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Centralised Procedure from A to ZCentralised Procedure from A to Z Oral Explanation - DecisionChris Walker, Amgen Limited1st Foresight Training Course, Pavia, Italy, September 3rd 2008

Tell me if I speak to quicklyI would like the session to be interactive where possibleThere will be some overlap with yesterday consolidating t yeste day co so dat ginformation from other speakers

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Centralised Procedure from A to Z 1 - Oral Explanation PhaseChris Walker, Amgen Limited1st Foresight Training Course, Pavia, Italy, September 3rd 2008

Centralised Procedure timeline

• Oral Explanation leading to CHMP opinion

• Possible Appealpp

• Commission Decision

EC decision

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Who has experience with th h f ththese phases of the centralised procedure ?Has anyone been through an oral explanation / rean oral explanation / re-examination ?

European Structures / Committees Management board Permanent SecretariatExecutive Director

support

COMPCommittee for Orphan

Medicinal (human) Products

HMPCCommittee for Herbal

Medicinal Products

CVMPCommittee for

VeterinaryMedicinal Products

PDCOPaediatricCommittee(July 2007)

CHMPCommittee for

Medicinal Products for Human Use

Opinion

Experts, Working Parties, Advisory Groups

EC

Commission Standing Committee Council

p

Community Decision

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Committee roles

Orphan COMP– Review orphan designation– May provide expertise to CHMP on whether data presented

from a ‘small population’ is satisfactory

Paediatric committee PDCO– Ensure Paediatric Investigation Plan (PIP) agreed –

waiver/deferral/data– Appropriateness of data generated / formulation to support

paediatric usepaediatric use

No aim to discuss CVMP or HMPC

Partners in the Centralised ProcedureEUROPEAN COMMISSION

CHMP EMEA APPLICANT

Standing Committee

CHMP EMEA APPLICANT

Rapporteur / Co-rapporteur

Evaluation team

Peer reviewers

Primary contact

Technical company experts

(Clinical / Regulatory / other

Product Team Leader (PTL)

CHMP members

SAGs / External experts

disciplines)

Senior Management

External expertsEMEA Product

Team

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Dialogue is imperative at all stages

Types of potential dialogue– Telephone calls between applicant and PTL may be

i f l/f t di d l d l i ti l iinformal/frequent regarding procedural and logistical issues – PTL discussions may include timetable for responses and

requests for time extension– Formal correspondence will be captured in writing– Face to Face meetings may be required and can be useful. – These may have to align with CHMP meetings for Rapporteur

availability– Can meet with Rapporteurs separately or together

Dialogue is imperative at all stages

A chance for clarity– Applicant is not present at CHMP meeting / alongside the

reviewers as they assess the applicationreviewers as they assess the application – Dialogue is your opportunity for

• Question clarification (post D120/D180 LOQs) • Discuss scientific rationale for question• Discuss timeline for response• Discuss response strategy (not in accordance with guidance)• Build trust / transparency

– Rapporteurs and PTLs can give opinions on a proposed response strategy and key things to cover but cannot give anresponse strategy and key things to cover, but cannot give an estimation of ‘adequacy’

– Rapporteurs will use this meeting to plan experts to involve in the review of the response

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EMEA document offers guidance on formal dialogue

CPMP/2270/02 Guidance on the Rapporteurs meetings with Applicants on the CPMP list of questions

– Meeting 1-2 hrs, ‘rules of engagement’ described– Logistics of request and meeting– Minutes recorded from meeting by Applicant and shared with

EMEA/CHMP

Industry insight into successful dialogue

Science based / ethical approach

High quality submissions

Probe for understanding and expectation

Explain any misunderstandings in the AR/LOQ

Discuss possibility of introduction of ‘new’ pertinent data

Bringing external experts can be influential and bring an external perspective ‘independent’ of the applicant

Ensure team is empowered to make decisionsEnsure team is empowered to make decisions

Ensure pre-reads are provided early to ensure adequate preparation time for the Rapporteurs

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Oral Explanation Phase

EMEA document offers guidance for OE’s

CPMP/2390/01 rev.1 Guidance to Applicants on CPMP oral explanations in relation to centralised applications

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Oral Explanation TimetableSTEP 1 (Day 180) – List of outstanding issues adopted by CHMP

STEP 2 (Cl k t 1 ) PSTEP 2 (Clock stop- 1m) – Prepare written documents / OE, and gain feedback from Rapporteur/EMEA.

STEP 3 (Clock stop) – CHMP plenary discussion, feedback to applicant

STEP 4 Final OE presentation (electronic and hard copies) submitted. ( p )Day 181, Oral Explanation, Applicant debrief (CHMP trend in vote)

STEP 5 Finalisation of CHMP opinion

STEP 1 – LoOI communicated

CHMP draft a list of outstanding issues ‘LoOI’ to be addressed by the applicant in a joint assessment report

Types of objections (Major/other) described in earlier presentation– Types of objections (Major/other) described in earlier presentation

Applicant provided LoOI and list is adopted and officially sent by CIG (central information group)Applicant given 1 month to respond to LoOI and prepare – Response to some OIs will be in written format– Some responses may suit/demand an Oral Explanation.

Applicant can propose an OE– Applicant can propose an OE– If > 1 month preparation required applicant must justify (eg

extensive written responses)– CHMP may choose to consult Experts (Working parties/External)

Month/Date for OE agreed (PTL/Applicant)

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STEP 2 – Applicant preparation

Clarification meeting can be requested – Meeting or TC with Applicant/Rapporteurs/PTL– Aim to clarify scientific rationale behind the request and verify

understanding and expectations– Meeting will not review suitability of proposed Applicant response– Opportunity to demonstrate science based response

Each (concise) written response should include– Statement of rationale and approach– Description of impact to proposed SmPC and PIL– Conclusion

Response should not include new data– Only ‘very limited new data’ is envisaged to be presented at this stage due to review

time constraints beyond Day180 (Likely on new relevant safety data)– New analyses may only be included from eg follow up of previously submitted studies

Response – Should include copy of revised SmPC/PIL– Will propose Commitments (Follow up measures/ Specific obligations) if applicable

STEP 2 – Applicant preparation

Day -10 (prior to OE)– Provide copies of written response documents in paper

and electronic format at least 10 days prior to OE meetingand electronic format at least 10 days prior to OE meetingdate

– Responses will be addressed to the CHMP Chair, CHMPMembers and the EMEA PTL

Day -7 (prior to OE)– PTL confirms assigned time for OE meeting– Applicant provides list of proposed attendees

(maximum 10), a CV for each and their role in the OEN t i t t t k PTL i d f h b d ll– Note: important to keep PTL appraised of changes, name badges allow entrance to EMEA building

– Describe technical support required eg OHP– Applicant provides draft presentation– Further TC can be arranged with Rapporteur if required

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STEP 3 – CHMP review Applicant Information

Rapporteurs review Applicant draft response

CHMP pre-meeting/discussion (‘Plenary discussion’)CHMP pre meeting/discussion ( Plenary discussion )– Rapporteur summarises applicant response, impact to SPC and

proposed commitments– CHMP discuss and refine LoOIs to be addressed in OE– Additional questions may be posed or specific detail / expectation

modified

Rapporteurs / PTL provide feedback to Applicant– New questions or changes in emphasis communicated to

Applicant (note may be only briefly before OE)– Rapporteur can (exceptional) request meeting with Applicant to

discuss questions

STEP 3 – Practical preparations

Applicant team meet and stay locallyRehearse presentationspBrainstorm questions and responsesAgree assignments for handling questions on specific topicsAgree company position and negotiation scopeBrief/discuss with external experts in attendancepAvailability of printed materials / final presentation– 60 paper copies at least 2 hours before the OE meeting– Need printing capabilities for last minute changes

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CHMP delegate room

- Room holds max. 114 delegates

E h i h- Each station has a screen, microphone and headphones

- Lectern for presentation has link to the screens

- Videoconference facilities are available

-Presentation from laptop, USB drive, diskette, CD-Rom, Video, Slides, Transparencies.

- No mobiles !

Applicant may receive a seating plan

2005 edition of a seating plan

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CHMP attendees

- Chair (Dr Eric Abadie)Abadie)

- Vice Chair (Dr Tomas Salmonson)

- 1 Scientific expert member from each MS (and 1 alternate)

- 1 scientific member1 scientific member from NO and IS (observers)

- 4/5 co-opted members

STEP 4 – Oral Explanation

Expect a 60 minute meeting– Ensure concise presentation, limit presentation to 30 minutes, allow time

for questions. CHMP will likely have prepared some questions from the plenary sessionplenary session

– Address the chair person and the broader CHMP– Present outstanding issues in sequence individually– Describe key SmPC changes and proposed Commitments– Expect a science based question and answer session

Applicant leaves meeting room and waits– CHMP discuss Applicant presentation / responses– CHMP chair verifies CHMP trend opinion on approvability– PTL / Rapporteur provide initial feedback to the Applicant pp p pp

of ‘Trend’ / Orientation of CHMP– If scientific opinion is divided formal voting takes place

• 20/30 present for validity• Majority required ie minimum 16 votes

– Approvability is a Benefit:Risk evaluation

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Amgen experience of OEs

Amgen has 6 marketed centralised products. Only 2 have led to oral explanations prior to approval.

O &Vectibix had an OE at D180 & during re-examination.– First OE led to a negative opinion, upholding major objections– 2nd OE post SAG-O was positive

Aranesp had a positive OE– Met with BWP to resolve some outstanding CMC issues– OE had 2 OIs (Clinical and Safety), outcome successful

Four other marketed products had no OEsFour other marketed products had no OEs– Kepivance / Kineret / Mimpara / Neulasta

One product had no major objections prior to approval

Panitumumab MAA Chronology

Scientific advice Original application

Day 120responses

Day 180 responses

Oral Explanation

UK & NO Rapporteurs

Negative opinion

Request for re-examination

June 2007

Rapp meeting

July 2007

Detailed grounds for re-examination

July 2007

Rapporteur ARs

Aug 2007

SAG-O

Sep 2007

Oral Explanation

Sep 2007

2003 - 2006 May 2006 Dec 2006 Mar 2007 April 2007

FR & ES Rapporteurs

May 2007

SPC & FUM negotiations

19-21st Sep 2007

Final positiveopinion

20th Sep 2007

File MaintenanceSPC translationsCommission phase

19-21st Sep 2007

Commission Approval

Dec

FR & ES Rapporteurs UK & NO Rapporteurs

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OE experience contd

Dialogue has been positive and useful

CHMP has been well prepared for the meetingCHMP has been well prepared for the meeting

Can consider introductory/background aspects to presentations superfluous or limit content/time

Industry team preparation time is invaluable

Logistics can add stress

O t t di i t b dd d hOutstanding issues must be addressed here so ensure experts available

Approvability ?

Positive trend– PTL/Rapporteur de-brief applicant– Further SmPC / PIL modifications agreed in

a short timeframe (team empowered to make decisions !)– Revisions to commitments agreed

Negative trend– PTL/Rapporteur de-brief applicant– Options discussed

• Withdrawal• Appeal• No action

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STEP 5 – Finalising the CHMP Opinion

OE + 5d– Applicant sends final revised (English) product information

Letter of undertaking provided for commitments– Letter of undertaking provided for commitments

OE + 10d– PTL provides Rapporteurs with revised draft CHMP Assessment

report, Draft opinion, Draft Summary of opinion

OE + 25d– Rapporteurs provide feedback to PTL– Pre-final drafts provided to CHMP membersPre final drafts provided to CHMP members

Next CHMP Plenary session (DAY 210)– Adoption of CHMP opinion– Information becomes public

Withdrawals

Why– Applicant cannot answer questions / does not have complete

d t k t it ldata package to permit approval– ‘Business reasons’ - No longer an intention to pursue

marketing– Product rejected in another market with likelihood of same

scenario in EU. Corrective action to be taken.– CHMP has Major objections to approvability which are

unresolvable currently – insufficient time / lack of scientific understanding ?understanding ?

– New Safety signal post filing

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Withdrawals

When – An applicant can withdraw at any point throughout the review

lcycle.– If withdrawals take place prior to D120 no CHMP document

exists to help author the withdrawal EPAR (wPAR)– wPAR preparation coordination by PTL

• Refers to Day of procedure of withdrawal• Information presented for review• CHMP conclusion to date

R f ithd l i h li k t ithd l• Reason for withdrawal, inc. hyperlink to company withdrawal letter

• Consequence for patients eg safety risk identified in review, impact to clinical studies

Withdrawal statistics 129 withdrawals of 726 MAs; Decline in number of withdrawals from EMEA data

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Future of OE’s / Dialogue

Oral Explanations likely will continue to be an important part of the centralised approval process, especially where opinion is split within CHMP on ‘major deficiencies’split within CHMP on major deficiencies

As Medicines/Technology complexity increase will need to utilise the European expert community

Dialogue and interactions throughout the process will continue to be important

Science based dialogue will ensure applicant builds the trust of the PTL/ Rapporteurs/ CHMP

Applicants / EMEA / CHMP should consider the approval process a partnership that results in medicine delivery for patients

QUESTIONS ?QUESTIONS ?

Comments /Input from Dr Abadie