The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has

launched a Notification Scheme for selected clinical trials as part of

a joint project with the Department of Health (DH) and the Medical

Research Council (MRC) on risk-adapted approaches to trial management.

The Scheme may be used for clinical trials involving medicinal products

authorised in any Member State of the European Union, where these


-     relate to the currently licensed range of indications, dosage and product form;                

-     involve off-label use, where this use is “established practice and

supported by sufficient published evidence and/or guidelines”.

Placebo-controlled trials will not be eligible for the Notification

Scheme, nor will trials in which the marketed product has been modified

- for example, through over-encapsulation. The scheme will apply,

though, in the case of repackaging and/or relabelling of marketed


14-day timeline

Once the MHRA has received a valid notification submission, sponsors

will be sent an acknowledgement letter informing them that the trial

may go ahead 14 days after receipt of the notification, providing the

MHRA has not raised any objections.

If the agency does raises any objections, the submission will be

treated as a standard request for clinical trial authorisation and an

assessment carried out in the usual manner, with a time line of 30 days

from the receipt of the original notification.

“A risk assessment based on the potential risks associated with the use

of the investigational medicinal product should be made by the

sponsor,” the MHRA states. Background documentation on how to do this

is provided on the agency’s website as part of a new section on the

Notification Scheme.

Joint project

The Scheme is the first initiative under the MRC/DH/MHRA Joint Project

on Risk Adapted Approaches to the Management of Clinical Trials of

Investigational Medicinal Products. The second part of the project will

involve guidance on risk-proportionate approaches to the management and

monitoring of clinical trials.

The risk-stratification project was initiated by an ad hoc working

group co-chaired by Professor Janet Darbyshire director of the MRC’s

Clinical Trials Unit, and Professor Kent Woods, chief executive of the


The working group includes representatives of academic researchers and

research governance managers, medical charities, the DH and the

licensing authority.

As a paper drawn up by the working group points out, the current

regulatory framework for clinical trials in the UK and the EU “allows

for a range of risk-adapted approaches that may simplify the processes

for initiating and conducting” some trials.

These adaptations “are largely related to how much is known about the

investigational medicinal product (IMP)”, it adds. The paper proposes a

simple three-tiered risk categorisation approach, based on the

marketing status of the IMP and standard medical care.

GCP concerns

The European Union’s Clinical Trials Directive, 2001/20/EC, makes

compliance with the principles of Good Clinical Practice (GCP) a legal

requirement for everyone in the EU involved in the conduct of any

clinical trial with a medicinal product, the paper observes.

While the Directive recognised that there are commercial and

non-commercial sponsors of clinical trials, “it made no distinction

between them with regard to the GCP requirements”, the working group


The European Commission has proposed, and consulted on, ‘specific

modalities’ guidance for non-commercial trials to indicate where

certain aspects of GCP could be relaxed for these particular studies,

the paper notes. However, the guidance has never been published.

This vacuum has contributed to non-commercial trialists, and in

particular sponsors of non-commercial research, believing that they

“must manage all aspects of trial conduct and GCP in a similar way to

commercial sponsors”, the working group says.

As a result, and despite there being a degree of flexibility in how the

principles of GCP can be applied, “many organisations have had concerns

about not meeting all of the statutory requirements for the conduct of

clinical trials”.

In turn, the paper adds, some organisations, and particularly those

operating in the public sector, have become reluctant to participate in

clinical trials, while others have taken a risk-averse approach

requiring “additional processes which have increased the cost and

complexity of clinical trials unduly”.