What is the declaration of Helsinki?
Set of Ethical principles regarding human experimentation or clinical trials
What does IRAS Stand for and what is it used for?
Integrated Research Application System
Submission of UK CTA for both MHRA and Ethics approval
What do you call the updates to a CTA post approval?
Substantial Amendment-
anything that has the potential to impact safety, quality or scientific interpretation of the trial.
Non-Substantial Amendment - minor protocol errors, funding or logistics that has no impact on the trial or its participants.
UK SI for IMPs?
2004/1031 as amended by 2019/744
Describe the different types of clinical trial?
Phase 0 - Healthy - micro-dosing
Phase 1 - Healthy volunteers - 10-30 participants - understand ADME, Safety and Tolerability.
Phase 2 - Patients and Healthy volunteers - 100 participants - therapeutic efficacy
Phase 3 - Patients - >3000 - further safety / efficacy data, side effects and method development.
Phase 4 - Post Marketing Surveillance, Side effects and New Indictaions
What are the legal duties of an IMP QP?
IMP’s are manufactured and assembled to GMP, PSF and CTA
IMP / Comparators Imports from 3rd Countries are manufactured equivalent to GMP
Tested in compliance with the PSF
Certify in a Register or equivalent
What is the Clinical Trial Reg in the EU and when was it Implemented?
536 /2014 - 31st Jan 2022
What is the IMP GMP Regulation in the EU?
2017 /1569
What Guidance documents do we have for IMP’s?
Eudralex Vol 4 - Annex 13 / Annex 16
Eudralex Vol 10 - Clinical Trials Guidance
Where are the legal duties of an IMP QP found?
UK
SI 2004/1031 Part 6
2017/1569
What documents should be included in your PSF?
Annex 13:-
Specifications / Analytical Methods for Starting materials
Intermediate bulk and Finished Product Specifications and Methods
In Process Testing and Methods
Approved Label Copy
Relevant Clinical Trial Protocols
Randomisation Codes
Technical Agreements
Stability Data
Storage and Shipment Conditions
What Are the labelling requirements for IMP’s?
Name / Address of Sponsor
Dosage Form
Route of Administration
Batch Number
Trial Reference Number
Patient ID
Name of Investigator if different from sponsor.
Directions for Use
‘For Clinical Trials Use Only’
Storage Conditions
Expiry Date
‘Keep out of reach of children’
What is in an IMPD?
Provides Info on the drug substance, IMP, Comparator and Placebo.
Quality data 1 Similar format to the Quality section of the CTD:
General properties
Info on Manufacturing
Controlof materials
Impurities
Specification Justification
Container Closure
Stability
Non-Clinical Pharmacology and Toxicology Data
Previous Clinical Trial and Human Experience Data.
Overall Risk to Benefit Ratio
What is in a CTA?
Covering Letter (With PO)
MIA (IMP) of Manufacturers / Importers
Labels
IMPD / sIMPD
Clinical Trials Protocol
Investigators Brochure
QP Declaration
What is IRAS?
Integrated Research Application System
Combine MHRA Approval and Ethics Approval for CTA in UK
What are the new modifications of a CTA and what do they mean?
A substantial modification is
Route A
Anything that could impact safety of participants or reliability / robustness of data in clinical trial.
Route B - for changes already approved in EU EEA or USA
No significant safety concerns from modification or with IMP currently
- Trial is not first in human, limited changes to protocol or IB
Modification of an important detail - do not significantly impact the safety or rights of CT participants but authorities need to be aware for administration purposes
Minor Modifications - can be implemented at any time without informing licensing authorities or ethics committee at the point of implementation . Sponsor must keep records.
What was the amendment to 2004:1031 post Brexit?
744
Why do we do stressed development studies for IMPs?
Understand degradation pathways, aid formulation development, assess potential mutagenic impurities and develop stability indicating methods.
Why do we perform development stability studies?
Confirm re-test period of proposed drug substance or the shelf life of the proposed drug product.
Support development activities such as formulation, packaging, manufacturing and process development. These studies may include predictive stability studies such as accelerated stability programs.
What are the types of auxiliary medication that could be used in a clinical trial?
Rescue Medication
Challenge Agents
Medicinal products used to assess the end point in a clinical trial
Background Treatment (Considered the current standard of care)
What is IRT and what is it used for in Clinical Trials?
Interactive Response Technology
Randomisation and Trial Supply Management
- Automation of inventory management
- Automation of drug dispensing
- Patient visit and inventory data centralised
- Emergency Code Breaking Patients
A separate system is created for each study.
What is in a clinical trial protocol ?
Its purpose is to ensure:
- trial is ethical
- scientifically valid
- safe
- complies with regulatory requirements
Contains:-
- Object of study
- Study Design
- Eligibility criteria
- Treatments / Procedures
- Statistical considerations
- Standard of Care
- Ethical rationale
What is the two stage release process for IMPs?
1) QP Certification - sometimes referred to as Technical / GMP approval ensure the IMP is manufactured to GMP
2) Regulatory approval- responsibility of the sponsor but can be delegated and is to ensure that the trial meets the terms of the CTA
What is an sIMPD and when can it be used?
A sIMPD (simplified Investigational Medicinal Product Dossier) is a condensed version of the full IMPD that may be submitted instead of a full dossier in specific circumstances, when the regulator already holds or can easily access the necessary data.
- Product has already had an IMPD approved
- There is a commercially available product authorised.
