Science and Technology CommitteeWritten evidence submitted by the Association of the British Pharmaceutical Industry (ABPI)

Introduction

A.1 The Association of the British Pharmaceutical Industry (ABPI) welcomes the opportunity to submit evidence to the Committee’s inquiry into clinical trials. Clinical trials are vital in order to demonstrate efficacy and safety of new medicines and are a regulatory requirement for every new medicine. In addition, clinical trials provide important information on the best ways of treating diseases with new medicines. Treatments discovered and developed in the UK help to save lives, reduce suffering and improve quality of life for millions of people all over the world. The UK has traditionally been at the forefront of international medicines research—only the USA has discovered and developed more medicines.

A.2 ABPI is committed to greater transparency in clinical trial information and in particular, the reporting of the occurrence and results of clinical trials. We believe access to trial information is vital and in the best interests of patients and the practice medicine—and that summary clinical trial results should be made available for both new and existing medicines.

A.3 Many steps are already being taken towards this goal:

(a)Since 2012, current and future trials must be registered within 21 days of enrolling the first patient and results, positive or negative, must be published within one year of marketing authorisation (or study completion for marketed products).1

(b)ABPI is looking at a new, compliance monitoring system to ensure that the registration of clinical trials and publication of summary results takes place. A transparency toolkit will also be made available to assist companies with robust internal processes for compliance.

(c)For trials conducted in the EU from May 2004, summary reports will be made available via a central database (EudraCT), once the system has been upgraded by the end of 2013.2

(d)The ABPI has also produced guidelines to help improve access to clinical trial information including the ABPI Best Practice Model for the Disclosure of Results and Transparent Information on Clinical Trials and the Clinical Trial Transparency guidelines, produced with the Ethical Standards in Health and Life Sciences Group (ESHLSG) in 2012.3 Both sets of guidelines are currently being reviewed.

A.4 We believe that one of the areas where more could be done is in the disclosure of information from past trials. The process of improving transparency is, however, an international one, governed by EU legislation. The industry in the UK is therefore working with partners in Europe and internationally to ensure that action is taken. We are working with our member companies and experts to participate in the European Medicine Agency’s (EMA) working groups to find a real, effective and practical solution for the publication of summary results from clinical trials. As well as a global issue, this is also a complex issue. One challenge is to improve transparency while ensuring that disclosure policies protect patients: the consent a patient had provided at the time a study was conducted may not cover the general release of their data, even if the data had been effectively anonymised. In addition, it is important to protect both the integrity and effectiveness of the overall research and regulatory process and commercial information. The legitimate interests of companies in the protection of IP must also be protected in an appropriate way.

A.5 As well as improving transparency to clinical trial information, we believe that patients and the practice of medicine would benefit most when unnecessary regulatory hurdles to conducting clinical trials in the UK are removed. More progress is also required on attracting investment in research as the benefits of hosting clinical trials in the UK are well established, both for patients and society at large. Ambitious policy responses are therefore required for the UK to become and remain competitive as a centre for clinical research. We support the Government’s efforts to streamline the regulation of clinical trials and to create a more positive environment for research in the NHS through the life sciences strategy.

A.6 From HIV to cardiovascular disease, neurological conditions to oncology, the pharmaceutical industry researches, develops and delivers medicines that radically improve patients’ quality of life and bring a wide range of benefits to society. Clinical trials are a vital part of this and the UK pharmaceutical industry is committed to acting in the best interests of patients and to ensuring that patients continue to have access to the most effective treatments.

A.7 Please note that throughout this document, the term “clinical trials” refers to all interventional, commercial sponsor led clinical trials, except where otherwise specified.

Question 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?

1.1 Yes, ABPI agrees that the European Commission’s proposed revisions to the Clinical Trials Directive make positive steps to address the main barriers to conducting clinical trials in the EU, which would be beneficial for the UK. The current Directive has seen variation between member states on processes for submission, assessment and authorisation of clinical trials, timelines and safety data reporting, for example.

1.2 Revising the Directive as a Regulation will create a simpler, more efficient and uniform legal and regulatory framework for the authorisation and conduct of clinical trials in Europe. ABPI supports the proposed single submission of a Clinical Trial Authorisation (CTA) through an electronic portal with a coordinated assessment process resulting in a single decision per Member State (encompassing Regulatory Authority and Ethics Committee opinions) and competitive timelines for decisions. ABPI calls on the UK Government to ensure the UK can meet these timelines to ensure competitiveness.

1.3 At a national level, a significant administrative hurdle is the need to obtain separate NHS research and development (R&D) approval when the clinical trial is conducted in an NHS hospital or enrolling NHS patients. This is not addressed by the proposed Clinical Trials Regulation, but the Health Research Authority (HRA) has proposed to test a system for a single unified assessment for all research within the NHS (see response to Q. 2 for an assessment at a national level).

1.4 Overall, it is important that the Commission’s proposals remain as intended for this legislation through the EU co-decision process and that all parties aim for agreement at first reading to avoid potential delays as a result of the upcoming European Parliament elections.

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

2.1 ABPI strongly supported the creation of the HRA in 2011 to streamline regulation and to protect and promote the interests of patients and the public in health research. Streamlining regulation and making the UK a more attractive location to conduct clinical trials is at the core of the HRA’s remit. Just over a year after its establishment, we believe it is too early to judge the effectiveness of the HRA in a comprehensive manner. Certainly, more can and should be done to make the UK a more attractive location to conduct clinical trials.

2.2 The HRA provides the Integrated Research Application System (IRAS), a UK-wide e-submission system through which applications for regulatory and governance approvals for health research are made. It is also the Appointing Authority for Research Ethics Committees (RECs) in England and provides the National Research Ethics Service (NRES), which regulates and guides ethics committees.

2.3 In addition, the Department of Health has agreed to the HRA’s proposal to test the potential benefits of a simplified and streamlined HRA assessment for all research in the NHS. The devolved nature of the NHS means that trials often require many separate grants of permission, particularly where research is to be carried out across multiple sites, run by different NHS organisations. Securing several different permissions is an administrative burden for trial sponsors and does not provide additional protection for patients. A single HRA assessment would combine and replace aspects of the current review by NHS Research and Development and RECs. A single HRA assessment could potentially improve both study set-up times and the quality and consistency of ethical review, as well as improving transparency around the process.

2.4 ABPI believes the HRA should focus on building and maintaining competitive timelines for starting research studies in the UK, with particular emphasis on delivering the commitment to recruit the first patient within 70 days of receiving a valid research application, while consistently ensuring the delivery of patient recruitment to time and target.

2.5 The HRA also has a clear remit focused on protecting patients and would be well placed to ensure that precise information is given to Ethics Committees and trial participants on where to find trial registration details and ultimately, summary results.

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

3.1 The pharmaceutical industry supports enhanced transparency of clinical research and safety information. Already, current and future trials must be registered within 21 days of enrolling patients and summary results, positive or negative, must be published within one year of marketing authorisation or within twelve months of study completion for marketed products.4

3.2 It is widely reported, however, that some clinical trial information is not in the public domain. It is true that compliance with the requirement to register clinical trials and posting of their summary results could be further improved, and we propose mechanisms to achieve this in our response to Question 4.

3.3 The charge that pharmaceutical companies withhold clinical trial information is commonly associated with a report published in 2012.5 This report relates to a study of all trials completed in 2009 which met the criteria for mandatory registration and summary results posting on www.clinicaltrials.gov under FDA regulations from 2007. The authors reported that 22% of all trials meeting the criteria were registered and had summary results posted; the figure was 43% for industry-sponsored trials and 9% for academic trials.

3.4 At the Thirteenth Annual Pharmaceutical Regulatory and Compliance Congress and Best Practice Forum held in the United States in November 2012, a presentation by Dr Ann Meeker-O’Connell from the US Food and Drug Administration (FDA) challenged the results of the above mentioned study, finding several flaws in the analysis. The US FDA’s preliminary review of Prayle’s results found that instead of 77.9% of trial summary results being overdue, 34.6% trial results were overdue by January 2011. Updating this analysis to May 31 2012, 21.1% of trial results were overdue, a compliance rate of 78.9%.6

3.5 ABPI is undertaking its own research to ascertain the extent to which pharmaceutical companies publish the results of clinical trials sponsored by them, irrespective of prevailing requirements. All company sponsored clinical trials conducted in patients for all new active substances (NAS) (excluding vaccines and combination products) approved by the European Medicines Agency (EMA) during 2009–11 inclusive are being evaluated. This involves:

Checking of the European Public Assessment Report (EPAR) for all studies conducted in patients in the individual Marketing Authorisation Application (MAA).

Searching for all registered trials in the major international registries and company clinical trial registers.

Searching PubMed for all publications (limited to clinical trials), viewing the abstract field and matching to trial registry identifiers where they appeared in the abstract.

Cross-matching trial identification numbers from all sources, and minimizing duplication as far as possible.

Checking the dates that the studies were entered in a publicly available clinical trial registry (noting those that were not entered).

Ascertaining which studies have reported results (either in the academic literature or in a section of the registry) by one year after the later of the date of first approval of the product or the date the study was completed.

Referring queries back to the companies concerned.

3.6 The research is still ongoing, but ABPI found that for the 12 new products approved in 2010, the levels of trial registration and publication clearly exceed those quoted in Prayle et al, and are more in line with the FDA’s preliminary findings—see table below.7 Our analysis shows that the publicly available evidence base for new medicines has improved in recent years. The research also suggests that clinical trials conducted prior to the existence of mandatory requirements or industry guidelines were less likely to be posted on registries and less likely to be published individually; this was particularly the case for smaller, early phase trials. In addition, problems commonly arise where products changed ownership after licensing deals or company mergers and acquisitions.

ABPI analysis of clinical trial registration and publication of summary results for all company sponsored clinical trials in patients for the 12 new active substances approved by EMA in 2010

Year

Trials registered and summary results
posted/published within 12 months (%)

Trials registered and summary results
posted/published (as of 31 January 2013) (%)

2010

115 of 145 (79%)

176 of 191 (92%)

NOTE: Of 213 trials identified as complete as of end of January 2012, 68 were non-evaluable due to the absence of one or other of the key assessment dates (eg, the precise date of study completion is missing or summary results have been posted, but the date of posting is not available). For some of these products, this includes trials conducted before any mandatory requirements for reporting summary results were in place. We are conducting a similar analysis for all NAS approved by EMA in 2009 and 2011.

3.7 It is important to stress that regulatory authorities have access to all the relevant information as part of the approval process for new medicines, and regular updates thereafter. A Freedom of Information (FOI) request can be made for any document within the MAA for any approved product. Certain documents should however be redacted to prevent personal data (as protected under European and national data protection laws) and commercially confidential information being disclosed, in consultation with the MAA holder.

3.8 Work is already underway to improve access to clinical trial data for existing medicines. Summary reports for clinical trials since 1 May 2004 will be entered on the EudraCT database when it has been upgraded to accept them later this year. EudraCT is the European Clinical Trials Database of all clinical trials within the scope of the EU Clinical Trials Directive.

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

4.1 There are a number of steps which can be taken to ensure that clinical trial information can become more open in the future. Some immediate steps which ABPI recommends are:

(a)The global nature of clinical development means that an international approach is required. International agreement is needed on which trials to include in transparency measures (for example, all trials in humans, including healthy subjects, or all trials in patients) and on definitions of terms such as “study completion”. Good Clinical Practice (GCP) is an international quality standard that is provided by the International Conference on Harmonisation (ICH), an international body that defines standards which governments can transpose into local legislation for clinical trials. ICH could be a mechanism to achieve harmonisation of an international approach. In the interim, ABPI recommends that MHRA Good Clinical Practice inspections should be able to assess compliance with trial registration and publication of summary results requirements.

(b)For all trials, the patient informed consent agreement between a trial participant and the sponsor should include a statement from the sponsor that the summary results will be made publically available. Precise information must be given to trial participants on where to find trial registration details and ultimately, summary results. Investigators and Ethics Committees should all receive summary results not later than posting dates of the results on the registry. These are activities which HRA should ensure are implemented immediately for all clinical research in the UK.

(c)One global portal to which all clinical trials registries can be linked would be ideal. For now, www.clinicaltrials.gov and www.clinicaltrialsregister.eu should be used. Companies may wish to also maintain their own clinical trial register, which should cross-reference the entries in the international registries with the unique trial identifiers. Companies could state where disclosures can be found on their websites, as part of their compliance statements. Medical journal editors should demand that the unique trial identifier is mentioned in the abstract of journal publications.

(d)Already, Marketing Authorisation Applications must be accompanied by all relevant clinical trial information. ABPI recommends that for an MAA to be valid, the EMA in Europe and MHRA in the UK should require that all trials submitted as part of the application have been entered into an international registry, and the unique trial identifier from the registry must be listed against each trial.

(e)It is important to understand what kind of information is required to be disclosed, and what kind of information is being called for. Currently, semi-structured summary information for Phase II-IV clinical trials for licensed medicines can be disclosed through www.clinicaltrials.gov within 12 months of completion. With an upgrade of EudraCT planned to be completed in 2014, trials summary report information for Phase II-IV adult clinical trials conducted in the EEA for licensed drugs are to be disclosed within 12 months of completion and paediatric clinical trials of any origin when included in a Paediatric Investigation Plan are to be disclosed within six months of completion.

ABPI is closely following the progress of the five working groups set up by EMA to advise on the specific mechanisms that will govern whether and how final clinical study reports (CSR) and all available clinical trial information could be accessed by researchers and other interested parties. EFPIA, ABPI’s European equivalent, has set up five parallel groups, each led by an industry representative who sits on the respective EMA group. The output from this work is critical as it will ensure that there is a consistent and clear understanding of what level of information should be released, in what format and when. ABPI will respond to the outputs of the EMA working groups in Q2 2013.

(f)Compliance is, of course, critical. ABPI is preparing a clinical trial transparency toolkit (comprising good practice guideline, process flowchart, template SOP, compliance checklist etc) to assist companies to comply with their obligations. These will be available on the ABPI website during Q3 2013. In addition, ABPI will appoint a third party service provider to monitor compliance with current and future industry codes of practice on clinical trial transparency. ABPI will take on the responsibility for reporting non-compliance in relation to trial registration and posting of summary results to the Prescription Medicines Code of Practice Authority (PMCPA), or where applicable to the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA).8

4.2 All of the above initiatives should be taken for new clinical trials. There is also the additional issue of improving disclosure of information from past trials for existing medicines, where there are significant complexities over release of information. The EMA and EFPIA are currently looking at all of these issues as part of their work. The complexities include:

(a)Patient consent: complete annoymisation of patient data may not always be possible. Even if patient data is anonymised and all patient identifiers are removed, some patients may not have given their consent to release of their data from past trials.

(b)Orphan (or rare) diseases: it is much more difficult to protect patients’ identities for clinical trial information for medicines for orphan diseases.

(c)Different data formats: clinical trial information has been presented in quite different formats over time and between different companies and any system for release of this information would need to take this into account.

(d)Paper archives: much information for past clinical trials is held in paper format. Making all information available would require this information to be reproduced in electronic format.

(e)Volume of information: releasing all information for all trials would be an enormous undertaking. It is not unusual for a full CSR to be several thousands of pages in length. www.clinicaltrials.gov already has over 140,000 registered trials.

(f)Ownership of information: many medicines are bought and sold as part of licence deals or company acquisitions across the world. In some cases, there is insufficient clarity over responsibilities in connection with management of clinical trial information within legal agreements.

(g)Start date: a grandfathering clause date would need to be set before which it would be impractical and of questionable benefit to release clinical trial information for medicines. A mechanism for deciding this date needs to be agreed.

(h)Different regulatory regimes: clinical trial legislation and requirements have changed over the years, resulting in different sets of information being collected and analysed in different ways, especially across different EU member states prior to the EU Clinical Trials Directive.

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

5.1 The international governance framework for clinical trial transparency already exists and is workable if appropriate attention is paid to detailed implementation. In the US, the FDA has made greater strides in this regard. The regulation is clear and the database employed, www.clinicaltrials.gov, is widely acknowledged as being user-friendly and easy to navigate for companies and researchers alike.

5.2 The most significant barrier to clinical trial transparency has been, and still is, monitoring and enforcement. Given the current trend towards greater transparency in all walks of life, the time is ripe to put in place robust measures to make clinical trial information easily accessible for patients, researchers and healthcare providers, as outlined in the response to question 4.

About the Association of the British Pharmaceutical Industry (ABPI)

The ABPI represents innovative research-based biopharmaceutical companies, large, medium and small, leading an exciting new era of biosciences in the UK.

Our industry, a major contributor to the economy of the UK, brings life-saving and life-enhancing medicines to patients. Our members supply 90% of all medicines used by the NHS, and are researching and developing over two-thirds of the current medicines pipeline, ensuring that the UK remains at the forefront of helping patients prevent and overcome diseases.

The ABPI is recognised by Government as the industry body negotiating on behalf of the branded pharmaceutical industry, for statutory consultation requirements including the pricing scheme for medicines in the UK.

February 2013

1 ABPI Code of Practice for the Pharmaceutical Industry Second 2012 Edition, http://www.abpi.org.uk/our-work/library/guidelines/Pages/code-2012.aspx

2 European Union Drug Regulating Authorities Clinical Trials database, https://eudract.ema.europa.eu

3 ABPI Best Practice Model for the Disclosure of Results and Transparent Information on Clinical Trials, (produced 2007, revised 2008), http://www.abpi.org.uk/our-work/library/guidelines/Pages/best-practice-model.aspx Clinical Trial Transparency guidelines, Ethical Standards in Health and Life Sciences Group, 2012, http://www.eshlsg.org/wp-content/uploads/ESHLSG-Clinical-Trial-Transparency-Principles-and-Facts.pdf

4 ABPI Code of Practice, 2nd Edition (2012), http://www.pmcpa.org.uk/thecode/Pages/default.aspx
International Federation of Pharmaceutical Manufacturers and Association’s (IFPMA) Joint Position on Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases (2010), http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/20100610_Joint_Position_Publication_10Jun2010.pdf

5 Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study, Prayle et al, 2012, http://www.bmj.com/content/344/bmj.d7373

6 PhRMA Press release, http://phrma.org/media/releases/phrma-statement-clinical-trials-bad-pharma and personal communication

7 op cit. Prayle et al.

8 Prescription Medicines Code of Practice Authority http://www.pmcpa.org.uk/Pages/default.aspx International Federation of Pharmaceutical Manufacturers & Associations http://www.ifpma.org/

Prepared 16th September 2013