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Seltene Helden?

Orphan Drugs und Seltene Erkrankungen in Deutschland

10. IGES Innovationskongress

Europäische Gesetzgebung und Trends

18. Oktober 2013, Berlin

Dr. Alexander Natz

A. Allgemeiner Überblick: Aktuelle Gesetzgebungsverfahren

B. Der Schutz von “Commercially Confidential Information”

C. Bindungswirkung der Ausweisung als “Orphan Medicinal Product”

Übersicht

A. Allgemeiner Überblick: Aktuelle Gesetzgebungsverfahren

New legislation / delegated acts / impelmentation: • Transparency Directive (Amended COM proposal 20.03.2013)

• Clinical Trials Regulation (COM proposal 17.07.2012)

• Medical Devices / IVD regulations (COM proposals 26.09.2012)

• Horizon 2020 / Funding (COM proposal 30.11.2011)

• API Importation from third countries into the EU (deadline 02.07.2013)

• Delegated acts Unique Identifier (Falsified Med. Directive) (likely in 2014)

• Delegated / Implementing Acts und Fees Pharmacovigilance (02.07.2012)

• EU GDP Guideline (released 07.03.2013 / applicable 08.09.2013)

• Plus: Access to MA and CT Data via EMA/NCA/CT database; recast

Directive 2001/82/EC, EMA Fee Regulation, Variations Reg. (EC) 1234/2008

EU Regulations / Directives / Guidelines / Implementation 2013 - 2016

Intended changes by COM proposal:

• Transfer of ECJ case law (demand-side-related measures) – positive

• No mandatory EU list of national prices – welcomed

• HTA-procedures in scope of Directive – positive

• Results of MA (Q/S/E) shall not be questioned in P&R decision – welcomed

• Time limits for P&R decisions - positive

• Managed entry agreements remain confidential – welcomed

• Public procurement law (not Transp. Directive) governs tenders – positive

• No specific provision on personalized/stratified medicine – negative;

• No inclusion of medical devices – negative.

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Transparency Directive: EUCOPE Position

Transparency Directive: Orphan designation - no re-assessment at

national level

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Article 13(1) COM 2013 168

Additional proof of quality, safety, efficacy or bioequivalence

In the framework of pricing and reimbursement decisions, Member States shall

not re-assess the quality, safety, efficacy, bioequivalence or biosimiliarity of the

medicinal product or the criteria for orphan designation which have already

been assessed during the marketing authorisation procedure.

EUCOPE Position: This is welcomed;

However for consistency with other amendments to this article, it might be useful

to amend Article 2 (Definitions) to include the definition of orphan medicinal

products, as well as the definition of the criteria for orphan designation.

Transparency Directive: Proposed measures related to price transparency

• The Commission proposal did not establish the set up of a database for national

prices;

• However, MEPs tabled an amendment requesting more price transparency,

stating that competent authorities shall publish in an appropriate publication (…)

a complete list of medicinal products covered by their health insurance

systems, the prices of which have been fixed (…) with the prices which may

be charged for such products.

• In the course of the discussions, this request has been partly included in Recital

15a stating that the Commission and the Member States should (also) examine

how to continue to co-operate on the functioning of the EURIPID price

information database, which provides EU wide added value in terms of price

transparency.

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Transparency Directive: Commission statement on plans to set up a

price database

Industry Commissioner Tajani on 10 December 2012 on Parliamentary Question E-

009635/2012 from 22 October 2012:

“Setting up or maintaining a medicine price database falls outside the EU

competences (Article 168(7) TFEU) since it touches upon the substance of the

decisions regarding pricing of medicinal products and their inclusion in the scope of

health insurance systems“

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EUCOPE: the mid-sized companies perspective

EUCOPE represents

• 900+ mid-sized companies via the associations EMIG, BPI, BioDeutschland, SwedenBio, IML, PEF

• Board represents, inter alia, companies from Sweden, UK, Bulgaria, Italy, Greece, Germany, the Netherlands

• Companies represented, inter alia, B. Braun, SigmaTau, Ferring, Grifols, Norgine, Biogen Idec, Celgene, Alexion, InterMune, Biotest, BioMarin…

• Recognized stakeholder by EMA, European Commission and the European Parliament.

EUCOPE Positions

• http://www.eucope.org/en/positions/

EUCOPE general objectives (see: www.eucope.org)

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B. Der Schutz von “Commercially Confidential

Information”

Der Schutz von “Commercially Confidential Information”

I. Aktuelle Gesetzgebungsverfahren:

Vorschlag KOM VO Klinische Studien

Vorschlag KOM VO Medizinprodukte

II. Geplante EMA Verwaltungspraxis: Proaktive Veröffentlichung von

Studiendaten

III. Anhängige Gerichtsverfahren im Hinblick auf derzeitige

Rechtslage: VO 1049/2001 (InterMune / AbbVie Fälle)

IV. Selbstverpflichtung der Industrie (PhRMA-EFPIA Prinzipien)

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Commission Proposal for a Clinical Trials Regulation

Commission Proposal (emphases added):

Article 78 - EU database

1. The Commission shall set up and maintain a database at Union level (hereinafter,

the ‘EU database’). The Commission shall be considered controller of the database.

The EU database shall contain the data and information submitted in accordance

with this Regulation.

(…)

3. The EU database shall be publicly accessible unless, for all or parts of the data

and information contained therein, confidentiality is justified on any of the

following grounds:

– protecting personal data in accordance with Regulation (EC) No 45/2001;

– protecting commercially confidential information;

– ensuring effective supervision of the conduct of a clinical trial by Member States.

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Commission Proposal for a Clinical Trials Regulation

Tabled Amendments by MEPs (emphases added):

1. Recital 20a:

• “[…]For the purposes of this Regulation, in general the data included in

clinical study reports should not be considered commercially confidential

once a marketing authorisation has been granted or the decision-making

process on an application for marketing.”

2. Recital 25a (new)/Article 34(3)(1)/Annex IIIa

• The sponsor shall submit the full clinical study report within 30 days after

marketing authorisation has been granted or if the sponsor has decided not to

submit an application for marketing authorisation. Annex IIIa enlists the elements

of the “summary of the results of the clinical trial”, which includes, inter alia,

• “7. The protocol and its subsequent modifications.”

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Comission Proposal for a Medical Devices Regulation

Article 53 - Electronic system on clinical investigations (emphases added)

1. The Commission shall (…) set up and manage an electronic system to create

the single identification numbers for clinical investigations referred to in Article 51(1)

and to collate and process the following information:

(a) the registration of clinical investigations in accordance with Article 52;

(b) the exchange of information between the Member States and between them and

the Commission in accordance with Article 56;

(c) the information related to clinical investigations conducted in more than one

Member State in case of a single application in accordance with Article 58;

(d) reports on serious adverse events and device deficiencies referred to in Article

59(2) in case of a single application in accordance with Article 58.

(…)

3. The Commission shall be empowered to adopt delegated acts in accordance with

Article 89 determining which other information regarding clinical investigations

collated and processed in the electronic system shall be publicly accessible to

allow interoperability with the EU database for clinical trials on medicinal products for

human use set up by Regulation (EU) No […/…]. Article 52(3) and (4) shall apply.

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Commission Proposal for a Medical Devices Regulation

Tabled Amendments by MEPs (emphases added):

(…) The Commission shall also ensure that healthcare professionals have

access to the electronic system. The information referred to in points (d)

and (da) of Article 53 shall be accessible to the public in accordance

with Article 52(3) and (4).

2a. Upon a reasoned request, all information on a specific medical

device available in the electronic system shall be made accessible to

the party requesting it, save where the confidentiality of all or parts of the

information is justified in accordance with Article 52(3).

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EMA Draft Policy “Publication and access to clinical-trial Data”

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EMA Draft Policy Paper for Public Consultation “Publication and

access to clinical-trial Data” – Status Quo

• Currently disclosure of data only after request of third party

according to the provisions of Regulation 1049/2001

• In the future EMA intends to proactively disclose data to the public:

the draft policy includes three different levels of access, together with

corresponding conditions for publication and use, depending on the type

of data involved

• Draft policy published on 24 June 2013

• Stakeholders had until 30 September 2013 to submit their comments on

the Agency’s proposals

• The new policy shall (officially) enter into force as of 1 January 2014

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EMA Draft Policy Paper for Public Consultation “Publication and

access to clinical-trial Data” – EUCOPE Concerns

1. Definition of CCI

“For the purpose of the policy, CCI shall mean any information that is not in the public

domain or publicly available and where disclosure may undermine the legitimate

economic interest of the owner of the information. CCI falls broadly into two

categories: trade secrets (including formulas, programs, process or information

contained or embodied in a product, etc.) and commercial confidences.”

2. Scope of CCI identified by EMA so far

“CT data/documents containing CCI: a small number of CT data/documents can

contain CCI. This applies to information such as details of the investigational

medicinal product itself, some in vitro studies, or bioanalytical data characterising the

product (points 2.7.1, 5.3.1 and 5.3.2 of Annex I).”

3. Lack of Protection of CCI

“The Agency respects and will not divulge commercially confidential data or

information. In general, however, CT data cannot be considered CCI; the interests of

the public health outweigh considerations of CCI.”

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Pending Court Cases – Intermune/EMA & AbbVie/EMA - Overview

• InterMune and AbbVie challenged decisions of the EMA to disclose to

third parties, under EU public access to documents rules (Regulation

1049/2001), detailed pre-clinical, quality and clinical data

(InterMune) contained in the dossier supporting its successful

application for an EU marketing authorisation for their products.

• Decision on interim measures taken by the General Court on 25 April

2013, granting InterMune’s and AbbVie’s application for an interim

injunction preventing the EMA from releasing the contested

information pending the Court’s decision on the substantive

issues.

• EMA filed an appeal with the Court on July 5 which was heard on 14

October 2013.

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Pending Court Case – InterMune vs EMA – General Court’s view in the

decision on the interim measures, T-73/13 I

Rn 45: "... The EMA failed to make a detailed assessment of the

arguments and evidence submitted by the applicants about the

confidential nature of the information at issue before adopting the contested

decision, Nor did the EMA conduct the slightest weighing up in order to

determine whether there was a specific overriding public interest justifying

its disclosure. Instead, contrary to its earlier consistent decision-making

practice, the EMA applied an inflexible, purely mechanical policy

approach of complete disclosure of the disputed documents, on the basis

of an alleged automatic priority in favour of the general public interest in

transparency."

Rn 46: "... the EMA failed completely to address those detailed

arguments in the contested decision. The contested decision is thus

based on an inflexible policy favouring disclosure."

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Pending Court Case – InterMune vs EMA – General Court’s view in the

decision on the interim measures, T-73/13 II

Rn 52: "... This involves a question of principle affecting the functioning

of the pharmaceuticals and biotechnology sector in Europe and

worldwide..."

Rn 53: "... but rather requires an in-depth examination in the context of

the main proceedings. At that time, the Court, when it adjudicates upon the

substance, will have to examine, inter alia, the possible relevance for

resolving the dispute in the main proceedings of the case-law relied upon

by the applicants in order to justify the confidential treatment to be given to

the information at issue, namely Commission v Éditions Odile Jacob."

Rn 54: "... In any event, it is not obvious from the documents in the file

that, following that weighing up of interests, the balance will clearly be

in favour of the public interest defended by the EMA."

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Industry’s readiness to share data - Efpia/PhRMA Principles for

responsible Clinical Trial Data Sharing

• Commitment 1: Enhancing Data Sharing with Researchers

Anonymized patient-level data, study-level data, protocols, and complete clinical

study reports (CSRs);

Upon request from qualified researchers;

Researchers encouraged to publish results.

• Commitment 2: Enhancing Public Access to Clinical Study Information

Following approval in the US and EU;

Companies will post Clinical Study Report (CSR) synopses, at a minimum;

Full CSRs available to researchers under terms of Commitment 1.

• Commitment 3:Sharing Results with Patients who Participate in Clinical Trials

Provide factual summary of clinical trial results to research participants;

PhRMA and member companies will work with regulators to facilitate appropriate

communications to patients;

Ensure that summaries are not considered pre-approval promotion;

Explore appropriate communications mechanisms (e.g., through investigators,

web sites, and other means).

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EUCOPE Position on protection of Commercially Confidential Information

• It is generally acknowledged that clinical trial data may contain commercially

confidential information;

• Responsible public bodies including EMA carefully assess document by

document whether or not a piece of information must be considered commercially

confidential;

• The consultation of the marketing authorisation holder before disclosure

remains mandatory not only where third parties’ request access to this information

but also where the information is proactively disclosed by EMA;

• It is furthermore acknowledged that the disclosure of commercially confidential

information is not per se justified by an overriding public interest but that it has

to be decided on a case-by-case basis under participation of the marketing

authorisation holder whether the disclosure of commercially confidential data is

justified by an overriding public interest;

• No data will be disclosed before the grant of the marketing authorisation.

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C. Bindungswirkung der Ausweisung als

“Orphan Medicinal Product”

Superiority of EU Law over national

• The CJEU has held in the “Masterfoods Ltd. v. HB Ice Cream Ltd. et al”

decision that:

“It is also clear from the case-law of the Court that the Member States'

duty under Article 5 of the EC Treaty to take all appropriate measures,

whether general or particular, to ensure fulfilment of the obligations

arising from Community law and to abstain from any measure which

could jeopardise the attainment of the objectives of the Treaty is binding

on all the authorities of Member States ...”

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Price Regulation at National Level - Competency

Limits towards Member States‘ Competency on Price Regulation

• This principle holds true irrespectively of the competency of the Member States

to control their healthcare spending and regulate prices of medicinal products.

Article 168(7) TFEU provides the following:

“Union action shall respect the responsibilities of the Member States for the

definition of their health policy and for the organisation and delivery of health

services and medical care. The responsibilities of the Member States shall

include the management of health services and medical care and the allocation

of the resources assigned to them.“

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Restrictions on National Competency

• The CJEU recently reiterated this principle in case C-185/10

(Commission/Poland):

“It must be noted in that respect, first, that although EU law does not detract from

the power of the Member States to organise their social security systems and to

adopt, in particular, provisions intended to govern the consumption of

pharmaceutical products in order to promote the financial stability of their

healthcare insurance schemes, the Member States must, however, comply

with EU law in exercising that power (Joined Cases C-352/07 to C-356/07, C-

365/07 to C-367/07 and C-400/07 A. Menarini Industrie Farmaceutiche Riunite

and Others [2009] ECR I-2495, paragraphs 19 and 20).“

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EU decisions – Operative Part and Reasons

• Generally, only the operative part has a binding effect.

• An assessment of whether or not the criteria for an orphan designation

are fulfilled is not part of the operative part of the Commission’s decision.

• Nevertheless, the CJEU and the General Court have also decided on the

question whether the grounds of a decision can produce binding legal

effects. In a decision of 15 May 1997 the CJEU held that (emphasis

added):

“..., it should be stated that the operative part of an act is indissociably

linked to the statement of reasons for it, so that, when it has to be

interpreted, account must be taken of the reasons which led to its adoption.”

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EU decisions – Operative Part and Reasons

• Furthermore, in a judgement issued on 20 November 2002 (T-251/00)

the General Court stated that:

“Although the courts have consistently held that only the operative part

of an act is capable of producing binding legal effects and, thereby, of

having adverse effects, nevertheless the statement of the reasons for an

act is indispensable for determining the exact meaning of what is stated

in the operative part.”

• Accordingly, although it is only the operative part that is legally binding,

the extent of the binding effect has to be of the grounds that led to the

decision.

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EU decisions – Scope of the Commission’s decision

• The Commission’s decision to grant an orphan designation is based upon the

respective opinion of the Committee for Orphan Medicinal Products (COMP)

which examines any application.

• Article 3 (1) Regulation (EC) No 141/2000:

• To qualify for an orphan designation, a medicinal product:

must be intended for the treatment, prevention or diagnosis of a disease that

is life-threatening or chronically debilitating and the prevalence of the

condition in the EU must not be more than 5 in 10,000; or

that it is intended for the diagnosis, prevention or treatment of a life-

threatening, seriously debilitating or serious and chronic condition in the

Community and that without incentives it is unlikely that marketing of the

medicinal product would generate sufficient returns to justify the investment

needed for its development; and

no satisfactory method of diagnosis, prevention or treatment of the

condition concerned can be authorised, or, if such a method exists, the

medicine must be of significant benefit to those affected by the

condition.

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Binding Effect of Orphan Designation on Member States – Re-

Assessment by the EMA

• Re-Assessment of Criteria of Article 3 Regulation (EC) No 141/2000

foreseen in EU law

• The fact that the findings of the orphan designation cannot be challenged by

Member States‘ authorities alone is also established in Article 8(2) Regulation

(EC) No 141/2000.

• Article 8(2) Regulation (EC) No 141/2000 reads as follows:

• “This period may however be reduced to six years if, at the end of the fifth year, it

is established, in respect of the medicinal product concerned, that the criteria laid

down in Article 3 are no longer met, inter alia, where it is shown on the basis of

available evidence that the product is sufficiently profitable not to justify

maintenance of market exclusivity. To that end, a Member State shall inform

the Agency that the criterion on the basis of which market exclusivity was granted

may not be met and the Agency shall then initiate the procedure laid down in

Article 5. The sponsor shall provide the Agency with the information necessary

for that purpose.“

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Binding Effect of Orphan Designation on Member States – Re-

Assessment by the EMA

• Article 8(2) of Regulation (EC) No 141/2000 requires the Member State to

substantiate its doubts concerning the profitability of the product and submit

appropriate data to justify these doubts in order to initiate the procedure:

“The Member State in question should provide the rationale for its doubts and

include appropriate data justifying why at least one of the original designation

criteria of the orphan medicinal product concerned may no longer be met. In

preparing its information to the Agency, the Member State may use data which

supported the initial designation, held by the Agency.“

• The existence and detailed codification of this procedure under EU law

underlines that the Member States may not re-assess the findings of the

orphan designation on their own initiative.

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Summary

1. Member States are bound by the European Commission’s decision to designate a

medicinal product as an orphan medicinal product and may not question this decision or the

reasons on which the decision is based.

2. For legal reasons, it is not possible to artificially split indications in order to receive the

benefits of an orphan medicinal product marketing authorisation.

3. The German legislation followed the principle of precedence of EU law partly by

introducing individual provisions in the SGB V for orphan medicinal products with a yearly

turnover of less than EUR 50 million within the GKV. This necessary incentive could serve as an

example for other EU Member States as it is in compliance with binding provisions of EU law and

respects the orphan designation granted under Regulation (EC) No 141/2000.

4. For legal reasons this necessary incentive should be extended to all orphan medicinal

products rather than being reduced to a threshold of EUR 30 or EUR 25 million. Any

complete denial of an additional benefit of an orphan medicinal product authorised under EU law

in national pricing and reimbursement decisions is likely.

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Vielen Dank für Ihre Aufmerksamkeit

Dr. Alexander Natz, LL.M.

Director General

European Confederation of Pharmaceutical Entrepreneurs

(EUCOPE)

Rue d‘Arlon 50

1000 Brussels / Belgium

Tel.: 0032.2.290.8671

natz@eucope.org