Clinical trials transparency: the journey so far

pharmafile | May 12, 2014 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  ABPI, NHS, alltrials, rawal, transparency 

There has been considerable publicity over the last year or two about transparency of information in clinical trials. However, activity on this topic dates back to the 1980s, ever since the risk of publication bias was recognised and the utility of registries to help minimise it was first proposed. 

Whilst both regulators and the global industry have been working to improve the situation since around 2000, we do acknowledge that initial progress was slow. It is therefore very heartening to see recent strides the industry has made to deliver the transparency agenda.

There is now broad agreement that all clinical trials in patients should be conducted to pre-defined protocols, and that the results of all this research should be publicly available to benefit future patients and to avoid unnecessary repetition of trials.

Over the last 20 years, various initiatives have been introduced to establish the principles that all clinical trials in patients (including key elements of trial design) should be registered on public registries at the time the trial begins recruitment, and at least summary results of all trials should be posted on similar registries or databases.

Ideally, the results of all trials should be submitted for publication in the scientific literature, regardless of whether the results are positive or not. Before I take a look at a more detailed history of the transparency debate, the first question I want to address is where are we now as an industry? 

Many studies have been reported which aim to check the degree to which previous transparency initiatives have worked. Many of these have investigated:

• A subset of all trials

• Trials completed during a specific time period

• Trials posted in a single registry

• Trials published in the scientific literature

• The posting of summary results of trials in a single registry. 

Because they do not cover the full range of trials of various phases, sizes, durations and complexities, none of these studies on their own give an accurate picture of disclosure of trials related to any individual medicine approved for use in patients. 

Even in a study purporting to check compliance with the FDA requirements for disclosure in clinicaltrials.gov, the paper’s conclusions have subsequently been challenged by the FDA. To answer the question, though – where are we now as an industry?  

In 2012, the ABPI commissioned research to look at transparency related to trials on all the medicines approved by the EMA in a three-year period for use in patients. This showed that overall disclosure of industry-sponsored trials related to newly approved medicines has reached almost 90 per cent. Thus the frequent contention that “half of all trials remain unpublished” is now misleading.

The results of our study demonstrate the fact that the research-based biopharmaceutical industry has been working towards transparency for a number of years. In 1992, representatives from the ABPI met Sir Iain Chalmers, one of the founders of the AllTrials campaign.

Some action by individual companies followed including the creation of registries, but unfortunately this did not gain sufficient momentum, leading to increasing disillusionment on the actions being taken by the industry. 

However, despite this slow movement, transparency initiatives were still in progress. In 1997, the FDA Modernisation Act in the US resulted in a national register being set up, and the US registry clinicaltrials.gov has been live since 2000. 

This was followed up by the first industry commitments, spearheaded by the international, European, American and Japanese trade associations in 2005. The first IFPMA Joint Position Paper adopted the principles of transparency in terms of trial registration and the reporting of summary results in the public domain by the global biopharma industry.

However, implementation of these commitments was not initially mandatory, instead it was left to individual companies to implement this and has therefore been somewhat piecemeal. Despite this, the paper was updated in 2009, and was followed up with a companion Joint Position by the industry supporting publication of the results of trials in the scientific literature. 

These voluntary commitments soon became requirements, and here in the UK in 2008, the ABPI included the principles of trial transparency in the ABPI Code of Practice. Indeed, we were one of the first national industry associations to require this, and as of 2012 the IFPMA code has also included this as a requirement for its members.  

In parallel with the development of these industry positions, the international committee of medical journal editors (ICMJE) first supported the principle of registration by requiring all trials (whether academic or commercially sponsored) to have been entered onto registries if they were to be accepted for publication. Like the initial industry commitments, these were recommendations and implementation by different journals has been somewhat variable. 

So why has progress been so slow?

This slow progress reflects the fragmented and inconsistent approaches around the world to implementation of measures to address trial transparency, and the need by our global industry to take account of the variations in requirements in different countries when designing processes to support the principles for improving this transparency.  

One of the challenges facing industry is that, while new drug development is a global undertaking, registries have been established in various countries and both the IFPMA – and the WHO – hosted portals linking to the primary registries. The result of this is that there is considerable duplication for a global company; while a single global registry would be ideal, this is now impractical and unlikely to be achievable.

In addition, the links between the journals in which clinical papers are published and the trial registry entries remain incomplete – it remains difficult in many older cases to be sure whether a trial has been published or not. 

Local member companies (often affiliates of multinational companies with headquarters outside the UK) are often not directly responsible for the trials involved in the global development of new medicines, and certainly not for compliance with the provisions of individual codes outside their own country. 

So the implementation of the IFPMA Joint Positions, while fully endorsed by the US, European and Japanese industry associations, has been carried out by different means and at different speeds from company to company and country to country.

Why is trial transparency so important?

The issue of publication bias has been one of the key drivers for increasing transparency of clinical trials. Selective publication of positive data has the potential to mislead, with positive results over-estimating the relative value of a medicine. In extreme cases, an inferior medicine may be used and fail in a patient when a better alternative is available. However, it is important not to allow this issue to throw doubt on the value of all medicines.

While publication bias in the scientific literature is well-recognised, there are relatively few examples of medicines where it has been unequivocally demonstrated that unpublished data from randomised controlled trials would have significantly changed the assessment of that medicine’s value. Indeed, it has been recognised that the impact of bias depends upon the specific circumstances, and that wider use of registries will reduce both the incidence and impact of this bias. 

Why haven’t we tackled this issue faster?

In the past, the scientific process was described as the testing of hypotheses; often, if a hypothesis was disproved, the results were inconclusive, or the initial methodology was called into question, the study and its results would not be published. Publication would only follow if the hypothesis was revisited, the experimental design substantially modified and the results available more clear-cut. 

Nevertheless, it is now generally accepted that, as clinical trials are experiments on people, the results of all such studies should be made available publicly; so that the data can benefit future patients, and to avoid unnecessary duplication, even if the results are not as positive as the initial hypothesis would like. 

Historically, the process of new drug development has been sequential though, with a changing R&D model such as the implementation of adaptive trial designs, this may change. At each stage, patient safety is the paramount concern. A potential new medicine is not taken into human subjects until extensive laboratory studies indicate that it should be well tolerated and that it may have a significant beneficial effect in the disease under investigation. 

Each stage is primarily designed to support the decision to proceed – or not – to the next stage, so when this decision was negative, it was not usually a priority to publish, rather to move on to investigate the next potential new medicine, ultimately with the aim to deliver innovative new medicines to patients as soon as possible.

In terms of pure numbers of clinical trials, many trials are small Phase I and II trials, which reflect the careful, stepwise approach to the development of new medicines, designed to minimise the risk to volunteers and patients during early exposure to a novel compound.

In the past, these types of trials were generally not considered worthy of publication individually; they provide the collected information on tolerability, dose ranging, pharmacokinetics and pharmacodynamics in patients and initial efficacy which informs the decision to proceed to Phase III – the larger randomised, controlled trials upon which the regulatory submission is largely based. 

Often, in the past, the data from Phase I and II studies would have been collected and published as a single paper after the medicine had received regulatory approval. If the decision was either not to progress to Phase III, or (as a result of inconclusive Phase III results), not to submit to regulatory authorities, or a rejection following the application to regulatory authorities, these studies may well not have been either submitted or accepted for publication.

When two or more randomised, controlled trials have been undertaken, it is sometimes possible to pool the results in a meta-analysis, which can give an indication of the overall benefit of the medicine in a wide group of patients. 

However, because they involve small patient numbers, and are often not comparative, Phase I and II trials would make a very small contribution to these systematic reviews. This means the effect of the absence of publications on these trials may not skew the analysis of the benefit-risk ratio by as much as has been claimed.

Also, while many clinical studies form part of the process of developing and registering new medicines, many others are carried out by research institutes, hospitals and individual researchers. Thus, the overall collection of clinical trials undertaken globally is a broad mixture of trials of different types, phases, sizes, durations and complexities.

How can we address these challenges?

Transparency in itself (i.e., the measures to ensure no study can be carried out and then its existence and results hidden if the results are inconclusive or negative), should be sufficient to prevent any significant impact of study publication bias in the future; the registration and posting of results of all trials will ensure that no randomised controlled clinical trial in patients is selectively hidden. 

Now, the discussion has moved on to how we ensure more detailed, individual patient-level data on the key randomised, controlled trials is readily available to researchers conducting meta-analyses and systematic reviews. This will better support informed medical decision-making, but formulating the additional requirements for sharing patient-level data to facilitate further research must be done in the context of legitimate commercial concerns, as well as ensuring patient confidentiality. 

The recent flurry of activity both here within the UK and globally over the last few years contrasts with the slow initial progress amongst all stakeholders to implement suggested changes to tackle clinical trials transparency. 

AllTrials was launched in January 2013 – shortly after this, the House of Commons Select Committee on Science and Technology conducted its investigation into clinical trials here in the UK, to which the ABPI submitted oral and written evidence.

The US implemented further legislation in the FDA Amendment Act of 2007, which underpinned the usage of clinicaltrials.gov, first for registration of specified trials, and then for the posting of summary results. The US registry, clinicaltrials.gov, now provides a highly user-friendly platform for a large proportion of studies. 

Meanwhile, the European regulator (the EMA) was left somewhat behind, partly due to the original EudraCT being set up as a regulatory vehicle, not a transparency vehicle. However, the EMA has sought to address this from now on, and the latest version of EudraCT will enable posting of results and it now requires retrospective population of the database back to 2004. 

At the same time, across Europe, the Clinical Trials Directive of 2001 is being replaced by a European regulation, the text for which has been recently approved by the EU parliament. This contains explicit transparency requirements, including the need to register trials, supply technical and layperson summary results within a defined time limit and also supply detailed clinical study reports for all medicines once they have completed market authorisation assessment.

In July 2013, the European and American trade associations launched the ‘EFPIA/PhRMA Joint Principles for Responsible Clinical Trials Data Sharing to Benefit Patients’. These principles reaffirm the commitments by the global industry to enhance data sharing with researchers and public access to clinical study information, to share results with patients who participate in clinical trials, publically certify procedures for sharing clinical trial information and reaffirm their commitments to publish clinical trial results. 

Since the implementation on 1 January, we have seen a number of announcements from companies outlining how they are sharing trial data with qualified researchers. Here in the UK, the Health Research Authority (HRA) has also been given a formal requirement to ‘promote transparency’ in the Care Bill currently going through the UK parliament.

Meanwhile, here at ABPI, we have continued to be proactive. In addition to our commissioned research, we have:

• Held stakeholder workshops with all parties

• Published an online clinical trial transparency toolkit to provide good practice guidelines, compliance checklists and template standard operating procedures for pharmaceutical companies

• Given oral and written evidence to the House of Commons Science and Technology Committee inquiry into clinical trials

• Run a master class with the British Association of Pharmaceutical Physicians on the industry requirements in the UK and Europe regarding clinical trial transparency. 

The medical scientific community has come a long way on the road to transparency since the risks of publication bias were first noted. We are very close to the situation where all trials designed as part of global development of new medicines are registered in advance, and the results made publicly available. 

I do, however, recognise that the system is not yet 100% perfect, but I do know that the ABPI and its member companies are committed to continuous improvement. Given how far we have come, I am very excited about what the future holds for this important area of work.

Dr Bina Rawal is the medical, innovation and research director for the ABPI