Clinical Trials - Science and Technology Committee Contents

2  Regulation and governance of UK trials

What are clinical trials?

8. There is no single definition for the term "clinical trial" and it can be used to describe several different types of research. Most commonly, the term refers to trials testing the effectiveness of experimental drugs. For example, Cancer Research UK told us that it used the term "only when referring to a clinical trial of an investigational medicinal product" (CTIMP),[19] using the alternative phrase "clinical study" when referring to other types of research conducted on humans.[20] The Medical Research Council (MRC) took a different approach, explaining that it considered clinical trials to include trials of investigational medicinal products (IMPs) but also trials "of medicines not defined as IMPs, or of devices or other interventions, such as surgical techniques or behavioural therapies".[21] In this Report, we employ a broad definition similar to that offered by the MRC, considering clinical trials to be experiments conducted on humans that are designed to assess the safety and efficacy[22] of a particular health intervention, be it a drug, medical device, surgical procedure, diagnostic test, public health programme or any other type of intervention.

9. Clinical trials are typically categorised into four phases, with each phase progressing only if the previous phase has been deemed a success:

  • Phase I trials aim to determine how the human body responds to an intervention and how it will tolerate increasing doses. They can be high risk and therefore usually only involve very small numbers of healthy volunteers, or patients who are ill and have few other treatment options available to them.
  • Phase II trials involve larger groups of patients—sometimes up to several hundred—and test for the first time whether a treatment works for a particular condition. They do this by helping to establish the most appropriate dosage, and by testing the treatment's efficacy.
  • Phase III trials are large trials that aim to definitively assess a treatment's efficacy for a given condition. Large numbers of participants—often several thousand—may be necessary to provide reliable evidence and to enable scientists to identify less common side-effects of the treatment under investigation. Phase III clinical trials often cost many millions of pounds to design and conduct, and can continue for several years.[23]
  • Phase IV trials occur after a treatment has been licensed for marketing. They are conducted for the purpose of safety surveillance (pharmacovigilance) to detect rare or long-term adverse effects in the wider patient population, and to compare further a treatment's performance against competitor products or current medical practice.[24] Phase IV trials are not specifically dealt with in this Report as they are subject to a somewhat different regulatory environment than other trial phases.[25]

Later phase trials, particularly phase III, often take the form of randomised-controlled trials (RCTs).[26] In a typical RCT, trial participants are randomly split into two groups, one of which receives the experimental treatment, the other of which receives either the standard treatment for that condition, or, if no treatment is available, a dummy treatment known as a placebo.[27] Where possible, RCTs are often also "double blind", meaning that neither the participant nor the clinician knows which of the two groups the participant belongs to, thereby minimising opportunities for bias to influence the results. Clinical trials can be conducted by commercial organisations hoping to develop a new product or by charities and publicly-funded researchers for various non-commercial purposes, such as testing a new use for an existing drug, comparing the performance of two alternative treatments already approved by regulators, or establishing the value of a new public health intervention such as a screening programme. Box 1 provides an example of a non-commercial phase III RCT.
Box 1: The COIN trial[28]

    The COIN trial was a phase III trial that took place between March 2005 and May 2008. It was a non-commercial trial designed to test options for the treatment of advanced bowel cancer, and was funded by Cancer Research UK, the MRC, the Experimental Cancer Medicine Centre and the NIHR Cancer Research Network.

    The COIN trial focused on two distinct questions of importance to patients with advanced bowel cancer. Firstly, whether adding the drug cetuximab—developed by the pharmaceutical company Merck and licensed for use in the EU in 2004[29]—to standard chemotherapy could benefit patients by increasing lifespan, and secondly, whether taking breaks from standard chemotherapy could improve patients' quality of life while having minimal impact on lifespan.

    The trial recruited 2,445 patients from the UK and Ireland and split them into three groups. Group A, the control group, was treated with continuous chemotherapy, group B was treated with chemotherapy plus cetuximab, and group C was treated with intermittent chemotherapy.

    Results from the trial demonstrated that, on average, patients given cetuximab alongside chemotherapy did not live any longer than patients treated with chemotherapy only. It also found that people who had received continuous chemotherapy lived, on average, six weeks longer than those who received intermittent treatment, but that patients receiving continuous chemotherapy also suffered from more side effects and underwent an average of ten weeks of additional treatment.

    Cetuximab is not currently recommended by NICE for the treatment of advanced bowel cancer, having not been found to be cost-effective.[30] However, trials into the effectiveness of the drug in treating a particular sub-group of patients have recently taken place.[31]

10. The imprecision and inconsistency of terminology surrounding clinical trials has proved to be problematic. For example, Dr Catherine Elliott, the MRC's Director of Clinical Research Interests, told us that a common reason for grant-holders failing to comply with their terms and conditions was "a difference in definition" between what the two parties considered to constitute a clinical trial.[32] Dr Janet Wisely, Chief Executive of the Health Research Authority (HRA), stated that the HRA needed to be "absolutely clear what we mean" when categorising types of clinical research, and told us that the HRA was currently in the process of defining what it considered to constitute a clinical trial.[33]

11. Clarity in use of the term "clinical trial" is essential. The establishment of consistent terminology would be an important first step towards making the UK an easier place to conduct clinical research. We recommend that the Government agrees a set of simple definitions for the terms "clinical trial", "clinical study" and "clinical research" and ensures their consistent use across the Health Research Authority, Medicines and Healthcare Products Regulatory Agency, Medical Research Council, National Institute of Health Research and the NHS.

Regulatory and governing bodies for UK trials

12. The regulation and governance of UK trials is shared between three main bodies:

a)  The European Medicines Agency (EMA): the EMA is the EU agency responsible for "the scientific evaluation of medicines developed by pharmaceutical companies" for use in the European Union.[34] Before being legally permitted to market a medicine in the EU, a company must receive marketing authorisation either from a specific country or, more commonly, through a centralised procedure led by the EMA, which results in the award of a single marketing authorisation valid across all EU states.[35] While not currently directly responsible for the authorisation of clinical trials, the EMA holds significant amounts of clinical trial data and uses this when making regulatory decisions.[36]

b)  The UK Medicines and Healthcare products Regulatory Agency (MHRA): the MHRA, an executive agency of the Department of Health, is responsible for the regulation of medicines, medical devices and healthcare equipment in the UK. It is also legally responsible for approving UK-based trials through its clinical trial authorisation process.[37]

c)  The Health Research Authority (HRA): the HRA was established in December 2011 as a Special Health Authority, with a remit to "promote and protect the interests of patients and the public in health research".[38] Although not currently legally responsible for the conduct of clinical trials, it has a number of governance functions, including operating the National Research Ethics Service and the integrated research application system, a UK-wide e-submission system through which applications for various regulatory and governance approvals can be made.[39]

The European Clinical Trials Directive

13. The primary legislative instrument regulating clinical trials in the UK is the European Clinical Trials Directive (CTD), which sets out requirements for EU Member States participating in clinical trials of investigational medicinal products (CTIMPs). CTIMPs include most trials involving active pharmaceutical products such as drugs and vaccines, but exclude trials of non-medicinal interventions such as behavioural therapies and surgical techniques and "non-interventional" trials in which an approved medicine is prescribed in the usual (and non-randomised) manner with no additional diagnostic or monitoring procedures.[40] As such, the CTD applies to many, but not all, of the clinical trials currently taking place across the UK and Europe.

14. The CTD, passed by the EU in 2001, was implemented in the UK through the 2004 Medicines for Human Use (Clinical Trials) Regulations.[41] Under the terms of these regulations, before a CTIMP can begin it must obtain Clinical Trials Authorisation from the MHRA, in addition to approval from an accredited Research Ethics Committee, currently managed through the HRA. All clinical trials conducted within the NHS, regardless of whether or not they fall within the scope of the CTD, also require sign-off from a Research Ethics Committee and, like all health research conducted in the NHS, are subject to approval from each NHS organisation taking part in the research—a process known as NHS R&D approval.[42] Some trials also require additional authorisation from bodies such as the Human Tissue Authority, the Human Fertilisation and Embryology Authority, the Administration of Radioactive Substances Advisory Committee and the National Offender Management Service.[43]

15. According to Sir Alasdair Breckenridge, former MHRA Chairman, the CTD was intended 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".[44] However, Sir Alasdair stated that "adoption of the CTD had a series of unintended consequences", which, according to the Academy of Medical Sciences, have led to the UK's strength in health research being "threatened".[45] As a result of similar concerns across Europe, the CTD is now undergoing revision and is expected to be replaced by a new Clinical Trials Regulation in 2016.[46] The CTD and the proposed new Regulation are discussed further in the next Chapter.

19   Clinical trials of investigational medicinal products, or CTIMPs, are discussed further in para 13 Back

20   Ev 90, para 5 Back

21   Ev 106, para 2; Q 39 [Dr Catherine Elliott] Back

22   See footnote to para 2 for a definition of "efficacy" Back

23   Manhattan Institute for Policy Research, Stifling new cures: the true cost of lengthy clinical drug trials, March 2012 Back

24   Parliamentary Office of Science and Technology, POSTnote: Clinical Trials, October 2011; "Types of trials: Phase 1, 2 , 3 and 4 trials", Cancer Research UK,, accessed September 2013 Back

25   "Overview of medicines legislation and guidance: pharmacovigilance", MHRA,, accessed September 2013 Back

26   "About randomised trials", Cancer Research UK,, accessed September 2013 Back

27   A placebo is defined as any therapeutic procedure which has an effect on a patient, symptom, syndrome or disease, but which is objectively without specific activity for the condition being treated. For ethical reasons, placebos are only used in clinical trials if no standard treatment is available. Back

28   "A trial looking at treatment for advanced bowel cancer (COIN trial)", Cancer Research UK,, accessed September 2013; "COIN trial in advanced bowel cancer - results presented at ECCO/ESMO conference and NCRI meeting", Medical Research Council,, accessed September 2013 Back

29   "Human Medicines: Erbuitux: authorisation details", European Medicines Agency,, accessed September 2013 Back

30   "TA242: Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy", National Institute for Health and Care Excellence,, accessed September 2013 Back

31   "A trial looking at chemotherapy and cetuximab for advanced bowel cancer (COIN-B)", Cancer Research UK,, accessed September 2013 Back

32   Q 49 Back

33   Q 152 Back

34   "About us", European Medicines Agency,, accessed September 2013 Back

35   Including the European Economic Area countries Iceland, Liechtenstein and Norway; "What we do: marketing authorisations", European Medicines Agency,, accessed September 2013 Back

36   "Special topics: clinical trials in human medicines", European Medicines Agency,, accessed September 2013 Back

37   "Licensing of medicines: clinical trials for medicines: is a clinical trial authorisation (CTA) required?", MHRA,, accessed September 2013 Back

38   Ev 103, para 1 Back

39   Ev 99, para 2.2 Back

40   "Is it a trial of a medicinal product?", MHRA,, accessed September 2013; Council Directive 2001/20/EC, Article 1 Back

41   The Medicines for Human Use (Clinical Trials) Regulations 2004 Back

42   Department of Health, Governance arrangements for research ethics committees, May 2011, Section 2.3; "Approval requirements: NHS R&D approval", National Research Ethics Service,, accessed September 2013 Back

43   "Approval requirements: NHS R&D approval", National Research Ethics Service,, accessed September 2013 Back

44   Ev w33, para 1 Back

45   Ev w33, para 3; Ev 79 para 2 Back

46   "Fostering EU's attractiveness in clinical research: commission proposes to revamp rules on trials with medicines", European Commission press release, 17 July 2012 Back

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© Parliamentary copyright 2013
Prepared 17 September 2013