IMP's Flashcards
What are the differences between the various stages of clinical trials?
MHRA website guidance for applying for a CTA
(Phase 0 - Microdosing) - small number of human volunteers take 1/100 of the therapeutic dose to obtain Pharmacokinetics information earlier. Primarily to trial safety.
Phase I - (small number of human volunteers). determines the therapeutic range. <typically ‘healthy’ male volunteers> determines dose-effect relationship, side effects and Pharmacokinetics.
Phase II - (several hundred patients). refines dose and length of treatment, identify common side effects. To determine safety and efficacy, bioavailability and proof of concept - Therapeutic Exploratory
Phase III - (several thousand patients), influence the prescribing and patient info. Therapeutic Confirmation, forms basis of MAA. Advantage vs comparator, drug interactions,
Phase IV - (On the marketed product), long term harms and benefits of a medicine and new uses for it. Dose optimisation, drug-drug interactions, additional indications, epidemiology and post-marketing surveillance required by CAs.
What changes are there in clinical trials?
Clinical Trials Regulation: 536/2014 (Repealing Directive 2001/20/EC) - effective 6 mo after the EC publishes EU CT portal and database (ETA Q3 2019) (APE, ALO!)
- Adverse events reported on a Web based system
- Publically accessible data used to support CTA
- EMA portal for 2 part application and CTA content harmonised (scientific re study and ethics re CT site(s))
- Auxiliary medicinal products replace NIMPs, so don’t cover Non-medicinal agents
- Low intervention CT have less stringent rules re: monitoring and approval timelines - IMP is used per MA and Safety and Efficacy is known.
- Orphan medicinal products (for rare disease) will be fostered
- Directive 2003/94 (GMP) will be repealed 6 mo after the EC publishes EU CT portal
- GMP for IMP 2017/1569 Regulation - applies 6 mo after the EC publishes EU CT portal, incorporatessome of the gaps regarding QP certification (536/2014 only requires certification to GMP compliance)
- Revised annex 13
- GMP for Human medicinal product 2017/1572 Directive - transpose into national law by 31Mar2018, apply 6 mo after the EC publishes EU CT portal
What is an Ethics committee? What do they do and why?
Research Ethics Committees (REC) typically in the UK consist of up to 15 members, 1/3rd of whom are lay (broadly, this means their main professional interest is not in a research area, nor are they a registered healthcare professional). They safeguard the rights, safety, dignity and well-being of research participants, independently of research sponsors.
They review applications for research and give an opinion about the proposed participant involvement and whether the research is ethical. RECs are entirely independent of research sponsors (that is, the organisations which are responsible for the management and conduct of the research), funders and investigators. This enables them to put participants at the centre of their review.
What is a ‘Clinical trial protocol’?
would you expect to see in this?
What sections are particularly important to the QP?
most current definition is in 536/2014:
Protocol = a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial. The term ‘protocol’ encompasses successive versions of the protocol and protocol modifications;
ICH E6(R1) Good Clinical Practice. Protocol contents:
- General Information
- Background information
- Trial Objectives & Purpose
- Trial Design
- Selection and withdrawal of subjects
- Treatment of Subjects
- Assessment of Efficacy
- Assessment of Safety
- Statistics
- Direct Access to Source Data/ Documents
- Quality Control & Quality Assurance
- Ethics
- Data Handling
- Financing & Insurance
- Publication Policy
- Supplements
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What is a clinical trial?
Eudralex vol 4. Annex 13:
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of one or more investigational medicinal
product(s) with the object of ascertaining its/their safety and/or efficacy.
Supply of packaging materials, how would you sample?
Eudralex vol 4. Annex 13:
Instruction to process, package and/or ship a certain number of units of investigational medicinal product(s).
What is a ‘low intervention’ clinical trial
Eudralex vol 4. Annex 13:
‘Low-intervention clinical trial’ means a clinical trial which fulfils all of the following conditions:
(a) the investigational medicinal products, excluding placebos, are authorised;
(b) according to the protocol of the clinical trial: (i) the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or (ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and
(c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden
to the safety of the subjects compared to normal clinical practice in any Member State concerned;
Describe what is meant by ‘randomisation’ and ‘randomisation codes’
Eudralex vol 4. Annex 13:
- Randomisation = The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
- Randomisation Code = A listing in which the treatment assigned to each subject from the randomisation process is identified.
Who is the ‘Sponsor’ in relation to a clincial trial?
Eudralex vol 4. Annex 13:
An individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial.
Who is the ‘Investigator’ in relation to a clincial trial?
Eudralex vol 4. Annex 13:
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.
What is an IMP?
Eudralex vol 4. Annex 13
IMP = Investigational Medicinal Product
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.
Why is GMP important for IMPs?
Eudralex vol 4. Annex 13:
In clinical trials there may be added risk to participating subjects compared to patients treated with marketed products.
The application of GMP is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same IMP used in the same or different clinical trials, and that changes during the development of an IMP are adequately documented and justified.
What are some of the additional risks for IMP/ clinical trials compared to commercial products?
Eudralex vol 4. Annex 13:
- Added complexity (lack of fixed routines, variety of clinical trial designs, consequent packaging designs, need, often, for randomisation and blinding, and increased risk of product cross-contamination and mix up.
- May be incomplete knowledge of the potency and toxicity of the product and a lack of full process validation
- Marketed products may be used which have been re-packaged or modified in some way.
These challenges require personnel with a thorough understanding of, and training in, the application of GMP to IMP. Co-operation is required with trial sponsors who undertake the ultimate responsibility for all aspects of the clinical trial including the quality of IMP. The increased complexity in manufacturing operations requires a highly effective quality system.
What is a NIMP and what will this term change to in new clinical trial regulation?
Eudralex vol 4. Annex 13:
NIMP= Non-investigational medicinal product
- Products other than the test product, placebo or comparator which are supplied to subjects participating in a trial. May be used as support or escape medication for preventative, diagnostic or therapeutic reasons and/or needed to ensure that adequate medical care is provided for the subject. They may also be used in accordance with the protocol to induce a physiological response. These products do not fall within the definition of IMP and may be supplied by the sponsor, or the investigator.
The sponsor should ensure that they are in accordance with the notification/request for authorisation to conduct the trial and that they are of appropriate quality for the purposes of the trial taking into account the source of the materials, whether or not they are the subject of a marketing authorisation and whether they have been repackaged. The advice and involvement of a QP is recommended in this task. «< For example: Anticipated emergency situation: A clinical trial where a new biotechnology product is to be given for the first time to humans. The protocol requires availability of appropriate medicinal products needed for the treatment of anaphylactic shock.»_space;»
Redifined in 536/2014 New Clinical Trial Regulation:
Auxiliary medicinal product = a medicinal product used for the needs of a clinical trial as described in the protocol, but not as an IMP.
What is ‘reconstition’ in respect of a clinical trial and what authorisations are required for this?
Eudralex vol 4. Annex 13:
Both the total and partial manufacture of IMPs, as well as the various processes of dividing up, packaging or presentation, is subject to a manufacturing authorisation. This authorisation, however, shall not be required for reconstitution. For the purpose of this provision, reconstitution shall be understood as a simple process of:
* dissolving or dispersing the IMP for administration of the product to a trial subject,
* or, diluting or mixing the IMP(s) with some other substance(s) used as a vehicle for the purposes of administering it,
(Reconstitution is not mixing several ingredients, including the active substance, together to produce the IMP)
The process of reconstitution has to be undertaken as soon as practicable before administration.
This process has to be defined in the clinical trial application / IMP dossier and clinical trial protocol, or related document, available at the site.
Give examples of clinical trial design
ICH Topic E 9: STATISTICAL PRINCIPLES FOR CLINICAL TRIALS
- Parallel Group Design
The most common clinical trial design for confirmatory trials. Subjects are randomised to one of two or more arms, each arm being allocated a different treatment. These treatments will include the investigational product at one or more doses, and one or more control treatments, such as placebo and/or an active comparator.
- Crossover Design
In the crossover design, each subject is randomised to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons. In the simplest 2×2 crossover design each subject receives each of two treatments in randomised order in two successive treatment periods, often separated by a washout period.
- Factorial Designs
In a factorial design two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments. The simplest example is the 2×2 factorial design in which subjects are randomly allocated to one of the four possible combinations of two treatments, A and B say. These are: A alone; B alone; both A and B; neither A nor B. In many cases this design is used for the specific purpose of examining the interaction of A and B.
- Multicentre Trials
Multicentre trials are carried out for two main reasons. Firstly, a multicentre trial is an accepted way of evaluating a new medication more efficiently; under some circumstances, it may present the only practical means of accruing sufficient subjects to satisfy the trial objective within a reasonable time-frame. Multicentre trials of this nature may, in principle, be carried out at any stage of clinical development. They may have several centres with a large number of subjects per centre or, in the case of a rare disease, they may have a large number of centres with very few subjects per centre. Secondly, a trial may be designed as a multicentre (and multi-investigator) trial primarily to provide a better basis for the subsequent generalisation of its findings.
What is a CTA and what does it contain?
In the UK, a Clinical Trial Authorisation (CTA) from Medicine and Healthcare Products Regulatory Agency (MHRA) is required for a Clinical Trial of an Investigational Medicinal Product (CTIMP). For international trials in Europe, an application to the competent authority in each member state is required.
Contents:
- Section A: Trial Identification*
- Section B: Identification of the sponsor responsible for the request*
- Section C: Applicant Identification
- Section D: Information on each IMP *
- Section E: General Information on the trial*
- Section F: Population of Trial Subjects
- Section G: Proposed Trial Sites/Investigators in the Member State*
- Section H: Competent Authority/Ethics Committee*
- Section I: Signature
- Section J: Check List
- in IMPD
What is an IMPD and what does it contain?
Regulation 536/2014: IMPD= Investigational Medicinal Product Dossier
- The IMPD shall give information on the quality of any IMP, the manufacture and control of the IMP, and data from non-clinical studies and from its clinical use.
- The IMPD should be provided in a clearly structured format following the CTD format of Module 3 and include the most up-to-date available information relevant to the clinical trial at time of submission of the clinical trial application.
Sections are presented for: - Drug Substance: Module S (S.1 – General Information, S.2 – Manufacture, S.3 – Characterisation, S.4 – Control of the Drug Substance, S.5 – Reference Standards or materials, S.6 – Container Closure System, S.7 – Stability,
- Investigational Medicinal Product: Module P (P.1 – Description and Composition, P.2 – Pharmaceutical Development, P.3 – Manufacture, .P.4 – Control of Excipients, P.5 – Control of IMP, P.6 – Reference standards, P.7 – Container closure system, P.8 – Stability
- Appendices: Module A (<not applicable for IMPD?? A.1 – Facilities and Equipment>, A.2 – Adventitious Agents Safety Evaluation, A.3 – Novel Excipients, A.3 – Novel Excipients,
- Placebo and equivalent for modified comparator/ reference product: Module P (P.1-8)
- Placebo: Info as per IMP where relevant. Also cover; masking differences in terms of taste, smell and look, test to differentiate between test and placebo products, shelf life for duration of trial. Stability studies if reason to expect placebo will undergo degradation or changes to key characteristics.
- Comparator/ Reference Product: Info as per relevant requirements from IMP. Also cover; any additional substances added to authorised product and reference relevant pharmacopoeia or in-house monograph, modifications influencing quality of product (function, safety and efficacy)- demonstrate as comparable. Solid oral dosage forms -comparative dissolution profile, All manufacturing sites, proposed batch formula and modification steps including IPCs, specification and methods; description, ID of API and any other control parameters. If significant modification, consider impact to impurities etc and ensure suitable control. Shelf life for duration of trial. Stability studies if significant modification to comparator.
- Regional Information: Module R.
What is ‘Blinding’
Eudralex vol 4. Annex 13:
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and doubleblinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). In relation to an investigational medicinal product, blinding shall mean the deliberate disguising of the identity of the product in accordance with the instructions of the sponsor. Unblinding shall mean the disclosure of the identity of blinded products.
What is GCP and what is the QP specifically concerned with in GCP?
Regulation 536/2014: GCP = Good Clinical Practice
- A set of detailed ethical and scientific quality requirements for designing, conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial are reliable and robust.
- Principles that have their origin in the World Medical Association’s Declaration of Helsinki.
(When designing, conducting, recording and reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a case, the ICH guidelines on GCP should be taken appropriately into account for the application of the rules set out in this Regulation, provided that there is no other specific guidance issued by the Commission and that those guidelines are compatible with this Regulation.) - QP specifically interested in: Maintaining PSF, Appropriately packaging/ labelling for relevant markets, ensiring trial is being performed from an approved centre, Sponsor responsibilities are understood, responsibilities, communication lines/ agreement clear, clinical trial data integrity.
What is a comparator?
Eudralex vol 4. Annex 13:
An investigational or marketed product (i.e. active control), or placebo, used as a reference in a clinical trial.
If a product is modified, data should be available (e.g. stability, comparative dissolution, bioavailability) to demonstrate that these changes do not significantly alter the original quality characteristics of the product.
The expiry date stated for the comparator product in its original packaging might not be applicable to the product where it has been repackaged in a different container that may not offer equivalent protection, or be compatible with the product. A suitable use-by date, taking into account the nature of the product, the characteristics of the container and the storage conditions to which the article may be subjected, should be determined by or on behalf of the sponsor. Such a date should be justified and must not be later than the expiry date of the original package. There should be compatibility of expiry dating and clinical trial duration.
What is the ‘Declaration of Helsinki’?
The World Medical Association (WMA) has developed the Declaration of Helsinki <in 1964> as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.
Principles related to clinical trials include:
“Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights.”
“Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications.”
What should be included in the assessment of each IMP batch for QP certification prior to release?
Eudralex vol 4. Annex 13 details requirements for batch assessment:
- GMP and MA
- Audits of manufacturer
- Docs to certify the Manufacturer is authorised fo rthe IMP
- batch records re: compliance with the PSF, the order, protocol and randomisation code. (deviations or planned changes completed)
- production conditions
- the validation status of facilities, processes and methods;
- examination of finished packs;
- test results
- stability reports;
- conditions of storage and shipment;
