Science and Technology CommitteeFurther written evidence submitted by Sense About Science

THE RATIONALE FOR FULL AND RETROSPECTIVE CLINICAL TRIAL REGISTRATION AND REPORTING, FOR RESEARCH, INNOVATION AND EFFECTIVE HEALTHCARE

1. Improving Treatments for Patients

With full information about effects and side effects, a better risk/benefit calculation can be made by doctors, and individual patients. Healthcare commissioners and regulators can make a more accurate cost/benefit assessment which ensures that the treatments available are those that are truly the most effective.

With full information we would expect greater confidence all round that full information about risks and benefit is known. It will also reduce the potential for flipping between “wonder drug” and “killer drug” stories and their associated effects among patients of overoptimistic demand (people failing to report side effects, taking others’ medication etc) and suddenly stopping medication.

2. Improving Research and Innovation

The effect of publishing the full reports of clinical trials will be to provide a richer research base for both industry and academia. This means greater potential for collaboration and interdisciplinary work, more productive research, and potential value from unused Intellectual Property.

Scientific research is self correcting. Research advances through critical analysis and review, which are essential for identifying flaws in study design, statistical errors, missed observations of both benefits and risks and the best ways to conduct further research. This process has been necessarily partial because of partial publication. Full publication will restore this vital part of the research checking process, which is the basis of greater confidence in research findings whatever their provenance.

Efficient reviews. A large proportion of the time currently spent on systematic reviews by organisations such as the Cochrane Collaboration, publicly funded clinical researchers as well as by companies seeking information about proposed applications, goes on attempting to discover what has been done already rather than on assessing it.

3. Avoiding the Waste of Pointless Repetition of Studies

Clinical trials cost; UK cost per patient of a clinical trial: 9, 758 euros.1

Contractors report that they are asked to conduct research for one entity and do so even though they have already conducted similar work under a confidential contract for another entity and know that the intervention does or doesn’t work.2

Conducting clinical trials on patients to discover something that has already been discovered, however unintentionally on the part of those conducting the research, is misleading participants, wasting resources on expensive and unnecessary research and putting patients at unnecessary risk.3 For years, patients who had suffered a heart attack were prescribed drugs to prevent heart rhythm abnormalities. By 1990, it was estimated they were killing between 40,000 and 70,000 per year. Had a trial conducted in 1980 suggesting the drugs were lethal been published, this catastrophe might have been prevented.4

The “Burden”

It is necessary, in the case of full Clinical Study Reports and their equivalent, to ensure that any data that would identify patients are not made public. GSK, in its undertaking to make reports available going back to its formation as a company, has made clear that it can achieve this through redacting that information. Other companies are considering doing this too, and yet others are considering whether as a first step they should retrospectively publish all summaries, with redaction taking place on receipt of a request for the full report.

In the case of future reports, greater care can be taken to separate information which cannot be published, so this administrative burden is temporary and should be viewed as part of the necessary remedial measures to overcome failures in transparency to date.

Academics are already required, according to the Helsinki Declaration, to make the results of trials available: “Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research. Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical reporting.”

This means all results according to what was planned in the trial protocol, not just a summary of the results (we already know that summaries of results are generally highly misleading, see, for example: Gøtzsche PC. Believability of relative risks and odds ratios in abstracts: cross-sectional study. BMJ 2006;333:231–4).

March 2013

Appendix 1

STATEMENTS BY THE PHARMACEUTICAL INDUSTRY ON CLINICAL TRIAL TRANSPARENCY

1. Correspondence between the AllTrials campaign and the Association of the British Pharmaceutical Industry.

2. GSK statement announcing support for the AllTrials campaign and our response.

3. Roche statement on new process for accessing clinical trial data and our response.

4. ABPI statement on new clinical trial transparency measures.

5. Correspondence between the AllTrials campaign and the Association of the British Pharmaceutical Industry.

Association of the British Pharmaceutical Industry (ABPI) statement on AllTrials.net

18 January 2013

The pharmaceutical industry has been and continues to be committed to evolving and addressing the issues relating to transparency in clinical research.

Throughout the industry, companies are publishing increasing amounts of clinical data. Following a change to the ABPI Code of Practice in 2012, companies are obliged to publish all clinical trial results within one year of marketing authorisation and publically register new clinical trials within 21 days of the first patient being enrolled.

In common with alltrials.net, the ABPI believes greater transparency of clinical trial results, and appropriate access to trial data, past and present, is in the best interests of patients and medicine. However, this can only be true where proper attention is given to some crucial considerations.

Firstly, there is a need to protect patient confidentiality and personal data. At present, disclosure policies protect patients’ personal data and consent is not given for their data to be utilised by other third parties, for different purposes and at different times.

In addition, the release of commercially confidential information could undermine investment in the research and development of future medicines. This is ultimately not in the interests of patients, who would not be well served by dis-incentivising research based biopharmaceutical companies and commercial organisations from other life sciences sectors from making the substantial investments and shouldering the risks that are necessary to develop new innovative medicines.

Furthermore, the disclosure of all clinical trial results, past and present, would involve making vast amounts of data, held in an enormous variety of formats across the world, accessible for medicines long established as safe and effective by the clinical community. Release on reasonable request, via a transparent and accountable process, may be a more pragmatic way forward and this debate is on-going. We believe there must be measures in place to ensure that the raw data from clinical trials can only be shared with trustworthy and competent scientific institutions that are capable of conducting appropriate analyses.

Throughout these discussions, it is important to recognise that research is a truly global activity, with the UK supplying less than 2% of patients to global clinical trials. As part of a global industry, we are actively engaging with our European and international counterparts, as well as many other stakeholders, to input into these on-going discussions.

Finally, the debate around clinical trial transparency is important but it is essential that patients have confidence that the medicines their doctors prescribe for them are appropriately safe and effective. However much data is published—or not—the regulatory authorities have access to all the relevant data as part of the approval process for new medicines.

Response from AllTrials to ABPI statement

23 January 2013

On 18 January 2013 the ABPI put out a statement on AllTrials, but the statement does not address the things that AllTrials is calling for.

AllTrials calls for the publication of clinical study reports from all clinical trials since the 1990s and for all trials to be registered. It is not a campaign for releasing individual patient data. The only mention made of publishing clinical trials results in the ABPI response is with reference to the ABPI Code of Conduct, which is only for new trials rather than earlier trials relating to treatments currently in use. The ABPI’s statement appears to contradict the Code by saying that there are commercial reasons not to follow it.

The development of new treatments, patient confidence and regulatory oversight can only benefit from having full information about the trials that have been done before and what they have found. It is important that industry engages with this issue. We are not campaigning on access to individual patient data; that is a separate issue. Please can you respond to our call for access to clinical study reports and summary trial results on all trials for currently used treatments.

Reply from ABPI to AllTrials statement

24 January 2013

Many thanks for your email to Stephen Whitehead which has been passed to me to respond on behalf of the ABPI.

Like you, we do believe that greater transparency of clinical trial results, and appropriate access to trial data, past and present, is in the best interests of patients and medicine. We also agree that all trials should be registered, which is a requirement of the ABPI Code of Practice.

Regarding the call from the AllTrials campaign for the publication of clinical study reports from all clinical trials since the 1990s, we support greater access to trial data but as you are aware, this is a complex issue since research and development is an international endeavour. As such, the UK cannot act in isolation. This is why we support the European Medicines Agency’s initiative to disclose trial information and the creation of working groups to examine the many complexities in making disclosure feasible. We believe it is necessary to wait for the outcomes of the working groups in order to establish systems and processes to disclose CSRs in line with the EMA final recommendations.

As we acknowledge in our statement, the debate around clinical trial transparency is important but it is also essential that patients have confidence in the medicines their doctors prescribe and understand that the regulatory authorities have access to all the relevant data as part of the approval process for new medicines, regardless of how much data is “published”.

The ABPI welcomes your contributions to this important debate and we do believe there is much common ground. Please do feel free to contact me if you would like to discuss this in person.

AllTrials asks ABPI some direct questions

29 January 2013

Thank you for your reply. Your comments are still on the subject of individual patient data. As our last response to you emphasised, AllTrials is calling for publication of clinical study reports for all treatments in use internationally. Your position on this is as unclear as it was before you issued two replies. There is no need to wait until 2014 for an EMA consultation on individual patient data to end before answering our questions on clinical study reports. Attempts to address transparency have suffered from these kinds of irrelevant delays since first being raised in the 1980s, which suggests that industry does have objections to the publication of clinical study reports for treatments in current use. If so, these should be set out clearly and specifically. Perhaps a better way to clarify it would be for ABPI to answer directly the following questions:

Do you agree that clinical study reports etc should be provided for all treatments in current use (and that where these are not available an account given of this by the Principal Investigator)?

Do you agree that this information should be publicly available?

Will you amend your 2012 guidelines to this effect?

Will you support an amendment to the EU Clinical Trials Regulation to this effect?

What, if any, are your commercial objections to publication of clinical study reports?

What kind of situations do you think would justify withholding clinical study reports?

ABPI answers

1 February 2013

Many thanks for your email and questions. We have responded below.

Our overarching belief is that greater transparency of clinical trial information is in the best interests of patients. We are supportive of the EMAs efforts to identify the best way to do this and are engaged in the discussion on how it can be done.

Do you agree that clinical study reports etc should be provided for all treatments in current use (and that where these are not available an account given of this by the Principal Investigator)?

In principle, ABPI is in favour of sharing CSRs; however this needs to be done in a way that is responsible, reliable and reproducible across the world since clinical research is a global activity. The EMA working groups are going to report on the mechanics of exactly how to do this, therefore it would be prudent to await the results of their work, which will be later this year.

Do you agree that this information should be publicly available?

In principle, yes. But there has to be a process involving the company in identifying what elements should not be disclosed due to data privacy concerns or to protect commercially confidential information. Our industry would urge civil society to prioritise what studies are most important to release. It is simply impossible for regulators and companies to release all study reports at once. Companies would rather spend time developing new medicines than going through millions of pages of historic data. Also, there must be a process of coordinating this process among the regulatory agencies—the same study reports have been submitted to agencies all around the world.

Will you amend your 2012 guidelines to this effect?

The discussions on release of data are being carried out at a European level through EMA and, from an industry perspective, through the European Federation of Pharmaceutical Industries and Associations (EFPIA). EFPIA has indicated it is open to discuss future changes to its Code depending on on-going discussions with EMA. ABPI would ensure its Code was aligned to the wider European position.

Will you support an amendment to the EU Clinical Trials Regulation to this effect?

We support rules that require the publication of all clinical studies. For studies intended to support marketing authorisation applications, the studies should be made public once the product is approved.

What, if any, are your commercial objections to publication of clinical study reports?

As clinical study reports, until now, have been written for a regulatory audience and assuming confidentiality, they may describe commercial plans of the company. For instance, the development strategy for future studies on new indications may be described to put the particular study in context. In some cases, companies may consider that a particular study design is a trade secret that competitors can learn from. Furthermore, study reports often include appendices with detailed information on analytical methods (chemical and physical) and on the manufacturing of the clinical trials material. This is a key area the EMA working groups will examine.

What kind of situations do you think would justify withholding clinical study reports?

In general patient identifiable data and commercially sensitive information can be redacted rather than the study report withheld. However, when a company does not have a patent for a product it relies on “regulatory data protection” to get the necessary market exclusivity to recoup the investment made. This period is 10 years in the EU. If the entire file with all studies is released other companies can get approvals around the world. Anyone can get an approval as long as they submit the necessary data—regulators do not require that they generate the data themselves. This would not support the development of innovative medicines.

Appendix 2

GSK STATEMENT ANNOUNCING SUPPORT FOR THE ALLTRIALS CAMPAIGN AND OUR RESPONSE

GSK announces support for AllTrials campaign for clinical data transparency

5 February 2013

GSK today further demonstrated its commitment to clinical trial transparency by announcing its support for the AllTrials campaign. The campaign is calling for registration of clinical trials and the disclosure of clinical trial results and clinical study reports (CSRs) to help drive further scientific understanding.

GSK already publicly discloses a significant amount of information about its clinical trials. The company registers and posts summary information about each trial it begins and shares the results of all its clinical trials—whether positive or negative—on a website accessible to all. Today this website includes almost 5,000 clinical trial result summaries and receives an average of almost 11,000 visitors each month. The company has also previously committed to seek publication of the results of all of its clinical trials that evaluate its medicines to peer-reviewed scientific journals.

Expanding on this, GSK is committing to make CSRs publicly available through its clinical trials register. CSRs are formal study reports that provide more details on the design, methods and results of clinical trials and form the basis of submissions to the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory agencies. From now, GSK will publish CSRs for all of its medicines once they have been approved or discontinued from development and the results have been published. This is to allow for the data to be first reviewed by regulators and the scientific community. Patient data in the CSRs and their appendices will be removed to ensure patient confidentiality is maintained.

In addition, while there are practical challenges, the company also intends to publish CSRs for clinical outcomes trials for all approved medicines dating back to the formation of GSK. This will require retrieval and examination of each historic CSR to remove confidential patient information. Given the significant volume of studies involved, the company will put in place a dedicated team to conduct this work which it expects to complete over a number of years. Posting will take place in a step-wise manner, with priority given to CSRs for its most commonly prescribed medicines.

Patrick Vallance, President, Pharmaceuticals R&D, GlaxoSmithKline, said: “We are committed to being transparent with our clinical trial data to help advance scientific understanding and inform medical judgment. Our commitment also acknowledges the very great contribution made by the individuals who participate in clinical research. All those involved in the conduct and publication of clinical research, whether healthcare companies like GSK, academia or research organisations, have a role to play in ensuring that the data they generate are made publicly available to help bring patient benefit.”

Separately, in October 2012, and going further than the call made by the AllTrials campaign, GSK announced it would develop a system where researchers will be able request access to detailed anonymised patient level data that sit behind the results of clinical trials to enable additional scientific inquiry and analyses to help further scientific knowledge.

Response to GSK statement form Tracey Brown, Director, Sense About Science

6 February 2013

“GSK signing up to the campaign is very important, of course, because they are a large global player in clinical research so they have a lot of potentially useful information to share, but also because they are finding a way to put in place the infrastructure needed to do this. Which makes it realistic for others and sets a new standard. Their position will also make it possible to have a sensible discussion with regulators about the way that they make information available. And it will hopefully put a stop to the ridiculous obfuscation and foot-dragging that have characterised reactions to AllTrials from some other parts of industry.

I think that since AllTrials went live it is becoming clearer by the day that this is moving in only one direction, as thousands of doctors, researchers and members of the public signed up and organisations have joined them. It’s clear from their statement about the practical details that GSK has been thinking about this issue for some time; AllTrials’ influence has really been in getting the decisive public commitment.

GSK say in their statement that they owe it to patients who have taken part in their trials. I think that is very, very true. Companies who have yet to take this seriously should ask themselves where they want to be on that duty a few years from now.”

Appendix 3

ROCHE STATEMENT ON NEW PROCESS FOR ACCESSING CLINICAL TRIAL DATA AND OUR RESPONSE

26th February 2013

Roche launches new process for accessing clinical trial data

Independent body to grant access to patient-level data for scientific review

Roche today announced that it is expanding access to its clinical trial data for third party researchers. Roche will work with an independent body of recognised experts to evaluate and approve requests to access anonymised patient-level data. Roche will support the release of full clinical study reports (CSRs) for all its licensed medicines via regulatory authorities and make available any CSRs that cannot be provided by these authorities upon a researcher’s request.

“We understand and support calls for our industry to be more transparent about clinical trial data with the aim of meeting the best interests of patients and medicine,” said Daniel O’Day, Chief Operating Officer of Roche Pharma. “At the same time, we firmly believe that health authorities need to remain the gatekeeper for drug assessment and approval. We believe we have found a way in which patient data can be provided to third party researchers in a legitimate environment that ensures patient confidentiality and avoids the risk of publishing misleading results or giving rise to public health scares and consequences.”

Roche continues to provide all information requested by health authorities who approve medicines for patient use. Public access to results from clinical trials is also provided via rochetrials.com and clinicaltrials.gov in a summary form. Roche will also submit results to the European Union database, EudraCT as soon as this public archive becomes operational.

Roche is supporting the European Medicines Agency (EMA) in its commitment to the proactive publication of data from all clinical trials supporting the authorisation of medicines. Roche is a member of one of the EMA advisory groups working on the new EMA data access guidelines. The policy is scheduled to come into force early 2014.

Amendments to the Roche data transparency policy include:

Access to patient data sets: An independent body will assess the scientific validity of requests for anonymised patient-level data, with the requested data made available within a secure system following agreement. Access to patient data will be available for those clinical trials which have been submitted together with an application for a medicine’s registration and will be available after the completion of regulatory reviews in the U.S. and European Union. This process will come into effect in 2013. Roche is in discussions with other pharmaceutical companies to see if this can be an industry-wide initiative.

Access to CSRs: Roche supports the release of full CSRs, summaries and safety updates for its approved medicines by the EMA. In line with relevant country or regional laws, this information will be edited in consultation with Roche to ensure patient confidentiality and to protect legitimate commercial interests, including intellectual property rights. Roche will provide any CSR on request that cannot be obtained from the EMA for third party researchers with this specific process coming into effect by April 2013. This will enable access to all Roche CSRs for researchers.

Tamiflu (oseltamivir) data

Roche acknowledges the specific public interest in data transparency concerning the antiviral Tamiflu. Health authorities worldwide have received all the information they have requested regarding Tamiflu.

Of 74 completed Roche sponsored Tamiflu 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 trials which are completed but not yet in the public domain to be posted.

Roche supports a fair, transparent and independent way of addressing data transparency regarding Tamiflu. To do this, a MUlti-party Group for Advice on Science (MUGAS) will be set up by four renowned scientists in the field of influenza to look at data on Tamiflu, identify any unanswered questions and agree on a statistical analysis plan. Following an agreement, Roche will provide access to all requested Tamiflu clinical trial data for the analyses.

The four scientists will invite independent experts and third parties to their meeting, which is scheduled to take place in June. The four scientists are Prof Albert Osterhaus, Erasmus Medical Centre Rotterdam; Prof Menno De Jong, Academic Medical Centre Amsterdam; Prof Arnold Monto, University of Michigan and Prof Richard Whitley, University of Alabama.

Response to Roche statement form Tracey Brown, Director, Sense About Science

26 February 2013

“Does Roche expect applause for announcing that it will continue to keep clinical trial findings hidden? They’re on another planet. Thousands of people are calling for all clinical trials to be registered and the findings published. Patients, researchers and practitioners are petitioning organisations and regulators for change all over the world. Just today the UK’s Health Research Authority signed up, joining a throng of research organisations, regulators, patient groups and professional bodies. GSK has announced that it will publish all the CSRs available since its formation as a company. That is genuine progress and an answer to patients who participated in those trials. Roche’s response is poor. Which bit of All and Trials do they not understand?”

Appendix 4

ABPI STATEMENT ON NEW CLINICAL TRIAL TRANSPARENCY MEASURES

27 February 2013

ABPI announces new clinical trial transparency measures

The ABPI has today announced that it will put in place measures to monitor compliance to the clinical trial transparency provisions contained in the ABPI Code of Practice. An independent, third party service provider will be appointed to undertake this work, and the ABPI will take on the responsibility for reporting to the PMCPA non-compliance with trial registration and posting of summary results.

These measures support the current requirement in the ABPI Code of Practice which stipulates that current and future trials must be registered within 21 days of enrolling the first patient, and results must be published within one year of marketing authorisation or one year from completion for marketed products.5

From quarter three this year, a new toolkit is also to be introduced that will provide good practice guidelines, compliance checklists and template standard operating procedures for pharmaceutical companies.

In addition, the ABPI will host a series of workshops with all relevant stakeholders to explore how best to address the issue of historical data, and disclosure requirements, to meet two distinct needs—firstly, improve transparency for patients, public and health care professionals in general and secondly, access to the relevant data that are necessary for the advance of certain types of research.

Commenting, Stephen Whitehead, Chief Executive of the ABPI, said:

“The ABPI is a strong advocate for transparency in clinical trial data and so I am pleased to announce the introduction of new measures which will encourage greater compliance. Hiring a third party provider to ensure that companies fulfil their obligations in the ABPI Code of Practice to register clinical trials and publish summary results, is a significant step and illustrates how seriously we take this issue.”

“On the issue of historical data we also want to ensure that we work collaboratively with all health stakeholders and international colleagues to agree a pragmatic approach which is in the interests of patients while protecting the commercial research model. The pharmaceutical industry has always accepted that making data more transparent is important, but all parties must now decide together how exactly this is achieved.”