PIP ModificationsW k hWorkshop

C il Olli i & A lik JCecile Ollivier & Angelika JoosCo-Chairs

23/10/2009

The views and opinions expressed in the following PowerPoint slides are those of

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Please note that the case used for this workshop is only used for illustrative purposes and does not contain any real data.

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PIP for pandemic influenza vaccines

• Condition: Influenza• Proposed PIP indication: prevention ofProposed PIP indication: prevention of

infection by influenza virus in the context of pre pandemic and pandemicscontext of pre pandemic and pandemics

• Waiver: < 2 monthsD f l f 2 6 th• Deferral for 2-6 months

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Key binding elements

• 1 prospective open-label single-arm study• At least 300 patients

– At least 50 2 < 6 m– At least 50 6 < 12 m

At least 50 12 m <3y– At least 50 12 m <3y– At least 50 3 < 9 y– At least 50 9 <18 y

• Initiation: no later than Dec 2009• LPLV no later than May 2010

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Key binding elements

• Safety-follow up for 6 months as part of RMP– At least 4000 patients

• At least 500 = 2 m < 2 yAt least 500 2 m < 2 y• At least 500 = 2 < 9 y• At least 3000 = 9 < 18 y

– Specific AEs of interest:Specific AEs of interest:• febrile convulsion, • polyneuropatie incl. Guillain-Barre syndrome

• If the safety profile of different doses is notIf the safety profile of different doses is not satisfactory immediate interaction with EMEA/PDCO is required.

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Questions on each issue

• Do you need a modification?• When should you submit yourWhen should you submit your

modification request?

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Issue # 1: initiation of study

• You have obtained NCA and EC approval in USA, which allows site pp ,ready in Dec 2009.

• There are still outstanding CTA and ECThere are still outstanding CTA and EC approvals in several other EU countries.

• The FPE in the US site is on January• The FPE in the US site is on January 17, 2010.

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Issue # 2: AEs

• During the first days of enrollment in the US you discover that the highest y gvaccine dose triggers more safety reports in children than you would p yexpect.

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Issue # 3: enrollment

• By April 2010 you have enrolled 280 patients worldwidep

• 2 < 6 m = 15• 6 < 12 m = 60• 12 m <3 y = 70• 3 < 9 y = 45• 9 <18 y = 90

• LPLV is targeted for 28 May 2010

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Issue # 4: GCP violation

• During the monitoring of the study you discover that one site in South America had stored the vaccines under wrong conditionsstored the vaccines under wrong conditions for 4 hours.

• 10 children 6 < 12 m were vaccinated, but did not observe any AEsnot observe any AEs.

• Nevertheless, this GCP violation warrants that the subjects are excluded from the data janalysis.

• Enrollment of additional 10 children 6 < 12 m will move LPLV to 2 June 2010

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will move LPLV to 2 June 2010.

Issue # 5: initial application

• Your initial MA submission is planned for 15 July 2010.y

• How should you plan modification and compliance checks?compliance checks?

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Issue # 6: Safety follow-up

• 4100 children were included in a 6 month safety follow-up, including 505 y p, gbetween 2 m < 2 y

• In November 2010 you realise that 10In November 2010, you realise that 10 of these patients did not come to their scheduled follow-up visit because theyscheduled follow up visit, because they had moved to another country.

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Issue # 7: Multiple issues

• Do you need one modification or several modifications?

• Which modification(s) can not be submitted with others modifications

• Which modifications would you submit together?

• When should you submit your modification(s) request(s)?

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E ll t iEnrollement issues

• Competing trials• Complexity of paediatric trials (e g :Complexity of paediatric trials (e.g.:

parent(s) or legal guardian(s) to make decisions about trial participation)decisions about trial participation)

• Higher screening failure rate than expectedexpected

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L i ti l iLogistical issues

• Outstanding CTAsOutstanding CTAs• Longer approval by Ethics Committees

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P l iProtocol issues

• Requirement to study the non-interference of your vaccine with the yability to respond to other vaccination

• Vaccination schedule with 2 injectionsi t l 21 d t ( i t lapproximately 21 days apart (an interval

of 20 to 35 days is acceptable)

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T i th it tiTo summarise the situation

• Due to all those issues, your company is starting to work on a revised protocol, g p ,you are not sure when it will be ready

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Recommendations

• To anticipate• To planTo plan• To liaise with your EMEA coordinator

T k i th li ti• To work in the compliance perspective

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Accronyms

PIP Paediatric Investigational PlanRMP Risk Management PlanPDCO Paediatric CommitteePDCO Paediatric CommitteeNCA National Competent AuthorityEC Ethics CommitteeCTA Clinical Trial ApplicationFPE First patient enrolledGCP G d Cli i l P tiGCP Good Clinical PracticeMA Marketing authorisationLPLV Last patient last visit

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LPLV Last patient last visit

European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use

7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 40

E-mail: mail@emea.europa.eu http://www.emea.europa.eu

Doc. Ref. EMEA/PDCO/xxxxxx/200x EMEA-xxxxxx-PIPxxx-yy

OPINION OF THE PAEDIATRIC COMMITTEE ON THE AGREEMENT OF

A PAEDIATRIC INVESTIGATION PLAN AND A DEFERRAL AND A WAIVER Scope of the application Active substance(s): Vaccine strain(s) (Invented) name: DIA Condition(s): Influenza Pharmaceutical form(s): Suspension for injection Route(s) of administration: Intramuscular use Name/corporate name of the PIP applicant: DIAOct09 Basis for opinion Pursuant to Article 16(1) of Regulation (EC) No 1901/2006 as amended, DIAOct09 submitted for agreement to the EMEA on {date} an application for a paediatric investigation plan for the above mentioned medicinal product and a deferral under Article 20 of said Regulation and a waiver under Article 13 of said Regulation. The procedure started on {date}.

EMEA/PDCO/xxxxxx/200x Page 2/11

Opinion 1. The Paediatric Committee, having assessed the proposed paediatric investigation plan in accordance with Article 17 of Regulation (EC) No 1901/2006 as amended, recommends as set out in the appended summary report:

• to agree the paediatric investigation plan in accordance with Article 18 of said Regulation,

• to grant a deferral in accordance with Article 21 of said Regulation,

• to grant a waiver for one or more subsets of the paediatric population in accordance

with Article 13 of said Regulation and concluded in accordance with <Article 11(1)(a) of said Regulation, on the grounds that the specific medicinal product is likely to be ineffective or unsafe in part or all of the paediatric population> <Article 11(1)(b) of said Regulation, on the grounds that the disease or condition for which the specific medicinal product is intended occurs only in adult populations.> <Articles 11(1)(b) of said Regulation, on the grounds that the disease or condition for which the specific medicinal product is intended does not occur in the specified subset(s) of the paediatric population.> <Article 11(1)(c) of said Regulation, on the grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for paediatric patients.>

<The Icelandic> <and> <the Norwegian> Paediatric Committee member(s) <do (does) not> agree(s) with the above-mentioned recommendation of the Paediatric Committee. <The <Icelandic> <and> <Norwegian> divergent position(s) is (are) appended to this opinion.> 2. The measures and timelines of the agreed paediatric investigation plan and the subset(s) of the paediatric population and condition(s) covered by the waiver are set out in the Annex I. This opinion is forwarded to the applicant and the Executive Director of the Agency, together with its annex(es) and appendix. London, {date} On behalf of the Paediatric Committee Dr Daniel Brasseur, Chairman

EMEA/PDCO/xxxxxx/200x Page 3/11

ANNEX I

THE MEASURES AND TIMELINES OF THE AGREED PAEDIATRIC INVESTIGATION PLAN AND THE SUBSET(S) OF THE PAEDIATRIC POPULATION AND CONDITION(S)

COVERED BY THE WAIVER

EMEA/PDCO/xxxxxx/200x Page 4/11

A. CONDITION(S) Influenza

B. WAIVER • Condition

Influenza

The waiver applies to: Children from birth to less than 2 months − <All subsets of the paediatric population from birth to less than 18 years of age.>

<Preterm newborn infants>, <Term newborn infants (from birth to less than 28 days)>, <Infants and toddlers (from 28 days to less than 24 months)>, <Children (from 2 to less than 12 years)>, <Adolescents (from 12 to less than 18 years)> <other subset(s)>

− for DIA, suspension for injection, intramuscular use; − <on the grounds that the specific medicinal product is likely to be ineffective.>

<on the grounds that the specific medicinal product is likely to be unsafe.> <on the grounds that the disease or condition for which the specific medicinal product is intended does not occur in the specified paediatric subset(s).> <on the grounds that the specific medicinal product does not represent a significant therapeutic benefit as clinical studies(s) are not feasible.> <on the grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments.> <on the grounds that the specific medicinal product does not represent a significant therapeutic benefit as the needs are already covered.> <on the grounds that clinical studies cannot be expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the paediatric population.>

C. PAEDIATRIC INVESTIGATION PLAN

• Condition to be investigated

Influenza

• Proposed PIP indication

Prevention of infection by pandemic influenza virus (H1N1 strain) in the context of a pandemic

• Subset(s) of the paediatric population concerned by the paediatric development From 2 months to less than 18 years.

• Formulation(s) Suspension for injection, intramuscular use

EMEA/PDCO/xxxxxx/200x Page 5/11

• Studies

Area Number of studies Description

Quality Suspension for injection

Non-clinical Not applicable.

Clinical • Immunogenicity and Safety Study of an Intramuscular vaccine in Healthy Children and Adolescents Aged 3 to 17 Years

• Immunogenicity and Safety Study of an Intramuscular vaccine in Healthy Infants and Toddlers Aged 6 to 35 Months

• Immunogenicity and Safety Study of an Intramuscular vaccine in Healthy Infants Aged 2 to 6 Months

Measures to address long term follow-up of potential safety issues in relation to paediatric use: Yes

Date of completion of the paediatric investigation plan: By May 2010

Deferral for some or all studies contained in the paediatric investigation plan: Yes

EMEA/PDCO/xxxxxx/200x Page 6/11

1. STUDIES TO BE PERFORMED ACCORDING TO THE SPECIFIED TIMELINES FOR INFLUENZA

• PHARMACEUTICAL FORM

Suspension for injection, intramuscular use Timeline for completion: by <month> <year>.

• NON-CLINICAL

Not applicable.

Type of study

Objectives

Test system/species (age of the animal) <and model if relevant >

Age of the animals should be included. In general do not include strain. No need to include number of animals.

Route of administration and doses

Include the dose only as appropriate.

Duration of dosing

Initiation

By <month> <year>

Completion

By <month> <year>

• CLINICAL

Study identifier(s) Standard PIP non adjuvanted / known adjuvant

Type of study, study design Prospective open-label single-arm study

Study objective(s) (Dose-finding,) immunogenicity and tolerability study

Study population and subset definition (incl. stratification)

Children and adolescents from 2 months to less than 18 years. (This may be part of a combined adult and paediatric study/investigation.)

Number of study participants by paediatric subset (e.g., age, sex, stratum)

At least 300 total participants in five subsets of 2 months to less than 6 months (at least 50), 6 months to less than 12 months (at least 50), 12 months to less than 3 years (at least 50), 3 to less than 9 years old (at least 50), and 9 to less than 18 years old children and adolescents (at least 50) must1 be investigated.

Main inclusion criteria Healthy children and adolescents from 2 months to less than 18 years old

Main exclusion criteria Study duration (by each phase, incl. run-in, active treatment and follow-up)

EMEA/PDCO/xxxxxx/200x Page 7/11

Dosage, treatment regimen, route of administration

Vaccination schedule with 2 injections approximately 21 days apart (an interval of 20 to 35 days is acceptable), and with at least a 14-day interval from other vaccines. In infants from 2 months to 6 months of life the first dose must be given between 2 and 2.5 months of life (before other vaccines). For adjuvanted vaccines, if data on reactogenicity are not available in children from 6 to 36 months, infants from 2 to less than 6 months must not be included in the study before reactogenicity has been assessed in the older subset (interim analysis after the second injection). (Preliminary data could indicate that for a second step a one dose-priming schedule may suffice for part or most of the population. A 1-dose + placebo approach could be explored in this second stage) Booster: Among the participants of all subsets (in at least 30 for each subset as above, which must include all patients being tested for NT in each group), a booster dose must be studied. (The booster will be administered 6 or 12 months after the first vaccination [priming], depending on the evolution of the pandemics [attack rate remains low or slow in phase 6]. The objective is to identify the potential need for boosting in all or part of the paediatric population and to measure antibody persistence.) Sampling approach Before each of the 2 vaccine doses and after the 2nd dose, a blood sample is to be collected, i.e. at day 0, immediately before the second dose, and 20-40 days after the second dose (3 samples in total) for immunogenicity. Pre- and postbooster samples must also be drawn in the boosted participants. for measurement of HI or SRH as primary endpoint, and NT in all included patients that were previously tested for NT.

Control(s) No control arm

Primary endpoint(s) with time point(s) of assessment

Immune responses after second injection, to be assessed using the so-called CHMP criteria for influenza vaccines (haemagglutination-inhibition [HI] assay or SRH [SRH preferred] in all participants) Immunogenicity sample collection must be done pre and post vaccination.

Other outcomes with time points of assessment

• Neutralisation test [NT] after first and second injection (the three samples must be drawn from the same subjects) in: − at least 30% of participants for each subset of children 3 years and older; − at least 50% for those 6 months to less than 3 years; − at least 90% of those 2 to less than 6 months. • HI or SRH (SRH preferred) after first injection in at least 90% of participants. • Pre- and postbooster immunogenicity by HI or SRH; pre- and postbooster NT in all included patients that were previously tested for NT.

Main secondary endpoint(s) with time(s) of assessment

EMEA/PDCO/xxxxxx/200x Page 8/11

Statistical plan Include the population analysis (Intent to treat – per protocol. Include if interim analysis(es).

Stopping rule(s) Only if specific for the trial.

Rescue treatment Only if appropriate.

Measures to minimise pain and distress

(Only if specific.)

Plan for specific follow-up Safety Safety endpoints should be collected using the same protocol for data collection as for the prospective cohort study described in the CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be submitted with the Marketing Authorisation Application for Pandemic Influenza vaccines – Rev. 1 (EMEA/359381/2009). (Based on the interim safety and immunogenicity data collected during the investigations of an adjuvanted vaccine, both full dose and at least one lower dose might have to be investigated simultaneously in different study arms. If the safety profile of the full dose raises major concerns, the full dose may be omitted.) See also specific measures below. Effectiveness The end-point for effectiveness must be determined based on the options proposed, namely a best combination of ECDC recommendations (protocols available in June 2009), and national plans, including availability.

External Data Safety Monitoring Board

No Safety to be reported as per Risk Management Plan Should be foreseen

Date of initiation No later than December 2009 <after the benefit/risk is established in adults/subsets> <after completion of>

Date of completion (last patient, last visit)

By May 2010

Studies and trials have to be registered with the EudraCT database. All investigational medicinal products used in the studies or trials must be registered in the EudraVigilance Medicinal Product Dictionary by the sponsor. 2. SPECIFIC MEASURES FOR LONG TERM FOLLOW-UP OF POTENTIAL SAFETY

ISSUES AND EFFICACY IN RELATION TO PAEDIATRIC USE TO BE PROPOSED AT THE TIME OF SUBMISSION OF THE RELATED APPLICATION

Safety Measures to monitor safety of the vaccines must be implemented as per the CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be submitted with the Marketing Authorisation Application for Pandemic Influenza vaccines – Rev. 1 (EMEA/359381/2009). Once the vaccine is in use, at least 4000 children in 3 cohorts of infants 2 months to less than 2 years (at least 500), children from 2 years to less than 9 years (at least 500) and 9 to less than 18 years (at

EMEA/PDCO/xxxxxx/200x Page 9/11

least 3000), must be included in a safety cohort and followed for at least 6 months after the last dose. Adverse drug reactions of special interest (e.g. febrile convulsion, polyneuropathies including Guillain-Barrè syndrome) must be explicitly identified and reported. Case control studies could be necessary and screening method studies might be helpful to detect modifications of vaccine effectiveness over time (e.g. the strains drifts). All available pre-authorisation data on immunogenicity and safety must be included in the Safety Specification of the RMP. Immunisation of pregnant women and paediatric use of vaccines Special attention should be given to pregnant women. Babies born during a pandemic period are at risk unless the mother is efficiently protected. Maternal vaccination should be considered, with the aim of not only documenting maternal antibody response, but also vaccine impact on acquired neonatal antibodies, and clinical development of the newborn. 3. REMINDER Studies and trials have to be registered with the EudraCT database. All investigational medicinal products used in the studies or trials must be registered in the EudraVigilance Medicinal Product Dictionary by the sponsor. Studies or trials which are inconclusive or not interpretable will be considered non-compliant. The Clinical trials should be performed in accordance with Good Clinical Practices and for those conducted outside the community they should be carried out in accordance with the ethical standards of Directive 2001/20/EC. The Applicant must ensure that measures to minimise pain and distress are implemented during the whole paediatric development.

EMEA/PDCO/xxxxxx/200x Page 10/11

<ANNEX II

INFORMATION ABOUT THE AUTHORISED MEDICINAL PRODUCT>

EMEA/PDCO/xxxxxx/200x Page 11/11

EU Number Invented name Name

Strength Pharmaceutical form

Route of administration Packaging Content

(concentration)Package size

Procedural Advice question 14: http://www.emea.europa.eu/htms/human/paediatrics/pips_procedural.htm#14

How do I apply for a modification of an agreed PIP?

If you wish to submit a request for modification of an already agreed PIP, a procedure similar to the submission of the initial application for Paediatric Investigation Plan/waiver applies.

1. A letter of intent, normally to be sent 2 months before the planned submission date of the complete application for modification of an agreed PIP, should be sent as for an initial application. The letter of intent shall cite the original EMEA PIP number and the date and number of the latest EMEA decision. The scope of the proposed modification of the agreed PIP shall be briefly summarised.

2. Applicants will be informed of the names of the assigned Rapporteur, Peer Reviewer and the EMEA Paediatric Coordinator immediately after start of procedure, when they will also receive the EMEA number for the modification procedure. This number should then be clearly mentioned on all related correspondence. As far as possible, the PDCO will appoint the same Rapporteur and Peer Reviewer for the modification procedure as for the initial PIP application(s). The PDCO may involve, if necessary, additional experts. The paediatric co-ordinator will also remain the same, as far as possible.

3. Applicants should submit their application according to the published deadlines for submission, which have been set according to the Paediatric Committee (PDCO) meetings. Applicants should submit the application to the EMEA and to all PDCO members and alternates at the same time, in parallel. The requirements are analogous to those for the initial application.

4. The application should include the request for modification of an agreed paediatric investigation plan, a new electronic application form (part A, as for initial PIP application), and the supporting scientific documentation. The scientific documentation should follow the same structure as for an initial paediatric investigation plan (parts B-E), but only the relevant sections supporting the change should be completed. The need / rationale for the modification of the agreed PIP should be clearly indicated in the request for modification of an agreed paediatric investigation plan.

5. The draft Summary Report will be sent to the applicant for information after the first discussion (Day 30). The PDCO may invite the applicant for a teleconference, or for an oral explanation. The PDCO shall adopt an opinion at day 60, refusing or accepting the proposed changes. The updated annex of the PDCO Opinion will not simply address the agreed modifications, but it will list all the measures and timelines of the new agreed PIP: the unchanged ones and those newly modified (including timelines).

6. The EMEA will forward the opinion, including the summary report, to the applicant. The post-opinion phase and the decision making phase will follow the same procedures as for the initial PIP application. When publishing the decision on a modification of an agreed PIP, the original decision, being superseded, will be removed from the EMEA website.

European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use

7 Westferry Circus, Canary Wharf, London, E14 4HB, UK

Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 40 E-mail: mail@emea.europa.eu http://www.emea.europa.eu

REQUEST FOR MODIFICATION

OF AN AGREED PAEDIATRIC INVESTIGATION PLAN 1 Please add some information relevant to this application EMEA (agreed) PIP number: Date of the latest EMEA decision(s) on the PIP: EMEA decision number: A copy of the EMEA decision should be annexed. 2 Reasons for applying for a modification of the EMEA decision (Please provide the main reasons in the table below [ref. Art. 22]. The detailed scientific justification should be provided in the relevant documentation. Tick all that apply.) Is the modification required for administrative changes?

Yes No Is the modification required for changes in either measures or timelines as stated in annex I of the decision?1

Yes No If yes, please specify:

Changes in the timelines as stated in annex I of the Decision

Changes in the measures as stated in annex I of the Decision, specified as follows:

New/changed WAIVER request (tick all that apply) New/changed condition or indication Change in subset(s) of the paediatric population, pharmaceutical form(s) and route(s) of administration covered

Modification of the PAEDIATRIC INVESTIGATION PLAN (tick all that apply)

Additional new condition/indication to be investigated Modification of condition/indication to be investigated Modification of subset(s) covered Change in formulation(s) Modification of key binding elements (not time lines) of studies/measures

Other (please specify: )

1 Modifications may not be necessary for changes that increase the scientific strength as per the current key binding elements, e.g., double-blind instead of open-label study, or changes that would no impact compliance check, such as “210 patients evaluable” when the key binding element was “At least 175 evaluable patients”.

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3 Please provide a list of the modification(s) of the measures and timelines as stated in the annex 1 of the Decision (only include measures/timelines to be modified; add more lines in the table, if necessary)

Current key binding element

Proposed change(s) Justification for change (max. 250 words) (include number of section in the scientific documentation)

4 Please specify which part(s) of the scientific documentation have been modified and are

submitted (Parts B to F) Please indicate which are all the revised sections of the documentation (tick all that apply)

Part A; please specify the relevant sections Part B; please specify the relevant sections Part C; please specify the relevant sections Part D; please specify the relevant sections Part E; please specify the relevant sections Part F

Date ___________________________________ Signature ____________________________________