedure

Sponsor sends written request Purpose: Reach agreement on design/trial size Binding for sponsor and FDA after trial start Exemptions:

– With written agreement of sponsor & FDA– If Director/FDA Reviewing division determines “a substantial

scientific issue essential for determination of safety or effectiveness of trial” was identified after testing began.

Timing: Usually response within 45 d after submission

CDER ADVISORY COMMITTEES

Anesthetic and Life Support Drugs Anti-Infective Drugs Antiviral Drugs Arthritis Drugs Cardiovascular and Renal Drugs Dermatologic and Ophthalmic Drugs Drug Safety and Risk Management Endocrinologic and Metabolic Drugs Gastrointestinal Drugs Nonprescription Drugs Oncologic Drugs Peripheral & Central Nervous System Drugs Pharmaceutical Science Psychopharmacologic Drugs

Use

First product in a particular class Major new uses Products that have significant public attention/controversy Major guidelines Significant safety/efficacy issues FDA seeks input by panel of outside expertsdue to sponsor

disagreement with FDA decision Matters involving divergent scientific opinions Rx => OTC switches Further info: www.AdCommBulletin.com

Meetings with the FDA

Who is responsible: Homepage– Contact CSO (Consumer Safety Officer) or Project

coordinator for a certain area

– Discuss information needs fo the proposed meeting

– Prepare briefing book in accordance with guidance docs

– Discuss all deviations with CSO

Responsibilities of applicant

Prepare agenda for meeting

Briefing Book (all relevant infos, structure of briefing book in accordance with IND/CTD)

Define participants from company and FDA as well

Internal procedures?

Preparation of development plan– CMC

– Preclinical

– Clinical Development Plan• Outline of clinical trials

• Plan including timelines

• CCDS: Company Core Data Sheet

• TPP: Target Product Profile

– Regulatory Plan

Why?

Company has to show that own internal planning process intact and plan available (competence of company)

Authority wants plan beforehand

Company always in driver‘s seat

What‘s next?

Define responsibilities within company– One person finally and eventually responsible

– Timelines are defined

– A GANTT chart is available

Preparation of briefing

One message defined

Questions to be defined– Clear questions

– No open questions

– Determination of company positions

Wrong questions

Does the FDA have additional thoughts on how to show superiority of our product against the competitor

Can you think of further tox testing?

Should we do other work in analytics supporting our data?

Good questions

We deem our clinical program appropriate to show xyz. Does the agency agree?

As discussed in the briefing book the animal model leads to a clear proof of principle for our new drug candidate. Do you agree?

What next?

Rehearse, then rehearse, and then…rehearse

Devils Advocate

Finally

Submit meeting request only after the draft of the briefing book is already in good shape

Neue Dokumente

65

Themen

New regulation on paediatric development in place– Starting point: Better medicines for children initiative

– Details

– Derived guidance information

Consequences for the pharmaceutical industry

Chances

Risks involved

66

Why?

US system seen as a success by EU commission and politicians in countries of EU

Political climate – Pharmaceutical industry is greedy

– Pharmaceutical industry earns a lot of money

– Image of pharma industry is bad

– They (pharma industry) have not done enough for children

– Pharma industry acts only when forced

67

The Regulation

“REGULATION (EC) No 1901/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92 (Supplementary protection certificate),Directive 2001/20/EC (Clinical trial directive), Directive 2001/83/EC (general EU drug legislation)and Regulation (EC) No 726/2004 (EMA and centralised procedure)”

68

Protection of Intellectual Property- Options -

Patents Supplementary Protection Certificates (SPCs) Protection against utilisation of documentation of first

applicant:– EU Directive 2001/83, as amended, Art 10

Orphan medicinal products Paediatric development

69

Validity of Different Measures

Patent– 20 years from submission of application to expiry

– Best protection because:• Monopoly for defined substance in a market

• Breach is expensive

70

SPC

Acts as if it were a patent extension

Comes into force after patent expiry

Maximum duration 15 years

Maximum monopoly time extension: 5 years

Definition:

71

How is it defined?

A supplementary protection certificate is a legal title that extends the duration of the exclusive patent right, solely in respect of medicines or plant health products obtained by patent, in order to make up for the time that has elapsed between the date of the patent application and the authorisation for marketing of the product.

This certificate is valid from the date of expiry of the patent for a period equivalent to the time that has elapsed between the date of the patent application and the authorisation for marketing of the product less five years, but can in no case have a term of more than five years.

72

SPC and How it Works: An Example

The Paediatric Regulation and its Consequences

74

Status

The Council of Health Ministers reached political agreement on 9 December 2005. The proposal for a Regulation on Medicinal Products for Paediatric Use passed the European Parliament and came into force on the 11th of January 2007 (30 days after publication in the official journal)

Full information available on the homepage of the EU commission:

http://pharmacos.eudra.org/F2/Paediatrics/index.htm

Regulation EC No 1901/2006 - Content

76

AIMS AND OBJECTIVES OF THE REGULATION

To improve the health of children in the European Union.

The objectives include:– Increasing the development of medicines for use in children

– Ensure that medicines used to treat children are:• Subject to high quality research

• Appropriately authorised for the use in children

• Coming with adequate information on the use of medicines in children

• Achieving these objectives without unnecessary clinical trials in children

• Not leading to delays in the authorisation of medicines for adults

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Scope

The Regulation covers products– Under development

– Authorised and covered by intellectual property rights

– Old products, i.e. those no longer covered by intellectual property rights (This group will not be part of today’s discussion)

Following the Paediatric legislation is mandatory for the first two groups

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Main Components of New Regulation

Paediatric Committee (PDCO)

Paediatric Investigation Plan (PIP)

Work to be performed by PDCO

Additional mandatory tasks to be performed by the pharmaceutical industry

Benefit system

79

Opinion of PDCO within 60 days

Applicant accepts

Final opinionand decision of EMAon PIP within 10 days

Re-examination with new

Rapporteur (60 days)

Appointment of Rapporteur

Submission of PIPby company

Assessment of PIP, PDCO or company

may request meeting

How does the Paediatric System work?

EMA submits opinion

to applicant within 10 days

Yes

No

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The System is Mandatory (26 July 2008)

No validation of a submission for Marketing Authorisation without results of all studies performed in agreement with a PIP

A submission as above may be for: – New molecular entity (NME)

– New pharmaceutical form

– New indication

– New route of administration

As long as it is either patent or SPC protected

81

Waivers for Paediatric Investigations

Wrong age group (adult diseases like Alzheimer’s)

No significant therapeutic benefit over existing treatments– Definition of “significant benefit” pending since years

– Pharmaceutical entrepreneur will always argue for additional benefits (no “Me Too”)

Medicinal product likely to be unsafe or ineffective in children

82

Paediatric Committee

Established in July 2007 with its inauguration meeting at the EMA

Membership (3 years, renewable): – 5 members of the CHMP (Committee for Medicinal

Products for Human use)– 1 member from each member state not already represented

by a CHMP member as above– 3 members appointed by commission (public call for

interest – from patient associations)– Every member has an alternate – a person to represent the

member and to vote in the member’s absence– Experts when necessary on an ad hoc basis

83

Paediatric Committee

Tasks– Prepare own rules of procedures

– Evaluate PIPs

– Assess the fulfilment of PIPs

– Forward opinion to the EMA

– Establish an inventory of paediatric medicines needed• Industry: may lead to studies to be required for certain

products

– Recommend a symbol for paediatric medicines: so far no recommendation

84

Paediatric Investigation Plan - PIP

Guideline from EU commission

Contains information on format and content

Defines the paediatric population (in accordance with regulation) as birth to 18 years (excluding 18 years) in accordance with ICH E 11 (neonates, infants, children, adolescents)

85

Paediatric Investigation Plan – PIP (2)

Administrative information

Overall development of the medicinal product (not just in the paediatric population) including prevalence and incidence in children, potential significant benefit (compare with orphan requirements)

Waivers including justification (EU speak: “grounds”)

86


Overall paediatric development strategy– Selected age group

– Relation between adult and paediatric development

– Existing paediatric information

– Therapeutic need

– Strategy regarding non-clinical development

– Clinical aspects• PK/PD studies

• Efficacy and safety studies including synopses

– Timelines for the development

87


Submission after human pK data becomes available (i.e. as early as end of phase I)

Consultation with Paediatric Committee (PC) at an early stage of development encouraged

No fees for meetings with PC

PC decides eventually on the need of paediatric trials

88

Benefits

PIP has been fully adhered to:– 6 Months additional SPC (supplementary protection

certificate) time for the entire product, not just the paediatric indication (even if development fails)

– 2 years of additional data exclusivity time for Orphan Medicinal Products

– Condition to obtain benefit: • Data of paediatric development are being described in the

Summary of Product Characteristics and in the Patient information Leaflet

89

Consequences for Industry

Paediatric development/waiver becomes mandatory in the EU

PIP needs to be developed at an early stage in development (before or during phase II)

Adherence to PIP is being followed by EU Commission, non-fulfilment may lead to penalties including publication of non-adherence

90

Consequences for Industry (2)

Filing of an NME will only be possible as of July 2008 if:– PIP has been discussed with PC and accepted by PG

– PIP has been adhered to, i.e. • All studies of PIP have been performed and are part of the

marketing authorisation application (CMC for a potential additional pharmaceutical form, preclinical evaluation of juvenile animals, clinical trials)

– Or if waiver has been accepted

– Or if deferral has been agreed with PC

91


Filing of additions to existing marketing authorisations (approved drugs) including new indications, new dosage forms and new routes of administration will have to be accompanied by a PIP as on chart before

Transition period: January 26, 2009

All currently licensed and still patent or SPC protected products need to have a PIP, if further developments are being done or planned

92


Paediatric development must not cause a delay in making available new drugs to the public

Paediatric protection is being granted only if– The product is available in all countries of the EU

– It is being launched within 2 years after approval in the EU

The centralised procedure becomes mandatory for new molecular entities

Experience

Validation at EMA has become a major hurdle:– Additional developments in other therapeutic areas

– Broaden the scope of development

– Interpretation of regulation different between EMA and PDCO

– Waiver requests: do not need validation, but validation requested

Overall: Idea is good but implementation needs further work

93

94

Finally

The Paediatric regulation provides for an additional 6 months of data protection

Children will become an integral part of development

Additional resources will become necessary to fulfil the tasks

Sceptics see the EU system of drug approvals heavily burdened on the new task– We have first examples for “non filability” due to lack of

accepted PIP

Strategische Zulassungsplanung im Unternehmen – die richtige Zulassungsstrategie für ein neues Antihypertensivum und ein Arzneimittel bei Lungenhochdruck

Vor- und Nachteile der einzelnen Verfahrenswege in Abhängigkeit von Produkttyp und Patent- und Unterlagenschutzlaufzeit

Fragen: – Gibt es noch Patentschutz?

– Wie lange

– Welche anderen Schutzmöglichkeiten gibt es?• EU

• US

CP oder DCP bei Neuzulassungen?– Welche Gründe gibt es für ein DCP bei neuen Substanzen?

• Vermarktung????

– Was spricht für ein CP?• Rolle des Rapps

• Audits und ihre Bedeutung

RMS im Dezentralen und MR-Verfahren– Was muß der RMS leisten, was wäre ein „nice to have“?

Einschluss welcher CMS in „erster Welle“ beim DCP

Länderbesonderheiten in den Dezentralen Verfahren

Vielen Dank

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