An agency of the European Union

ATMPs guideline on Safety and Efficacy follow-up and risk management

Presented by Caroline Voltz-Girolt EMA Product Lead - Oncology, Haematology and Diagnostics Office Scientific and Regulatory Management Department

The views expressed in this presentation are personal and do not represent the EMA and its Committees and/or Working Parties

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Basis and Context - the regulator’s perspective

•  A MA is granted based on a positive Benefit-Risk balance

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Product development Marketing Authorisation

(MA)

•  Generating Quality, Safety, Efficacy data - defining the safety and efficacy of the product

Full

MAA

• Annex II: •  PAES delegated act: •  (a) surrogate endpoints •  (b) combination •  (c) sub populations •  (d) long term efficacy •  (e) real –life conditions (vaccines)

•  (f) change of standard of care

•  (g) new scientific factors

•  PASS

Exce

ptio

nal c

ircu

mst

ance

s •  Specific obligations

•  Comprehensive data cannot be provided based on rarity

•  Based on scientific grounds)

•  Ethics

•  B/R positive •  Comprehensive data

will never be provided

Con

ditio

nal M

A

• Specific Obligations:

•  Seriously debilitating / life threatening diseases

•  Emergency •  Orphans

•  B/R positive; •  Comprehensive data

will be provided; •  Unmet medical need •  Public health benefit

outweighs the risks

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- Additional evidence needed for aspects key to B/R - Potential changes to PI

Annual re assessment

Need for annual renewal

Basis and Context - tools

Basis and Context - the regulator’s perspective

•  A MA is granted based on a positive Benefit-Risk balance

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•  Risks identified during the evaluation of a MA should be minimised and/or further characterised (Post-Authorisation Safety Study (PASS))

Marketing Authorisation (MA)

Post-marketing

ATMP guideline on S&E Follow-up and risk management

•  Published in 2008, currently under revision

•  Efficacy and safety follow-up as part Art. 14 of ATMP Reg.

•  Scope:

–  Specific safety concerns for ATMPs

–  Guidance on risk minimisation measures

–  Methodology to design and set up PASS/PAES with specific S&E objectives

–  Pharmacovigilance system –  Management and reporting

of AEs and PSURs

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500006326.pdf

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ATMPs specific

Study designs

Risk minimisations Pharmacovigilance

A multidisciplinary guideline

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Ensure agreements are in place with different parties (when applicable): •  Hospitals •  Blood and tissue establishment •  Registry owners •  Raw materials/starting materials manufacturers •  Medical device manufacturers •  Patients: o  To allow the use of patients’ data collected in clinical trials,

compassionate use programmes or through registries for regulatory purposes.

o Obtain signed informed consent forms to allow for these data to be provided for the agreed regulatory purposes

Recommendation – Getting the data

Safety concerns – defining the risks

To start early in development already in order to define the identified / potential risks and gaps in knowledge

Risks related to: •  Quality characteristics, storage, distribution •  Patient associated conditions, underlying disease, concomitant

treatments/ interactions with other products •  Reconstitution procedures •  Scaffolds, matrices, biomaterials, medical devices •  Administration procedure / re-administration •  Persistence of product in patients •  For HCPs, care givers, close contacts, risk to the environment

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Safety concerns – Defining risks for CAR-T cells

Risk of leukapheresis

Risks related to the raw materials used

Risks related to transport, storage conditions

Risks related to the administration (e.g. Cytokine

release syndrome)

Hypersensitivity

Risk of 2ndary malignancy?

Risk of infections

Neurological events

Prolonged cytopenias Hypogammaglobulinemia

Routine risk minimisation measures: •  To manage risks through contraindications (e.g. hypersensitivity),

warnings and precautions in SmPC (e.g. cytokine release syndrome, neurological events, infections, febrile neutropenia…)

•  Additional monitoring (black triangle) •  Restricted prescription (experienced physicians in the disease)

Additional risk minimisation measures: •  Controlled access programmes (e.g. accredited centres, trained/

experienced physicians..) •  Educational programmes (also training on administration) •  Targeted communications

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Risk minimisation measures for CAR-T cells

Methodology to follow when designing post-authorisation studies: •  Define precisely the study objective(s) •  Consider the appropriate study design and the data source: •  Extension phase of pre-authorisation trials •  Clinical trial (randomised controlled trial?) •  Observational studies (cohort study, case control study, use of

external controls, using health care database… ) •  Registry

•  Define a statistical analysis plan which will obtain a reliable estimate of the effect.

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Efficacy and safety follow-up studies

Use of Registries: •  Can play an important role in monitoring the safety of

medicines

•  Can be used to measure the safety and efficacy of individual products in routine clinical practice

•  EMA initiative to make better use of existing registries:

–  Defining same data collection (core data elements), –  Harmonised protocols and data structures

Efficacy and safety follow-up studies

Take home messages

•  Exciting times for ATMPs field

•  Collaborative effort to deliver safe and effective treatments

•  EMA working with FDA and HC through Clusters meetings

•  Use of registries

•  Workshop planned on 9th February (TBC)

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Tomas Boran

Rob Hemmings

Pierre Demolis

Julie Williams

Maura O’Donovan

Sol Ruiz

Romaldas Maciulaitis

Acknowledgement

Rocio Salvador-Roldan

Thank you for your attention

Caroline.voltz@ema.europa.eu European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

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