Access to documents - the new approach of the European Medicines Agency
This article was originally published in SRA
Birgit Wolf, Elisabeth Fournier-Qezari, Marianne Koehne, Helene Thybo and Merete Schmiegelow discuss the EMA's new policy on disclosure and consider its implications for drug makers.
With the implementation of its access to documents policy in December 20101,2, the European Medicines Agency is able to provide wider public access than ever before to the documents it holds. Dossiers submitted by pharmaceutical companies for marketing authorisations can now be released upon request (reactive disclosure) after a regulatory decision is taken; proactive disclosure is planned in a second step. The new policy means that many documents that hitherto have only been accessible to the agency or to other regulatory bodies will in future be available to anyone who wants to see them.
This article aims to give an overview of the legislative setting and principles about disclosure, in particular regarding the marketing authorisation dossiers of authorised medicines. While there are basic provisions on access to documents held by the EU institutions in general, EU pharmaceutical legislation also provides some rules on release of information. In addition, there are prerequisites regarding the reliance on data for marketing authorisation applications in the pharmaceutical legislation. The possible regulatory implications are discussed, as is the recently released EMA guideline on what constitutes "commercially confidential information" and "personal data" in a drug marketing authorisation application3,4.
There are two aspects of the legislative framework that one should consider with regard to a regulatory perspective of disclosure of documents/information on medicinal products: the institutional/procedural provisions governing all EU institutions and bodies; and the provisions laid down in the pharmaceutical legislation.
The principles of the EMA policy on access to documents are laid down to Regulation (EC) No 1049/20015 regarding public access to European Parliament, Council and European Commission documents. This regulation grants a right of access to EU institution documents and aims to establish rules ensuring the exercise of this right and promote good administrative practices on access to documents.
One intention of the regulation (originating from the policy area of “Institutional affairs”) is to enable EU citizens to understand the way in which the EU and EU bodies function. According to Article 73 of Regulation (EC) No 726/20046 on the authorisation and supervision of medicines, this regulation on access to documents is also applicable to the EMA.
While Regulation (EC) No 1049/2001 is primarily about dealing with requests for public access to documents within a reasonable time (reactive disclosure), proactive disclosure (ie making documents directly accessible to the public in electronic form or through a register) is encouraged. Access is subject to some exceptions listed in Article 4 of Regulation (EC) No 1049/2001. Documents may therefore need to be redacted prior to release to, for example, protect personal data and commercial confidential information. However, there is an exception to the exceptions and a document can be released when there is an overriding public interest justifying disclosure. As regards third-party documents (in the context of the EMA policy on access to documents, this would relate to scientific data submitted by companies), the EU institutions, at least in case of doubt, “shall consult the third party with a view to assessing whether an exception is applicable”.
As mentioned above, Regulation (EC) No 1049/2001 applies to the EMA without giving further details on the type of documents. In addition, there are other legal obligations on the EMA and national competent authorities to actively publish information concerning authorisation and supervision on medicinal products. These are laid down in the pharmaceutical legislation (Directive 2001/83/EC7, Regulation (EC) No 726/2004 and related legislative pieces (eg the Paediatric Regulation8) and are, of course, somewhat different from the characteristics involved with the “access to documents" policy.
Well-known documents released in the context of these provisions include public assessment reports, scientific opinions and outcome of post-authorisation assessment (renewals, variations) as well as information on adverse reactions. With the new pharmacovigilance legislation9, there will be an increased level of transparency especially with regard to the communication of safety issues. Figure 1 shows that there is a continuous release of information from the EMA and/or national competent authorities throughout the drug development and lifecycle of a medicinal product, providing regular information on the status and outcome of the assessment.
EMA policy on access to documents
Prior to the implementation of the final EMA policy on access to documents, parts of marketing authorisation dossiers could already be released upon request. With the new policy, however, the scope of what can be released was notably extended.
The revised “output table”10 attached to the policy document, which lists the various documents concerned and gives details with regard to when and how access is granted, has been modified. A noteworthy change to the previous draft output table involves the access to documents submitted by applicants and marketing authorisation holders. These documents originated by pharmaceutical companies and submitted to the EMA for scientific evaluation can now be disclosed either on request or proactively after decision making.
This revision appears to have been triggered by a recent decision of the European Ombudsman11. Based on a complaint relating to a request to access documents held by EMA (in this case, clinical study reports as part of a marketing authorisation dossier), the ombudsman conducted an inspection. This resulted in the ombudsman’s decision that, in contrast to the (initial) interpretation of the EMA, the requested documents did not contain information that would undermine the commercial interest of the originator company and thus full access should be granted.
In accordance with Regulation (EC) No 1049/2001, the EMA policy anticipates that documents should be redacted before disclosure in order to protect information contained therein that cannot be disclosed (commercial confidential information or personal data). In view of the lack of a legal definition of “commercial confidential”, the EMA and the Heads of Medicines Agencies have defined it as “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”12.
Following the recommendations from the EMA to define a common approach for active publication and disclosure upon request, the EMA and HMA have now published, after a three-month period of public consultation from June to September 2011, a final guidance document on the identification of commercially confidential information (CCI) and protection of personal data (PPD) within the structure of the marketing authorisation dossier13. The intention is to have a common approach that will be applied by regulatory authorities in the European Economic Area, to identify which parts of a marketing authorisation dossier can or cannot be released in response to access to documents requests. The basic principles for application of the guidance are further laid down in a separate document14. It basically limits the scope of what regulatory authorities earlier have considered as CCI in a marketing authorisation dossier. For example, full clinical study reports and major parts of non-clinical reports including test data can be disclosed; redacting, as foreseen in Regulation (EC) No 1049/2001, will now merely refer to PPD (eg information on individual patients, staff) and to information on quality and manufacturing of a medicinal product plus some contractual arrangements between companies.
Possible regulatory implications
The pharmaceutical legislation defines several regulatory pathways for obtaining a marketing authorisation as summarised in Table 1.
The periods of data and market exclusivity from the initial authorisation of the reference product are defined in Article 10(1) of Directive 2001/83/EC and Article 14(11) of Regulation (EC) No 726/2004.
Often referred to as “8+2+1”, these periods relate to:
the eight years of data exclusivity after which a valid application for marketing authorisation, relying on the data of the reference product, can be submitted;
the ten-year period of market exclusivity from initial authorisation of the reference product after a medicinal product containing the same active substance which relies on the data of the reference product can be placed on the market; and
the additional year by which the ten-year period may be extended in case of authorisation of new therapeutic indications representing a significant clinical benefit in comparison with existing therapies during the first eight years since the initial marketing authorisation of the reference product.
The increasing amount of information included in the marketing authorisation dossiers of references products that now become available in the public domain might generate cases of improper use of non-clinical and clinical data of the originator medicinal product. Some of the regulatory pathways outlined in Table 1 might be misused to circumvent valid data protection rules.
This concern is underpinned by the commission view articulated in the Pharmaceutical Committee meeting summary record of March 200915. The commission called the attention of the committee to several issues of application of the pharmaceutical acquis (body of law), in particular:
With regard to reliance on non-clinical and clinical data contained in the dossier of a reference medicinal product under data protection, the commission representative explained “that, during the period of data protection of a medicinal product, the data contained in the pre-clinical and clinical file of that product cannot be relied on by other applicants or the authorities in the procedure to ascertain the safety and efficacy of other products which are shown to be bioequivalent, whether in the framework of Article 10 of Directive 2001/83/EC or under other procedures (Articles 8(3)or 10a). In such circumstances, the reliance by applicants or competent authorities on preclinical and clinical data contained in the dossier of that product within the EU or in third countries, obtained through access to documents or freedom of information legislation, to grant marketing authorisation to another product would lead to a circumvention of the data protection rules of Directive 2001//83/EC (or Regulation (EC) No 726/2004)”.
With regard to well-established use applications, the commission stressed “that authorisations under Article 10a of Directive 2001/83/EC should be based on the proper demonstration of the well known and wide use of the substance concerned, and it should be avoided that the use of Article 10a leads to a circumvention of data protection rules in the pharmaceutical acquis”.
With more and more data of the originator's marketing authorisation dossier being made available, there is a need to ensure a robust enforcement of the data protection established in the pharmaceutical legislation.
Indeed, it is critical to ensure that an application for marketing authorisation of a medicinal product containing a substance already authorised in the EU and relying on data of the originator can only be submitted when the data protection period established in the pharmaceutical acquis for the reference product has elapsed, independently of the regulatory pathway used.
In Chapter 1 of Volume 2A of the Notice to Applicants16, there is the following statement concerning well-established use applications: “assessment reports such as the EPAR for Community marketing authorisations which are made publicly available by competent authorities for reasons of transparency cannot be considered to supply sufficient information to meet the requirements of Annex I of Directive 2001/83/EC”. One might consider that is no longer sufficient considering the amount of information being disclosed on reference products.
As laid down in Regulation (EC) No 1049/2001, any person (without basically giving reasons why they want to have access and for what purpose) may request a document held by the EMA, eg a marketing authorisation dossier (or access it via a electronic register after the dossier has been proactively released by the agency). It should be highlighted that there may well be a considerable difference in intent and reason for request for access to documents between academic researchers or healthcare professionals who would like to view the data in context of their professional activities, and a person who is requesting data with the intention to use it in an unfair manner to support a marketing authorisation application. It remains to be seen how the new openness in the EU and the new approach regarding release of marketing authorisation dossiers will work in practice in a globalised world. Although this article focuses on the EU region, there is some likelihood that in non-International Conference on Harmonisation regions (ie outside the EU, the US and Japan) where there is a less strict adherence to regulatory rules and execution of data protection, non-innovators might obtain marketing authorisation based on the originator’s data released in the EU.
It is acknowledged that there are increased expectations from civil society with regard to openness and transparency. The intention to create a better understanding of the rationale of decisions relating to medicinal products, and thus increase the credibility of the regulatory process, is a meaningful driver of the new EMA approach.
However, with regard to the new approach of the EMA and the execution of Regulation (EC) No 1049/2001 in the highly competitive field of medicinal products, the need to have the right balance is fundamental. The data protection rules established in the pharmaceutical legislation, which comprise a legitimate relevance, have to be respected. In light of the revised EMA access to documents policy, a reinforcement of the statements made by the commission in March 2009 would truly be helpful to ensure a common approach in the EU.
In addition, the proactive release of high amounts of complex scientific data to the public may create another issue with regard to “overload of information” or misinterpretation of data released without any context. Therefore, any process or action to put the released data in this certain context to avoid misleading and potentially dangerous conclusions would be desirable, so that the increased transparency is in the end beneficial for civil society and especially patients.
The authors wrote this article in consultation with other members of RING, the Regulatory Intelligence Network Group whose creation as an industry forum in 2006 was prompted by the emergence of a new profession of regulatory intelligence specialists in the pharmaceutical industry. RING comprises representatives from some of the largest companies in the industry and aims to centralise non-confidential regulatory information. Its objective is to increase the efficiency and recognition of regulatory intelligence by sharing processes, practices and experience in non-product specific and non-confidential areas.
1. European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use), POLICY/0043, EMA/110196/2006, 30 November 2010, www.ema.europa.eu/docs/en_GB/document_library/Other/2010/11/WC500099473.pdf
2. EMA widens public access to drug information, Scrip Regulatory Affairs, 1 December 2010
3. HMA/EMA Guidance document on the identification of commercially confidential information and personal data within the structure of the marketing authorisation (MA) application – Release of information after the granting of a marketing authorisation, 27 March 2012, www.ema.europa.eu/docs/en_GB/document_library/Other/2012/03/WC500124536.pdf
4. EU-wide consensus on confidential commercial data in drug marketing applications, Scrip Regulatory Affairs, 28 March 2012
5. Regulation (EC) No 1049/2001 regarding public access to European Parliament, Council and Commission documents, 31 May 2001, OJ, L145, 43-48, www.europarl.europa.eu/RegData/PDF/r1049_en.pdf
6. 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, 30 April 2004, OJ, L136, 1-33, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0001:0033:en:PDF
7. Directive 2001/83/EC on the Community code relating to medicinal products for human use, 28 November 2001, OJ, L311, 67-128, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:311:0067:0128:en:PDF
8. Regulation (EC) No 1901/2006 on medicinal products for paediatric use, 27 December 2006, OJ, L378, 1-19, http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf
9. Directive 2010/84/EU on pharmacovigilance amending Directive 2001/83/EC on the Community code relating to medicinal products for human use,, 31 December 2010, OJ, L348, 74-99, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:0074:0099:EN:PDF and Commission Regulation (EU) No 1235/2010 amending, as regards pharmacovigilance of medicinal products for human use, 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, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products,
10. Output of the European Medicines Agency policy on access to documents related to medicinal products for human and veterinary use (EMA/127362/2006), www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/11/WC500099472.pdf
11. Case 2560/2007/BEH, Decision of the European Ombudsman closing his inquiry into complaint 2560/2007/BEH against the EMA, 24 November 2010, www.ombudsman.europa.eu/en/cases/summary.faces/en/5646/html.bookmark
12. HMA/EMA recommendations on transparency: Recommendations on release of information with regard to new applications for medicinal products before and after opinion or decision on granting of a marketing authorisation, EMA/484118/2010, November 2010, www.ema.europa.eu/docs/en_GB/document_library/Other/2010/12/WC500099536.pdf
13. See References 3 and 4
14. Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA Applications, 27 March 2012, www.ema.europa.eu/docs/en_GB/document_library/Other/2012/03/WC500124537.pdf
15. Pharmaceutical Committee Human – Summary record of the 65th meeting (PHARM 572), 16 March 2009, http://ec.europa.eu/health/files/pharmacos/docs/doc2009/2009_09/pharm_572%20_summary_record_16_march_2009_%20final_en.pdf
16. Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1 – Marketing Authorisation (updated version – November 2005), Brussels, ENTR/F2/BL D(2002), http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_2005-11_en.pdf
Birgit Wolf is global regulatory intelligence manager at Bayer Pharma AG, based in Germany. Elisabeth Fournier-Qezari is director, regulatory intelligence, Europe and other regions, at Sanofi, based in France. Marianne Köhne is head of the regulatory intelligence office at Boehringer Ingelheim GmbH in Germany. Helene Thybo is corporate regulatory intelligence specialist at Leo Pharma and Merete Schmiegelow is director, regulatory policies and intelligence at Novo Nordisk in Denmark. Contact email: email@example.com.