Science and Technology CommitteeWritten evidence submitted by the BioIndustry Association (BIA)

(1) Do the European Commission’s proposed revisions to the Clinical Trials Directive address the main barriers to conducting clinical trials in the UK and EU?

1. The conduct of clinical trials in the EU is a highly regulated process ensuring patient safety and the reliability and robustness of data that is generated. These rules are set out in the “Clinical Trials Directive” (2001/20/EC). Limitations of this legislation have been highlighted in the years since its introduction by a wide range of stakeholders for its disproportionate regulatory requirements, high costs, and in particular a lack of harmonisation of the applicable rules necessary for multinational clinical trials. This has contributed to a decline of clinical trials in the EU of 25% between 2007 and 2011.

2. The BIA fully supports the European Commission’s proposal for a new Regulation on clinical trials (hereafter referred to as the proposed Regulation). The proposed Regulation can achieve more harmonisation, transparency and consistency in the approval and conduct of clinical trials across the European Union (EU), while maintaining high standards of patient safety, robustness and reliability of clinical data.

3. The proposed Regulation offers an improved, simplified and more efficient regulatory framework for clinical trials. This is critical to strengthen Europe’s competitive position as a global player for translational research and clinical development of medicines.

4. To ensure the benefits are realised and multi-state clinical trials are made easier to conduct care should be taken in legislation drafting of any amendments to ensure that the obligations and requirements are sufficiently precise, clear and unconditional.

5. While the proposed Regulation is very welcome and does, on the whole, represent a progressive change to the European framework for the conduct of clinical trials, there are specific points worthy of further consideration and refinement. Such issues are raised below before comments on more specific aspects of the proposed Regulation are also provided.

6. The BIA has concerns that the European Commission has defined new terms in the proposed Regulation. A distinction between clinical trial and clinical study (articles 2(1) and 2(2)) is unnecessary and should be aligned with agreed international guidelines to ensure no unintended consequences particularly taking into account the different types of clinical research undertaken in the EU.

7. The proposed Regulation cannot be looked at in isolation and must be considered alongside other existing pharmaceutical law, for instance the obligations on post-authorisation studies to gather further long term data outlined in the EU pharmacovigilance legislation.

8. Once the clinical trial authorisation has been granted and accepted by all participating Member States, a faster process to extend a clinical trial to additional Member States is essential.

9. There also appears no scientific justification for the longer assessment timelines for advanced therapy medicinal products.

10. The BIA can make the following more specific observations relating to key aspects of the proposed Regulation. These specific aspects are relevant as they address some of the main barriers clinical trial applicants face when conducting multi-state trials.

Authorisation procedure

11. The BIA supports the submission of one clinical trial application dossier in accordance with defined and harmonised requirements through a single EU portal for consideration by all the Member States where the clinical trial is to be carried out. The designation of one contact point per Member State is also welcomed in order to facilitate coordination and management of a clinical trial application. The proposal to introduce a clear distinction between aspects that are assessed through collaboration between Member States from those aspects that have to be assessed individually by each concerned Member State is a pragmatic and welcome approach.

12. Moreover, removal of the duality of national competent authorities and ethics committees’ decisions by mandating a single decision on the conduct of a clinical trial by each concerned Member State is another welcome feature.

13. We further support the defined timelines for each Member State to take a single decision on the conduct of a clinical trial on its territory. It is important these timelines are not lengthened. The tacit approval of a clinical trial application based on the Part I assessment conclusion if the defined timelines are not met is also welcome.

14. Where additional reviews by institutions are required by national law for a clinical trial, this must be coordinated as part of the overall assessment and provided within the timeframe specified.

15. Finally on this point, the BIA welcomes the flexibility provided by the proposed Regulation for continued support by Member States for single country trials and early phase research.

EU Portal and EU Database

16. The BIA welcomes the proposed establishment of a single EU portal to manage regulatory submissions and accompanying database for storage of all the relevant information and data.

17. Building on this it will be crucial to involve all stakeholders, including small and medium-sized enterprises (SMEs), academic institutions and research charities, in the process of developing the future EU portal. This can ensure the new portal is efficient, user friendly, secure and improves on current practice.

Risk Adaptation of the Regulation

18. The introduction of a risk-adapted approach to the regulation of clinical trials which is proportionate to the extent of current knowledge and takes account of prior experience with the product or the same class of products, as well as the type of intervention, is welcome. It will be crucial that the same approach to conducting clinical trials is applied by all academic/non commercial and commercial sponsors in the interests of patient protection.

19. The concept of a “low-intervention clinical trial” is also a merited step. It is right that, for such trials, the assessment timelines are reduced and requirements for such trials further simplified.

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

20. The HRA is a newly formed NHS organisation established on 1 December 2011 as a Special Health Authority. The purpose of the HRA is to protect and promote the interests of patients and the public in health research. Moreover, the HRA was established following the government’s Arms Length Bodies review and A new pathway for the regulation and governance of health research report by the Academy of Medical Sciences (AMS). This work was considered of importance by a wide range of stakeholders due to the perception that the UK was becoming an increasingly difficult location in which to conduct clinical trials. This was due to a number of factors including increased costs, bureaucracy and difficulty with patient recruitment and trial start up times.

21. The HRA was therefore also set up to ensure the environment for conducting clinical trials in the UK was streamlined, transparent and competitive as per other jurisdictions. The BIA was an active participant in this review conducted by the AMS.

22. The BIA has welcomed the establishment of the HRA and believes it can play a powerful role in reducing the cost and improving the speed of initiating clinical trials in the UK whilst promoting proportionate standards. The HRA has displayed an open and transparent spirit of engagement since its establishment which has been warmly welcomed by the sector.

23. The UK National Research Ethics Service (NRES) is now housed within the HRA. The BIA supports this move and would welcome additional consolidation of other relevant functions or competencies within the HRA to ensure, as far as is practically possible, a single point of contact for clinical trial applicants. This is particularly important for bioscience SMEs where any unnecessary delay or bureaucracy can have a detrimental effect on their ability to operate in future or raise finance.

24. The competencies of the HRA should be considered alongside other organisations involved in the clinical trial application and assessment process. The HRA therefore must work closely with the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health Research (NIHR) with the aim of creating a unified approval process which is proportionate and easily navigable for stakeholders. The HRA should not seek to duplicate activity undertaken elsewhere.

25. Activities undertaken by the NIHR should be considered here as they seek to improve the ease of conducting clinical trials in the UK. The NIHR does this, primarily, through its Translational Research Partnerships (TRPs) and Clinical Research Networks (CRNs). The BIA supports these initiatives which can also have a positive impact on the UK’s clinical trial environment.

26. Underpinning all of these activities are Research and Development approvals at individual NHS Trusts (known as R&D Trust approvals). These have long been recognised as a key delaying factor which affects the competitiveness of the UK as a location for clinical trial activity.

27. BIA members often highlight the added cost, both in terms of staff and time and financial outlays, which are incurred because of the administrative burden of obtaining R&D Trust approvals from NHS Trusts. While it is fair to state there are Trusts with an excellent research history this is not uniform across the UK. This is an issue for any clinical trial sponsor that wishes to undertake clinical trials in numerous sites across the UK. Sponsors will clearly often want to perform trials in different sites to ensure the best chance of recruiting the necessary patients from across the UK. Different NHS Trusts will often request additional information that either duplicates requests from other authorities, concerns information already provided or is not materially necessary for the research in question. This leads to the situation whereby conducting trials can be demonstrably cheaper and more efficient in other jurisdictions.

28. This point regarding the financial cost of R&D Trust approval is an important one to emphasise and while is of concern to companies of any size has a particular effect on SMEs. Innovative bioscience companies are often pre-revenue and equity-backed as they develop their products for areas of unmet medical need. Delays to the commencement of clinical trials, which can be ongoing for months if not longer, act as a significant drain on the companies’ finite resources. It also often delays the triggering of any milestone payments that have been agreed by a company with its partners as such payments will be dependent on completion of recruitment of patients to a clinical trial for example. Investors are aware of these additional costs and delays caused by R&D Trust approval practices and can perceive the UK negatively as a result.

29. The government are taking steps to address this issue. For example, NIHR funding is now dependent upon NHS Trusts meeting recruitment targets. Furthermore, the HRA is looking into the feasibility of single assessment procedures encompassing all relevant NHS Trust approvals relating to the sites in which a trial will take place.

30. Such an approach holds promise to improve the environment for conducting clinical trials in the UK and would provide the best opportunity for other government initiatives to succeed also.

31. It remains the BIA’s hope that the establishment of the HRA will foster a more streamlined and favourable environment for conducting clinical trials in the UK although it is too early to make a judgement on progress.

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

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

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

32. As these questions all relate to transparency and disclosure of clinical trial data the BIA will answer them together.

33. The BIA and its membership fully support the need for sensible and proportionate regulatory policies underpinning the legal framework designed to promote openness and transparency in clinical development. The BIA believes that all stakeholders in the life sciences sector, be they academic, medical research charities or industry, are supportive of transparency on clinical trials information. Clinician and patient confidence regarding the safety and efficacy of medicinal products are recognised as of vital importance to the sector and appropriate transparency has a key function in this regard.

34. There should be an expectation that the results of all trials relating to the marketing authorisation of a medicine should be publicly available to ensure patient and clinician confidence in the prescribing of such medicines. The European Public Assessment Reports (EPARs) which are made available to the public by the European Medicines Agency (EMA) provide a summary of the data upon which a marketing authorisation is granted.

35. It is worth pointing out there are many existing provisions already in place to facilitate public access to clinical trials information, for example EU Clinical Trials Register and US Clinicaltrials.gov. Dedicated web portals have also been created to facilitate public access to information pertaining to the on-going clinical trials and their results, for example IFPMA Clinical Trials Portal.

36. Given that such information exists it is important to understand what transparency and disclosure is required and at what stage of a product’s clinical development. Of course, patient safety is the core underpinning concern in all clinical trials but beyond this a large amount of data is involved in the running of a clinical trial and regard should be given to the value of know-how and expertise in the clinical development process and an appreciation of the ongoing investment into the sector. These issues are relevant in so far as they relate to products that have not yet been approved and where clinical development is ongoing before a marketing authorisation application is submitted.

37. To provide context, such know-how or trade secrets could relate to methods of manufacture and certain underlying technological approaches or processes involved in the development of an innovative product. They represent a considerable investment in intellectual effort, inventive skill, time and money, but may not be capable of protection by the mainstream law of intellectual property.

38. This should be considered alongside the changing nature of drug development and that increasingly many of the innovative developments in the sector are based on collaborations and partnerships between a variety of stakeholders including academia, medical research charities, SMEs and multinational biopharmaceutical companies. Protection of know-how provides a key factor underpinning such partnerships (examples of which are provided in the appendix of this submission). The loss of such protection would dramatically impact upon investment into the sector, thus removing a key pillar for collaborative research and development of medicines designed to improve patient outcomes and care.

39. Whilst Regulation (EC) 1049/2001 regarding public access to documents held by European institutions promotes greater openness in the works of the institutions, it also considers the need to ensure that certain specific public and private interests should be protected by way of exceptions. Article 4(2) of the Regulation provides, amongst other things, that European institutions shall refuse access to a document where disclosure would undermine the protection of commercial interests of a natural or legal person including intellectual property.

40. BIA members also highlighted as a key legal challenge for clinical trial sponsors the need to reconcile between the disclosure of clinical data as proposed and the compliance with EU data privacy rules as set forth by Directive 95/46/EC (on the protection of individuals with regard to the processing of personal data) and reflected in the scope of the informed consent form signed by the patient. It should be noted that for trials carried out so far the patient has not consented to the disclosure of personal data identifiers to the public nor to the regulatory authorities under such a new process.

41. Beyond the legal considerations and the EU strict data privacy framework, the limitations of the informed consent given by the trial subject with regard to the possible uses of the clinical trial data are also an important ethical/medical consideration and cannot be understated in the current discussion. These aspects are currently being considered by the EMA developing its policy on access to clinical trial data.

42. It is the BIA’s considered view that a balanced approach should be taken to ensure that the means to achieve greater transparency should not be done in such a way that will undermine Europe’s international competitiveness in basic, applied and translational life sciences research.

43. Finally, the BIA would consider regulatory bodies as the appropriate and natural holders of clinical trial data. As such, it should be these bodies that are responsible for the release of clinical trials information in discussion with the data holder. Furthermore, the premature release of patient level data prior to the granting of a marketing authorisation would allow other individuals to conduct analyses of the data which could compromise the regulatory agency review of the data, and undermine the public confidence in the decisions of the regulators.

APPENDIX

Listed in the table below are some examples of partnerships and collaborations. These are all recent examples announced within the last six months and represent only a sample of all such activity. Such partnerships and collaborations are increasingly a part of medical developments as the expertise of different organisations are brought to bear on a specific product or technology. A single drug, for example, could easily pass through the ownership of four or more organisations before it is finally available for patients. Each aspect of this development chain brings different expertise and know-how of importance to the development of the medicine and the value of confidential information, referred to above, is of paramount importance in such collaborations.

Historically, the UK has a rich tradition of being considered as a hub for strategic partnerships between academia, medical research charities, SMEs and established pharmaceutical/biotechnology companies. Many important and revolutionising discoveries and inventions through applied and translational research originated here. Examples include the discovery of atracuronium, the first non-depolarising non-steroidal skeletal muscle relaxant, at the University of Strathclyde in the 1970s, and temozolomide, an orally active alkylating agent authorised for treating an aggressive form of brain tumour, in the 1980s at University of Aston, Birmingham. Both are commercially successful medicines.

UK Medical Research Council and AstraZeneca

Collaborative agreement worth initially £7 million to discover 22 compounds

Apitope and Merck Serono

Collaborative agreement to develop new drugs for the treatment of multiple sclerosis

UK Health Protection Agency and US government

£14 million funding from the US government to develop anthrax vaccine

Led by GlaxoSmithKline and University of Manchester, collaboration of six pharmaceutical companies, thirteen Universities and four SMEs from across Europe

A public-private partnership worth £21.2 million to develop sustainable biological and chemical alternatives to finite materials, such as precious metals, which are currently used as catalysts in the manufacture of medicines

University of Oxford as the academic lead institution for StemBANCC

Five-year research programme worth £53 million involving academic and industry partners across eleven countries. Its objective is to develop human-induced pluripotent stem cells

Summit plc and Wellcome Trust

Award, up to £4 million, to support translational research of a novel compound being developed as a specific antibiotic for treating infections caused by C. difficile.

Oxford Biotherapeutics and Menarini

A strategic collaboration, potentially worth up to £800m, to develop and manufacture a portfolio of novel antibody-based cancer drugs.

About the BIA

Established in 1989, the BioIndustry Association (BIA) exists to encourage and promote a financially sound and thriving bioscience sector within the UK economy and concentrates its efforts on emerging enterprises and the related interests of companies with whom such enterprises trade. The BIA represents innovative healthcare-focused bioscience companies, including over ninety% of biotech medicines currently in clinical development in the UK. BIA members are at the forefront of innovative scientific developments targeting areas of unmet medical need and this innovation will lead to better outcomes for patients, the development of the knowledge economy, and economic growth.

February 2013

Prepared 16th September 2013