Science and Technology CommitteeWritten evidence submitted by Roche

1. Introduction

1.1 Roche is a leading manufacturer of innovative medicines in a range of therapeutic areas, including cancer, rheumatoid arthritis and infectious diseases, such as hepatitis C and influenza. Many of our treatments have changed the standard of care in difficult to treat conditions, extending and enhancing the lives of millions of patients.

1.2 We operate two autonomous research units, as well as 150 research partnerships all over the world, to foster diversity of research and translate science into medicines. In 2012 we invested nearly 8.5 billion Swiss Francs in research and we now have 72 new molecular entities in clinical development. Last year there were 2,280 clinical trials in operation involving Roche medicines, involving 35,720 healthcare centres across the world. In total, 326,642 patients were involved in these trials.

1.3 Clinical trials are critical for determining the safety and efficacy of new medicines and the clinical value of diagnostic tests. They also provide important information on the cost effectiveness of a treatment or diagnostic test and how a treatment improves quality of life. This information is shared with regulatory authorities and payers in order to gain marketing approval and, ultimately, reimbursement. Roche also publishes the results of our clinical trials through numerous channels, such as peer reviewed journals and online, as we recognise that healthcare professionals, researchers, patients and the public are also interested in knowing about potential new therapies.

1.4 We therefore have a good deal of expertise in the issues associated with conducting clinical research, including ways in which data and findings can be published. As such, we welcome the Committee’s inquiry and this opportunity to contribute evidence. As previously outlined in a letter to the Chair, we would be happy to provide oral evidence. Given the recent publicity relating to our decision around disclosure of patient-level clinical trials data on oseltamivir (Tamiflu), we have also extended an offer to the Committee to share in detail Roche’s data on this medicine, as well as to answer any specific questions the Committee may have regarding the data and to discuss the reasons for the approach we have taken.

2. 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?

2.1 As one of Europe’s largest sponsors of clinical trials we see the changes being introduced through the new clinical trials regulation as positive. A single portal for a submission, with harmonised decision-making is a major simplification and the proposal to introduce a timeline for the ethical committee approvals is most welcome.

2.2 The main barriers to conducting clinical trials in the UK are not the same as across the EU. From our experience in conducting significant numbers of trials throughout Europe it is clear that the clinical trials environment varies hugely between EU member states. Different countries interpret and implement international regulatory requirements in different ways, some with a much less legalistic approach than others. The UK has taken an excessively rigid approach, and conducting clinical trials in the UK is becoming increasingly costly and bureaucratic.

2.3 Barriers and enablers to conducting clinical trials in the UK can be categorised as follows:

Cost: the cost of conducting clinical trials in the UK can be much higher than in other countries. The reason for this appears to be twofold. The UK has a particularly intensive approach to implementing regulation compared to other countries, and the NHS does not see clinical trials as part of its day to day operation, but instead a marginal activity which is priced accordingly. Whilst standard of care interventions (such as the set number of scans a patient with a particular condition would normally receive) are charged at standard tariff prices, any additional activity required to meet rigorous clinical trial standards tends to be priced much higher—often up to 100% higher.

Time: establishing trials in the UK and getting levels of recruitment up is often a more time consuming process than in other EU countries. Local inconsistency is the main source of delay. Each NHS organisation interprets compliance with regulations differently, and this manifests itself in wide variations in local processes to gain approval. Furthermore, the wide-ranging remits of organisations such as ethics committees can lead to many clinical trials being delayed. There is a perception that the relatively slow recruitment to trials in the UK is indicative of how trials are perceived in the NHS, and this makes arguing the case for centring trials in the UK a more challenging one.

Quality: whilst the quality assurance standards in the UK are extremely comprehensive, the NHS is inherently a risk-averse environment and this filters down to individual provider units such as radiotherapy and pharmacy. This risk-aversion will increasingly have an opportunity cost in terms of being able to host the most advanced, high quality clinical trials. In addition, because the NHS is often a “low and slow” adopter of innovative new medicines, the standard of care is not always of the same quality as in comparable EU health economies, and this makes the NHS a less attractive clinical trials environment. Similarly, there is lower motivation to undertake trials in an environment where the population is unlikely to benefit from the outcome.

These views are not held by Roche alone, and were confirmed by the Academy of Medical Sciences in their 2011 report A new pathway for the regulation and governance of health research, which concluded that “a complex and bureaucratic regulatory environment is stifling health research in the UK.”

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

3.1 The HRA has been given a significant and appropriate role in protecting patients and the public in health research. However, there are concerns that it has not been given the resources to achieve its role effectively and therefore may be at risk of either scaling back its remit or slowing down its work and the research and trials that rely upon it. The HRA should be appropriately funded or given access to alternative funding routes.

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

4.1 Bringing a new medicine to market involves conducting extensive clinical trials, often involving thousands of patients. Pharmaceutical companies therefore generate a huge amount of data on a particular medicine. This data is gathered to meet the requirements of Health Authorities globally, including the provision of patient-level data to the US Food and Drug Administration (FDA), and support them in reviewing the safety and clinical effectiveness of a medicine. Much of these data will also be reported in peer-reviewed publications and many manufacturers publish summaries of all their trials, both positive and negative.

Publication of trial data

4.2 Since 2007 Roche, along with other pharmaceutical companies, committed to disclose protocols of trials and the subsequent trial results in a public registry (ClinicalTrials.gov) and have published these on our own registry (Roche-trials.com) since 2005. In addition, any medicine for which marketing authorisation is sought is subject to full disclosure to regulatory authorities around the world, in accordance with local regulations. The vast majority of health authorities request specific and extensive information on a medicine when reviewing its approval. The EMA bases its approval of a medicinal product or a new indication on clinical study reports and can also include full data listings of anonymised data and aggregated summary data. Once approved, safety data is supplied on an ongoing basis and in annual summary reports (periodic safety update reports). The US FDA also receives the same data as the EU, but in addition receives the electronic patient-level data files, which it has the capacity to reanalyse.

Tamiflu

4.3 Roche has recently been the subject of concerns raised about transparency of clinical trial data following our inability to agree with a group of academic reviewers the release of patient-level clinical trials data on Tamiflu. We stand behind the robustness and integrity of our data supporting the efficacy and safety of Tamiflu, which has been shared with all relevant regulators according to their requirements and guidelines. When considering the case of Tamiflu, it is important to note that:

Tamiflu has been reviewed and approved by regulatory authorities in over 80 countries and over 95 million patients have received this medicine since it was first licensed and made available.

Clinical trials and real-life experience from flu pandemics have shown that Tamiflu is effective in reducing the severity and duration of symptoms in those infected with flu and decreases the risk of developing the illness if there is contact with an infected individual.

Various analyses of Tamiflu show a benefit in reducing the duration of symptoms, fever and time to return to normal sleep, health and activities, as well as reducing occurrence of lower respiratory tract complications (including bronchitis) requiring antibiotics in infected patients.

Tamiflu is recommended as a flu antiviral by public health bodies worldwide including the US Centers for Disease Control & Prevention (CDC), the European Centre for Disease Prevention & Control (ECDC) and the World Health Organization (WHO).

The US FDA has just extended the license for Tamiflu, now approving its use in children two weeks of age and over. This recent approval further substantiates the safety and efficacy of Tamiflu.

4.4 Over the past 15 years Roche has been the sponsor for 81 trials into Tamiflu. Of these, one was terminated before any patients were enrolled, and 74 are now completed. Of the 74 completed Roche sponsored trials, 71 (or 96%) are in the public domain either as a primary publication or secondary publication or on Rochetrials.com. Arrangements are underway for the three sponsored studies which are completed but not yet in the public domain to be posted.

4.5 Roche receives requests regarding the release of clinical trial data from academic and independent institutions worldwide. As part of this, we request an analysis plan and signed confidentiality agreement. Given some of the complexities inherent in making available patient-level data which was generated many years ago on the basis of consent forms which were never intended to enable such access. In addition the merit for any request should be assessed to ensure that the pre-planned analyses are based on clearly defined scientific and clinically relevant questions.

4.6 In relation to an initial request from the Cochrane Acute Respiratory Infections Group for access to data on Tamiflu, we provided large volumes of information in 2009 which we believe was sufficient to answer their questions. The reviewers questioned and did not sign a confidentiality agreement. In circumstances where concerns are raised about the detail of a confidentiality agreement, it is usual to investigate alternative arrangements that protect patient confidentiality, commercial sensitivities and provides them with the reassurance they require. In this instance, no such discussion was had, a mutually acceptable position was not reached and therefore patient-level data was not released to the review group.

4.7 Roche has subsequently shared Tamiflu data with another academic group under the scope of an agreement covering these necessary issues.

4.8 We maintain the highest ethical standards in the conduct of our clinical trials and transparency of our interactions with all external parties for all of our medicines. We recognise, however, that following the debate about Tamiflu, there is legitimate policy interest in our data. Roche is confident in the data supporting Tamiflu and that and this is why we have offered to share in detail Roche’s data on Tamiflu with the Committee, answer any specific questions it may have and discuss the reasons for the approach we have taken.

5. How could the occurrence and results of clinical trials be made more open to scrutiny? Who should be responsible?

5.1 The medicines licensing system was established for very good reasons. It is vital that new treatments are assessed to ensure that the benefits to patients outweigh any potential risks for the condition in question. For this reason, and in order to maintain public confidence in medicines, the relevant licensing authorities need to remain the gatekeeper for drug approval. Provision and review of patient data should be conducted in a legitimate, independent and appropriately resourced environment to avoid the risk of offering false hope to patients or, conversely, giving rise to public health scares and consequences. Accordingly, the complete liberalisation of access to all data on medicines, without sensible assessment mechanisms in place, would not be without difficulties. Inappropriate data analysis and interpretation can lead to inconsistent messages regarding a given medicine and how best it should be used, and there are examples, such as the scares around MMR vaccines, that highlight the importance of handling data in a responsible way.

5.2 That being said, there is also legitimate interest from healthcare professionals, researchers, patients and the public into issues relating to the efficacy and safety of medicines, as well as in understanding what new therapies are in development. Accordingly, we recognise the importance of transparency and we support efforts to enable greater transparency of clinical trial results. We also understand that pharmaceutical companies have an important role to play in both facilitating and supporting this.

Role of pharmaceutical companies in supporting transparency

5.3 It is important to note that the demands for access to patient level data have increased significantly in recent years. Unfortunately many of the trials of today’s medicines were conducted many years ago when the imperative for transparency of patient-level data was somewhat less. As a result, they were not always conducted in a way which supported easy disclosure of patient-level data and, in some circumstances, the wording of the patient consent forms makes this very difficult to achieve. We believe this challenge lies at the heart of much of the current debate about the transparency of trials and is something that we are committed to addressing.

5.4 We support moves to increase transparency and believe that these are best achieved on a cross-industry basis. In doing so, it will be important to consider how transparency can be improved:

Prospectively, ensuring that clinical trial conduct and patient consent is delivered in such a way which maximises the transparency about medicines of the future.

Retrospectively, ensuring that more data are available on medicines in standard use today for which trials were conducted some years ago.

5.5 This is why we, along with many other stakeholders, offer our support to the European Medicines Agency (EMA) in their commitment to the proactive publication of data from all clinical trials supporting the authorisation of medicines. As a member of one of the EMA advisory groups, we are keen to see the results of deliberations on how proactive publication of data can be taken forward. We understand that a draft EMA policy will be available in June 2013 allowing us to prepare for the full implementation of the policy which will come into place on 1 January 2014.

5.6 Additionally, Roche is developing a policy and a process to make patient level data available: either to external researchers where a confidentiality agreement is in place and the scientific validity of the request has been reviewed by an independent third party, or for the scientifically valid request to be analysed by a third party. It is our intention to make this raw data available, but to be rigorous about the scientific standards of the requests and the quality of the analysis. We believe this to be in the interest of the trial participants and the patients and prescribers who use the medications.

Additional scrutiny of Tamiflu

5.7 In the specific case of Tamiflu, and in addition to the offer we have extended to the Committee to review and discuss the data we hold, we are taking steps to facilitate further independent review. We are seeking to establish an independent multi-party advisory board comprising expert clinicians, academics and independent institutions to look at the data on Tamiflu, identify any medically relevant unanswered questions and agree on a statistical analysis plan to address these. Given the Cochrane Acute Respiratory Infections Group’s interest in Tamiflu, it may wish to be part of this advisory board.

Real world data

5.8 Roche believes, when considering the overall benefit-risk of a medicine, all available data should be taken into account. This includes both formal clinical trial data as well as “real world” data generated during a medicine’s routine clinical usage. This approach offers important insights into how a medicine can be used to maximum effect, supports evaluations of cost effectiveness, informs pricing and enables authorities to ensure that treatment is delivering value for money.

5.9 There are already good examples of real world surveillance of drug efficacy, although more can and should be done. For example, the WHO conducts detailed global surveillance of influenza resistance to anti-virals such as Tamiflu. Clinical trials and reallife experience from the 2009–10 flu pandemic have shown that Tamiflu is effective in reducing the severity and duration of symptoms in those infected with flu and decreases the risk of developing the illness if there is contact with an infected individual.

5.10 Equally, efforts are underway to collect data on the usage, efficacy and safety of anticancer medicines in routine NHS use, through the development of the Systemic Anti-Cancer Therapy (SACT) database, which will collect data on every cancer patient who receives cancer drug therapy in England.

5.11 We would welcome the Committee’s recommendations on how best the collection and use of real world data can be improved as part of wider efforts to enhance the transparency of data.

6. Lessons from other countries

6.1 We provide health authorities around the world with all the data they request when assessing the benefits and risks of our medicines. However different national licensing authorities take different approaches to assessing and analysing data.

The vast majority of health authorities request specific and extensive information on a medicine when considering whether to grant marketing authorisation. The U.S. Food & Drug Administration (FDA) specifically requests anonymised patient datasets whereas the European Medicines Agency (EMA) does not. The FDA re-programmes and reanalyses the data in order to verify the analysis performed by the company. The EMA rather interrogates the sponsor and requests additional analysis or reanalysis from the company directly.

6.2 There are benefits and drawbacks to both this approach and that adopted by the EMA. The more information that is supplied to regulatory bodies, then the greater the cost that is associated with analysis and securing approval. Ultimately these costs will need to be borne either directly (through additional funding to the regulator) or indirectly (through higher medicines costs) by the taxpayer. It is for policymakers to determine whether or not this additional cost is justified by the benefits which may be incurred by submission of anonymised patient-level data.

February 2013

Prepared 16th September 2013