QUEEN'S BENCH DIVISION
MANCHESTER CIVIL JUSTICE CENTRE
Strand, London, WC2A 2LL
B e f o r e :
| The Queen (on the application of Richmond Pharmacology Ltd)
|The Health Research Authority
|Sense about Science
Parishil Patel (instructed by DAC Beachcroft LLP) for the Defendant
Jonathan Price (instructed by Bryan Cave LLP) for the Interested Party
Hearing date: 16th July 2015
Crown Copyright ©
Mr Justice Jay:
The Essential Factual Background
"The HRA will make trial registration for clinical trials a condition of REC approval from September 2013. The HRA will consider and agree which categories on [sic] studies on the IRAS (Integrated Research Application System) will fall within the condition, and also agree a reasonable timeframe for the registration as part of the condition. Clinical trials are studies with any clinical intervention, including drug trials."
"The HRA is proposing that the sponsor declaration is updated to require the sponsor to declare that all clinical trials in active recruitment have been registered, including those which were approved before September 2013 i.e. before it was a condition of the REC opinion. (01 April '15)[my emphasis]"
"I confirm that
9. Specifically, all clinical trials, given a favourable opinion by a [REC] within the Health Department's Research Ethics Service since 30 September 2013 and those given a favourable opinion prior to this date and currently in active recruitment in the UK, have been registered on a publically accessible register in accordance with existing duties of sponsors and the [HRA] requirements and extended compliance checks. [i]"
"HRA Requirement to Register Clinical Trials as a Condition of REC Favourable Opinion
On 30 September 2013 registration of clinical trials in a publicly accessible database became a condition of the REC favourable opinion. The studies for which registration is mandated are the first four categories on the IRAS filter question number 2 [including the phase 1 clinical trials germane to these proceedings]
From 30 September 2014, Sponsors are asked when submitting REC applications that they have registered trials as per the above requirement.
From 01 April 2015, the HRA will extend compliance checks against this existing responsibility to all trials in active recruitment, including trials receiving favourable opinion before 30 September 2013. Sponsors unable to provide that assurance should contact the HRA and arrange for deferrals to be put in place according to the procedures established in September 2013. Please note this process will not affect the decision on the current application at this time, although sponsors should be aware that measures to support compliance may be introduced in due course subject to further consultation.
For further information and detailed guidance about this requirement, including examples of accepted registers and the process for requesting deferral of registration, please refer the HRA website at: http://www.hra.nhs.uk/resources/during-and-after-your-study/transparency-registration-and-publication."
How the HRA is improving transparency within research
The HRA has a duty to promote transparency and we developed plans for transparency in health research which were first published in May 2013. The HRA is leading on practical measures to ensure the duties of researchers and sponsors to register studies and to make findings available are fulfilled, and that patients and the public can have confidence that they do.
Clinical trial registration
The HRA introduced a simple check on sponsor compliance with duties to register on 1 April 2015. This uses the sponsor declaration on a new Research Ethics Committee (REC) application to set out the duties and to ask for sponsors to confirm that they are compliant. Sponsors unable to declare compliance may advise the HRA and request a deferral through the HRA registration policy. Please refer to the linked information below for more information and guidance on this requirement.
Researchers should note that the HRA registration policy expects registration before the first participant is recruited and sets out it is a breach of the favourable ethical opinion if clinical trials are not registered within 6 weeks of the first participant being recruited. Increasingly others such as funders and publishers are setting standards for transparency. Some publishers will not publish studies where the study is not registered before the first participant is recruited.
The HRA is separately developing plans for further measures and potential sanctions for non-compliance, which it expects to consult on later in 2015. These would run in shadow form until the new EU Clinical Trial Regulation comes in to force, which will require sanctions for non-compliance with Regulation's transparency requirements.
Request for deferral of requirement to register:
In recognition of the need to ensure transparency as well as maintaining UK competitiveness applicants may request to defer registration and the HRA is maintaining a register of these requests.
The HRA acknowledges that within Phase 1 research particularly, there is sensitivity of some commercially confidential information. The EU Clinical Trials Regulations are expected to come into force in 2016 / 2017. The European Medicines Agency (EMA) has consulted on proposals for transparency rules to implement in the IT infrastructure, which will support the implementation of the new EU Clinical Trials Regulation. These included proposals to allow the possibility of a short deferral of registration for Phase 1 healthy volunteer studies.
Further information and guidance:
Our key messages and Questions & Answers on transparency (Version 4.0 PDF July 15) "
"HRA and Research Transparency
Clinical trial registration
Key messages and Q&A
Please note this document supersedes previous versions. The HRA is a listening organisation and this latest Q&A may not be fully consistent with previous consultation documents but does represent an accurate position when written.
22 May 2015
The HRA has a duty to promote transparency and researchers, sponsors and funders correspondingly having responsibilities to participants in research, patients and the wider public and research communities.
In order to fulfil its statutory responsibilities to promote transparency, the HRA introduced a simple compliance check on sponsor duties to register on 1st April 2015. This uses the sponsor declaration on new Research Ethics committee (REC) applications to ask sponsors to declare that they are compliant. Sponsors unable to declare compliance may advise the HRA and seek a deferral through the existing HRA registration policy.
Researchers should note that the HRA registration policy expects registration before the first participant is recruited and sets out that it is a breach of the favourable ethical opinion if clinical trials are not registered within 6 weeks of the first participant being recruited. Increasingly others such as funders and publishers are setting standards for transparency. Some publishers will not publish studies where the study is not registered before the first participant is recruited.
The HRA is separately developing plans for further measures and potential sanctions for non-compliance which it expects to consult on later in 2015, and run in shadow form until the new EU Clinical Trial Regulation (EU Regulation 536/2014) comes in to force, which will require sanctions for transparency alongside other good and safe practice for clinical trials. The compliance check introduced by the HRA will not affect existing or new REC applications at this time. The HRA will though actively monitor and report on compliance.
1. Key messages
1.1. Transparency is fundamental to the role of the HRA to promote and protect the interests of patients and the public in health research. The HRA has a duty to promote research registration and sponsors and investigators have existing responsibilities to register to meet governance and best practice requirements.
1.2. The HRA expects registration of all clinical trials before the first participant is recruited in line with the WHO, Declaration of Helsinki and Research Governance Framework.
1.3. Many journals require registration before the first participant is recruited. Failure to do so may prevent publication in key journals, such as the BMJ, which actively implement that requirement.
1.4. Since 30 September 2013 the HRA has identified trial registration as a specific ethical requirement within the existing duties of the sponsor, and it has been a condition of the Research Ethics Committee (REC) opinion to register clinical trials. Failure to do so within 6 weeks of the recruitment of the first UK participant is therefore a breach of the favourable ethical opinion unless a request to defer registration has been granted by the HRA and is still valid.
1.5. The HRA has offered a deferral option where there is not currently a legal requirement (see 2.5) to register, noting the commercial sensitivities of some areas of research, notably within early phase trials.
1.6. Since 1 April 2015, the HRA has updated the sponsor declaration to provide a compliance check point on sponsor duties for registration.
1.7. The HRA considers that a sponsor is meeting registration requirements when either the research has been registered in a publicly accessible trial registry (including that provided from EudraCT) or when an application has been made to the HRA for deferral of registration and if agreed, is still valid.
1.8. The HRA is extending the compliance assurance to all studies in active recruitment in the UK in line with its duties under the Care Act to promote research registration. Assurances are expected to be made based on governance procedures by sponsors in line with arrangements for other key governance requirements to ensure good and safe conduct of health research.
1.9. Sponsors unable to provide such assurances may apply for deferral of registration of studies approved before September 2013 in line with the HRA deferral policy.
2. Q and A
2.4. Q: Do clinical trials include all phases of clinical trials / Does it include clinical trials in healthy volunteers as well as patients / Does it include commercial and non-commercial trials?
A: Yes, although the HRA recognises the need to maintain UK competitiveness and so we have put in place a simple mechanism to request deferral of registration where there are, for example, concerns of commercial confidentiality and there is not currently a legal requirement for registration. This is a deferral with a commitment to register later, not an exemption. Where a deferral is allowed, the expectation is that the trial will be registered at the point where the reason for the deferral request is no longer valid. For example, where the request for deferral of registration of a phase 1 clinical trial is agreed due to reasons of commercial sensitivity, registration is expected once the trial reaches phase 2 or immediately should the trial be terminated.
2.5. Q: How do the HRA registration requirements compare with current EU Clinical Trials legislation and future EU Clinical Trials Regulation?
A: The EU Clinical Trial Regulation (Regulation 536/2014) has not been implemented yet. However, the HRA requirements are consistent with the current legislation for clinical trials of medicines in patients, they extend the requirements for other clinical trials and the simple deferral option maintains UK competitiveness. The proposals also prepare the early trial community for the requirements that will be in the new EU Regulation. Registration is an existing duty for the sponsors of research of all clinical trials, even where it falls short of being a legal requirement in European legislation or regulation.
2.6. Q: Has the HRA introduced an option for exemption or deferral of registration?
A: The HRA has introduced a simple mechanism to request deferral based on a justification of the need for delay in registration and assurances that the studies will be registered later. The HRA may consider requests for exemption from registration, but has set out that it does not expect to grant exemption although it does recognise the need for deferral to maintain UK competitiveness, particularly for early phase trials.
2.7. Q: How can a sponsor representative realistically declare that all trials have been registered when the responsibility for doing so may sit with others rather than the individual signing the REC declaration?
A: In line with many other equally important governance requirements, the HRA would expect the assurance to be based on policies, procedures and controls.
2.8. Q: If the sponsor cannot provide the assurance will it delay my application?
A: No, the sponsor can sign either to provide the assurance or by notifying through the deferral process that they cannot provide assurance and need to request deferral for previous studies in active recruitment. Sponsors and researchers should note the intention of the HRA to consult on administrative measures later in 2015 and that the new EU Clinical Trial Regulations will introduce sanctions for non-compliance with the Regulation's transparency provisions. There are no sanctions in place at this time and the compliance check will not affect new or existing REC approvals.
2.9. Q: Why is the HRA taking these steps now ahead of the new EU Clinical Trial Regulations?
A: Transparency sits at the heart of the HRA's duties to patients and the public, pragmatic solutions and promoting transparency is a specific duty for the HRA under the Care Act. Progress made now also prepares the UK for the forthcoming EU Clinical Trial Regulations and have enabled the UK to contribute to the discussions and debate on the transparency provisions from an informed position.
2.15. Q: How do sponsors of multiple clinical trials ensure they are complying with HRA requirements?
A: Assurances are expected to be based on sponsor policies and procedures and appropriate controls, as would be undertaken with any important governance requirements for an organisation.
2.16. Q: If a sponsor has registered all clinical trials since September 2013 will they have complied?
A: Since 1 April 2015 sponsors need to have complied with requirements in place since September 2013 and in addition will need to provide assurance for any research given a favourable ethics opinion prior to September 2013 and still in active recruitment, or to notify the HRA through the deferral mechanism if they are not able to provide that assurance.
2.17. Q: What does HRA consider is the acceptable timeframe for registration?
A: Unless a request to defer registration has been submitted and agreed by the HRA, the latest registration is expected to occur is 6 weeks after the recruitment of the first UK participant.
The HRA expects earlier registration and sponsors will be aware that some journals require registration ahead of the first participant being recruited. This is expected best practice.
2.18. Q: What happens if a Sponsor does not comply with registration requirements?
A: Registration is a condition of the REC favourable opinion for that trial, so if a Sponsor does not register the clinical trial or does not put in place a deferral of registration with the HRA then the trial will be in "serious breach". Where the HRA becomes aware that a clinical trial is in serious breach action will be taken in accordance with REC standard operating procedures.
2.19. Q: What sanctions are there for non-compliance?
A: There are currently no specific sanctions although the HRA will actively monitor and report on compliance. Failure to register could technically enable the REC to reconsider its ethical opinion in line with REC SOPs, the HRA does not expect the REC to take such action and is working with REC members, other stakeholders and with legal advice on a set of administrative measures for further consultation later in 2015. The new EU Clinical Trials Regulations will require Member States to have legal sanctions for non-compliance with transparency provisions of the Regulation.
2.21. Q: How do sponsors confirm to HRA that their clinical trial is registered?
A: If the sponsor has registered the trial before the application for ethical review is submitted then the details of registration should be included in the application form. Where registration occurs after submission of the initial application the sponsor does not need to tell the REC immediately but registration should be confirmed and details provided at the first opportunity (i.e. submission of substantial amendment or progress report, whichever is earlier).
2.22. Q: (May 2015) Why has the additional text been added to the sponsor declaration?
A: The further clarification is consistent with the information on IRAS that remains as updated on 1st April to extend the compliance checks to studies in active recruitment in the UK. The update, further distinguishes where the clauses on the declaration relate to important terms that are not at this time a consideration for the REC. These are the long established HRA transparency provisions to publish a research summary and registration of studies approved before September 2013 as part of the HRA statutory duties to promote transparency." [N.B. the significance of the bold italics is explained under paragraph 47 below]
"I confirm that:
6. The duties of the sponsors set out in the Research Governance Framework for Heath and Social Care will be undertaken in relation to this research.
7. The statutory responsibilities of sponsors set out in the Medicines for Human Use (Clinical Trials) Regulations 2004 will be undertaken in relation to this trial.
Please note: The declarations below do not form part of the application for approval above. They will not be considered by the REC.
9. Specifically, for submissions to the RECs, I declare that any and all clinical trials approved by the HRA since 30 September 2013 have been registered on a publically accessible register in compliance with the HRA registration requirements for the UK, or that any deferral granted by the HRA still applies."
"Further or alternatively, the HRA have acted unlawfully and are continuing to act unlawfully by:
(a) 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 publication has not been included as a condition of a REC favourable opinion; and
(b) regulating or seeking to regulate sponsors and those conducting clinical trials against this supposed legal duty."
The Legal Framework
"The HRA's Functions
(1) The main functions of the HRA are
a) functions relating to co-ordination and standardisation of practice relation to the regulation of health and social care research;
b) functions relating to research ethics committees.
(2) The main objective of the HRA in exercising its functions is
a) to protect participants and potential participants in health and social care research and the general public by encouraging research that is safe and ethical, and
b) to promote the interests of those participants and potential participants and the general public by facilitating the conduct of research that is safe and ethical (including by promoting transparency in research).
(6) A reference to research that is ethical is a reference to research that conforms to generally accepted ethical standards.
(7) Promoting transparency in research includes promoting
a) the registration of research;
b) the publication and dissemination of research findings and conclusions;
c) the provision of access to data on which research findings or conclusions are based; "
"(5) The HRA must
(a) keep under review matters relating to the ethics of health and social care research and matters relating to the regulation of such research;
(6) The HRA must publish guidance on
(a) principles of good practice in the management and conduct of health and social care research;
(b) requirements, whether imposed by enactments or otherwise, to which persons conducting health or social care research are subject."
"The accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine, as for instance reflected in the 1996 version of the Helsinki declaration. "
"Good Clinical Practice
1. The rights, safety and well being of the trial subjects shall prevail over the interests of society.
2. Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his tasks.
3. Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects.
4. The necessary procedures to secure the quality of every aspect of the trials shall be complied with.
The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.
Clinical trials shall be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996)."
"1. The rights, safety and well-being of the trial subjects shall prevail over the interests of science and society.
2. Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his tasks.
3. Clinical trials shall be scientifically sound and guided by ethical principles in all respects.
4. The necessary procedures to secure the quality of every aspect of the trial shall be complied with.
5. The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.
6. Clinical trials shall be conducted in accordance with the principles of the Declaration of Helsinki. [NB. the original wording of the 2004 Regulations provided "Clinical trials shall be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice and the requirements of these Regulations."]"
"the Declaration of Helsinki adopted by the World Medical Assembly in June 1964, as amended by the General Assembly of the Association in October 1975, October 1983, September 1989 and October 1996."
The Declaration of Helsinki was subsequently amended in 2000, 2008 and 2013, with certain "clarifications" to articles 28 and 29 (not relevant for our purposes) being made in 2002 and 2004. The 2013 version of the Declaration, adopted in Fortaleza, Brazil, included the following:
"35. Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of their research. Researchers 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. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. "
This wording did not appear in the 1996 version. The wording of paragraph 35 appeared for the first time in the 2008 version (under paragraph 19). The wording of paragraph 36 also appeared in the 2008 version (under paragraph 30) but the word "researchers" was missing.
"40. The HRA are the sector regulator for the clinical research community in the UK. It is thus vital that they are clear in their statements about what companies engaged in this field are required to do as a matter of law and what practices the HRA recommend the clinical research community to follow but which are not legal requirements. There is, I regret, a marked lack of transparency by the HRA in identifying the difference between "rules" and "recommendations of good practice". Understanding the difference between mandatory rules and recommendations of good practice is vitally important for the clinical research community. We are obliged to follow rules in every case, regardless as to whether we agree with the rule or not. 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. Statements of general good practice in one area may well not be appropriate in a particular case or even be wholly inappropriate. We need to be able to tell whether we can make a case to justify a departure from a recommended form of good practice or have to comply with a rule, regardless as to how inappropriate it appears in an individual case."
"6. 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. This has already been explained to the Claimant, most recently in the HRA's response to the application to amend (see paragraphs 57-60), and a letter from the HRA's solicitors to the Claimant's solicitors.
7. I do not discuss the nature of the duties on those sponsoring or conducting trials where a condition of registration is in place as part of the REC's favourable ethical opinion, as the Claimant does not take issue with our action in relation to these trials: see paragraph 7 of Mr Wright's witness statement.
8. However, the HRA does assert that sponsors and all those involved in research with human participants (consistent with wording in the [RGF]) have other responsibilities and standards to ensure that trials are registered. It is over-simplistic and inaccurate to argue, as the Claimant does, that the only obligations on researchers are to comply with legal requirements, with respect to registration or even more broadly."
"6. However, it appears to me that the Claimant is suggesting that sponsors and others conducting clinical trials are only obliged to register those trials, or are only subject to regulation or to an obligation to describe or explain their actions where there are relevant legal requirements. While I do not comment on the legal merit of these allegations, what I would say is that there can be many requirements for a clinical trial to be registered. These requirements are not limited to legal duties. In fact, sponsors and those conducting clinical trials have other responsibilities to register a clinical trial, such as ethical and moral responsibilities, standards, and good practice.
8. Furthermore, in case it is not obvious to the court, I should explain the importance of trial registration. Put simply, without it, the research and medical community cannot be sure it has the full picture on the benefits and dangers of any drug. Suppose ten unregistered trials are conducted on a drug. Seven demonstrate positive results, and are published in the literature. Three demonstrate no real benefits, and are not published, or are abandoned early. Unless there is a way to establish at the least that ten trials were initiated, a doctor reviewing the literature will be misled by seeing only the ten positive trials into believing that the drug is more universally beneficial than is the case "
I do not lose sight of the point that phase 1 trials are not designed to assess efficacy.
The Claimant's Case
The Case of the Interested Party
The Case for the Defendant
Discussion and conclusions