Science and Technology CommitteeWritten evidence submitted by Sir Alasdair Breckenridge

I write this submission in my personal capacity and as a former chairman of the Medicines and Healthcare products Regulatory Agency (MHRA).

In order to better understand my responses to the questions posed, I provide a shortbackground to the present Clinical Trials Directive (CTD) and the proposed Clinical Trials Regulations (CTR).


1. Clinical trials in the UK are currently regulated under the European Clinical Trials Directive (CTD) (2001). The aims of the CTD are to afford greater protection to subjects in clinical trials, to ensure the quality of clinical trials and to harmonise regulation and conduct of trials throughout Europe.

The CTD, being a Directive, had to be transposed into UK law and this was carried out in 2004, one of the earliest transpositions of this Directive in European member states.

2. Under the CTD:

ethics committees were established on a legal basis,

each clinical trial had to have a sponsor,

for the first time phase I studies in healthy volunteers had to be authorised by a National Competent Authority(NCA), and

NCAs were given the authority to carry out inspections for Good Clinical Practice (GCP), Good Manufacturing Practice (GMP) and Pharmacovigilance.

3. But adoption of the CTD had a series of unintended consequences:

The number of clinical trial applications fell by 25% between 2007 and 2011. In UK, the number of commercial trials fell by 22% over the same period.

The costs of the resulting bureaucracy and resource requirements to handle paperwork doubled.

Delays in starting trials increased by 90%.

4. Specific problems with the implementation of the CTD include:

Inconsistent interpretation of the Directive among member states made the conduct of multinational clinical trials difficult (of some 25,000 clinical trials being conducted in Europe, some 25% are multinational).

The type of studies regulated by the CTD were subject to different judgements among member states. For example, in UK, a study on a feeding formula for newborn babies was judged to be a trial to be reguated under the auspices of the CTD, whereas in Netherlands the same protocol was judged to be outside the remit of the CTD.

The concept the “one regulatory size fits all” implying that low risk studies with well understood drugs had to be regulated with the same rigour as trials of new molecular entities where ther risks are unknown, was challenged.

Academics who were not accustomed to working under strict GCP, found the new arrangements burdensome and frequently unnecessary.

Some definitions used in the CTD and arrangements for reporting of adverse reactions were open to several interpretations.

5. In July 2012 the European Commission produced proposals to revise the CTD.

The most important of these are:

The European authorisation of clinical trials will be carried out as Regulations (CTR), not a Directive. As a result, different interpretations of the rules by member states should diminish and multicentre multinational clinical trials should be facilitated.

Submissions will be by a single dossier submitted via a single EU portal.

National Competent authorities will still be responsible for local and ethical considerations of clinical trials which will be carried out within fixed time frames.

A risk based approach to the authorisation of clinical trials would be adopted.

New indemnity and new safety proposals have been suggested in order to reduce the burden on non commercial sponsors of clinical trials (although details of these proposals are currently sketchy and previous experience suggest that these may be unnecessarily unwieldy).

The European Commission reserves the right to monitor the conduct of these regulations and to carry out inspections.

6. The Select Committee now wishes to gather evidence on five matters.

(1) Do the European Commission’s proposed revisions to the CTD address the main barriers to conducting clinical trials in Europe and the CTD?


The Commission’s proposals are generally to be welcomed and, as shown above, should address many of the concerns which have been highlighted.

In particular, the authorisation of clinical trials under a Regulation rather than a Directive should facilitate the conduct of multicentre, multicountry trials, as will the adoption of a single submission via an EU portal. As with many of these new proposals, however, more details are needed on how they will be implemented. It is not clear whether all member states will have access to IT systems which will permit the single portal to operate as planned.

The adoption of a risk based approach to the authorisation of trials, which the UK has advocated strongly, represents an important step forward. But it is important that clear definition is made as to the terminology used eg, “low intervention” and “non intervention” trials, phraseology not currently widely used in regulation.

Further, the proposal that studies involving licensed medicines with good safety records for already agreed indications should be classified as “low intervention” requires careful scrutiny. If the dose, route of administration of the product or type of patient studied differs from those in the licence, appropriate proportionality considerations should be applied.

(2) What is the role of the Health Research Authority (HRA) in relation to clinical trials and how effective has it been to date?


The HRA was created in 2011 to protect and promote the interests of patients and public in health research, and is now being established in primary legislation. The HRA will coordinate the regulation of health and social care research in the UK.

With respect to clinical trials the HRA will work closely with MHRA and the National Institute for Health Research (NIHR) to create a unified approval process for clinical trials. A harmonious relationship between the three bodies is critical for the promotion of clinical trials in the UK.

One of the most important roles of the HRA is to coordinate the National Research Ethics Service (NRES) whose functions were previously provided by the National Patient Safety Agency and Strategic Health Authorities, both of which have been disestablished. Another important function of the HRA will be to complete service improvements such as a UK-wide e-submission through IRAS (Integrated Research Application Service).

The documentation so far provided by HRA is generally perceived as being helpful to sponsors of clinical trials.

It is too early to give an opinion on how the relationship between the various parties involved in authorisation of clinical trials will develop and this must be kept under close scrutiny.

(3) What evidence is there that pharmaceutical companies withhold clinical trial data and what impact does this have on public health?

There are two aspects of this problem:

Data relevant to the registration of clinical trials.

Data relevant to the results of clinical trials.

With respect to registration of clinical trials, in Europe all clinical trials reviewed by the EU since May 2004 have been entered on the data base EudraCT. Until recently, this database was accessible only to sponsors of the particular trial and to regulators, but not to the public. In March 2011, however, it was agreed that a EU Clinical Trials register should be created containing the aims of a trial, its design, name of its sponsor, and status of the trial and all these should be made available to the public.

In contrast, in the US matters moved more rapidly. Under the Food and Drugs Administration Modernisation Act (1997) the National Institutes of Health were charged with creating a public information resource (clinical which would contain information on all clinical trials approved as Investigational New Drugs (INDs), and would show the purpose of the trial, eligibility of subjects to participate and location of the trial. The Food and Drugs Administration Amendment Act (2007) reiterated these points and also legislated for reporting of basic results of clinical trials.

Details of public availability of the results of clinical trials present a more complex picture. A balance has to be reached between data which are commercially confidential and those whose disclosure is in the public interest. While a new medicine is undergoing review by regulatory authorities, it is reasonable that these clinical data should be confidential to the sponsor and the regulator. Once regulatory approval has been obtained, all clinical trial data, whether beneficial to the approval or not should be accessible and in the public domain. Many of the major sponsors of new medicines have agreed to this and have made supporting statements. Facts however belie this position and there are several recent widely publicised instances of the refusal of drug companies to release relevant information on the regulatory trials by which marketing authorisation of specific products has been obtained. Further, the means by which such data is made public by companies can leave much to be desired. An abstract in a minor medical journal is not a suitable vehicle for important clinical trial information of public health interest.

In 2012, the European Medicines Agency has agreed that such clinical trial data should be publically available, but has also said that further work is necessary on the timing of this change.

The impact of the availability of clinical trial data is the assurance of the transparency of regulatory decisions. As long as important relevant clinical data remains the preserve of sponsors of new medicines and those who regulate them, concern will continue as to the veracity of regulatory decisions. Public health deserves better.

Regulators already do publish public assessment reports which give the basis of their decisions, including some clinical data supporting the licensing decisions, but more openness is needed.

(4) How could the occurrence and results of clinical trials be made more open to scrutiny? Who should be responsible?


From the response to question 3, it would appear logical that the responsibility for releasing clinical trial data on medicines which have been authorised for marketing should lie with regulatory authorities. The legal basis for enforcing this is not currently clear. In this way, there could be assurance that all clinical trial data was made available, including details of those trials which were not supportive of approval, ie negative trials.This would take considerable resource and time and the question arises if this should become part of the regulatory function.

The alternative approach would be to have a legal requirement that marketing authorisation holders must disclose all the clinical trial data that they have submitted to NCAs at submission and this should be published on grant of the licence. This would also require further legislation.

(5) Can lessons about transparency and disclosure of clinical data be learned from other countries?


The pharmaceutical industry operates as a global enterprise, and applications for marketing authorisation of important new medicines are usually made simultaneously to several regulatory authorities who maintain regular scientific contact and frequently have memoranda of understanding which permit sharing of information. In particular, decisions on major regulatory issues such as those concerning drug safety are closely coordinated by the respective agencies. Where differing decisions which are reached based on the same data these may be due to differences in legal frameworks (eg as in the case of rosiglitazone in US and Europe).

The scientific basis of regulations are coordinated via the International Conference on Harmonisation of technical products (ICH), which ensures that similar standards apply in the main international arenas. While in broad terms ICH standards have been an effective means of maintaining and improving medicines regulation, increasing criticism has been made of ICH, especially with respect to Good Clinical Practice (GCP) guidelines which in many instances appear obstructive and rigid. The procedures involved in the CTR should be seen as helpful to all stakeholders.

February 2013

Prepared 16th September 2013