UK HRA to review 'confusing' drug trial registration requirements
This article was originally published in SRA
The UK Health Research Authority is to review its requirements for the registration of clinical trials of drugs after a judge ruled that while it was appropriate for the HRA to take account of both legal and ethical obligations in its work, the wording of some of the material on its website regarding the obligation to register Phase I studies was "defective" and "confusing"1,2.
Richmond Pharmacology, which sought a judicial review after the HRA amended its sponsor declaration to make the registration requirement retrospective3, claimed victory, saying that companies sponsoring Phase I trials "retain control over whether and when they wish to make public the registration of previously conducted trials"4.
The HRA said it was "a matter of great regret that there has been a public challenge to research transparency in the UK" although it did acknowledge that there was "a point of ambiguity regarding the source of duties to register".
Sense About Science, which intervened in the case, said Mr Justice Jay had ruled that the HRA has a clear legal right to check researchers' compliance with ethical and legal requirements to register and publish clinical trials, although it noted his view that the HRA materials were "too confusing to allow them to do that now"5.
The case revolved around changes that the HRA made to its trial registration requirements in 2013 and 2014. In May 2013, the authority published a paper on "The HRA interest in good research conduct", in which said it would make trial registration (including Phase I) a condition of regulatory ethics committee (REC) approval as of September 30, 2013. This would include publishing details of these trials on publicly accessible websites. A revised sponsor declaration was introduced for applications made to RECs after September 30, including a commitment to abide by the publication requirements.
Then in October 2014 the HRA said that from April 2015 it would extend the registration requirements to all trials in active recruitment, including those approved before September 2013 (ie, before such registration was a condition of the REC opinion). It said sponsors unable to provide that assurance should contact the HRA and arrange for a deferral according to procedures established in September 2013.
On March 19, Richmond Pharmacology challenged the proposed change to the sponsor declaration on five judicial grounds, claiming among other things that it was unlawful to force sponsors to retrospectively register trials that were approved when no such requirements applied.
The HRA countered that by changing the wording on the sponsor declaration it had not intended to impose a retrospective condition or make the grant of a favorable REC opinion conditional. While it introduced the new form in April as planned, in order to avoid full-blown judicial review proceedings it decided on May 22 to revise the wording, removing the section referring to trials given a favorable REC opinion before September 30.
Richmond, however, took issue with some of the information that the HRA continued to disseminate unchanged on its website. It dropped its five original grounds and filed an amended ground claiming that the HRA had acted unlawfully by asserting that sponsors and those conducting clinical trials are under a legal duty to register their trials on a publicly accessible website and/or to publish data about the outcome of the trial where no enforceable commitment has been given to trial publication and where publication has not been included as a condition of a REC favorable opinion.
Discrepancies
The case thus became focused on the apparent discrepancies between the information on the sponsor declaration and that on the HRA's website. Barrister Jonathan Price, representing Sense About Science, argued that the case was "in danger of evaporating into a disappointing semantic wrangle over the nuanced meaning of various passages in websites". He said the right analysis was that there is a legal requirement arising under EU and domestic law to register and publish the results of Phase I trials.
Dr Janet Wisely, HRA chief executive, said: "The HRA does not assert that there is a legal duty to register a trial where there is neither a specific REC condition of registration or an express promise of registration in the REC application."
Richmond's witness Dr Ulrike Lorch said there was a "marked lack of transparency" by the HRA in identifying the difference between "rules" and "recommendations of good practice". Sponsors are obliged to follow rules in every case, regardless as to whether they agree with the rule or not, Lorch said. "However, if something is regarded by the HRA as being 'good practice' there can be sound reasons in an individual case why it should not be followed for a particular piece of clinical research."
The judge was not impressed by Price's claim that there was a legal requirement to register and publish: "Although initially attracted by Mr Price's arguments, I cannot accept them. Given that a breach of the requirements of good clinical practice attracts criminal sanctions, sponsors and researchers are entitled to clarity and precision as to what exactly is entailed."
Accordingly, he continued, it follows that registration and publication are not a legal requirement in relation to pre-September 2013 approvals, because these were not promised or made a condition of such approvals, and there is no power under the Clinical Trials Regulations to amend conditions or impose them retroactively.
The amended sponsor's declaration, dated April 1, 2015, did not state that there was a legal requirement to register and publish the result of Phase I trials approved before September 30, 2013, the judge said. However, he noted that some of the wording on the HRA's website was "arguably to the contrary effect".
"In my judgment, this is defective, confusing wording which falls well short of the certainty and transparency obligations which are incidental to the rule of law. In any event, given the specific faults I have identified, I would now expect the Defendant [the HRA] as a responsible public body to cast a self-critical eye over the whole of its website material in this domain."
Richmond claims success
Law firm LHS, acting for Richmond Pharmacology, said it had "succeeded in a landmark judicial review" which "gives the global pharmaceutical industry certainty and confidence in the UK regulatory process". In upholding the judicial review brought by Richmond Pharmacology, "the court has found that the UK clinical trials regulator, the Health Research Authority (HRA), must be clear about what constitutes ‘guidance’ and what constitutes legal obligations," LHS said.
Oliver Wright, solicitor at LHS, said: "The law is now clear and there can be no confusion for the pharmaceutical sector about what constitutes guidance from the regulator and what constitutes legal obligations.”
The HRA said it was "disappointed that on a very narrow issue introduced late in the day, we have been found wanting on a point of ambiguity regarding the source of duties to register". However, the court has recognized that it is appropriate for the HRA to take account of both legal and ethical obligations in its work, said Wisely. "We will review the material identified by the judge to ensure that it is lawful."
She added: "Where the nature of the source underpinning an HRA statement is material, the HRA has highlighted the difference between legal and ethical obligations and the consequence that flows from the distinction. Our Standard Operating Procedures have from 2004 recognised that breaches will be managed appropriately for both legal and ethical obligations."
She said the HRA was "grateful that Sense About Science participated in the claim. We are also grateful that the Ethical Medicines Industry Group (EMIG) supported the HRA in the case and made clear that the claimant was not representative of the wider clinical research community."
AllTrials, which campaigns for transparency in clinical trials and works closely with Sense About Science, said: "The main argument Richmond (at the last minute) had asked the Court to rule on was that the HRA is acting unlawfully by asserting that there is an overarching legal requirement for everyone running every clinical trial to register it. The judge is clear that the HRA never claimed there was such an overarching legal requirement." While the judge declined to rule that there is an overarching legal duty to publicly register all trials, "he did point out that this will change in 2016 when the new EU clinical trials law is enacted".
"The case, which started out with half a dozen broad arguments put forward by Richmond, ended up being about the meaning of some wording on some pages of the HRA's website that were not updated when the sponsor’s declaration was, and whether those words were significant or not," AllTrials claimed.
Síle Lane, director of campaigns at Sense About Science, described the judgment as "a fantastically clear and comprehensive setting out of the legal and ethical requirements for clinical trial registration". She said the HRA had been given "a clear mandate" to continue raising awareness of the requirements to register trials and to check researchers’ compliance with those requirements.
"We’re in a time of legislative change as the new EU clinical trials law is going to be adopted into UK law over the next year, so we need to be alive to the discussions that will go on during that process," Lane said. "This case has shown us clearly the arguments that people and organisations like Richmond will be making during those discussions."
The Association of the British Pharmaceutical Industry added its voice to the fray, noting that it had "long been an advocate of greater transparency in clinical trials" and was "pleased to finally see the full details of this judgement and the review so that we can add our views"6.
Virginia Acha, ABPI executive director of research, medical and innovation, said: "We have been fully engaged on clinical trial transparency with members and stakeholders through meetings and technical workshops and we welcome the progress achieved by all parties in reaching a consensus in approach for the disclosure of clinical trial information. We look forward to continuing to work with the Health Research Authority to ensure that the UK is a robust and internationally leading place to undertaken clinical research at all phases of study."
References
1. Richmond Pharmacology v The Health Research Authority: Judgment, 28 July 2015, www.bailii.org/ew/cases/EWHC/Admin/2015/2238.html
2. HRA statement, 28 July 2015, www.hra.nhs.uk/news/2015/07/28/statement-from-the-hra-on-the-judicial-review-of-16-july-2015/
3. UK presses on with trial transparency despite legal challenge, Scrip Regulatory Affairs, 29 May 2015
4. Richmond Pharmacology statement, 29 July 2015
5. AllTrials/Sense About Science statement, 28 July 2015,www.alltrials.net/news/ongoing-judicial-review-against-the-health-research-authority/
6. ABPI statement, 28 July 2015, www.abpi.org.uk/media-centre/newsreleases/2015/Pages/280715.aspx