The do's and don'ts for drug makers under EMA trial data publication policy

As the European Medicines Agency prepares to implement its policy on the proactive publication of clinical trial data, it is bracing itself for the inevitable disputes with pharmaceutical companies on what constitutes commercially confidential information in a clinical study report and should, therefore, not be made public.

The EMA has clarified that it would only hold off from publishing the disputed information in a clinical study report if the company concerned provides the agency with evidence that it has approached the court for interim relief. To ensure that companies do not endlessly delay the publication process, companies will be allowed only 20 calendar days to approach the court for interim relief.

"We are mindful of the rights of all applicants [ie drug sponsors] to have recourse to the court if they completely disagree with the conclusions of the EMA [on what constitutes commercially confidential information]," said Stefano Marino, head of EMA's legal department. "For that reason, we will wait for 20 calendar days and we consider this as a sufficient time for a company to file an interim relief application before the general court… It is very important that you not only notify the EMA that you disagree with us and are, therefore, considering going to the court… but you will [also] have to give us evidence that this [ie, the court case] has happened," Mr Marino said.

At the end of the 20-day period, Mr Marino said the EMA wants to see evidence that a company has actually notified its pleadings to the court and, therefore, there is a new case pending before the court. He explained that the EMA is being insistent on this front because from its experience with the access to documents policy, it has seen "several times" that companies get "very annoyed" by some decisions of the EMA and threaten the agency with court action.

"But then, they perhaps consult with their senior management and then the senior management changes their mind [and no court case follows]… So [for disputes under the policy on publication of clinical trial data], we will wait patiently for a company's decision [on whether it agrees with the EMA's conclusions on what constitutes commercially confidential information] and if an interim relief application is filed, we will certainly not publish the relevant documents," he added.

Mr Marino was speaking at a webinar organized by the EMA on 24 June to help stakeholders anticipate the requirements of its policy on the publication of clinical data^1-3.The EMA intends to be ready to implement the policy by the end of April 2016.

The EMA's chief policy advisor, Noël Wathion, explained that in cases where interim relief is sought, the agency will hold back the publication of only the disputed information. If, for example, a company has 10 clinical study reports and there is no dispute regarding nine reports, then the EMA would publish the nine reports as agreed. The tenth report would also be published, but without the disputed portions. On top of this, the EMA would issue a note to inform the public that a part of the document was under dispute before the court and had, therefore, been redacted. The aim is to ensure that "there is full transparency and that we do not delay the publication of data that are not being disputed," said Mr Wathion.

Companies proposing to classify any clinical trial data as commercially confidential would have to justify their claim with product-specific information. The EMA's head of access to documents service, Anne-Sophie Henry-Eude, warned that if sufficient detail is not provided then such justifications would be deemed as either insufficient or irrelevant by the agency. General statements, such as "information is commercially confidential, competitively sensitive and includes intellectual property and trade secret information" or "disclosure of these elements will harm company's commercial interests because it may enable third party access to business-critical information" are not acceptable, Dr Henry-Eude explained.

The EMA is aware that redactions on the grounds of commercial confidentiality can become less justified over time (eg information deemed commercially confidential at present may get into public domain later on). However, the EMA will not reassess the redacted clinical reports once these are published. As the agency expects to publish around 14,000 reports per annum, it points out that conducting regular reviews of whether the commercial confidentiality clause is still justified is "unmanageable". For this reason, information that is once redacted from a report on ground of commercial confidentiality will not be reviewed and the redacted clinical reports would be left as such. Mr Wathion explained that anyone who disagrees with a redaction due to this reason, "will be referred to the possibilities offered under the access to documents scheme", where such requests would be handled on a case-by-case basis.

Five-step implementation

The policy on publication of clinical trial data will be implemented through a five-step process, which involves:

1) Companies submit two sets of clinical trial reports to the EMA – While one set would facilitate the scientific review process, the second set would be a redacted version that the company wants to be made public. The redacted version would contain the company's proposals on what information it thinks should be classified as commercially confidential. Also, it would contain proposals on protection of personal data.

The so-called redaction proposal can be submitted by a company any time between day 181 and day 220 of the marketing authorization procedure. This means, it can be submitted either 30 days before the EMA's drug evaluation committee, the CHMP, issues its opinion or within 10 days of the CHMP's opinion, Mr Wathion explained. In case a company withdraws its marketing authorization application, then the redaction proposal would have to be submitted within 30 calendar days.

In addition, companies will have to submit three additional documents: a declaration stating that the clinical reports submitted for scientific evaluation are the same as that submitted for publication (ie to be made public) with the exception of proposed redactions; a completed justification table for each of the proposed redactions pertaining to commercially confidential information; and an anonymization report explaining the approach used by a company to anonymize personal data.

Companies that do not submit the redaction proposal will receive three advanced warnings during the procedure for marketing authorization/extension of indications. Specifically, warnings will be issued with the validation letter, at the day 180 list of outstanding issues/with the request for supplementary information, and with the CHMP opinion letter. In case of withdrawn marketing authorization applications, two warnings will be issued – with the validation letter and with the withdrawal letter to the company.

2) Redaction consultation – After receiving a redaction proposal by a company, the EMA would initiate redaction consultation to ensure that only duly justified redactions of commercially confidential information are allowed. There will be only one round of consultation between the EMA and the company, "though there will be the possibility to have exchanges, to clarify issues… but of course it should not be a never-ending story… There will be only one round which will result in the EMA [issuing a] conclusion that companies can agree, disagree or partly agree upon," explains Mr Wathion.

To help companies comply with these requirements, the EMA is working on three guidance documents on: the submission of clinical reports intended for publication; redacting commercially confidential information in clinical reports; and the anonymization of clinical reports. The EMA is gathering feedback on these guidelines through targeted consultations with industry and the next meeting is due to take place on 6 July. The guidelines are expected to be finalized and published after the summer.

3) Publication – Based on the outcome of the redaction consultation, the company will be asked to update the proposed redacted documents to reflect the EMA's conclusions regarding commercially confidential information. The company would then be asked to submit a final redacted document for publication.

The EMA will publish the final redacted document only after the procedure has been finalized at the EU level, ie following the European Commission's decision to grant or refuse marketing authorization/extension of indication/line extension or following receipt of a letter from the company notifying the withdrawal of the application.

The final redacted clinical reports will be published within 60 calendar days of the commission's decision or within 150 calendar days of receiving a company's letter notifying the withdrawal of the application. This timeframe includes the 20 calendar days for a company to seek interim relief from the court if there is disagreement with the EMA.

Also, the European public assessment reports (EPARs) would be made available before the final redacted clinical reports are published so that the public is provided with the rationale for the scientific decision on an application. "It would not make sense to first publish the underlying scientific documents on which the [CHMP's opinion] was based and to then publish the rationale for the decision-making later on," said Mr Wathion.

4. Presentation of the redacted published clinical reports – The EMA will apply a watermark to the clinical reports prior to their publication. This will be done to emphasize the prohibition on the use of information in these reports for commercial purposes. The watermark will state: "This document cannot be used to support any marketing authorisation application and any extensions or variations thereof".

Among other things, the EMA has looked at multilingual aspects of the website on which these reports will be published. Due to the lack of resources, the agency has decided that the data protection notice, the terms of use, and the website navigation will be available in English only.

5. Management of external users – Persons wanting to access the redacted clinical reports would have to accept the terms of use. The EMA is creating tools to deal with user registration and user account management.

The EMA's policy on publishing clinical trial data was adopted by the agency's management board last year. It applies to new marketing authorization applications and Article 58 applications submitted under the EU centralized procedure after 1 January 2015. In the case of extension of indication applications and line extension applications for existing centrally authorized products, the policy will apply to submissions made after 1 July 2015.

The EMA will decide later this year the date by which the policy will also apply to other post-authorization applications for existing centrally-authorized products.

References

1. EMA press release, 29 June 2015, www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/06/news_detail_002356.jsp&mid=WC0b01ac058004d5c1

2. Current status of European Medicines Agency policy on publication of clinical data - Stakeholder webinar, 24 June 2015, www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2015/06/event_detail_001163.jsp&mid=WC0b01ac058004d5c3

3. Wait over for landmark EMA policy on trial data access, Scrip Regulatory Affairs, 3 October 2014