Developing Medicines For Paediatric Populations EU Perspective Didem Crosby Senior Regulatory Affairs Manager F. Hoffmann–La Roche Ltd

Disclaimer The specific cases cited in this presentation are merely examples, and should not be considered as generalisations for all PIP procedures in the EU. Opinions and observations presented are based on my personal experience and may not necessarily reflect the views of F.Hoffmann-La Roche.

Contents The EU Paediatric Investigation Plan (PIP) Procedure Strategic Considerations in the PIP era Adapting to the new way of thinking in the PIP era Conclusions

The EU Paediatric Investigation Plan (PIP) Procedure

The Paediatric Regulation (EC) No 1901/2006 Aims to bring a brighter future for child health … Resulted in a dramatic change for the industry [and the regulators]

The EU PIP Procedure 140 days (or max 290 d) EMEA validation (Summary report) 30 days + potential clock-stop for clarification PDCO evaluation and opinion 60 days Day 30 1st PDCO Day 60 2 nd PDCO discussion - OE possible - adoption of opinion or LoI Opinion from EMEA to applicant 10 days Opinion becomes definitive in 30 days EMEA decision 10 days Opinion to be extended maximum 60 days Day 61 updated Summary Report Day 90 3rd PDCO discussion Max Day 120 4th PDCO discussion - OE possible - adoption of opinion Clock-stop max 3 months OR request for re-examination PDCO new opinion …or 170 days (or max 320 d) Letter of intent 2 months earlier

What happens after PIP Decision in the EU? Trial is initiated and/or completed as per the PIP Approvals obtained if trial(s) needs to be adapted to new circumstances When results are available, they are submitted to the PDCO along with a compliance report for compliance check After (TBC) the compliance check by PDCO, submission to the CHMP occurs to extend the indication or to include paediatric data in the SmPC/PIL. Upon receipt of Commission Decision, Patent/SPC extension to be filed (and it has to be 2 years prior to patent expiry).

Strategic Considerations in the PIP era

Critical questions to answer (1) Is a PIP really required for your product? –Is there a therapeutic need in paediatics? What is your target indication in adults? Are you likely to have additional indications in the future? Does the disease/condition exist in paediatric population? (could you request a product specific or class waiver?) Which paediatric age groups are affected by the disease? (could you request a waiver for some age groups?) What other treatment options are available for this conditions? –Does your product fall under Art 7 or 8? Authorised: Patent type – does it have a SPC extension or is eligible for one? Unauthorised yet? If the product falls under article 8, are there plans to extend indication or to register a new formulation? What is the [commercial] value of the 6 months’ patent extension?

Critical questions to answer (2) When is the patent expiry? –[How] can you complete all the necessary PIP related steps before patent expiry? When to submit the PIP? –If the product is already authorised, long before the patent/SPC expires ( in most cases means “yesterday”) –If unauthorised, at the end of phase 1 or completion of adult PK studies. When can the paed development start? –Do you need adult data first, and how robust does it need to be? –Extrapolation from adults possible? Or include children in adult trials? –Can you perform adult and paediatric studies in parallel or do they need to be sequential? –Is deferral appropriate? To initiate or to complete the study(ies)?

Critical questions to answer (3) Feasibility of running studies in that therapeutic area? –Are there enough peadiatric patients in all relevant age groups to obtain “meaningful” results? –Is it likely that patients/parents will be willing to participate? –Are investigators experienced in clinical trial conduct and are they familiar with GCP requirements? Is there paediatric clinical expertise in-house? Would you benefit from a formal scientific advice before initiating the PIP procedure? Can you register the paediatric indication globally?

Adapting to the new way of thinking in the PIP era The new environment

Regulators as “approvers” of our development plans Pre-PIP era: Company takes advice on development plans Regulators express their Opinion Company decides whether to take it while considering global development, portfolio management, finance etc. If plans change, Company decides whether to discuss with the regulators. Company/regulator interactions continue when the results are available. PIP era Industry formally submits development plans Regulators approve a plan which may or may not be identical to the Company’s plans. (discussions may continue) Company follows the approved plan If plans need to change, Company needs to obtain approval from the regulators. Company/regulator interactions continue throughout the execution of the plan and when the results are available. A shift in regulators’ role from an advisory role to an approver of development plans

Paediatric development plans are only that: PLANS EMEA/PDCO acknowledges plans are plans and are subject to change. –Modification procedures are in place to accommodate changes in plans –Attempts available to adapt “flexible” Opinions. The Company knows plans will change – and it may be a drastic change: –results from adults may be required first –new therapies may become available between PIP approval and study start  may create a feeling the effort is wasted. Due to the uncertainties, teams find it challenging to come up with precise plans, i.e.: –Commit to recruit number of patients / each age group –Completion of the plan at a specific time point –Detailed analysis plan and study outcomes.

Pressure to aim for “meaningful” results Meaningfulness is a subjective criteria – even in science! Different interpretation of meaningfulness by the Companies and EMEA/PDCO. Company It is meaningful to understand safety, get an idea of efficacy in this limited number of available paediatric patients. EMEA/PDCO It is meaningful if you attempt to establish clinically significant efficacy, and safety in paediatric patients. Mutual target = not to subject children to unnecessary trials.

EU focused development plan for global products What is acceptable to US doesn’t always seem to be acceptable to the EU. –Could lead to separate [smaller] studies to address the requirements of the two territories? –EU focused PIP studies reflect the clinical practice in the EU, not necessarily the rest of the world  their use for registration in the RoW?

Team juggling between PDCO, external advisory bodies and Company decision-makers PDCODiscussions mainly focus on science External advisory bodies/experts Scientific and operational discussions Politics Company decision-makers Company’s global portfolio management Therapeutic needs vs business rationale Contradicting views between external clinical experts and PDCO members – whose opinion prevails? Companies tend to give the priority to allocate necessary resources to meet legal obligations. New part of the equation

The triangle: PDCO, Competent Authorities and Ethics Committees PDCO ECCA Which one comes first? (in an ideal world sequential: PDCO  CA+EC) –Are the investigators willing to wait for 2-3 yrs before starting the trial from initial agreement to participate in study? Losing motivation? CAs requested modification to the protocol on safety grounds – needs to be discussed with PDCO? PIP to be modified? Cases of EC requesting PDCO approval for a paediatric study – not all paediatric studies are subject to approval by PDCO!

PIP Opinion/Decision is only the beginning In MA procedures Opinion/Decision = –A [tired] team that kept going for ~1 yr throughout the procedure –Achievement, success –Launch preparations –Celebrations ! = New project for the team In PIP procedures Opinion/Decision = –A [tired] team that kept going for ~1 yr throughout the procedure –Close monitoring of the study –Subsequent procedures, i.e. modifications, withdrawals –Continued resource allocation for as long as 5-7 years –Constant pressure to meet the conditions of the PIP until the compliance check is completed (could extend until patent/SPC expiry). = “Same” project goes on for years

Pressure for the reward Keep protocol aligned with the PIP to avoid risk of non-compliance  Potentially could lead to ~1-2 PIP modifications/year (each lasting ~6 months)  [Legal] definition of non-compliance (can be blur in some cases). If patent/SPC expiry is close, ensure study results don’t get delayed. –Particular challenge for products falling under the scope of Art 8! Avoid incompliance or inconclusive studies: i.e. major GCP violations, fraud occur for most patients –Not a major concern as industry standards strictly follow GCP.

Conclusions The Paediatric Regulation requires companies to commit to long-term investment (funding and resources) Teams need to establish a paediatric plan from a very early stage of development When plans need to change, approval from regulators must be sought in order not to risk compliance Teams need to develop creative ways to establish and execute paediatric development plans Both the PDCO and the industry is going through a steep learning curve = be prepared to adapt to changes at all times! Remember: after all, it could be your children benefiting from these ethically researched and authorised medicines in the future!

EU paediatric regulation: 1/reg_2006_1901/reg_2006_1901_en.pdfhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol- 1/reg_2006_1901/reg_2006_1901_en.pdf