presentation on Understanding how the EU Clinical Trials Directive could have a feedback impact on the revision of the MDD

1. CLINICAL TRIALS
DIRECTIVE
(REVISION) IMPACT
ON MDD REVISION
Clinical Evaluations and
Investigations
for Medical Devices
24 April 2013
Erik Vollebregt
www.axonadvocaten.nl

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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.”

8. 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”

9. 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) »

10. 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

11. 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

12. 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?

13. 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

14. 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

15. 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

16. 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:

17. Thanks for your attention
Erik Vollebregt
Axon Lawyers
Piet Heinkade 183
1019 HC Amsterdam
T +31 88 650 6500
F +31 88 650 6555
M +31 6 47 180 683
E erik.vollebregt@axonlawyers.com
@meddevlegal
B http://medicaldeviceslegal.com
READ MY BLOG:
http://medicaldeviceslegal.com