17 th Jul UK Clinical Trial Applications
UK Clinical Trial Applications
Following introduction of the Medicines for Human Use (Clinical Trials) Regulations in 2004, researchers must obtain a Clinical Trial Authorisation (CTA) from the Medicines & Healthcare Products Regulatory Agency (MHRA) and a favourable opinion from an ethics committee in order to legally conduct a clinical trial in the UK. These regulations implement EU Directive 2001/20/EC (‘The Clinical Trials Directive’).
There have been four amending regulations  and a number of other changes since 2004, including the introduction of Notified Applications by the MHRA and the European-wide EudraCT database in 2011, in an effort to improve efficiency without adversely impacting on public health.
Despite these developments, there was a decline in the number of clinical trials being conducted in the EU, in part due to the disproportionately onerous regulatory regime. In recognition of this, the European Commission adopted a proposal in 2012 to repeal The Clinical Trials Directive and address its shortcomings. Following numerous public consultations, EU Regulation No. 536/2014; the ‘Clinical Trial Regulation’, was published in May 2014 and is due to come into application in 2019.
Considering the future changes, this paper reviews the current regulatory procedure for CTAs in the UK and provides an overview of the current process by:
– Defining a clinical trial
– Outlining the legislation regulating them and the competent authority
– Outlining the documentation required for approval
– Outlining the procedure for application and
– Outlining the new Clinical Trial Regulation
Definition of a Clinical Trial
A clinical trial of a medicinal product is defined as a research study that involves human subjects, intended to:
– discover or verify the clinical, pharmacological and/or pharmacodynamic effects of an Investigational Medicinal Product (IMP)
– identify any adverse reactions to an IMP
– study absorption, distribution, metabolism and excretion of an IMP with the object of ascertaining the safety or efficacy of that product.
The MHRA has developed an algorithm to help researchers determine whether their proposed study is deemed a clinical trial within the scope of Directive 2001/20/EC, and therefore if MHRA authorisation is required.
Authorisation of Clinical Trials
In line with Directive 2001, clinical trials cannot be conducted in the UK without the prior assessment and authorisation of the MHRA’s Clinical Trials Unit. Researchers must apply for a clinical trial authorisation (CTA) for all interventional trials ranging from first-in-human studies for novel compounds, to studies where a marketing authorisation already exists for the IMP.
Alongside this, a favourable opinion must also be obtained from a relevant ethics committee before the trial can start so that the rights, safety, dignity and well-being of research participants are safeguarded.
These regulations apply to trials involving standard medicinal products, as well as advanced therapy medicinal products, those derived from human blood or human blood plasma and paediatric trials. Directive 2001 does not apply to clinical studies of the following:
– medical devices
– food supplements
– other non-medicinal therapies e.g. surgery
– non-interventional trials
Assessment of Risk to Participant Safety
All clinical trials bring some inherent risk to the safety of the participants, hence the need for a robust assessment process. However, the MHRA employs a range of risk-adapted approaches that can simplify the processes for initiating and conducting some clinical trials to support the advancement of human medicine in a pragmatic way. Broadly based on what is known about the IMP, trials are categorised into one of three types depending upon the potential risk to participant safety in relation to the IMP. These categories are outlined in Table 1.
The trial categories impact on the MHRA authorisation process, indicate potential changes to trial documentation requirements and inform the safety monitoring plan. For certain lower-risk trials, defined as ‘Type A’ trials, researchers can seek authorisation via the MHRA’s Notification Scheme, which is similar to the standard application process but has simplified requirements. Authorisation of a Type A trial under this scheme also permits simplification of the monitoring of participants’ safety during the trial, resulting in a more risk proportionate approach.
The IMP risk category has implications for all the other risks, but does not determine them, i.e. a Type A trial from an IMP perspective does not mean all the other associated risks are low. The risks associated with participant rights and reliability of results are multifaceted and cannot be simply categorised at the trial level. These risks must be assessed independently of the risks related to the IMP and may not allow for a risk-adapted model.
The proposed risk assessment process and a plan to mitigate or manage these risks should be included in the clinical trial application for assessment of a risk-proportionate approach to all trial activities.
Table 1: Categorisation of clinical trials according to risk 
*If a grading other than those indicated is felt to be justified the rationale and evidence should be presented in the CTA application.
Building a Clinical Trial Application
The clinical trial application includes a number of mandatory documents and requires input from several functions. The depth of detail included in the application will vary according to factors such as the IMP type, phase of the trial and available safety data for the IMP but it is compulsory to complete the European-wide, EudraCT clinical trial application form for all submissions. This is published in Volume 10 of EudraLex — The Rules Governing Medicinal Products in the European Union.
The submission is made in the name of the sponsor (pharmaceutical company/ charity/ hospital), who must be based in the EU or have a legal representative who is.
The first step towards building an application is to obtain a EudraCT number from the EudraCT website. This is required to conduct any clinical trial within EU member states and the European Economic Area (EEA), including the UK, and is used as the main identifier throughout the trial. It is added to the application form and is used in all correspondence with the MHRA, ethics committee and when reporting amendments or serious adverse events.
This unique identifier enables downloading and completion of the EudraCT trial application forms from the EudraCT website or IRAS (Integrated Research Application System) websites and ensures the project is recorded on the EudraCT database. The database is hosted by the European Medicines Agency (EMA).
Integrated Research Application System (IRAS)
Since March 2009 the IRAS has provided a single system for applying for permission and approval for health care research throughout the UK. It was introduced to end the duplication of information in separate forms and enables the completion of all data requirements to apply for authorisation from the MHRA within one system. The web site contains extensive guidance on completing an application.
Components of the Application
A complete, valid application contains the following documents:
– Signed cover letter (clearly stating if it is an application via the Notification Scheme)
– Clinical Trial Application form – in XML version and signed PDF version
– Investigators Brochure (IB) or document replacing the IB
– Investigational Medicinal Product Dossier (IMPD)/Simplified IMPD
– Non-Investigational Medicinal Product Dossier (if required)
– Scientific advice – A summary of scientific advice from any Member State or the EMA with regard to the clinical trial (if available)
– EMA Decision – A copy of the EMA’s Decision on the Paediatric Investigation Plan and the opinion of the Paediatric Committee (if applicable)
– The content of the labelling of the IMP (or justification for its absence)
– Manufacturer’s Authorisation/Importer’s Authorisation plus QP declaration on GMP for each manufacturing site
– Proof of payment
According to Article 2(h) of Directive 2001/20/EC, the protocol is ‘a document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial.’ The content and format should comply with the guidance in the community guideline on Good Clinical Practice (CPMP/ICH/135/95). It should include:
– A clear definition of the end of the trial
– A description of the plan for providing any additional care for the participants once their participation in the trial has ended, where it differs from what is normally expected for the medical condition of the trial participant.
– Details relevant to the assessment of the trial by an Ethics Committee, these would include:
a) a discussion on the relevance of the trial and its design
b) an evaluation of the anticipated risks and benefits
c) justification for including subjects based on gender and reproductive status and the inclusion of trial participants who are incapable of giving informed consent, or other special populations such as minors
d) details of recruitment for the trial and the process for informed consent
Investigators Brochure (IB)
According to Directive 2001/20/EC, the IB is ‘a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects.’
The IB content and format must comply with Article 8(1) of Commission Directive 2005/28/EC and the Community guideline on Good Clinical Practice (CPMP/ICH/135/95). It should be prepared using all available information and evidence that supports the rationale for the proposed trial and the safe use of the IMP in the trial.
If the IMP is authorised and it is proposed to be used as authorised, the IB may be replaced by the approved summary of product characteristics (SmPC) or SmPC equivalent in ICH countries.
If the conditions of use in the clinical trial differ from those authorised, the SmPC should be supplemented with a summary of relevant non-clinical and clinical data that support the use of the IMP in the clinical trial.
For trials where the IMP is already authorised but is only referenced according to the active substance, or for a multi-site international trial where the authorised SmPC for the IMP varies in participant countries, the sponsor should select one SmPC as equivalent to the IB for the whole trial.
Investigational Medicinal Product Dossier (IMPD)
Broadly following the structure and content of the Common Technical Document (CTD) within a marketing authorisation application (MAA), the IMPD contains the following information on the IMP – which includes any reference product or placebo:
– manufacture and control
– data from non-clinical studies
– information on its clinical use (if available)
However, whilst an MAA dossier emphasises quality of a product for wide use in patients, an IMPD should focus on risk. The depth and range of information provided in the IMPD will vary according to factors such as the nature of the IMP, state of development / clinical phase of the trial and patient population.
The IMPD may be submitted as a stand-alone document or as a simplified IMPD in certain cases. Simplified IMPDs are permitted when the IB contains the relevant preclinical and clinical information which is then cross-referenced in the IMPD, providing assessors sufficient detail to make a decision on potential toxicity and safety of the IMP in the proposed trial. This applies to Type C trials.
A simplified IMPD may also be possible where an IMP without marketing authorisation was the subject of a previously authorised clinical trial or where the drug substance is included in a medicinal product that is already authorised in an EU state.
The applicant may also replace the IMPD with the authorised SmPC if the IMP is already authorised in an EU/ICH member state and will be used unmodified in the trial. This applies to Type A and some Type B trials.
The IMP should be labelled in accordance with Article 15 of Commission Directive 2003/94/EC. Exemption from the requirement for trial specific labelling can be claimed if a statement to this effect is included in the CTA application.
Trial-specific labelling is not required where the IMP:
– has a marketing authorisation in the UK
– is being used within the terms of its marketing authorisation
– is dispensed to a trial participant in accordance with a prescription given by an authorised healthcare professional and is labelled in accordance with the requirements of Schedule 5 to the Medicines for Human Use (Marketing Authorisations) Regulations 1994.
A copy of the Manufacturer’s Authorisation for the manufacture of IMPs should be provided for each site involved in any manufacturing step in the preparation of the IMP, including assembly, packaging and labelling and the blinding of a comparator by over encapsulation.
The requirement for a manufacturer’s authorisation does not apply where:
– manufacture or assembly is in accordance with the terms and conditions of the marketing authorisation for the product
– assembly is carried out in a hospital or health centre by a doctor, a pharmacist or person acting under a pharmacist’s supervision; and the IMP is assembled exclusively for use in that centre, or any other hospital or health centre which is a trial site for the clinical trial in which the IMP is to be used.
Where manufacture occurs outside of the EU, the product has to be imported by the holder of a manufacturer’s authorisation covering the importation of IMPs. A copy of this authorisation should be submitted in the application along with a copy of the Qualified Person’s (QP) Declaration on Good Manufacturing Practice (GMP) equivalence to EU GMP.
Submission of the Application
The clinical trial application is submitted to the MHRA for assessment via the Common European Submission Portal (CESP) with the EudraCT clinical trial provided in XML format and all the other documents usually in PDF format.
If the application is successfully validated by the MHRA, the assessment period begins from the date of receipt and an acknowledgement letter is issued. If the submission is invalid, the deficiencies are detailed in a letter for the applicant to amend and resubmit.
Initial assessment is performed by the Clinical Trial Unit within 30 days of receipt of the valid application, however, applications for healthy volunteer trials and sponsor-determined Phase I trials in non-oncology patients may qualify for a shortened assessment time (average 14 days).
Following assessment, the applicant is sent a letter informing them of either:
– acceptance of the request for a clinical trial authorisation
– acceptance of the request for a clinical trial authorisation subject to conditions
– grounds for non-acceptance of the request for a clinical trial authorisation
Where the conditions of an ‘Acceptance of the request for a clinical trial authorisation subject to conditions’ notification are met, no further action is required by the sponsor. Where the conditions are not met, the application is considered invalid and the sponsor should submit a substantial amendment along with the relevant documentation to make the necessary changes.
If there are deficiencies or inadequacies in the application, a letter is sent giving notice of the grounds for non-acceptance and the right to amend the request. This may be responded to by making an amended request for trial authorisation within 14 or 30 days of receipt of the letter, dependent on the IMP type.
Following assessment of an amended request for trial authorisation, the applicant is notified of either:
– acceptance of the amended request
– acceptance of the amended request subject to conditions
– grounds for non-acceptance of the amended request
This is sent within 60 or 90 days of receipt of the original valid application, dependent on the IMP type. Phase 1 healthy volunteer studies will be assessed within an average of 14 days.
Where an amended request is not made or amended request not accepted, the application will be deemed to have been refused and so the sponsor should submit a new full submission if they want to proceed.
The majority of Type A trials conducted in the UK only require notification to the MHRA. This involves sending the standard EudraCT application form and accompanying documents in the usual way. If successfully validated, the Notification is acknowledged by the MHRA in writing and the trial can start 14 days from receipt of the Notification, as such the acknowledgement letter acts as authorisation for the trial.
If the submission is not valid, the reasons will be communicated and a new submission containing all the necessary components should be provided.
If the MHRA finds deficiencies in the Notification (but does not deem it invalid) the submission is treated as a standard request for authorisation with the initial assessment performed within 30 days of receipt of the valid notification.
Changes During Evaluation
Following submission, updated or additional supporting documentation may be submitted before the MHRA starts the assessment phase. If a sponsor chooses to do this, the assessment starts from the date of receipt of the revision, rather than the date of the original application.
Withdrawal of a CTA
Applicants may withdraw their request for trial authorisation at any point prior to the MHRA having reached a final decision on authorisation.
Research Ethics Committee (REC) Approval
To legally conduct a clinical trial involving an IMP in humans, a favourable opinion from a REC is required in addition to MHRA approval. This is to promote and facilitate ethical research by ensuring the rights, safety, dignity and well-being of actual and potential research participants are safe guarded in line with principles of Good Clinical Practice (GCP) according to ICH Guidelines for the Harmonisation of Clinical Trials – the most important consideration in all clinical trials.
The application for ethical review may be made in parallel or in sequence with the application for CTA and seeks the opinion of a National Research Ethics Service (NRES) (or equivalent services in Scotland, Wales and Northern Ireland) appointed ethics committee.
If asked to follow a particular course of action by a REC, as part of a provisional or conditional opinion, the requirements are mandatory unless specifically revised by that REC.
Revision of the Clinical Trials Directive
Between 2007 and 2011 there was a 25% decrease in clinical trial applications in the EU and a fall of 22% in commercial trials in the UK over the same period. Much of the decline has been attributed to shortcomings in Directive 2001/20/EC, resulting in the creation of a disproportionately onerous regulatory regime, excessive cost and a lack of harmonisation in the assessment and application of rules in multinational trials – criticisms that have come from patients, researchers and industry.
To address these concerns, public consultations into clinical trials were held in 2008/9 and 2011, so that in 17 July 2012, the European Commission adopted a “Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC”. The EU Regulation No. 536/2014 was published in the Official Journal of the EU (OJEU) on the 27 May 2014 and will come into application in 2019.
The Clinical Trial Regulation will replace the Clinical Trials Directive, becoming law throughout the member states. It has ambitions of reducing costs and improving efficiency, without adversely impacting on trial participants and public health, as this change in legal form will reduce the scope for difference interpretation between Member States and for the introduction of additional, individual national requirements.
The main changes to the application and authorisation process are:
– A single submission and decision process for clinical trials to replace the practice of separate submissions to the National Competent Authority and Ethics Committees and separate approval by both.
– A single EU portal for the submission and reporting on the decision of all clinical trials in the EU (for single-state and multi-state trials).
– Information on the authorisation, conduct and results of each clinical trial carried out in the EU to be published in a database and made publicly available (subject to transparency rules).
– A flexible and swift assessment of multi-state clinical trials by setting up joint assessment by Member States co-ordinated by one Reporting Member State making it easier to conduct clinical trials in more than one member state.
– Clear and consistent timelines for the authorisation of clinical trials.
– The introduction of the concept of low-interventional studies to streamline, simplify and reduce the costs associated with lower risk trials in multiple ways.
– The explicit acceptance of co-sponsorship in trials.
Other changes as part of the Regulation affect the rules of informed consent in emergency trials, insurance and indemnification of clinical trials, GCP compliance and the supervision and reporting of trial results within and outside the EU.
The precise impact on the application process in the UK is uncertain but the MHRA has already implemented actions, pre-empting several of the proposed changes. These include the introduction of the concept of risk based management of trials, clear timelines and the permission of trials to be sponsored by more than one organisation.
Although the Regulation was adopted and entered into force in 2014, the timing of its application depends on confirmation of the full functionality of the EU portal and database. The Regulation then becomes applicable six months after the European Commission publishes notice of this confirmation. Due to technical difficulties with the development of the IT systems, the portal’s go-live date has been postponed, and as such the EU Clinical Trial Regulation is now due to come into application during 2019.
By law the Medicines for Human Use (Clinical Trials) Regulations 2004 requires MHRA approval of a CTA application, as well as a favourable opinion by a REC, before commencing a trial of a drug on human subjects in the UK. This draws on many directives and regulations put in place to protect subjects from potential harm. These cover aspects such as how, when and where trials are conducted, to ensure:
– that trials are conducted in accordance with the ethical principles and are consistent with GCP and the applicable regulatory procedures
– that before a trial is initiated, foreseeable risks are evaluated against the anticipated benefit for the individual, with proposals on how to mitigate potential problems
– a trial is only initiated if the benefits justify the risks
– clinical trials are scientifically sound and described in a clear detailed protocol
– the rights, safety and well-being of the trial participants are the most important consideration and prevail over all other interests of science and society
The forthcoming changes to the EU clinical trial landscape, with the application of the Clinical Trials Regulation, will still uphold the safety principles of the preceding law. However, with operational objectives of reducing the administrative burden, assessment timelines and operational costs caused by unnecessary regulation, there will also be real benefits for industry seeking to conduct clinical trials in Europe.
Ask us how we can guide you through the clinical trial application regulatory process.
 Adapted from ADAMON Project paper, excluding non-pharmacological interventions. Brosteanu et al. Risk analysis and risk adapted on-site monitoring in non-commercial clinical trials. Clinical Trials 2009: 585-596
The following sources were used when compiling this document:
European Commission Links:
Note for guidance on Good Clinical Practice, December 2016
Commission Directive laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use
The Medicines for Human Use (Clinical Trials) Regulations 2004
Commission Directive of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products
Communication from the Commission – Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)
The rule governing medicinal products in the RU Volume 10- Guidance documents applying to clinical trials guidance on investigational medicinal products (IMPs) and non-investigational medicinal products (NIMPs) (Rev. 1 March 2011)
Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC; 17/7/2012
SWD (2012) 201 final
Commission Staff Working Document Executive summary of the impact assessment report on the revision of the Clinical Trials Directive, 2001/20/EC, Accompanying the document Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC; 17/7/2012
Fostering EU’s attractiveness in clinical research: Commission proposes to revamp rules on trials with medicines Reference: IP/12/795 Event Date: 17/07/2012