EMA Updated Guidance on Good Clinical Practice for Advanced Therapy Medicinal Products, 2019
Found in Eudralex Vol. 10 Chapter V
Summary of Key Changes
This is an updated version of an existing guidance document for sponsors conducting clinical trials with Advanced Therapy Medicinal Products (ATMPs). This covers gene therapy medicines, somatic-cell therapy medicines or tissue-engineered medicines. This blog post summarises the key changes in the new version. This version already appears in the currently applicable version of Eudralex Vol 10 and it applies from now as it has been developed under the ATMP Regulation rather than the Clinical Trials Regulation.
On the whole information which is held elsewhere (e.g. general Good Clinical Practice (GCP) requirements, manufacturing guidance) has been taken out and now the guideline just addresses ATMP specific issues.
Definitions have been removed.
Chapters outlining responsibilities of Ethics Committee, Sponsor and Investigator have been taken out and the key responsibilities incorporated under new headings (e.g. Informed Consent).
New Section: 1.2 General Context
- Challenges with ATIMPs
- Manufacturing constraints and products with short shelf-life
- Mode of application
- difficulty of placebo control in some situations
- need for special training?
- Potential long term effects
- Feasibility of generating relevant non-clinical data
- Therefore adaptation of ICH GCP and implementation of additional measures may be necessary
New Section: 2. Clinical Trial Design
- Risks to patients and site staff
- Study population considerations
- Cohort size – also consideration of staggered treatment
- Blinding – may not be possible but subjects blinded if possible
- Placebo – must be justified if used
- Dosing – issues and considerations for dose determination and escalation
- End of trial – definition and long term follow up
New Section: 3. Non-clinical studies
Animal models may not be predictive and therefore need to document and justify rationale for pre-clinical approach or lack of pre-clinical research
Section: 4. Quality of the Investigational ATMPs (Manufacturing)
Reference to GMP for ATMPs (Eudralex Vol 4 part IV)
- General considerations – relating to potential issues/complications
- Tissues and Cells of Human origin – IMPD info on procurement and traceability
- Medical Devices – IMPD information required where medical devices are integral to the product or essential for the administration of the product
- Reconstitution – e.g mixing, thawing etc.
New Section: 5. Safe conduct of the clinical trial
- Information on the product – risks, interventions required, impact of previous and future treatments. Updates to IB
- ATIMP – handling, containment and disposal. Risks to subject and caregivers
- Risk-minimization measures – e.g. CRS risk – measures needed
New Section: 6. Upstream interventions on subjects and administration procedures
- Upstream interventions – example given is Leukapheresis in autologous setting – risks to subject, impact on product quality and description of procedures
- Administration – detailed instructions accounting for differences from standard practice, complexity and novelty and also whether sponsor representative presence is justified and required.
Section 7. Traceability
Reference to GDPR – traceability to be maintained using an anonymous coding system.
New Section: 8. Retention of samples
If manufactured quantities are small don’t have to keep samples for autologous products or matched donor ATMPs.
Retention period adjusted for shelf-life. Consideration of impact of retention conditions (e.g. cryopreservation).
If can’t keep product itself should keep copies of label.
New Section: 9. Protection of clinical trial subjects
- Informed Consent
- Long-term follow up
- Take into account duration of biological effect
- More detail on risk assessment
- Integration of long-term follow up with post marketing patient follow-up
- Remote follow-up – new section outlining processes
- Patient withdrawal, termination of trial or product
- Patient alert cards – not always required – dependent on characteristics of ATMP
- New Section: Administration of out of specification products – this can be done on investigator’s request if justified to avoid immediate hazard to subject. CA to be notified “swiftly”.
Section 10. Safety reporting
Further explanation of differential causality assessment.
New Section: 11. Monitoring
Need to cover compliance with traceability requirements, long-term follow-up and specific ATIMP handling and accountability requirements.
Sections Removed: Chapters on Protocol, IB and Essential Documents have been removed, along with the annex on Traceability Records