The European legislative framework is quickly moving towards transparency of the clinical trials data. The European Medicines Agency (EMA)’s Policy/0070, entered into force on January 1, 2015, marked a complete change of approach, moving from a reactive access, upon any interested parties’ request, to a proactive publication of the clinical trials data. This approach will be further straightened with the entry into force of Regulation (EU) No. 536/2014 on clinical trials (CT Regulation), expected in 2019, following the activation of the European portal and database. The purpose of ensuring the transparency of the clinical trials data has to be balanced with compelling interests, including, in particular, the protection of the commercially confidential information (CCI) of the sponsors. The criteria to identify what data shall be considered as CCI and what specific reasons might be given by sponsors to support a request for keeping certain data confidential are not clearly stated by the applicable regulations. Moreover, European case law has not discussed this issue in the merits yet and, thus, no clarifications have been provided so far. This article intends to trace the development of the EMA’s transparency policy, and make comparisons between the publication requirements under Policy/0070 and the CT Regulation, with particular regard to the issue of the protection of the sponsors’ CCI.
Med Access @ point care 2017; 1(1): e98 - e103
Article Type: REVIEW
- • Accepted on 03/10/2017
- • Available online on 09/11/2017
- • Published online on 10/11/2017
This article is available as full text PDF.
In October 2016, the European Medicines Agency (“EMA” or “Agency”) published the Clinical Study Reports (“CSRs”) related to 2 medicines, which were included in dossiers submitted to the EMA for the purpose of obtaining marketing authorization (1). This publication occurred pursuant to the EMA policy on the publication of clinical data for medicinal products for human use (“Policy/0070”), adopted by the EMA in 2014, which opened the new EMA’s approach to the transparency of clinical trial information: from a reactive access, upon any interested parties’ request, to a proactive publication of the information, which becomes accessible to everyone.
The new European policy on transparency grounds on an overturned approach to the confidentiality of clinical trial information: by considering them generally confidential, with the possibility of giving access to a third party on a case by case basis, to consider them generally public, except for certain types of information and for specific reasons.
This approach will be further reinforced with the entry into force of Regulation (EU) No. 536/2014 on clinical trials (“CT Regulation”), expected in 2019, following the activation of the European portal and database, where information on all clinical trials conducted in the European Union will be recorded and made available to the public.
Policy/0070 applies to all clinical data included in dossiers submitted to the EMA for the purpose of obtaining centralized marketing authorizations. They refer to all phases of trials performed to test the safety and efficacy of the medicinal products to be authorized.
CT Regulation applies to all clinical studies aimed at testing a medicinal product, which fulfils any of the following conditions: (i) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice; (ii) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or (iii) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects (2). Therefore, the transparency rules provided for by the CT Regulation apply to all data generated by the clinical trials as defined above, which coincide with interventional clinical trials. Observational studies are not included in the scope of the CT Regulation and thus, escape from the application of the relevant transparency rules.
The access to clinical trial data before the application of Policy/0070
Until the entrance into force of Policy/0070, on January 1, 2015, access to the documents held by the EMA was granted case by case by the Agency upon third parties’ request.
Regulation (EC) No. 726/2004 on the centralized authorization procedure clarified that Regulation (EC) No 1049/2001 on public access to European Parliament, Council, and Commission documents shall also apply to documents held by the EMA and that the Agency should adopt the arrangements for implementing such Regulation. In addition, it stated that “to ensure an appropriate level of transparency,” the EMA, in agreement with the Commission, “shall adopt rules to ensure the availability to the public of regulatory, scientific or technical information concerning the authorization or supervision of medicinal products which is not of a confidential nature” (Article 80).
On the basis of the above, the EMA adopted certain implementing rules in 2006, which classified the documents held by the EMA in public, restricted, or confidential, with corresponding different access regimes. In particular, a document whose disclosure would undermine the protection of, inter alia, commercial interests of a natural or legal person, including intellectual property, were classified as restricted.
The first change of approach was triggered by the policy on access to documents related to medicinal products for human and veterinary use issued by the EMA on November 30, 2010 (Policy/0043), on the basis of the principles established by the Regulation (EC) No. 1049/2001. Policy/0043 firstly states that: (i) “in principle, all documents of the EU Institutions and of the European decentralized bodies, such as the European Agencies, are accessible to the public”; and that however (ii) certain public and private interests, such as the privacy and integrity of the individual, or the commercial interests of a natural or legal person, shall be protected by way of exceptions in line with the provisions of Regulation (EC) No 1049/2001. The purpose of this Policy was to ensure that all documents originated, received, or possessed by the EMA were to be dealt to grant the widest possible access to the policies and activities falling under the EMA’s responsibilities.
Policy/0043 represents a first step towards transparency when compared to the previous EMA’s approach to the transparency of the documents submitted by sponsors, which were treated as presumptively confidential. This change was due to the recommendation of the European Ombudsman, issued following the compliances brought by the Nordic Cochrane Centre, after the EMA refused access to clinical study reports and corresponding trial protocols for 2 anti-obesity drugs. In this complaint to the Ombudsman, the Centre claimed that concerns for patients’ welfare should be given priority over concerns for the commercial interests of the drug industry. Upon investigations, the Ombudsman concluded that the documents did not fall within the commercial interests’ exception and, thus, the EMA should grant the access to any interested party (3).
From a reactive access to a proactive publication of clinical trials data under Policy/0070
Although Policy/0043 moved a significant step towards the transparency of the clinical trials information, stating the general principle that documents held by the EMA shall be considered as accessible to the public except for particular cases, the access to these documents was granted by the EMA only upon third parties’ request, on a reactive basis.
Policy/0070, adopted by the EMA on October 2, 2014 in accordance with Article 80 of Regulation (EC) No. 726/2004, marked a complete change of approach, establishing that information relating to clinical trials (and, in particular, the clinical study reports) are generally to be published on a proactive basis, since most of the information included therein are not confidential.
The new Policy/0070 applies to the clinical studies submitted to the EMA as part of a marketing authorization (MA) application after January 1, 2015, or as part of new indication or line extension applications relating to existing centrally authorized medicinal products after July 1, 2015. It was not intended to replace the existing Policy/0043, nor to limit in any way the application of the rights provided for by Regulation (EC) No. 1049/2001, which continues to apply to any request for access to documents held by the EMA that are not published pursuant to Policy/0070 (for instance, with respect to documents that do not fall within the scope of Policy/0070 as used to support an MA application filed before January 1, 2015).
Although it assumes that most of the information included in CSRs are not confidential, Policy/0070 recognizes that in a limited number of cases, CSRs may also include confidential information. Therefore, the interested party may ask EMA not to publish certain specific sections of CSRs, providing adequate justification for such redaction. One of the legitimate justifications not to publish certain information contained in the CSRs is the protection of the “commercially confidential information.”
Commercially confidential information (CCI) are defined in Policy/0070 as “any information contained in the clinical reports submitted to the Agency by the applicant/MAH that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant/MAH”. Therefore, applicants have to indicate the innovative content of the information they want to protect, and explain how the disclosure of such information could undermine their legitimate economic interest. The Policy does not actually help in the formulation of these justifications. It only provides some support in the identification of the items of the CSRs and the common technical document for the registration of pharmaceuticals that might be considered as CCI (see Annex 3 to the Policy).
To support the applicants in the redaction process, in March 2016 the EMA issued the External Guidance on the Implementation of the EMA Policy (“External Guidance”), which provides operative indications to identify the CCI (4). In particular, the EMA External Guidance clarifies which sections of the CSRs might contain CCI. This means that the applicant has to indicate what data included in those sections are to be considered confidential and explain accurately the reasons of such confidentiality. The External Guidance also describes in detail the redaction procedure: the final decision is under the EMA’s responsibility and the applicant is given a short term to ask the Court to suspend the effectiveness of such decision, if he/she disagrees on the EMA’s assessment. In such a case, the Agency limits the publication to non-disputed data.
In consideration of the above, it is essential that the applicant identifies the information that it wants to keep confidential at the time of submission to the EMA of the dossier for the marketing authorization for a medicinal product. Otherwise, the Agency will automatically argue that all the information contained in the CSRs can be published without the company having a real chance of opposing it.
According to Policy/0070, CSRs are published only when a final decision on the marketing authorization application has been taken by the EMA (or the request has been withdrawn by the applicant), in order to protect the Agency’s and the European Commission’s deliberations and decision-making process.
The implementation of Policy/0070 is planned in a stepwise manner: in a first phase, the publication of clinical data will relate to clinical reports only; in a second phase, it will also include the individual patients’ data (IPD). To that end, the EMA will have to find the most appropriate way to make IPD available in compliance with privacy and data protection laws and, to that end, a public consultation with stakeholders is planned.
Policy/0070 puts the EMA a step beyond other regulatory authorities and, in particular, the U.S. Food and Drug Administration (“FDA”) that does not release CSRs. In fact, the FDA currently treats CSRs as confidential commercial information, though in 2010 the FDA’s Transparency Task Force (established in 2009) found that the release of clinical trial results could be beneficial, and suggested that a “blanket policy against disclosure of this type of information may not be justified because there are significant public health benefits associated with the disclosure of this information, including reducing the costs and increasing the efficiency of research” (5). The transparency of clinical trials data continues to be a very debated issue in the US, as shown by an article recently published in the Journal of the American Medical Association by 2 researchers of Johns Hopkins Bloomberg School of Public Health, who called on the FDA to follow the EMA in proactively publishing CSRs, saying that the FDA’s position as the global leader in drug regulation “may be undermined” if it is not able to match the EMA’s efforts (6).
The publication of clinical trials data under the CT Regulation on clinical trials
The CT Regulation has made the transparency of the clinical trials one of its fundamental principles. This is because the European institutions have realized that, in the interest of public health and advancement in the pharmaceutical field, the scientific community needs access to the greatest possible amount of information concerning the clinical trials, including those submitted to support marketing authorization requests then rejected by the Commission or withdrawn by the party concerned.
With the establishment of the European database, all trials conducted in Europe will be recorded and made accessible to all European citizens. In particular, Article 80 and 81 give the EMA the responsibility to establish an EU Portal and Database. The EU Portal will be a single entry point for the submission of data and information relating to clinical trials required by the Regulation. The EU Database will contain all data and information submitted via the EU Portal. All clinical trials should be registered in the EU Database prior to being started.
Considering the strategic importance of the EU Portal and Database, the entry into the application of the entire CT Regulation is made dependent on their full functionality, which will be confirmed by an independent audit. EMA, together with the Member States and the Commission, are currently working in order to set up the Portal and the Database, whose finalization is expected in 2019.
According to the CT Regulation, all information in the EU Database “should be public, unless specific reasons require that a piece of information should not be published” (Recital 67). In particular, the Recital 67 states that, in order to ensure a sufficient level of transparency in the clinical trials, “the EU database should be publicly accessible and data should be presented in an easily searchable format, with related data and documents linked together by the EU trial number and with hyperlinks, for example linking together the summary, the layperson’s summary, the protocol and the clinical study report of one clinical trial, as well as linking to data from other clinical trials which used the same investigational medicinal product.” Moreover, as a rule, the start and end dates of the recruitment of subjects also should be published in the EU Database.
As with the previous regulations and policies, the CT Regulation also provides that publication of certain information can be avoided when their confidentiality can be justified on the basis of any of grounds listed below:
Protection of CCI;
Protection of personal data;
Protection of confidential communication between the Member States in relation to the preparation of the assessment report; and
Ensuring effective supervision of the conduct of the clinical trial by Member States.
With regard to the first ground, above, the protection of CCI, CT Regulation does not offer any definition or explanation on what CCI means. Therefore, it can be argued that the explanations provided for by the External Guidance can also apply to this case. Moreover, some significant indications come from the list of what is not CCI under the CT Regulation (Recital 68):
CSRs (only once the procedure for granting the marketing authorization has been completed or the application has been withdrawn);
the main characteristics of a clinical trial;
the conclusion of the assessment report (on Part I) for the authorization of a clinical trial and the decision on the authorization of a clinical trial;
the substantial modification of a clinical trial; and
the clinical trial results including reasons for temporary halt and early termination.
From the list above, it is clear that most of the information concerning clinical trials shall be considered to be, in principle, not confidential and can be published (with certain time constraints). However, considering the “legitimate economic interests of sponsors,” that the CT Regulation expressly recognizes (Recital 67), some of such information could be redacted on the basis of a case by case assessment.
In addition, another piece of legislation might help the stakeholders to identify the CCI: the new Directive No. 943/2016 on the protection of undisclosed know-how and business information against their unlawful acquisition, use and disclosure (Trade Secrets Directive), which will have to be implemented by the Member States by June 2018. Under this Directive, “commercial secrets” should include, at least in general terms, data on clinical trials, as they are attributable to the category of “technology information” and “know-how” set out in the recitals of the Directive, provided that they meet the following confidentiality requirements: (i) secrecy, in the sense that information is not generally known or easily accessible; (ii) commercial value deriving from their secrecy; and (iii) protection by measures that are appropriate to maintain secrecy. Therefore, if these requirements are not satisfied, the relevant data will be unlikely to be considered as confidential.
However, even if these requirements are met, certain data might not be considered confidential, since the reasons for maintaining confidentiality need to be “balanced” with other compelling interests. In fact, as Recital 11 clarifies, the Directive should not affect the application of EU or national rules that require the disclosure of information, including trade secrets, to the public or to public authorities. Nor should it affect the application of rules that allow or require any disclosure by public authorities of relevant information to the public, including, in particular, rules on the disclosure by the EU institutions and bodies or national public authorities of business-related information they hold pursuant to Regulation (EC) No. 1049/2001 or pursuant to other rules on public access to documents or on the transparency obligations of national public authorities.
Policy/0070 and CT Regulation have the common purpose to enhance the transparency of clinical trials in Europe, but they follow different paths. Therefore, they have a different scope of application.
The main differences between the publication made under Policy/0070 and the CT Regulation are highlighted in
Main differences between Policy/0070 and CT Regulation
|CSRs = Clinical Study Reports; CT = clinical trials.|
|Scope||Trials supporting a centralized authorization application, an Article 58 procedure (5), a line extension or new indication, regardless of where the study was conducted||All trials conducted in the EU (6) (and pediatric trials conducted outside the EU that are part of pediatric investigation plans)|
|Content||Clinical overview Clinical Summary CSRs Anonymization Report||All information generated during the life cycle of a clinical trial (e.g., protocol, assessment and decision on trial conduct, summary of trial results including a lay summary, study reports, inspections, etc.) with the exceptions described above|
|Timing||Data are published only after the conclusion of the authorization procedure (or the withdrawal of the application)||Data to support the request for authorization to conduct the trial: after the granting of such authorization|
|Information concerning the performance of the trial (e.g., amendments, inspections, etc.): during the conduction of the trial|
|Summary of the results and lay person summary: within 1 year from the end of the clinical trial|
|CSRs: only after the conclusion of the marketing authorization procedure (or the withdrawal of the application)|
The absence of clarifications from the case law on the limits to the publication
Since the adoption of Policy/0043 in 2010, several pharmaceutical companies have successfully objected to the EMA’s decisions to disclose their clinical reports upon third parties’ request. In all cases, the General Court ordered interim measures suspending the EMA’s decisions in order to prevent “serious and irreparable harm” to the applicants’ interests (7). During these disputes, the General Court stated that the balance between the public health interest that pushes toward transparency and the private commercial interest that needs confidentiality is not so “obvious” and disclosure requires a delicate assessment of the interests involved. However, in 2 cases (8), the Court of Justice (on appeal) overturned the injunctions and referred the cases back to the General Court to examine the possibility of a partial disclosure of the documents, stating that the companies had to explain “with a sufficient degree of probability” the likelihood of “serious and irreparable damage” caused by disclosure. Later, both proceedings were discontinued upon the applicants’ request; thus, no further rulings were issued by the General Court (9).
In all these cases, there were no decisions on the merits of the European courts, since these disputes were mainly resolved by negotiation and, thus, European case law has not yet provided any substantial clarifications on the interpretation of “commercially confidential information” and the scope of the relevant protection.
In particular, in the last case, by order dated March 1, 2017, the Vice-President of the Court of Justice of the European Union dismissed 2 appeals by the EMA against interim orders of the President of the General Court, thus upholding the suspension of the release of documents concerning the main clinical study report, which was included in the marketing authorization application dossier for Translarna marketed by PTC Therapeutics (PTC), requested by third parties under Regulation (EC) No 1049/2001. PTC requested that the report at issue be treated as confidential in its entirety. Nonetheless, that request was rejected by the EMA, which granted the third party applicant access to the entire report, subject to certain redactions made of its own initiative.
On July 20, 2016, the President of the General Court ordered that the operation of the decision at issue be suspended and that the EMA was not to disclose the report, stating that: (i) it was not obvious that the report at issue, taken as a whole, was not confidential; (ii) the balance of the interests in this case was in favor of granting the interim measures, since the public interest in transparency raised by the EMA was sufficiently satisfied, pending a ruling on the substance, by publication of the summary of the characteristics of Translarna, the patient information leaflet and the European public assessment report; and (iii) having regard to the harm that disclosure of the report at issue would cause PTC, the condition relating to urgency was also met. The EMA’s appeal against this decision was rejected by the Vice-President of the Court of Justice, who confirmed the existence of the grounds to grant the interim measures.
We will see whether this last case will eventually be examined in the merits and, in this case, whether the European Court will deal with the matter of confidentiality in a systematic way, providing guidance on what information is to be considered commercially confidential. Such a precedent would be very interesting for pharmaceutical companies and for the EMA itself, not only for the management of access requests under the previous legislation, but also for the evaluation of requests not to publish certain information contained in CSRs in accordance with Policy/0070 (and, in future, the CT Regulation).
EMA Policy/0070 and the CT Regulation follow the same path toward the transparency of the information connected to the performance of clinical trials. Their scope and purpose are not completely coincidental, and thus, certain clinical trials can escape from the application of the CT Regulation and be included in the scope of Policy/0070 and vice versa. However, most clinical trials conducted in Europe will be subject to both Policy/0070 and the CT Regulation. In these cases, there will be a duplicity of publication requirements and the same data could be published both on the EMA website and in the EU Database. Therefore, rules on the coordination of these databases are expected.
In addition, the European legislative framework described above suffers from the lack of a grounded interpretation of what CCI means, and thus, what can be published and what is to be redacted to protect the sponsors’ economic interests. European case law did not provide any significant indication on this, since no dispute has been discussed in the merits yet. However, some basic principles and guidelines can be learned by the few available decisions, such as: (i) the fundamental role of the balance between compelling interests (i.e., public health interest laying beyond transparency and private commercial interest) carried out by the EMA on first instance, and then, eventually, by the courts; (ii) the circumstance that the outcome of such balance is not obvious since all the circumstances of each case shall be carefully assessed; and thus (iii) the need for private companies to be as specific and concrete as possible in describing the grounds of any request to keep information confidential and in explaining what serious and irreparable damage could be caused by their disclosure.
While waiting for clarifications from case law, the EMA and the pharmaceutical companies are gaining experience on how to deal with the publication requirements and the requests for redaction. Any experience matured on the application of the Regulation (EC) No. 1049/2001 and the Policies/0043 and 0070 will obviously help to define the limits of the publication of the clinical trial information and to guide any future assessment of the confidentiality requirements under the CT Regulation.
A further element of uncertainty is represented by the future exit of the UK from the European Union (“Brexit”). As a consequence, starting from March 30, 2019, all EU primary and secondary law will cease to apply to the UK. This will have a significant impact on the clinical trials conducted in the UK, which will not be subject to the rules provided for by the CT Regulation. In particular, the UK will not be included in the unified system for submitting the requests for authorization to conduct clinical trials through the EU Portal (and, thus, any sponsor will have to submit a specific request to the UK authorities) and the relevant data will not be collected and published in the EU Database. However, conversely, data generated by clinical trials conducted in the UK will be subject to the transparency regime under Policy/0070, if they are included in a dossier submitted to the EMA to support a request for centralized marketing authorization. In any event, whether and to what extent the EU law will continue to be applicable or recognized in the UK after Brexit is subject to the ongoing negotiations between the UK and the EU institutions.
Regulation No. 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, Article 2. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf.Accessed October 10, 2017.
External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use, March 2, 2016, EMA/90915/2016. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/03/WC500202621.pdf.Accessed October 10, 2017.
See Abbvie v EMA, ( http://curia.europa.eu/juris/document/document.jsf;jsessionid=9ea7d2dc30d64347c18091a74c699a84b94769de3f12.e34KaxiLc3qMb40Rch0SaxyMaNv0?text=&docid=137241&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=793385);InterMune UK v EMA, Case T-73/13 ( http://curia.europa.eu/juris/document/document.jsf?text=&docid=137242&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=793905); Pari Pharma v EMA, Case T-235/15 ( http://curia.europa.eu/juris/document/document.jsf?text=&docid=178661&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=794040);PTC Therapeutics International v. EMA, Cases T-718/15 ( http://curia.europa.eu/juris/document/document.jsf?text=&docid=181921&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=794230) and C-513/16 ( http://curia.europa.eu/juris/document/document.jsf?text=&docid=188741&pageIndex=0&doclang=en&mode=lst&dir=&occ=first&part=1&cid=529349); Novartis Europharm v European Commission, Case T-269/15 ( http://curia.europa.eu/juris/document/document.jsf?text=&docid=179284&pageIndex=0&doclang=EN&mode=req&dir=&occ=first&part=1&cid=794561). All accessed October 10, 2017.