Guidance

Common issues: Non-Clinical

Updated 6 November 2023

From a non-clinical perspective, the most common GNAs relate to a lack of information about pivotal safety studies that have been submitted in support of the application and the nature of the contraceptive advice as outlined within the protocol. GNAs are also often raised because of a lack of justification for the starting dose in humans from a safety perspective and no description of the analytical methods used in the pharmacokinetic and toxicology studies.

1. Statement of compliance with OECD GLP for studies

All pivotal non-clinical studies, such as those studies identified in the relevant ICH guidelines that need to be conducted in accordance with Good Laboratory Practices (GLP), to support submissions for CTA applications must be conducted in a country that is a member of the OECD Mutual Acceptance of Data (MAD) programme in accordance with the OECD Test Guidelines and Principles of GLP.

As applications for CTAs do not include individual study reports, Sponsors should include a statement confirming the OECD GLP status and confirm whether or not the pivotal studies were conducted in a member of the OECD MAD programme either within the Investigator’s Brochure (IB) or within the covering letter. If any pivotal studies were NOT conducted within a country that is a member of the OECD MAD programme, this should be clearly stated and an explanation/justification as to why the Sponsor feels that these studies support the CTA application should be included.

2. GLP compliance and Advanced Therapy Medicinal Products

Compliance with GLP is expected for safety studies of test items in pharmaceutical products comprising information submitted in a CTA application dossier.

There is further information in the following guidance:

• The UK Good Laboratory Practice Regulations 1999, UK Statutory Instrument 3106
• OECD Mutual Acceptance of Data (MAD)
• OECD Principles on Good Laboratory Practice UK Government Good laboratory practice (GLP) for safety tests on chemicals

However, for some Advanced Therapy Medicinal Products, the only non-clinical safety data provided may be a component of a study addressing proof of concept or other pharmacodynamic study, which is a type of study that does not need to be compliant with GLP. In this circumstance, a justification of lack of GLP compliance for the full study may be accepted if this argument is presented in an application for a CTA.

Studies in which the biodistribution of the product is evaluated in combination with safety are expected to be in compliance with GLP.

Other reasons for lack of compliance with GLP may be considered in exceptional circumstances.

3. Details of analytical methods

Brief details of the analytical assays used for pharmacokinetic and/or toxicokinetic analyses and their limits of sensitivity should always be provided, either in the IB or in the IMPD, in which case a reference to these data should be included in the IB. The sensitivity, robustness and reproducibility of the assay provides reassurance when safety margins are based on exposure and when pharmacokinetic/toxicokinetic data are used as criteria around starting and stopping doses for the clinical trial.

4. Availability of data for review

For IMPs that are not currently marketed, the Sponsor is reminded to present the pharmacology, pharmacokinetics and toxicology aspects of the application in sufficient detail to allow a thorough review. A brief description of the methodology along with details of the results and overall conclusions of the non-clinical studies are required. A note to the reviewer to indicate that studies of a pivotal nature have been performed and can be provided upon request will constitute a GNA.

5. Justification of dose selection for first in human trials

For the first-in-human dose study, whether conducted in healthy volunteers or in a patient population, safety is the primary consideration. A justification for the proposed starting dose and the maximum dose to be used in the study must be detailed in the study protocol. It is useful to include an indication of the safety/exposure margins these doses will provide in relation to doses causing adverse effects in the non-clinical studies. However, where patients do not have established alternative treatments and the first human use is to be in patients, consideration should also be given to using doses that may be of potential therapeutic benefit to the individual patient in the trial, as estimated from in vitro and/or in vivo studies, including in animals, with the agent under development, or if shown to be relevant, with data from other agents.

6. Contraception recommendations

When compiling the contraceptive advice for a clinical trial, the Sponsor should consult the Clinical Trial Facilitation Group Recommendations related to contraception and pregnancy testing in clinical trials

The Sponsor should also note:

• sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. Within the protocol, sexual abstinence must be clearly defined as the usual and preferred lifestyle of the subject *the exact duration of contraceptive use after the last administration of the IMP should be clearly stipulated and justified on the basis of non-clinical and/or clinical data where applicable. Generally speaking, contraceptive measures should be in place for at least until the drug is eliminated (typically for the duration of 5 x half-lives).
• a combination of male condom with cap, diaphragm or sponge with spermicide (often referred to as double barrier methods) is considered to be an acceptable, but NOT highly effective, birth control method. Note that the use of a single barrier method together with a spermicide represents two methods of birth control.
• MHRA sometimes receives applications for a CTA in which the protocol has requirements for males to use contraception where an absence of contraceptive measures may have been agreed by the assessor for males based on the available non-clinical data. As this does not raise a safety concern, no objections are raised; however, it may impede subject recruitment and Sponsors should be aware that instances exist where an argument for a lack of contraception for males is acceptable. In brief, these circumstances are where the drug is not genotoxic and where there is a quantitative argument that shows that there is no risk from exposure at the concentrations likely in semen. Further details can be found in section 2.3 and cross references of Recommendations related to contraception and pregnancy testing in clinical trials
• for clinical trials that use an authorised product as an IMP or comparator agent, Sponsors should also check whether the approved Summary of Product Characteristics (SmPC) includes contraception advice. In those clinical trials where the choice of IMP is decided in a blinded randomisation method, the most stringent contraception advice should be the default for the trial.