IMPS Flashcards
What are Comparators?
Comparators are IMPS as are placebos as they are active parts of the trial
List the key documents required for the initial trial application (536/2014 Annex 1)?
CC PIGILE
* Clinical Trial Application Letter
* Clinical Trial Application Form
* Protocol
* Investigators Brochure -
* GMP dox (MIAimp, QP Dec, )
* IMPD - theres guidance on simplified IMPD in annex 1 of 526/2014
* Labels
* Evaluation Fees
What sort of things are called out to be included in a CTA letter?
first time in humans, gmos, narcotic, psychotropic, radiopharm or whether it’s a low intervention trial
What needs to be in protocol?
what’s on trial,
previous findings,
risks and benefits,
description of trial,
patient group and location, randomisation
What’s the point of an Investigators Brochure?
to provide the investigators and others involved in the clinical trial with information to facilitate their understanding of the rationale for, and their compliance with, key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures
What are the contents of a PSF (from Annex 13)
ARRMPITSSS
A - Approved label copy
R - Randomisation details
R - Reference and retention samples plan.
M - Manufacturing method
P - Protocol
I - IPCs
T - Technical/ Quality agreements
S - Supply Chain specs and methods (starting mats and pack mats)
S - Storage and transport conditions
S - Stability data
Basically, the essential documents necessary to manufacture to GMP and the CTA
Detail the protocol contents:
- Trial objectives and purpose
1B includes purpose to help investigator
* Non-clinical studies
* IMP and its properties
* Storage and handling instructions
* Effects in humans and possible adverse reactions
* Confidentiality statement
* Treatment of overdose - Trial design – end points, blinded, duration, statistical basis
- Benefit-risk assessment
- Selection and withdrawal of subjects
- Justification for including subjects who can’t give informed consent
- Plans for treatment after trial
- Assessment of safety, efficacy, stats used (ethical considerations)
- Finance and Insurance
Other than QP, what are the key roles in IMPS and what do they do?
- Sponsor – individual/company responsible for CT
- Investigator – person responsible for conducting CT at a trial site
- Manufacturer – any person engaged at the MIA IMP Holder
What sort of clinical trial are there?
Open / single blind / Double blind.
Parallel or crossover.
Double Dummy
Low Intervention
What is a low intervention clinical trial?
New to 536/2014
IMP is authorised, used within the terms of the MA or there’s safety evidence in the EU and the risk to patient is minimal
What’s in phase 1?
Dosing studies - find highest dose without side effects and how body excretes it.
20-100 healthy people (unless toxic).
Several months.
Don’t forget the Sentinel
What’s in phase 2?
Testing of drug on participants to assess biological effect and side effects - assumes no therapeutic effect. Also definite dose finding studies. 50 - 300 people with the disease
What’s in phase 3?
Randomised efficacy and safety studies. Generally double blind.
What’s in phase 4?
Post Marketing Surveillance. Looks for long term safety or possibly patient sub
What are non-interventional studies?
Non-interventional studies are all clinical studies other than clinical trial
How long can you pause a trial for before it si considered stopped?
If you’ve paused a trial then only have two years before it is considered stopped
What are the legal duties for the IMPS QP
1) For batches made in a member state, ensure that the investigational medicinal product is manufactured and checked in compliance with EU GMP, PSF and CTA.
2) IMP batches coming from 3rd country, that each batch is manufactured and checked in compliance with GMP equivalent to EU, PSF and CTA.
3) Where a marketed Comparator product is imported and documentation confirming it has been manufactured to GMP is not available then each batch has undergone all relevant analyses, tests and checks necessary to confirm its quality as per CTA.
4) Record in a Register that is kept for 5 years (after certification in GB and the last CT where the batch was used in EU)
What is a NIMP?
Auxiliary Medicine - rescue medicine, something to bring out the symptoms etc. They must be authorised.
What is QP Oversight?
When importing IMPS from EU, you need an MIA(IMP) and an assurance system to check that the batches have been certified by a QP in the listed country.
This system needs to be overseen by a QP but the QP doesn’t need to do the checking.
If importing IMPS from NI then when don’t you need QP oversight?
Imported IMP is going to be used in NI
IMPs are certified by NI MIA(IMP) QP.
What do you need the systems to ensure when you import IMPS (inc from NI)?
1) IMPS are not made available in GB clinical trial sites until QP certification has been verified.
2) IMPS are only shipped to sites on the UK trial application
3) UK QP has up to date documentation on the trial and the PSF
4) MHRA authorises the trial before IMP made available to the investigator.
How would you go about relabelling a batch with an extended expiry?
- Annex 13 details how to extend the expiry if you get new stability data. Need to relabel the packs, obvs.
- Should be performed at a location that meets the regulation 536/2014 (somewhere with a license, but can relabel at a hospital, health centre or clinic) by appropriately trained staff. Add an additional label and repeat the batch number and CT ref. May cover the old expiry, but not the old batch number.
- Document in a BD, own area, line clearance before and after. Discrepancies should be investigated and accounted for. Substantial or non-substantial – depends on what’s in the IMP dossier. If you’ve set yourself up for it, you can do it without substantial variation.
- Note: originally annex iv for 536/2014 states that the primary packaging would need to be relabeled if there was an expiry date change. This has now been amended to say that you don’t have to when primary and secondary are to remain together, or its in blister packs or small units such as ampoules (in which case label the secondary packaging).
What are the annual reporting guidelines?
- Sponsors must submit an annual safety report detailing monitoring and evaluation of the safety profile of the IMP. Includes recording the adverse events.
- There’s a good training document released by the EMA that covers the requirements of the annual report.
- Actors involved are the safety assessing member state and the trial sponsor.
o Sponsor generates the report and sends to saMS
o They review, provide requests for information (RFIs) to which the sponsor responds
What must the sponsor do with respect to insubstantial amendments
keep records of the amendments made and
send those records, or copies of such records, to the licensing authority, where the authority send him a notice in writing requiring him to provide those records, or copies of such records.
What licence do you need if importing NIMP from NI
a WDA(H), unless you are the Sponsor of the clinical trial
What licence do you need if importing an NIMP from an approved country?
And what if the country isn’t on the list?
importation from a listed country should use a wholesale dealer’s licence (WDA(H)). A Responsible Person for import (RPi) may be required. Guidance is available on importation of medicines from an approved country for import and the requirements for RPi.
Importation from a country that is not a listed country will require a manufacturers licence.
What licence is needed to store and distribute IMPS?
none but you need to be named on the MIA(IMP) of the manufacturer.
Anyone that works with you will need to get a variation on their licence.
What is a non-intervention trial
A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation.
No additional diagnostic or monitoring procedures shall be applied to the patients
What is an ‘investigator’s brochure’
A compilation of the clinical and nonclinical data relevant to the study of the IMP in human subjects
What are the requirements with respect to minors and others not able to give consent to be part of the clinical trial?
- Informed consent from legal guardian. Consent can be revoked at any time
- Trial explained to them in ways they can understand (with staff experienced in explaining to minors for minors)
- The minor can refuse if they are able to form an opinion and express it
- For minors:
- trial designed to minimise pain, discomfort and fear. Distress monitored &
ethics committee has paediatric expertise.
What if the sponsor wants to make substantial amendments to the trial?
If the amendments have an impact on the safety of the subjects or change the interpretation of the documents then need to go back to the competent authorities and ethics committee
What happens if a member state has objective grounds to think the conditions in clinical trial application are not being met
They can suspend or prohibit the trial – normally there’d be consultation with the sponsor
How long does a sponsor have to report fatal or life-threatening suspected unexpected serious adverse reaction in a clinical trial?
Who do they report to?
7 days
The licensing authority and the ethics committee
How long does a sponsor have to report non-fatal or life-threatening suspected unexpected serious adverse reaction in a clinical trial?
Who do they report to?
15 days
The licensing authority and the ethics committee
What is significant about reconstitution which means an MIA is not required?
The IMP must exist as an IMP before reconstitution
What needs to be on the IMP primary pack if it is small and supplied with secondary packaging?
a. Name of sponsor
b. Dose form, route of administration (not needed for orals), no. dosage units and (if unblind) patient and strength / potency
c. Batch number
d. Trial ref code
e. Subject id number
What do you need to ensure if the use-by / expiry date needs changing on an IMP?
Add a label with the new exp date and the batch number. Ensure it doesn’t cover the original batch number.
Where would you overlabel the exp date on an IMP
Normally at an authorised manufacturing site however, it may be done at the investigation site under supervision of the trial pharmacist. If this isn’t possible then may be done by CT monitors with training.
What controls are needed when overlabelling an Exp date?
Needs to be done to GMP. Need SOPs and if by someone else then there needs to be contract and tech agreement.
Needs to be second person checked.
Needs BD and documented in trial dox too.
How long to keep IMP ref and ret samples?
2 years after the end or stop of the last trial
Keep ret samples until after the clinical report
What’s different about IMP ret samples compared to commercial?
You can store them as written or electronic records if there;s enough info rather than as an actual thing
Describe the release process for IMPs
2 stage – QP certifies made to GMP, PSF, CTA etc and then the sponsor makes available to the trial
What does old annex 13 say needs to be assessed for batch certification?
- Batch records
- Production conditions
- Validation status of facilities , processes and methods
- Finished packs
- Tests after importation if appropriate
- Stability reports
- Storage and shipping conditions
- Manufacturer audit reports
- MIA (imp) or equivalent of manufacturer
- GMP compliance
When should decoding info be at the clinical site?
Before shipping to them
Who is responsible for destruction of IMPs?
The sponsor
What is needed before destroying IMPs?
Written authorisation from the sponsor
When can IMPs be destroyed?
When reconciled and any discrepancies from a trial site have been investigated and understood.
When the sponsor has given written authorisation.
What does a Sponsor need from the destruction of IMPs?
Written confirmation with dated certificate of or receipt for destruction.
Docs should identify batches and patient numbers and quantity destroyed.
