CLINICAL TRIALS DIRECTIVE (REVISION) IMPACT ON MDD REVISION

Clinical Evaluations and Investigations for Medical Devices24 April 2013

Erik Vollebregtwww.axonadvocaten.nl

Objectives today

• Alignment agenda for medical devices regulation?

• What can we see in the current proposals for clinical trial regulation and medical devices

regulation?

• Where is this taking us?

2

Introduction

• How might the new clinical regime for medical devices be influenced by that of medicines?

• Revision of MDD and of Clinical Trial Directive take place simultaneously

• MDR proposal borrows inconsistently from ICH 1996

• Call for “pharma-style” PMA has also led to adopting of controlled randomized trials as default standard in Roth-Behrendt ENVI report as always producing the most relevant results under any circumstance

Alignment?

• MDR plans of alignment with well-established practice at Union level in pharma may well conflict with practice at international level (e.g. GHTF / IMDRF, ISO)

• “(21) The definitions in the field of medical devices, for example regarding economic operators, clinical investigations and vigilance, should be aligned with well established practice at Union and international level in order to enhance legal certainty.”

• “(47) The rules on clinical investigations should be in line with major international guidance in this field, such as the international standard ISO 14155:2011 on good clinical practice for clinical investigations of medical devices for human subjects and the most recent (2008) version of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects”

Article 6 MDR proposal: Harmonised standards relating to among others clinical investigation still provide presumption of conformity

Scope

• “(51) This Regulation should only cover clinical investigations which pursue regulatory purposes laid down in this Regulation.”

• Medicinal products clinical trial regulation covers any interventional trial in scope of definition of clinical trial (art. 1 (1) and 2 (a))

• What will “regulatory purposes” mean?

• Explanatory note 3.6: “i.e. for obtaining or confirming regulatory approval for market access. Non-commercial clinical investigations that do not pursue a regulatory purpose are not covered by this Regulation.”

• No harmonisation of rules for interventional devices trials not for regulatory purposes

Definitons

• Concept of ‘sponsor’ is “introduced and aligned with the definition used in the recent Commission's Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use which aims at repealing Directive 2001/20/EC20”

• CTD 2 “(e) ‘sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial;”

• ISO 14155:2011 “3.40 sponsor: individual or organization taking responsibility and liability for the initiation or implementation of a clinical investigation”

• Delta seems to be

• Management• Liability• Implementation

Trial design

• Article 50 (3) MDR prop: “Clinical investigations shall be designed and conducted in a way that the rights, safety and well-being of the subjects participating in a clinical investigation are protected and that the clinical data generated in the clinical investigation are going to be reliable and robust.”

• Annex XIV, 2.1 “shall include adequate number of observations to guarantee scientific validity”

• Roth-Behrendt report for ENVI committee:

• “(33) […] Clinical investigations for medical devices, where made compulsory in accordance with this Regulation, shall include randomized clinical investigations in the appropriate target population and well-controlled investigations.”

• “Annex VI – Part II – paragraph 1 – point 1.11 “As randomized controlled investigations usually generate a higher level of evidence for clinical efficacy and safety, the use of any other design or study has to be justified. Also the choice of the control intervention shall be justified. Both justifications shall be provided by independent experts with the necessary qualifications and expertise.”

Clinical performance / efficacy?

• Medicinal products trials in CTD: “ascertaining its (their) safety and/or efficacy”

• MDR proposal [currently]: “demonstrate the safety and performance of their devices”

• MDR proposal: inconsistent language

• Explanatory note 3.6: “performance of the clinical evaluation needed to demonstrate the safety and performance of their devices”

• (34) ‘clinical investigation’ means any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a device;

• But:

• Article 26 requires “summary of safety and clinical performance”

Clinical performance / efficacy?• FURTHERMORE developments in Parliament:

• DRB report amendments says randomized controlled trials to prove clinical efficacy and safety - the use of any other design or study has to be justified

• “Performance should notably be understood broadly so as to encompass efficacy and benefit to the patient, which shall be checked in cases where clinical investigations apply. This is crucial to ensure that devices are technically achieving the aim for which they were designed and produced, but also bring benefit to the patient and are efficient when used in real-life.”

• ” Annex XIV – Part I – paragraph 2 – point 2.1. “Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the technical performance of the device, the clinical safety and efficacy of the device when used for the intended purpose in the target population and in accordance with the instructions of use, and the manufacturer's claims for the device as well as the safety, performance and benefit/risk related aspects referred to in Article 50(1) »   

Publicity of data / transparency• Clinical Trials Regulation proposal report ENVI:

• “(20) In order to increase transparency in the area of clinical trials, clinical trial data submitted in support of a clinical trial application should be based on clinical trials recorded in a publicly accessible database. Clinical trial data based on clinical trials conducted before the date of application of the present Regulation should be registered in a public register which is a primary or partnered registry of the international clinical trials registry platform of the World Health Organisation.

• “(20a) Clinical trial data should not be considered commercially confidential once a marketing authorisation has been obtained.”

• Article 34 (3): “3. Within one year from the end of a clinical trial, the sponsor shall submit to the EU database the clinical study report, including a lay summary of the clinical trial.

• Clinical study report (article 2 (30a): a report containing the full protocol and any subsequent modifications and dates thereof, a statistical analysis plan, summarised efficacy and safety data on all outcomes, and individual anonymised patient data in the form of tabulations or listings

Publicity of data / transparency

• So: two developments in medicinal products regulation proposal

• Clinical data not commercially confidential after market access

• How will that work? Automatically in the public domain?• What about article 39 TRIPS on protection of company confidential

information?

• Publication of clinical study report in public database

• i.e. full protocol and any subsequent modifications and dates thereof, a statistical analysis plan, summarised efficacy and safety data on all outcomes, and individual anonymised patient data in the form of tabulations or listings

Publicity of data / transparency

• Article 53 on clinical trials database for medical devices trials

• Amendment to (37): “Adequate levels of access for the public and healthcare professionals to those parts of Eudamed's electronic systems which provide key information on medical devices that may pose a risk to public health and safety is essential. Where such access is limited, it should be possible, upon a reasoned request, to disclose existing information for medical devices, unless the limitation of access is justified on grounds of confidentiality.”

• What is a ‘reasonable request’?

• When is limitation of access justified on grounds of confidentiality?

Publicity of data / transparency

• ENVI proposed Article 53 (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 on any of the following grounds:

(a) protection of personal data in accordance with Regulation (EC) No 45/2001;(b) protection of commercially sensitive information;(c) effective supervision of the conduct of the clinical investigation by the Member State(s) concerned.

• Article 60 (b): Commission can take implementing acts re the functioning of the electronic system in article 53

Interoperability of Eudamed and EUDRACT?• “(48) […] To ensure synergies with the area of clinical trials on medicinal

products, the electronic system on clinical investigations on medical devices should be interoperable with the future EU database to be set up in accordance with the future Regulation on clinical trials on medicinal products for human use.”

• Article 53 (2): When setting up the electronic system referred in paragraph 1, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article […] of Regulation (EU) No […/…]. With the exception of the information referred to in Article 52 [summary of clinical investigation], the information collated and processed in the electronic system shall be accessible only to the Member States and to the Commission.

• Article 60 (b): Commission can take implementing acts re the functioning of the electronic system in article 53

Structuring

• MDR proposal: “In line with the above-mentioned Commission's Proposal for a Regulation on clinical trials on medicinal products, also this proposal leaves it to the Member States to define the organisational set-up at national level for the approval of clinical investigations. In other words, it moves away from a legally required dualism of two distinct bodies, i.e. a national competent authority and an ethics committee.”

• Both the rapporteur for the MDR and IVDR proposal comes right back with a separate Ethical Committee proposal:

• “The Commission proposal also mirrors the provisions of the proposed regulation on clinical trials in which the reference to ethics committees has disappeared. However, your rapporteur believes that clinical investigations should only start after having been granted a positive evaluation result by an independent ethics committee.”

• Ethics Committees are also being put back in last Parliament rapporteurs proposal for Clinical Trials Regulation

Devil is in the details

• Significant spill over happening

• A lot of possible spill-over can still happen

• the medical devices regulation is not final yet• Commission can take implementing acts regarding whatever will go in the

clinical trials database (access levels)

• But, caution:

Thanks for your attention

Erik VollebregtAxon LawyersPiet Heinkade 1831019 HC AmsterdamT +31 88 650 6500F +31 88 650 6555M +31 6 47 180 683E erik.vollebregt@axonlawyers.com @meddevlegalB http://medicaldeviceslegal.com

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