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Clinical trial transparency: Letting the light in

Published on 06/11/17 at 12:33pm

Transparency is one of those words for which the exact meaning has become clouded by murkier connotations. The chances are that if most people were asked to associate the word with an event, it’s more than likely that the example would be negative, whether it be a lack of government transparency, an example of a tech firm refusing to be clear on its data use, or a company not being completely honest about its wrongdoing.

The certain thing about transparency when it comes to organisation is that, as more information is able to be accrued through the development of technology, achieving complete openness is always a work in progress.

The pharmaceutical industry is not exempt from this and recently there has been a gathering of pace behind transparency of practices from a number of angles. The European Federation of Pharmaceutical Industries and Associations (EFPIA)’s Disclosure Code was set up two years ago to ensure that payments made from pharmaceutical companies to healthcare professionals (HCPs) and healthcare organisations (HCOs) were made public. Each country was given leeway to implement the policy as they chose, but were given a deadline of June 2016 to make such information available. Payments included donations and grants to HCOs and related to fees for services or sponsorship to attend educational events for HCPs.

This has made it possible for members of the public to search through a database to find out if their own doctor has received payment from the industry. The HCPs do not necessarily have to agree to their names being aligned with a payment, in which case the payments are aggregated, but there is encouragement from all angles for more individuals to be open. The push is to promote a degree of transparency over where payments are going, how much the entail and to whom they are being paid.

In the case of the UK’s industry, the ABPI’s Disclosure UK 2017 revealed that 65% of HCPs and HCOs agreed to allow their name or the name of their organisation to be aligned with a payment from a pharmaceutical company. This was an improvement on the results from the 2016 collection of data, which showed 45% of individuals and organisations refused for their details to be disclosed. The rise in the number reporting payments displays the emphasis that is being placed on HCPs and HCOs to be open, alongside growing pressure on the pharmaceutical companies themselves.

This same push is being felt in clinical trials, with movements in the US and Europe calling for greater transparency to be brought to data gathered during the process. It has been a movement that has slowly been gathering momentum; the process really built up a head of steam in 1997 when the FDA Modernization Act came into being, creating a clinical trial website that companies were mandated to register on. It has continued since, with further steps taken by the FDA including the introduction of the ‘Final Rule’ in the US last year and the forthcoming EU regulation 536/2014, which will see further data released on the clinical trial process.

Cleaning the windows

The questions remains: why is this major push towards transparency across the board necessary? The first answer is because a lack of transparency can lead to the uglier side of the pharmaceutical world, where data that is not considered helpful is not published to protect certain medicines. The knock-on effect of this is clear – certain results that may prove useful for doctors when prescribing medicines are kept hidden.

However, there is an even larger impact. Researchers are entirely dependent, across all fields, on the body of knowledge that exists prior to them conducting experiments; with more clinical trial data available to researchers, there is a greater bank of data to test new hypotheses and to rule out certain experiments that have already been proven to be futile. Without the clinical trials publically available, this is not possible.

On a more fundamental level, there is also a level of duty towards patients who are prepared to undergo clinical trials. The process of arranging a clinical trial is notoriously difficult and expensive – one study from the Tufts Center for the Study of Drug Development pegged the cost of running a larger clinical trial study at $2.6 billion. It is widely acknowledged that a major part of the difficulty in running a successful clinical trial is the issue of keeping patients adherent to the medicine and to the study itself. According to Forte Research, the average dropout rate across all clinical trials is 30%.

The causes of the struggle to retain patients for clinical trials are numerous, but the major factor cited is the inconvenience burdened upon patients already struggling with an illness. Many persist through the burden placed on them because they believe that they are supporting academic research, ensuring that others may able to avoid the illness that has visited them. When clinical trial data is not published, it is then not only researchers who are let down but the patients who actively support the work of the industry.

Leading the way 

When it comes to the pharmaceutical industry, where the US leads others will follow. The Food and Drug Administration Modernization Act of 1997 required the US Department of Health and Human Services (HHS) to establish a registry of clinical trials, providing information on federally and privately funded clinical trials. The website that emerged from this, ClinicalTrials.gov, is still maintained today – it has been expanded and refined over time to require more transparency of data.

The latest move by the HHS in September 2016 to introduce the Final Rule requiring clinical trials to be registered on ClinicalTrials.gov, and for the results to be published on all research funded by the institution, was widely seen as an important step to ensuring that the movement towards transparency gained momentum.

Alongside this decision was a corresponding announcement from the National Institutes of Health revealing further steps for clinical trials it funded. To gain a better understanding of the particular reasons behind implementation of the Final Rule and how it has progressed in the intervening year, Pharmafocus spoke to NIH Associate Director for Science Policy, Dr Carrie Wolinetz, for more details.

In correspondence, Wolinetz detailed what it was designed to encourage:

“The Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11) clarifies and expands the regulatory requirements and procedures for submitting registration and summary results information of clinical trials on ClinicalTrials.gov, in accordance with FDAAA 801. The Final Rule is intended to make it clear to sponsors, investigators, and the public which trials must be submitted, when they must be submitted, and whether compliance has been achieved.

“Simultaneously with the publication of the Final Rule, NIH issued a final policy (“NIH Policy”) on the Dissemination of NIH-Funded Clinical Trial Information to promote broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov. Under this policy, every clinical trial funded in whole or in part by NIH is expected to be registered on ClinicalTrials.gov and have summary results information submitted and posted in a timely manner, whether subject to the Final Rule or not. Under the NIH Policy, submission of the same type of registration and results information would be expected and in the same timeframes as the trials subject to the Final Rule.”

Though a step in the right direction, there have been detractors of the move suggesting that a greater proportion of trials posted on the ClinicalTrials.gov website are not legitimate scientific endeavours. For instance, stem cell ‘trials’ have been listed on the register as clinical trials and yet when members of the public have searched for treatments in their region and struck upon one listed as a trial, they have been asked to pay a fee to ‘participate’ in the trial. Of course, what this means is that the trial subject is paying for the privilege of being a trial participant for a potentially risky treatment.

When asked about the worrying to side to making publically available any ‘trial’ that was registered on the website, Wolinetz replied:

“Study sponsors and investigators who are considered the ‘responsible party’ must submit the registration and results information for a clinical trial that is required by the Final Rule. The Final Rule applies to all ‘applicable clinical trials,’ which, in general, are most Phase 2-4 interventional studies of drug, biological and device products that are regulated by the FDA.

“The safety and scientific validity of a study listed on the ClinicalTrials.gov database is the responsibility of the study sponsor and investigators. To ensure that users are aware that many studies have not been evaluated by the Federal Government, the ClinicalTrials.gov site states that: ‘Listing a study does not mean it has been evaluated by the US Federal Government. Read our disclaimer for details.’ NLM staff do not verify the scientific validity or relevance of the submitted information beyond a limited quality control review for apparent errors, deficiencies, or inconsistencies.”

As problems such as these indicate, running a public database without the staff or funding to actively monitor ongoing trials is almost impossible. The current system is a next-best measure, ensuring that the public is able to easily access a comprehensive list of active clinical trials, though not having the funds with which to actively regulate and monitor those included.

One of the measures introduced by the Final Rule was a potential $10,000 per day penalty against those companies who failed to register a clinical trial with the website 21 days after the first patient was enrolled. For trials that were backed by NIH funds, the punishment was increased to the suspension or outright termination of grant or contract funding.

The bottom line of the move, however, is a push towards making sure that the public is aware of the clinical trials that are available and expands the additional data that has to be provided once the trials have finished. Wolinetz underlined the importance of this step:

“The NIH Policy promotes broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov. Disseminating this information supports the NIH mission to advance the translation of research results into knowledge, products, and procedures that improve human health. Clinical trials are vital to medical advances because they test new and existing health-related interventions, helping us understand whether they are safe and effective in humans when used as intended. Some clinical trials provide information about which medical treatments work best for certain illnesses or certain groups of people. As expressed by Dr Francis Collins, ‘The final rule and NIH policy…will help maximise the value of clinical trials, whether publicly or privately supported, and help us honour our commitments to trial participants, who do so much to help society advance knowledge and improve health.’”

Going global

Europe and the EMA have not been left behind by the changes, and the development of the EU Regulation No 536/2014 has been deemed another significant step towards ensuring that more clinical trial data is readily available to more individuals. It builds on the Directive 2001/20/EC to harmonise processes and requirements for clinical trials, but with increased provisions to improve transparency.

In particular, the regulation, which is predicted to come into force in 2019, will see one unified portal across European countries where all clinical trial data is submitted and published. The EMA announced that this database “should contain all relevant information as regards the clinical trial submitted through the EU portal. The EU database should be publicly accessible”.

Public access to the database has been labelled as of utmost importance, with the EMA stressing that this would protect public health, and would foster the innovation capacity of European medical research while recognising the legitimate economic interests of sponsors. No personal data of trial subjects will be made publically accessible by the database, but some of the information on those working on the trial, including the clinical trial investigators and sponsor staff, would be available.

The main clause of significant interest in the pursuit of transparency is the requirement that all clinical trial data should be made available within one year of completion of the clinical trial, irrespective of the trial outcome.

It is a big change and will be momentous for the pharmaceutical industry in Europe. In order to gauge the industry reaction, Pharmafocus spoke to a Sini Eskola, Director of Regulatory Affairs for the EFPIA:

“EFPIA and its member companies believe that sharing clinical trial data is in the best interests of patients, clinicians, medical research and the pharmaceutical industry. EFPIA is committed to working with stakeholders to ensure that clinical trial information is shared responsibly, while securing patient anonymity and continuing to support the development of innovative new treatments with appropriate arrangements for commercial-in-confidence information.

“The EFPIA/PhRMA Joint Principles for Responsible Clinical Trial Data Sharing, implemented on 1 January 2014, have underscored the commitment of the pharmaceutical industry to disclosing clinical trial data. EFPIA members have made significant progress in developing processes for clinical trial data access schemes, translating principles into practice. A member survey conducted in 2016 demonstrated that the majority of the member companies now have systems and processes in place to enable enhanced data sharing with the researchers and share results beyond the legal requirements. 

“In addition to the industry led initiatives, EFPIA welcomes the adoption of the EU Clinical Trial Regulation (536/2014) and the EMA’s Transparency Policy (Policy 0070). In both of these, EFPIA has taken an active role in bringing forward industry experience and viewpoint in the consultation of the draft Regulation and Policy and now in the implementation phase of them.”

The response from Eskola shows the organisations support of the recent changes that have arisen in the industry and emerging from the EMA itself. However, the very need for such regulation suggests that support amongst the industry has not always been as strong as it is becoming now. When asked why this movement has been a process of a number of years rather than an immediate change, Eskola explained:

“Making data transparent is not just ‘pushing the button’ and actually involves many aspects that need to be taken care of before it can be shared, particularly because the clinical data collected in the trials is extensive in both volume and complexity. 

“Patient data is key to making clinical research possible, and preserving the confidentiality of patients is vital to maintain trust throughout the process of clinical development. This data is stored and key-coded, in accordance with the patient’s consent, in a secure server that fulfils all requirements of national and European data protection rules and regulations. When making data available, preserving the confidentiality of patients’ information needs to be secured.”

With the transition towards greater availability of clinical trials results and data now an inevitable process, Pharmafocus enquired as to why this change has come about and what potential benefits could be reaped by pharmaceutical companies who are flexible to this end. Eskola suggested:

“EFPIA believes this has to do, partly, with the evolving environment that is driven by transparency, particularly here in Europe (legislative and other initiatives), but also due to the benefit the industry has seen by being more transparent with regard to how medicines are being developed, including more information about clinical research and results. EFPIA and our member companies have also listened to patients and researchers and are working together with them to ensure the best utilisation of the data.”

Applying some pressure

One of the major forces that has driven forward this evolving environment towards transparency is the work of AllTrials. The initiative is a collaboration between various institutions across the globe, with Ben Goldacre, of Bad Pharma-fame, as a central figure. The initiative is calling for all clinical trials, past and present, to be registered, as well as the methods and summary results to be reported.

In order to achieve this aim, AllTrials compiled and published a structured audit of 42 pharmaceutical companies’ clinical trial transparency policies and how their actions followed through with their commitments. Pharmafocus spoke with Dr Sile Lane, Head of International Campaigns and Policy at Sense about Science and co-founder of AllTrials, to talk about the results of the audit and how it is working to ensure that the pressure to reveal more data is maintained. Lane explained a little about how the initiative had arrived to campaign on the issue:

“This issue of around half of all clinical trials conducted not publishing their results has been known about since the early 1980s and written about in academic journals for a long time, so it couldn’t be said to be a new issue. However, what changed very recently was that a little bit more pressure had been put on the topic – Ben Goldacre had written his Bad Pharma book and heads of organisations, as well as people within politics, were beginning to pay attention. One day, Ben, members of Sense about Science, some folks from the British Medical Journal and from corporate collaborations happened to be in the same room. We began talking and all agreed: ‘this is the time to do something’.

“We all just had the same thought that this had been a problem for the last thirty years and now was the time for something to change. We were able to get a little bit of resources together to launch AllTrials. This initiative is calling for, at its heart, all clinical trials to be registered and their results to be reported. It’s now been joined by more than 720 organisations, all around the globe.”

With the backing of 720 organisations, which Lane pointedly noted included investors that have a combined financial clout of €3.5 trillion, there is now a momentum behind this movement that will be hard to stop. When asked about how pharma companies had initially reacted at the beginning of their campaign, Lane laughed:

“The reaction was mixed. There were some companies that took it very seriously and started really constructive conversations with us about the issues we were raising and what we would suggest, as well as our road map. GSK very quickly said, ‘yes, you’re right and we’re going to do something about this’, and joined the campaign. They made some very strong commitments to making past information available and, so far, are living up to those pledges. At the same time, there were two companies at court in Brussels trying to stop the EMA from making more clinical trial study reports available. So, there was a complete spectrum, from people going to court to try to stop clinical trial transparency to companies saying, ‘yes, we see which direction is history is moving and we’re going to do some thinking about this’.

“Generally, a lot of companies and definitely pharma industry groups talked a lot about the disadvantages of transparency. This appeared in what they called the ‘barriers’, such as patient confidentiality issues. However, when companies like GSK started making information available and were very open about what they were doing – what it was taking from them resources and cost-wise, and what it actually entailed to make a clinical study report available – it just swept all those complaints off the table because it showed what was actually realistic and that it wasn’t impossible to publish these reports without breaking patient confidentiality.”

As mentioned previously, in order to exert some pressure on pharma companies and to see how each tallied against each other in regards to clinical trial transparency, AllTrials published a public audit of companies’ public policy on the matter and their actual practices. This was ranked into a leaderboard and was made publicly available. Pharma companies are naturally competitive with one another in order to appear at the higher end of positive ranking systems, and Pharmafocus enquired of Lane if that was part of the intention in releasing the data to the public.

“Absolutely, it was certainly part of the reason,” she replied. “It shows that forward-thinking companies are necessary to show others what is possible. One of the reasons is so that everyone can learn from the best practice of the higher ranking businesses.

“Another driver behind publishing the report was to put information into the hands of organisations who were asking us how they could help – groups such as, patient support groups, investor groups and shareholders. They are then taking the results of the audit and using this in conversations with companies that they invest in. For instance, if they have a meeting with company X which has never made a commitment to making clinical trial data public, then they’re going to go in and ask them to do it, based on the information we’ve given them.

“Another reason we put the audit public was to make companies conscious of what they’re doing, even though that may seem an odd thing to need to do. During the research stage, quite a number of companies told us that what they do in practice turns out to be different from their public policy that we looked at for the audit. A handful said they were doing things better than what they posted publically, which made them conscious of that – which is a great result for us”.

An inevitable trend

One of the companies that ranked highly on the audit was LEO Pharma, taking second position. Pharmafocus reached out to get its perspective from the pharma industry-angle behind both the audit and clinical trial transparency in general.

LEO Pharma’s Vice President of Global Clinical Operations, Paul Hargreaves, responded to the position the company was awarded by AllTrials by pointing to the various parameters by which the company had succeeded:

“We have a firm belief that partnerships and collaborations are essential for making innovative treatments available to patients. It is therefore the general policy of LEO Pharma to seek a very high degree of transparency in clinical trials…We therefore welcome the results from AllTrials. LEO ranked 1st on the two parameters concerning release of summaries of our clinical trials and release of full clinical trial reports. We ranked 2nd on individual data-sharing, and we believe that these rankings accurately reflect the work we have undertaken.”

When asked how the company was planning on building on this public acknowledgement of its achievement within the area of clinical trials, Clinical Disclosure Specialist Vesela Kusheva commented:

“We believe that layperson summaries will provide more insight for the patients about their therapy and help them make better informed choices. Therefore, from early 2018, LEO will be publishing layperson summaries for all clinical trials in phase II-IV. In the EU, layperson summaries will become mandatory for trials with European sites when the new clinical trials regulation comes into force (currently expected to happen in late 2019). LEO will however start earlier and write layperson summaries for all trials regardless of whether European sites were included.”

With some companies, as mentioned by Lane, having previously showed a degree of reluctance to embrace the steady move towards greater transparency, Hargreaves elucidated what LEO had gained from the process and why the industry, more broadly, will stand to benefit from improved transparency:

“By making clinical information available, we advance the scientific understanding of skin diseases and enable patients and health professionals to make informed decisions about treatment. Understanding the science of the skin – and the everyday lives of people with skin diseases – is central to driving innovation at LEO Pharma.

“We believe that increasing transparency in the wider industry will increase the public understanding of how medicines are developed and approved as well as increase the overall level of trust in the industry, which benefits all. Increased understanding and trust is likely to lead to increased collaboration, which will enable even further scientific advancement in the direction most needed by the patients.”

Ben Hargreaves