# Presentation: 201908

## European Paediatric InitiativeExperience in Oncology

- Dr Agnès Saint Raymond
- & Dr Ralf Herold
- Scientific Advice, Paediatrics and Orphan Drugs Sector
- European Medicines Agency, EMEA
- FDA April 16 2008

## Objectives of the Regulation 

- Improve the health of children
- Increase high quality, ethical research into medicines for children
- Increase availability of authorised medicines for children
- Increase information on medicines
- Achieve the above
- Without unnecessary studies in children
- Without delaying authorisation for adults

## Main pillars

- Creation of a **Paediatric Committee**
**Measures for new/patented drugs**
**Measures for off-patent drugs**
**Paediatric Investigation Plans**
- Many other measures (information and transparency)

## Main pillars

**Creation of a Paediatric Committee**
- Expert Committee
- Mix of Academics and Agencies employees, including paediatric oncologists
- Meeting monthly at EMEA
- Scientific decisions
**Measures for new/patented drugs**
**Measures for off-patent drugs**
**Paediatric Investigation Plans**
- Many other measures (information and transparency)

## Paediatric Committee

**5 members from Approval Committee (CHMP)**
**22 representatives from other Member States **
**3 Patients/families’ representatives***
**3 Health Professionals representatives***

**1 elected  Chair**

**still to be appointed*

## Main pillars

- Creation of a **Paediatric Committee**
**Measures for new/patented drugs**
**Measures for off-patent drugs**
**Paediatric Investigation Plans**
- Many other measures (information and transparency)

## New drugs before approval

- Obligation to submit _results_ of _agreed_ Paediatric Investigation Plan (PIP)
- At time of Marketing Authorisation Application, OR Deferral of studies, OR Waiver of development
**Reward**: 6-month extension of the patent
**Conditions**:
- compliance with PIP
- results in product information
- approval in all Member States

## On-Patent marketed Drugs

- Obligation to submit _results_ of _agreed_ Paediatric Investigation Plan (PIP)
- When applying for new indication, new route of administration, and/or new formulation
- OR deferral of studies, OR waiver
**Reward**: 6-month extension of the patent
**Conditions**:
- compliance with PIP
- results in product information
- approval in all Member States

## Orphan drugs

- Among orphan drugs, 15-20% are for diseases only affecting children, 55% for diseases affecting both adult and children*
- Orphan drugs receive 10 years of market exclusivity in EU
- Orphan drugs must submit a Paediatric Investigation Plan
- Orphan drugs can get 2 additional years of exclusivity when they comply with PIP
- * *EU orphan designation data*

## Off-patent drugs

- Paediatric Use Marketing Authorisation (PUMA)
**Optional**
- Covers Paediatric Indication and Formulation
- Need for agreed Paediatric Investigation Plan
- Need for compliance and results in Product information
**Incentive**: Data protection of 10 years (*as for new products in EU*)

## Main pillars

- Creation of a **Paediatric Committee**
**Measures for new/patented drugs**
**Measures for off-patent drugs**
**Paediatric Investigation Plans**
- Many other measures (information and transparency)

## Paediatric Investigation Plan (PIP)

- Paediatric Investigation Plan proposed by company
- By end of phase 1 for new products
- Plan is discussed, modified, and agreed/refused by Paediatric Committee
- Followed by EMEA Decision
- Binding on company

## Paediatric Investigation Plans

- Define necessary data on Quality, Safety and Efficacy for use in the paediatric population   (0 – 18 years)
- _No explicit link with adult indication_
- Specify development timelines, including deferral of studies
- Define age-appropriate formulation
- Results according to agreed plan serves as basis for approval

## PIP Waivers/Deferrals

- On request from applicant or initiative of Paediatric Committee, for all or part of the paediatric population:
- _Waiver_ of development for ‘classes’ of indications, or for a specific product
- _Deferral_ of initiation of studies and/or completion
*Development is most often a combination of a plan with deferrals and waivers (population subset)*

## Life cycle of a Paediatric Investigation Plan

- Non-clin

- Phase 1

- Phase 2

- Phase 3

- Post Approval

- Modifications

- Paediatric Committee

**MA**

**PIP**

**Compliance**

## Life cycle of a Paediatric Investigation Plan

- Non-clin

- Phase 1

- Phase 2

- Phase 3

- Post Approval

**Compliance**

- Modifications

- Paediatric Committee

**MA**

**PIP**

- With deferral

## Applications and Indications

- Each PIP corresponds to an active substance (or a combination) from a company
- Each PIP usually covers more than one indication (e.g. high grade glioma and neuroblastoma)

## PIP and Waivers Applications

- August 2007 – April 2008:
- All Indications: 	326
- PIP/Waiver applications: 	178
*Authorised products*: 	*30 %*

- Update 3/18/2008

## PIP Therapeutic areas (%)

- CNS						6
- Cardiovascular				10
- _Oncology_					14
- Anti-infectives 				10
- Endocrinology / metabolism 	21
- Immunology / vaccines		11
- Other						28

## Oncology PIPs*

- Active substances
- Total 	18
- New: 	9
- Authorised:	9
- Cytotoxic / established / conventional: 	9
- Non-cytotoxic / innovative: 					6
- Supportive (antiemetics, growth factors) 3
- Written requests: 	8
- 	* Exclude full Waivers

- Update 3/18/2008

## Oncology PIPs*

- Number of conditions / indications in oncology (15 active substances):
- Total: 	52
- Adult condition only 	24
- Paediatric condition only 	26
- Front line-treatment 		11
- Relapse treatment 		15
- Adult and paediatric  	2
- * Excludes full waivers

## Class Waivers

- Published:
- Oropharyngeal epithelial cancer
- Lung cancer (small cell and non-small cell)
- Basal cell carcinoma
- Breast carcinoma
- Ovarian carcinoma
- Endometrial carcinoma
- Prostate carcinoma
- Hairy cell leukaemia
- Multiple myeloma

## Issues with PIPs/Waivers in paediatric oncology

- Low incidence for condition but exists
- Definition of condition
*Wider name = extended scope *
- Lower age range for studies:
- Glioma, neuroblastoma, rhabdomyosarcoma
*Which is the appropriate cut-off: 0 – 6 mo – 1 – 2 - 3 years? *
*Which minimal age for relapse / refractory disease? *

## Oncology PIPs

- Paediatric trials for 15 active substances:
- Completed 	17
- Proposed, ongoing 	6
- Total _per active substance_ 	~ 1.5
- Collaborative paediatric oncology group 	~ 6
- Proposed and _planned_ trials
- Phase 1/2 	4
- Phase 2 single arm 	10
- Phase 3 	4
- Combination therapy studies 	8
*Additional to Written Requests (n=3) **	**2*

## Paediatric condition/indication 

- Rhabdomyosarcoma 	3
- Non-RMS soft tissue sarcomas 	2
- Ewing sarcoma 	2
- Neuroblastoma 	3
- High-grade glioma (HGG) 	5
- Brainstem HGG 	1
- Leukaemia 	2
- Lymphoma 	2
- Carcinoma 	2
- Melanoma 	2
- ‘Any solid tumours’		3
*First-line treatment**	**	**	**10*
*Treatment of relapse or refractory disease **	**9*

## More Issues

- No corresponding development in adults (no proof-of-concept)
- Neonates: waiver very often requested
- Non-clinical data : highly variable level of details
- Models of paediatric tumours?
- Study design choice
- Studies deferred not described: Lack of overall strategy

## Slide 27

|  | US BPCA | US PREA | EU |
| --- | --- | --- | --- |
| Development | Optional
 | Mandatory if likely to be largely used and/or meaningful benefit | Mandatory
Optional for off-patent |
| Instrument | Written Request | - | Paediatric Investigation Plan |
| Timing  | End of phase 2 | End of phase 2 | End of phase 1 |
| Reward | 6 months exclusivity | - | 6 months patent |
| Drugs (section 505) | Yes
With exclusivity | Yes | Yes
 |
| Biologicals (most) | No | All | All |
| Orphan | Excluded  | Excluded  | Included  |
| Decision | FDA | FDA | EMEA Paediatric Committee |

## Main pillars

- Creation of a **Paediatric Committee**
**Measures for new/patented drugs**
**Measures for off-patent drugs**
**Paediatric Investigation Plans**
- Many other measures (information and transparency)

## Transparency measures

- PUBLIC ACCESS to:
- Decisions on Paediatric Investigation Plans
- Summary of content
- Timelines
- Results in Product Information
- Publication of Assessment Reports (public outcome of evaluation)

## Transparency measures

- PUBLIC ACCESS to EU Database of all clinical trials (*called EudraCT)*:
- protocol-related information
- results-related information
- All trials with at least a study site in EU
- All those performed outside EU if included in a Paediatric Investigation Plan

## Other measures

- Establishment of an EMEA network of paediatric research networks (*in particular paediatric oncology groups e.g. SIOP, ITCC*)
- Inventory of all paediatric uses of medicines in Member States
- To help define ‘paediatric needs’ for future Paediatric Investigation Plans

## Public funding for studies on off-patent drugs

- Off-patent drugs on EMEA Priority List of about 60 drugs
- EU funding (Framework Programme)
**	****~ **20-30 million Euros available in 2007
- 5 projects funded
- New call for proposals in July 2008

## TAKE HOME MESSAGES

- Successful implementation
- Paediatric oncology as a model:
- Consider Mechanism of action/Target of a drug rather than Adult indication
- Lack of Proof of concept in adults/ in children
- Lack of models of paediatric tumours
- Age groups to be included in trials
- Weak level of evidence proposed
- Collaborative approach highly needed

## Slide 34

## CHMP: Committee for Human Medicinal Products (EMEA ‘approval’ Committee)
CT: Clinical Trial(s)
EMEA: European Medicines Agency (ww.emea.europa.eu)
EU: European Union
EUDRACT: European Database of Clinical Trials
European Commission (pharmacos.europa.eu)
GCP: Good Clinical Practice
ICH: International Conference on Harmonization
MA: Marketing Authorisation (Drug Approval)
MS: Member State
PIP: Paediatric Investigation Plan
PUMA: Paediatric Use Marketing Authorisation

- CT: Clinical Trial(s)
- EMEA: European Medicines Agency (_**ww.emea.europa.eu)**_
- EU: European Union
- EUDRACT: European Database of Clinical Trials
- European Commission (_**pharmacos.europa.eu)**_
- GCP: Good Clinical Practice
- ICH: International Conference on Harmonization
- MA: Marketing Authorisation (Drug Approval)
- MS: Member State
- PIP: Paediatric Investigation Plan
- PUMA: Paediatric Use Marketing Authorisation