European Union: Transparency Of Pre-Clinical And Clinical Trial Data In The EU

Scope of this note

This note sets out the current legislation and guidance documents that require disclosure of pre-clinical and clinical trial data in the European Union (EU). It explores the position of the European Medicines Agency (EMA) in relation to disclosure and industry and other stakeholder responses. In particular, it discusses the current initiatives in relation to:

  • Proactive disclosure (that is, the information that is released by the EMA and other bodies).
  • Reactive disclosure (that is, how the EMA responds to requests for access to documents).

The EMA's policies do not apply to documents held by the national authorities. Many national competent authorities take a different view of disclosure and what should be considered as commercially confidential information and so withheld from disclosure. Those interpretations are not covered by this note.

Transparency of documents

The principle of transparency of documents is enshrined in the fundamental texts of the EU. The Treaty establishing the European Community (and its subsequent versions) notes that the European institutions should conduct their work as openly as possible, and that any citizen of the EU, and any natural or legal person residing or having its registered office in a member state, should have a right of access to documents of the EU's institutions. To implement this, the Access to Documents Regulation ((EC) 1049/2001) grants EU citizens and legal entities an express right to access documents held by European institutions.

In relation to medicinal products and the work of the EMA, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency requires that the Access to Documents Regulation should be applied to documents held by the EMA. To implement this, the EMA has chosen to interpret the general right of access very widely, and has stated that one of its key goals is the publication of clinical trial data for a product once the decision-making process on the application is complete. This is because of the perceived importance of establishing trust and confidence in the regulatory system, so the public has a better understanding of regulatory decision-making.

This broad policy of disclosure has been controversial. Many of the documents held by the EMA are documents from third parties, who have submitted data in order to obtain a marketing authorisation for each of their products. Thisis quite different from legislative or policy documents held by many other EU institutions. A wide interpretation of access does not recognise that the data submitted by companies could contain commercially confidential information. However, there is the perception that companies have, in the past, hidden "unhelpful" data and have not been pro-active in publishing negative data, which may influence how healthcare professionals and regulators view the safety and efficacy of the products. Indeed, in 2015, The Economist published an "interactive clinical trial simulator" to demonstrate the potential distortion that may occur if you selectively publish positive results, and supress unfavourable results, for a fictional product (see The Economist: Clinical trial simulator (29 July 2015)). As such, many believe companies cannot be trusted to release data about their products.

Commercially confidential information

The EMA accepts that "commercially confidential information" should not be disclosed. While there is no definition of "commercially confidential information" in the legislation, the EMA uses the following definition:

<

p>"... any information which is not in the public domain or publicly available and where disclosure may undermine the economic interest or competitive position of the owner of the information."

( EMA: European Medicines Agency policy on access to documents Policy/0043 EMA/729522/2016 (4 October 2018). Slightly different wording is used in other EMA documents, but the key elements of the definition are unchanged.)

Under this definition, the relevant information must be both confidential, and harm the economic interests of a company if it were disclosed.

There are significant differences of opinion on what data within the marketing authorisation dossier, other than manufacturing information, should be kept confidential under this definition. A wide approach to disclosure has been sought by academic researchers and patient groups through their related campaigns. While many pharmaceutical companies agree with disclosure of data for non-commercial purposes, industry has been more cautious about the wholesale disclosure of its data where the data can be accessed by competitors. Further, many companies consider certain information within the authorisation dossier to be confidential, and that disclosure would undermine the protection of their commercial interests (including intellectual property rights).

The EMA previously treated pre-clinical and clinical trial data as confidential, and refused disclosure of such data. However, in 2010, the European Ombudsman, who investigates complaints of maladministration by EU institutions, delivered a number of decisions that were critical of the approach of the EMA, including one relating to clinical study reports (European Ombudsman: Decision of the European Ombudsman closing his inquiry into complaint 2560/2007/BEH against the European Medicines Agency (24 November 2010)).

Following these decisions, the EMA has said that it does not consider pre-clinical data or data from clinical trials to be commercially confidential, and it has since released a substantial amount of trial data.

Information already released

Even before considering the Access to Documents Regulation and its application to the EMA, competent authorities in the EU already release a large amount of data concerning trials and contained within marketing authorisation dossiers. Once an authorisation has been granted, the relevant data is released. In particular, the publication of each European Public Assessment Report (EPAR) seeks to provide transparency of the basis on which the decision to grant a marketing authorisation has been made, and includes a summary of, and the conclusions reached on, the documentation (both clinical and pre-clinical) submitted by the applicant (Articles 12 and 13 of Regulation 726/2004, or its national equivalent for products subject to national assessment through the decentralised and mutual recognition procedures under Article 21(4) of Directive 2001/83/EC on the Community code relating to medicinal products for human use). The EMA also publishes detailed information about the decisions taken by its Committee for Medicinal Products for Human Use and other committees.

In relation to clinical trials specifically, the principle of providing information on clinical trials has been in place since the Declaration of Helsinki in 1968. This is a statement of ethical principles for medical research involving human subjects. As part of this, every research study involving human subjects should be registered in a publicly accessible database before recruitment of the first subject. There are also obligations with regard to the publication and dissemination of the results of 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."

( World Medical Association: WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (9 July 2018), paragraph 36.)

In the EU, this broad principle is reflected in the Clinical Trials Directive (2001/20/EC). Member states have an obligation under Article 11 of the Clinical Trials Directive to enter certain information about clinical trials onto the EudraCT database (see eudract.ema.europa.eu) and are required to make some of that information public, in particular in relation to paediatric trials (Article 57(2) of Regulation 726/2004 and Article 41(1) of the Paediatric Regulation ((EC) 1901/2006)). The EU Clinical Trials Register (see clinicaltrialsregister.eu) includes publicly available information extracted from the EudraCT database. Companies also have obligations under Articles 41(2), 45(1) and 46(1) of the Paediatric Regulation to supply information to the EMA concerning paediatric studies they have sponsored, or that they are aware are sponsored by others but conducted with their product. The European Commission guidance expands on these obligations and sets out details on the information to be included in the database, and the information to be made public. The guidance states that for all trials (paediatric and non-paediatric), result-related information should be supplied and made public within 12 months of the completion of the trial (not after grant of the marketing authorisation), including a summary of the results and conclusions ( Communication from the Commission regarding the guideline on the data fields contained in the clinical trials database provided for in Article 11 of Directive 2001/20/EC to be included in the database on medicinal products provided for in Article 57 of Regulation (EC) No 726/2004 (OJ 2008 C 168/02) and Commission Guideline on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 (OJ 2012 C 302/03) (October 2012 Commission guidance)).

In addition, self-regulatory codes of practice within the EU require disclosure of clinical trial information (although not covering pre-clinical data). The European Federation of Pharmaceutical Industry Associations (EFPIA), together with the International Federation of Pharmaceutical Manufacturers & Associations, Pharmaceutical Research and Manufacturers of America and Japan Pharmaceutical Manufacturers Association, have issued joint positions on the disclosure of clinical trial information via clinical trial registries and databases and on the publication of clinical trial results in the scientific literature (see Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases (10 November 2008) and Joint Position on the Publication of Clinical Trial Results in the Scientific Literature (10 June 2010)). These provide that:

  • Details of ongoing clinical trials should be registered within 21 days of initiation of patient enrolment in a publicly accessible database.
  • Results of clinical trials (irrespective of the outcome) should be posted no later than one year after the medicinal product is first approved and commercially available in any country; for trials completed after this initial approval, results should be posted no later than one year after trial completion.

These provisions are echoed in national codes of practice. For example, in the UK, the Association of the British Pharmaceutical Industry's Code of Practice states that companies must disclose details of clinical trials in accordance with the international Joint Positions (clauses 7.5 and 13.1, and the supplementary information thereto, Code of Practice for the Pharmaceutical Industry 2019 (1 January 2019)). Companies are required to publish on the homepage of their websites information on where details of their trials may be found.

A recent BMJ article sought to ascertain the level of compliance with the Commission's requirement that all trials post results within 12 months of completion, and to identify features associated with non-compliance (BMJ:Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource (12 September 2018)). The retrospective cohort study found that despite the provisions above, of the 7,274 trials where results were due, only 49.5% reported results, although trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68.1% compared to 11.0%).

The matter has been raised in the UK Parliament. At the end of October 2018, the House of Commons Science and Technology Committee published a report expressing concern that around half of all clinical trials fail to publish their results ( House of Commons: Research integrity: clinical trials transparency, Tenth Report of Session 2017–19 (23 October 2018)). The report is generally critical of the level of reporting of results of clinical trials, particularly by universities and NHS hospitals. It further notes its concern about "selective non-publication—'or publication bias'— of results" and the risk of the effects of such "bias" on the views of the medicine in clinical practice. The committee specifically recommends that the Health Research Authority (HRA), which manages the ethics committees for clinical trials in the UK:

  • Publishes a detailed strategy for achieving full clinical trial transparency, with a clear deadline and milestones.
  • Be provided with funding to establish a national programme to audit clinical trial transparency.
  • Introduces a system of sanctions to drive improvements in clinical trial transparency, such as withdrawing favourable ethical opinions or preventing further trials from taking place.

The committee also recommends that the UK government consult on whether to provide the HRA with the statutory power to fine sponsors for non-compliance.

Proactive disclosure

In 2014 the EMA adopted a policy on the proactive publication of clinical data (not pre-clinical data) supporting centralised marketing authorisations, known as "Policy 70" (see EMA: European Medicines Agency policy on publication of clinical data for medicinal products for human use, Policy/0070 EMA/240810/2013 (2 October 2014)). This was in response to a call from researchers and academics for greater transparency of clinical data. The policy applies to any new applications for centralised marketing authorisation made after 1 January 2015, and for extension of indication and line extension applications for centralised authorisations made after 1 July 2015. It does not apply to clinical data submitted before these dates, nor to applications made to national authorities.

Under the policy, after the EMA takes its decision, the clinical data within the application dossier (whether the study is conducted within the EU or outside) will be available on the EMA's website (see EMA: Clinical data) at the same time as publication of the EPAR. The data will be available in two forms:

  • To view by all those who register for the website.
  • To download and re-use by academics and for non-commercial research purposes.

Such disclosure will occur after the EMA's "decision", which includes not only a decision on grant of the authorisation, but also refusal or withdrawal of the application. This has caused some concern for industry, as in many cases, where an application has been withdrawn, the applicant intends to resubmit the data. The policy is stated to cover such data, but there is a question as to whether this may undermine a company's strategy for further research and development, and the re-submission of the data to support an authorisation.

All use is subject to the EMA's terms of use, whereby the use of the data must be for non-commercial purposes only. Commercial purposes include using the data to support an application to obtain a marketing authorisation, and any extensions or variations thereof for a product anywhere in the world, or selling, trading or supplying the data to a third party that has not agreed to the terms of use.

Commercially confidential information (using the EMA definition above) will be redacted. Examples of what is, in principle, accepted as commercially confidential information appear in Annex 3 to the policy. However, the policy contains the assertion that "in general", data within an application is not commercially confidential. Where redaction of commercially confidential information is proposed by the applicant, the EMA will conduct a consultation with the applicant, and the EMA will decide if the information should be redacted.

The EMA's terms of use for Policy 70 are for the benefit of any and all applicants or authorisation holders and, accordingly, each applicant or authorisation holder may, in its own right, enforce the terms of use directly. How this might operate in practice if an authorisation holder believes its data has been used in breach of the terms of use is unclear. The EMA also states that "[c]ourts may require the EMA to disclose the identity of the users who do not comply with the [terms of use] to the marketing authorisation holders/applicants" (see EMA: Questions and answers on the European Medicines Agency policy on publication of clinical data for medicinal products for human use EMA/357536/2014 (8 June 2015)). The terms of use are stated to be subject to English law but it is unclear whether the EMA considers that any challenge under the policy would be brought in the English courts, or in the European General Court. It is also unclear if these terms of use will be updated after the relocation of the EMA from London to Amsterdam.

The number of accounts and registered views/downloads has been steadily increasing since the introduction of Policy 70 (see EMA: EMA Clinical Data Publication (CDP), Joint meeting between the EMA's Patients' and Consumers' Working Party and the Healthcare Professionals' HCPs Working Party (18 April 2018)). Fifty-four sets of documents (comprising 36 initial marketing authorisation applications and 18 extension applications) have been published since 2016, comprising a total of 3,279 documents. This is compared to the 92 medicines that the EMA recommended for marketing authorisation, and 51 recommendations for extensions to the indications of authorised products, in 2017 alone. In terms of redactions, commercially confidential information was accepted in only 1.46% of documents (from the 4.4% proposed by marketing authorisation holders).

As part of its Brexit business continuity plan, the EMA is temporarily suspending the publication of clinical data under Policy 70 (see EMA: Press release, Brexit preparedness: EMA to further temporarily scale back and suspend activities (1 August 2018)). Data packages submitted before the end of July 2018 will be processed and published on the website, but new procedures submitted after 1 August 2018 will not.

Clinical Trials Regulation

Consistent with the EU-wide policy towards increased transparency, the Clinical Trials Regulation ((EU) 536/2014) also contains provisions in relation to increased transparency of clinical data (although not pre-clinical data). The Clinical Trials Regulation states that the sponsor of a trial conducted in the EU under the Regulation should submit a summary of the clinical results to the EU database within a year of the end of the trial. In addition, where the trial was intended to be used for obtaining a marketing authorisation (whether through the centralised procedure or via the national authorities), the applicant should submit the clinical study report 30 days after the marketing authorisation has been granted (or refused or withdrawn) (Articles 36 and 37, Clinical Trials Regulation).

Although the recitals state that "in general the data included in a clinical study report should not be considered commercially confidential once a marketing authorisation has been granted ..." (emphasis added) (recital 68), the Clinical Trials Regulation states that the EU database shall be publicly accessible unless, among other things, confidentiality is justified on the grounds of:

"... protecting commercially confidential information, in particular through taking into account the status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in disclosure"

(Article 81(4)(b)).

The Regulation contains no definition of commercially confidential information, and it is likely that in practice, the definition used by the EMA will be used in the context of the Regulation.

The Regulation, and data posting requirement, do not come into operation until the clinical trials portal and database has been set up and independently audited, and only six months after notification of the successful audit is published by the Commission. The operation of this database has been delayed a number of times, as the development of a system to cover so many aspects of the new Regulation is taking longer than expected. In October 2018, the EMA Management Board reported that the development of the auditable version of the portal and database is complete, and that its development has entered an "intensive phase of pre-testing". However, the formal audit will take place once the EMA has relocated to Amsterdam. As such, the current estimation is that the portal will be able to "go live" in 2020 ( EMA: EMA Management Board: highlights of October 2018 meeting (5 October 2018)).

Note that in terms of Brexit, the UK government has stated that it intends to align UK transparency provisions with those currently in operation in the EU, and intends to implement the Clinical Trials Regulation as far as possible ( Department of Health and Social Care: How medicines, medical devices and clinical trials would be regulated if there's no Brexit deal (3 January 2019)). For more information on the implementation, see Legislation Tracker, Brexit: EU legislation expected to apply or be implemented in UK pre-Brexit and during transition: tracker.

Reactive disclosure

Despite the existence of Policy 70, and the adoption of the Clinical Trials Regulation, documents concerning relatively few products have so far been released, and future disclosures are currently stalled. In the meantime, the EMA will release documents, including pre-clinical and clinical data, in response to requests made directly to it. This is the area that has, so far, caused the biggest controversy, and has led to litigation.

The Access to Documents Regulation grants EU citizens and legal entities an express right to access documents held by European institutions (see Transparency of documents). Article 4 contains exemptions to the right of disclosure, in particular where disclosure would undermine the protection of the commercial interests of a natural or legal person, including intellectual property rights, unless there is an overriding public interest in disclosure. Further, where third party documents are proposed to be disclosed in response to a request, the institution should consult with the third party in order to agree any necessary redactions. The timelines for responding to requests are short, as the Access to Documents Regulation states that an initial response should be provided within 15 working days, although this can be extended to 30 working days in exceptional circumstances.

This general right of access to documents applies to documents held by the EMA (Article 73, Regulation 726/2004), and the EMA has published a number of policy and guidance documents on how this right of access to documents will operate. In particular, in 2010, the EMA published a policy defining how it would respond to requests for access to documents related to medicinal products for human and veterinary use, known as "Policy 43". A revised version of Policy 43 came into effect on 4 October 2018, which has a broader scope as it also applies to documents that are not related to medicinal products for human or veterinary use ( EMA: European Medicines Agency policy on access to documents Policy/0043 EMA/729522/2016 (4 October 2018)). The policy states that the EMA will ensure the widest possible access to EMA documents concerning any matter related to the policies, activities and decisions falling within the EMA's remit and responsibilities. Access to a document will be denied only if one of the exceptions applies, and the exclusions set out in the Access to Documents Regulation are repeated, in line with the EMA's definition of commercially confidential information.

The EMA also published guidance on the application of Policy 43 to particular categories of documents and types of information held by the EMA (see EMA: Output of the European Medicines Agency policy on access to documents related to medicinal products for human and veterinary use EMA/127362/2006 (4 October 2018) and Output of the European Medicines Agency policy on access to documents non-related to medicinal products for human and veterinary use EMA/183710/2016 (4 October 2018); see also HMA/EMA Working Group on Transparency: HMA/ EMA guidance document on the identification of commercially confidential information and personal data within the structure of the marketing authorisation application - release of information after the granting of a marketing authorisation (14 March 2012)). In relation to the documents within an application for a marketing authorisation (although the guidance does not specifically refer to pre-clinical or clinical trial data), it is said that such documents will be considered as "non-releasable" prior to the final decision (approval, refusal, or withdrawal). However, oncethe relevant decision has been made, the documents will be considered as "releasable", and will be disclosed, subject to appropriate redactions.

The policy is well used. The EMA Annual Report 2017 indicated that the number of requests for access to documents received by the EMA had increased from 377 in 2014 to 844 in 2017, with 2,807 documents being released in 2017 (see EMA: Annual report 2017 (2 May 2018)). Note that the EMA has recently stated that, due to the high volume of requests resulting in an excessive workload for the EMA, it will no longer process requests from outside the EU (see EMA: Access to documents).

There are a number of questions relating to Policy 43. For example, unlike Policy 70, there are no terms of use associated with the policy, and the same rights of access are provided to everyone, including competitors. There are no restrictions or conditions on use, and the third party requestor is free to use the data worldwide as they wish, without being subject to confidentiality provisions. More practically, the timelines imposed on companies to review and redact the documents the EMA proposes to release are very short, and the process generally requires input from a number of business stakeholders.

In response to the broad scope of Policy 43, industry bodies such as EFPIA developed their own principles for sharing data, although the policy specifically excludes pre-clinical data (see EFPIA: Principles for Responsible Clinical Trial Data Sharing: Our Commitment to Patients and Researchers (18 July 2013)). These principles go beyond the legislative requirements, but allow marketing authorisation holders to retain some control over how their data is used by third parties when disclosed under these principles, rather than when the data is disclosed by the EMA under Policy 43. Under these principles, pharmaceutical companies will release, on request, anonymised patient- and study-level clinical trial data, along with full clinical study reports and protocols for US and EU approved medicines to "qualified scientific and medical researchers". Such release is subject to patient privacy and confidential commercial information protections. Data requestors are required to provide a rationale for their proposed research, along with their analysis, publication and posting plans; any potential conflicts of interest, including potential competitive use of the data; and the source of any research funding. Companies can therefore retain some control over the release, and ensure that confidential information is not provided to competitors, while also allowing wide access to data to academics and healthcare professionals.

Court cases relating to what is disclosed and what is exempt from disclosure

As a result of the difference in opinion on which data should be considered as commercially confidential information and therefore withheld from disclosure, the EMA has been subject to a number of challenges to its Policy 43.

The first wave of these cases was brought by InterMune and AbbVie ( AbbVie Inc and another v EMA (Case T-44/13R) EU:T:2013:221; AbbVie Inc. and another v EMA (Case T-29/13) EU:T:2014:695 and InterMune UK Ltd and others v EMA (Case T-73/13R) EU:T:2013:222). In these cases, the companies applied to the European General Court for annulment of the EMA's decisions that it would disclose the research-related documents contained in the marketing authorisation dossier, and applied for interim orders preventing the EMA from disclosing that information pending the court's decision. Several EU and US pharmaceutical trade associations and intellectual property rights associations sought to intervene to support the applicants. However, these cases did not proceed to judgment as they were resolved out of court, and the cases were withdrawn.

Since these cases were withdrawn, a series of others have been filed. On 5 February 2018, the General Court delivered three judgments concerning the application of the Access to Documents Regulation to documents held by the EMA ( Pari Pharma GmbH v EMA (Case T-235/15R) EU:T:2018:65; MSD Animal Health Innovation GmbH v EMA (Case T-729/15) EU:T:2018:67 and PTC Therapeutics International Ltd v EMA (Case T-718/15) EU:T:2018:66). A further decision was delivered on 25 September 2018 ( Amicus Therapeutics UK Ltd and another v EMA (Case T-33/17) EU:T:2018:595). In all cases, which concern both clinical and pre-clinical data, the General Court upheld the EMA's approach to disclosure, and rejected the arguments of the companies as to the confidential nature of the documents. In summary:

  • The General Court rejected the arguments of the parties that there was a general presumption of confidentiality over certain documents. The provisions on access apply to all documents held by the EMA.
  • As a result, each document, and all the information within it, needs to be considered on an individual basis to assess whether it can be withheld from disclosure under one of the exemptions. The General Court stated that information can be withheld from disclosure on the ground that it constitutes commercially confidential information in only limited situations where "specific" and "actual" evidence is provided to show how disclosure would seriously undermine a company's commercial interests.
  • The concern that a wide interpretation of access could undermine the EMA's decision-making, and lead to companies altering the amount of information provided to the EMA, was dismissed as invalid.
  • The EMA's application of its Policy is not in breach of the World Trade Organization's (WTO) Agreement on Trade-related aspects of Intellectual Property Rights (TRIPS) ( WTO: Agreement on Trade-Related Aspects of Intellectual Property Rights). Under TRIPS, where test results or data for new chemical entities must be submitted to authorities to gain an authorisation, the data must be protected from unfair commercial use, and member countries (including the EU) must protect such data from disclosure, except where necessary to protect the public. The applicants in these cases claimed that as TRIPS only applies to information that is secret, the EMA was breaching its obligations by disclosing the data. However, the court stated that the EMA's interpretation of what constitutes commercially confidential information is in line with the relevant legal provisions, and is consistent with TRIPS.
  • The EMA is not under an obligation to show that there is an overriding public interest justifying disclosure of the documents, unless the EMA takes the view that the documents are protected by an exception.

For more information, see Legal update, General Court confirms EMA approach to transparency (EU).

MSD Animal Health and Intervet International, and PTC Therapeutics, have appealed the General Court's findings to the Court of Justice ( MSD Animal Health Innovation and Intervet International v EMA (Case C-178/18P) and PTC Therapeutics International v EMA (Case C-175/18P)). In addition, ongoing cases that raise similar issues are pending before the General Court ( Intercept Pharmaceuticals v EMA (Case T-377/18)). It is therefore likely that further guidance from the court will be available in due course.

Summary table of disclosure regimes applicable to data held by the EMA

Law and Guidance

EMA's Proactive

Clinical Trials

EMA's Reactive

Policy 70

Regulation

Policy 43

(Regulation)

Data covered by

Data relating to all

Data within

Data relating

Data within

the policy

trials (paediatric

dossiers for

to all products

dossiers for

and non-paediatric)

products approved

(centralised,

products approved

conducted under

under centralised

decentralised

under centralised

procedure.

procedure, mutual

procedure.

the Clinical Trials

recognition

Directive.

procedure, national)

that includes trials

conducted under the

Regulation.

Location of trial

Trials with at least

Data submitted

Trials with at least

Clinical data

one site in the EU/

to the EMA and

one site in the EU

contained in

EEA; where the

contained in

conducted under the

the marketing

trial forms part

the marketing

Regulation.

authorisation

of a paediatric

authorisation

dossier, regardless

investigation plan,

dossier, regardless

of trial site location.

obligations also

of trial site location.

include studies

outside the EU.

Data that should

General information

Clinical data

General information

Any data held by the

be disclosed

about the trial; a

(including clinical

about the trial;

EMA.

summary of positive

overview, summary

summary of results;

or negative results.

of results, clinical

clinical study

study reports and

reports.

individual patient

data).

Timing

Within six months

After decision on

Summary results:

In response to a

of completion of the

authorisation (or

within a year of

request, usually

trial for paediatric

withdrawal/ refusal),

the end of the trial,

within 30 days.

trials, and otherwise,

at the same time as

unless scientific

within one year of

publication of the

reasons justify a

the end of the trial.

EPAR.

longer period of

Information should

time.

be posted earlier, if

already published in

Full results:

scientific journals.

within 30 days

of the marketing

authorisation being

granted (or refused

or withdrawn).

Position on

Only a summary is

"In general ... most

"... in general the

EMA considers

commercially

provided, so issue

of the information

data included in a

that clinical data

confidential

does not arise.

in clinical reports

clinical study report

are not CCI, and

information (CCI)

would not be

should not be CCI";

the interpretation is

considered CCI";

likely that the EMA's

subject to ongoing

EMA applies

definition will be

court cases.

standard definition,

used to determine

but interpretation

CCI, and this has

has not yet been

not yet been tested.

tested.

Application

Trials regulated by

1 Jan 2015 for new

Trials approved from

Any data held by the

the Clinical Trials

applications.

approximately 2020

EMA.

Directive, which took

onwards.

effect, at the latest,

1 July 2015 for line

on 1 May 2004.

extensions.

If past paediatric

(Policy suspended

trials are included

for submissions after

in a paediatric

1 August 2018.)

investigation plan,

or submitted under

the Paediatric

Regulation, they

should also be

included.

Sanctions

In relation to the proactive policies, which place obligations on marketing authorisation holders to disclose information about their clinical studies, penalties may be imposed on companies for not providing the results of paediatric clinical trials, under:

  • The Penalties Regulation ((EU) No 658/2007), which sets out financial penalties for infringement of certain obligations in relation to centralised marketing authorisations, and the obligations in the Paediatric Regulation; the penalty should not exceed 5% of the marketing authorisation holder's annual turnover in the EU, although daily penalties can be imposed if the infringement is ongoing.

From 28 January 2019 onwards, the "core elements" of the Penalties Regulation will now be set out in new Article 84a and Annex II of Regulation (EC) 726/2004 (as amended by Article 1(38) of Regulation (EU) 2019/5). For clarity however, Article 4(1) of the new Regulation specifies that the provisions of the Penalties Regulation will continue to apply unless and until repealed. Regulation (EU) 2019/5 also introduces new provisions regarding financial penalties, including the ability to impose penalties on entities other than marketing authorisation holders provided they form "part of the same economic entity" as the authorisation holder in question and: "(a) exerted a decisive influence over the authorisation holder"; or "(b) were involved in, or could have addressed, such failure to comply with the obligation by the authorisation holder" (Article 1(38), Regulation (EU) 2019/5).

The Clinical Trials Directive and Commission guidance do not contain sanctions for non-compliance where this relates to non-paediatric trials. However, the publication of clinical trial data is becoming an increasingly "hot topic" with the EMA and national competent authorities, and it is likely that authorities will increasingly rely on this guidance to "force" disclosure. For example, the fact that transparency and disclosure obligations are included in national codes of practice means that member companies who fail to comply may be subject to sanctions (including adverse publicity) in accordance with self-regulatory provisions under the relevant code (see, for example, the decision of the Prescription Medicines Code of Practice Authority in Director v Roche, Cases AUTH/2898/11/16 and AUTH/2901/11/16). The PMCPA has made similar enquires of companies following the September 2018 BMJ article.

In addition, under the October 2012 Commission guidance, where results are not posted within nine months of the end of a trial for paediatric trials, or 15 months for other trials, these trials will be "flagged" on the database.

Under the Clinical Trials Regulation, member states are required to put in place penalties to cover non-compliance with the transparency provisions (Article 94(2)). Such rules on penalties have not yet been implemented in member state implementing legislation.

Practical Tips

Transparency of pre-clinical and clinical data is generally increasing, with stakeholders expecting greater amounts of data to be released. Companies are advised to:

  • Ensure reporting of information about clinical trials is up-to-date, and the company has standard operating procedures on how, what and when information and data should be published.
  • If your company receives notice from the EMA of a request for access to documents under Policy 43, and the company wishes to seek redactions of commercially confidential information within the document, you should seek to explain to the EMA why disclosure could damage your commercial interests. Any reasons should be as specific as possible, including details of the expected harm the company would suffer if the information was released. Keep any requested redactions to a minimum; following the General Court's decisions, a position that entire documents are confidential is unlikely to be accepted by the EMA.
  • Make sure all regulatory submissions to the EMA are reviewed with the expectation that the document will be released to competitors. To the extent possible, ensure all commercially confidential information is removed, and all patent applications are made before submission.
  • Know what information is already available about the company's products, in public documents or published literature. It is unlikely that the EMA will accept that anything that is in the public domain can be redacted, even if the information in the relevant submission is not in the same form as the public information.
  • Determine the company's position on controlled access (such as under EFPIA's Principles for Responsible Clinical Trial Data Sharing). If competitors can obtain data directly from the company, they will not need to use the EMA's Policy 43.

Originally published in Practical Law

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Authors
Similar Articles
Relevancy Powered by MondaqAI
 
In association with
Related Topics
 
Similar Articles
Relevancy Powered by MondaqAI
Related Articles
 
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Mondaq Free Registration
Gain access to Mondaq global archive of over 375,000 articles covering 200 countries with a personalised News Alert and automatic login on this device.
Mondaq News Alert (some suggested topics and region)
Select Topics
Registration (please scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions