Guidance

Common issues: Clinical

Updated 12 January 2026

The most common clinical Grounds for Non-Acceptance (GNA) relate to the lack of an acceptable Reference Safety Information (RSI) section and unacceptable recording and reporting of adverse events (AEs) or serious adverse events (SAEs).

We also often raise GNAs because of a lack of information about appropriate risk mitigation strategies (including contraceptive requirements, dose escalation stopping criteria and appropriate eligibility criteria) as well as unacceptable unblinding procedures in case of a medical emergency. 

1. Unblinding in case of clinical emergency

When the Sponsor considers knowledge of the treatment assignment is necessary to determine the optimal medical management, the treating physician must have immediate and direct access to the unblinding procedure. The protocol must clearly state the trial-specific procedure for unblinding in case of a medical emergency. 

The Sponsor cannot require that the Investigator ‘must’ contact the monitor or make ‘every effort’ to contact the Sponsor/medical monitor before unblinding the trial treatment in case of a medical emergency. 

This is because, according to international guidelines, the treating physician (investigator) is responsible for the medical care of the individual trial subject (Declaration of Helsinki 3§ and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 4.3).

The coding system in blinded trials should include a mechanism that permits rapid unblinding (ICH Good Clinical Practice (GCP) 5.13.4). If the blinding is prematurely broken, it is the responsibility of the Investigator to promptly document and explain any unblinding to the Sponsor (ICH GCP 4.7).

Therefore, the Sponsor must not require or insist on being involved in the decision to unblind, stall or delay in any way the unblinding of trial subject treatment in emergencies, and a prompt unblinding procedure should be available to the study site. 

2. Contraceptive requirements 

The Sponsor must define in the protocol the acceptable methods of contraception for males and females, the duration of use (during study and/or after study drug administration), and the frequency of pregnancy testing. The measures mandated by the protocol must comply with the Investigator’s Brochure (IB) recommendations or the Summary of Product Characteristics (SmPC) requirements. 

Recommendations related to contraception and pregnancy testing in clinical trials have been developed by the Clinical Trial Facilitation Group. These have been discussed in the non-clinical section of this document.

In particular, Sponsors are reminded that abstinence is only acceptable as “True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.” The definition of abstinence must be included in the protocol. 

The definition of women of childbearing potential should be included in the protocol in line with the Clinical Trial Facilitation Group guidance. 

The study protocol should also contain detailed information on the possibility of an interaction between the Investigational Medicinal Products (IMPs) or the non-IMPs and hormonal contraceptives. A pregnancy testing ‘no more than 7 to 14 days before the study drug administration’ is recommended or the Sponsor must provide a rationale why this is not appropriate. 

3. Adverse event (AE) and serious adverse event (SAE) recording 

Recording of AEs and SAEs must start after the trial participant signs their informed consent and must be performed at least until the end of the systemic exposure to the IMP (five elimination half-lives) and depending on the trial design characteristics and objectives. A written rationale should be provided in the case that the sponsor does  not deem this applicable. 

The protocol must not automatically exempt disease progression events from reporting requirements. Provisions for recording disease progression as an adverse reaction/serious adverse reaction should be in place if disease progression is deemed related to IMP by the investigator. 

If disease progression is a trial endpoint the protocol must ensure periodic review of disease progression cases to identify potential IMP-induced increase of disease progression. 

When assessing the severity of adverse events/reactions occurring in healthy volunteers the investigator/Sponsor should take into consideration the fact that events which may be clinically acceptable to patients could be severe or unacceptable in healthy trial participants.

The use of grading scales designed for patients is not encouraged in healthy volunteer clinical trials; if any scale is used it needs to be adapted to the needs of healthy participants who are deriving no benefits from trial participation or otherwise justified. 

4. Serious adverse event (SAE) reporting 

Immediate reporting of SAEs is necessary to allow the sponsor to take the appropriate measures to address potential new risks in a clinical trial. Regulation 32(1) of the Medicines for Human Use (Clinical Trials) Regulations 2004 states “An investigator shall report any serious adverse event which occurs in a subject at a trial site at which he is responsible for the conduct of a clinical trial immediately to the sponsor”. 

It is important to further qualify what ‘immediate’ means to avoid misunderstanding and delays. Clarification can be found in EC guidance document 2011/C 172/01 (CT-3), Section 4.3, paragraph 29, which states “Immediate reporting should allow the sponsor to take the appropriate measures to address potential new risks in a clinical trial. Therefore, the immediate report should be made by the investigator within a very short period of time and under no circumstances should this exceed 24 hours following knowledge of the serious adverse event”. 

Reference to an SAE reporting time other than “within 24 hours” must be avoided (i.e. the use of “one business day” would not be acceptable). 

5. Reference safety information 

The cover letter should include identification of the reference safety information (RSI) that will be used to determine expectedness in the trial. The RSI is the information used for assessing whether a serious adverse reaction is expected, and this is contained in either the investigator’s brochure or the summary of product characteristics (SmPC). 

The Clinical Trial Facilitation Group has published Recommendations on Reference Safety Information. In line with CTFG guidance, the RSI must be in the form of a single table, where the nature of the ‘expected’ serious adverse reactions (SAR) must be listed by body system organ class and using preferred terms (PTs) according to the latest MedDRA version.

The use of grouped terms is not endorsed. The RSI tables must list only SARs that have been reported more than once, and fatal and life-threatening events must always be considered unexpected even if previous fatal and life-threatening SARs have occurred. 

If there are no ‘expected’ SARs for the IMP, a clearly defined section of the IB called RSI should still be present, followed by a brief text stating that no SARs are considered expected by the sponsor for expedited reporting and identification of SUSARs in the DSUR for the IMP. 

6. Extensive amendments to a trial protocol 

Sponsors are encouraged to contact the MHRA Clinical Trials Unit for advice if they plan to revise their approved protocol to such an extent that it may be more appropriate to submit an application for a new trial; for example, if the trial population, primary objectives or research hypothesis changes or if new IMPs are planned to be added to the study. 

7. Risk mitigation strategies for all IMPs 

To protect the safety of trial participants, all potential risks associated with the use of all the IMPs must be addressed in the protocol and risk mitigation strategies must be proposed. 

The Sponsor should ensure that all potential risks identified from the emerging/established profile of the IMPs are addressed in the protocol with risk mitigation measures or provide a justification for why such measures are unnecessary. 

An update to the European Medicines Agency (EMA) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products came into effect on 1 February 2018. 

It extends the existing EU guidance to address first-in-human (FIH) and early-phase clinical trials (CTs) with integrated protocols. The revision is intended to further assist in the transition from non-clinical to early clinical development and in identifying factors influencing risk for new investigational medicinal products (IMPs). Strategies for mitigating and managing risks are given, including: 

• principles on the calculation of the starting dose to be used in humans 
• the subsequent dose escalations 
• the criteria for maximum dose, and 
• the conduct of the trial inclusive of multiple parts 

8. Eligibility criteria 

The eligibility criteria must be compliant with the IBs and/or SmPCs of IMPs with marketing authorisation, particularly with respect to contraindications and contraceptive requirements. 

The eligibility criteria should be clear and absolute. Waivers or deviations of the eligibility criteria are not GCP compliant and therefore not acceptable. According to GCP ICH 4.3.1, the investigator is responsible for all trial-related medical decisions, therefore it is clear that it is the investigator’s decision and not the sponsor’s whether to enrol a patient or not.

In addition, as per GCP ICH 4.5.2, the investigator should not deviate from the protocol unless to eliminate a potential hazard and adding the ability to discuss case by case with the sponsor is essentially a protocol waiver and GCP breach.

As a consequence, the protocol should not include eligibility criteria that require prior discussion with the Sponsor (or sponsor representatives as medical monitor or chief investigator) in the context of an investigator decision and potential eligibility criteria waiver. 

9. Duration of treatment or objective/endpoint ‘until commercially available/marketing authorisation’ 

Under Commission Directive 2005/28/EC, clinical trials should be scientifically sound and guided by ethical principles in all their aspects. Study endpoints form part of the basis of the trial design and this in turn is critical for the scientific integrity of the trial and the credibility of the data formed.

If the study aims to assess efficacy and long-term safety, the trial endpoint should reflect this with clinical endpoint(s). A specified length of treatment should be proposed. Should circumstances indicate a requirement for further treatment beyond this specified period, this can be done via an amendment at a later date. 

A duration of treatment of ‘until commercially available/marketing authorisation’ and/or ‘administration of the IMP until commercially available/marketing authorisation’ cannot be considered a valid study objective/endpoint in an initial CTA application, in an extension phase of an ongoing trial or in an extension trial (for patients who were in previous trials of the IMP and/or for naïve patients). 

On the other hand, if the wording applies to the provision of the IMP to patients who are deriving clinical benefits either as part of an extension phase of the current trial (whose objectives are scientifically sound and have already been deemed acceptable) or after the end of the trial, treatment until commercially available/marketing authorisation can be deemed acceptable. Under the Declaration of Helsinki, the study protocol should contain information about the provision of treatment after the end of the trial to patients who are deriving clinical benefits from the IMP. 

10. Dose stopping criteria 

In first in man trials where no information is available about the safety profile of the IMP and/or healthy volunteer trials where the trial participants do not derive any benefit from trial participation, absolute dose escalation stopping criteria must be defined to protect the safety of the trial participants. 

In these cases the protocol should include the following dose escalation stopping criteria: In case of occurrence of an SAE considered to be at least possibly related to the IMP or in case of two severe or clinically significant AEs considered to be at least possibly related to the IMP, dosing will be stopped and the trial will be halted.

If a holding rule has been met and following an internal safety review it is deemed appropriate to restart dosing, a request to restart dosing, with relevant data, must be submitted to the MHRA as a request for a substantial amendment. 

11. Communication plan 

In first in man trials where no information is available about the safety profile of the IMP and/or healthy volunteer trials where the trial participants do not derive any benefit from trial participation, a system must be in place to ensure prompt communication of safety concerns among all the participating sites. 

A detailed coordination and communication plan must be provided in the protocol, including how the assignment of patients to a cohort will be undertaken, given potentially small cohort sizes and in cases where multiple international sites are involved. This plan should also address the circulation of safety data to all sites, and how this will be handled.