Understanding how the eu clinical trials directive could have a feedback impact on the revision of the mdd dublin 2013

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Understanding how the eu clinical trials directive could have a feedback impact on the revision of the mdd dublin 2013

  1. 1. CLINICAL TRIALSDIRECTIVE(REVISION) IMPACTON MDD REVISIONClinical Evaluations andInvestigationsfor Medical Devices24 April 2013Erik Vollebregtwww.axonadvocaten.nl
  2. 2. Objectives today• Alignment agenda for medical devices regulation?• What can we see in the current proposals for clinical trial regulationand medical devices regulation?• Where is this taking us?2
  3. 3. Introduction• How might the new clinical regime for medical devices be influenced by that ofmedicines?• 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 controlledrandomized trials as default standard in Roth-Behrendt ENVI report asalways producing the most relevant results under any circumstance
  4. 4. Alignment?• MDR plans of alignment with well-established practice at Union level in pharmamay well conflict with practice at international level (e.g. GHTF / IMDRF, ISO)• “(21) The definitions in the field of medical devices, for example regardingeconomic operators, clinical investigations and vigilance, should be alignedwith well established practice at Union and international level in order toenhance legal certainty.”• “(47) The rules on clinical investigations should be in line with majorinternational guidance in this field, such as the international standard ISO14155:2011 on good clinical practice for clinical investigations of medicaldevices for human subjects and the most recent (2008) version of theWorld Medical Association Declaration of Helsinki on Ethical Principles forMedical Research Involving Human Subjects”Article 6 MDR proposal: Harmonised standards relating to among others clinicalinvestigation still provide presumption of conformity
  5. 5. Scope• “(51) This Regulation should only cover clinical investigations which pursueregulatory purposes laid down in this Regulation.”• Medicinal products clinical trial regulation covers any interventional trial inscope 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 approvalfor market access. Non-commercial clinical investigations that do notpursue a regulatory purpose are not covered by this Regulation.”• No harmonisation of rules for interventional devices trials not for regulatorypurposes
  6. 6. Definitons• Concept of „sponsor‟ is “introduced and aligned with the definition used in therecent Commissions Proposal for a Regulation of the European Parliament andof the Council on clinical trials on medicinal products for human use which aimsat repealing Directive 2001/20/EC20”• CTD 2 “(e) „sponsor‟: an individual, company, institution or organisationwhich takes responsibility for the initiation, management and/or financing ofa clinical trial;”• ISO 14155:2011 “3.40 sponsor: individual or organization takingresponsibility and liability for the initiation or implementation of a clinicalinvestigation”• Delta seems to be• Management• Liability• Implementation
  7. 7. Trial design• Article 50 (3) MDR prop: “Clinical investigations shall be designed andconducted in a way that the rights, safety and well-being of the subjectsparticipating in a clinical investigation are protected and that the clinical datagenerated in the clinical investigation are going to be reliable and robust.”• Annex XIV, 2.1 “shall include adequate number of observations to guaranteescientific validity”• Roth-Behrendt report for ENVI committee:• “(33) […] Clinical investigations for medical devices, where madecompulsory in accordance with this Regulation, shall include randomizedclinical investigations in the appropriate target population and well-controlled investigations.”• “Annex VI – Part II – paragraph 1 – point 1.11 “As randomized controlledinvestigations usually generate a higher level of evidence for clinicalefficacy and safety, the use of any other design or study has to be justified.Also the choice of the control intervention shall be justified. Bothjustifications shall be provided by independent experts with the necessaryqualifications and expertise.”
  8. 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 theirdevices”• MDR proposal: inconsistent language• Explanatory note 3.6: “performance of the clinical evaluation needed todemonstrate the safety and performance of their devices”• (34) „clinical investigation‟ means any systematic investigation in one ormore human subjects, undertaken to assess the safety or performance of adevice;• But:• Article 26 requires “summary of safety and clinical performance”
  9. 9. Clinical performance / efficacy?• FURTHERMORE developments in Parliament:• DRB report amendments says randomized controlled trials to prove clinicalefficacy and safety - the use of any other design or study has to be justified• “Performance should notably be understood broadly so as to encompassefficacy and benefit to the patient, which shall be checked in cases whereclinical investigations apply. This is crucial to ensure that devices aretechnically 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 shallbe performed on the basis of an appropriate plan of investigation reflectingthe latest scientific and technical knowledge and defined in such a way asto confirm or refute the technical performance of the device, the clinicalsafety and efficacy of the device when used for the intended purpose in thetarget population and in accordance with the instructions of use, and themanufacturers claims for the device as well as the safety, performanceand benefit/risk related aspects referred to in Article 50(1) »
  10. 10. Publicity of data / transparency• Clinical Trials Regulation proposal report ENVI:• “(20) In order to increase transparency in the area of clinical trials, clinicaltrial data submitted in support of a clinical trial application should be basedon clinical trials recorded in a publicly accessible database. Clinical trialdata based on clinical trials conducted before the date of application of thepresent Regulation should be registered in a public register which is aprimary or partnered registry of the international clinical trials registryplatform of the World Health Organisation.• “(20a) Clinical trial data should not be considered commercially confidentialonce a marketing authorisation has been obtained.”• Article 34 (3): “3. Within one year from the end of a clinical trial, the sponsorshall submit to the EU database the clinical study report, including a laysummary of the clinical trial.• Clinical study report (article 2 (30a): a report containing the full protocoland any subsequent modifications and dates thereof, a statistical analysisplan, summarised efficacy and safety data on all outcomes, and individualanonymised patient data in the form of tabulations or listings
  11. 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 confidentialinformation?• 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 alloutcomes, and individual anonymised patient data in the form oftabulations or listings
  12. 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 andhealthcare professionals to those parts of Eudameds electronic systemswhich provide key information on medical devices that may pose a risk topublic health and safety is essential. Where such access is limited, itshould be possible, upon a reasoned request, to disclose existinginformation for medical devices, unless the limitation of access is justifiedon grounds of confidentiality.”• What is a „reasonable request‟?• When is limitation of access justified on grounds of confidentiality?
  13. 13. Publicity of data / transparency• ENVI proposed Article 53 (2a): “Upon a reasoned request, all information on aspecific medical device available in the electronic system shall be madeaccessible to the party requesting it, save where the confidentiality of all orparts of the information is justified on any of the following grounds:(a) protection of personal data in accordance with Regulation (EC) No45/2001;(b) protection of commercially sensitive information;(c) effective supervision of the conduct of the clinical investigation by theMember State(s) concerned.• Article 60 (b): Commission can take implementing acts re the functioning of theelectronic system in article 53
  14. 14. Interoperability of Eudamed andEUDRACT?• “(48) […] To ensure synergies with the area of clinical trials on medicinalproducts, the electronic system on clinical investigations on medical devicesshould be interoperable with the future EU database to be set up in accordancewith the future Regulation on clinical trials on medicinal products for humanuse.”• 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 forclinical trials on medicinal products for human use set up in accordance withArticle […] of Regulation (EU) No […/…]. With the exception of the informationreferred to in Article 52 [summary of clinical investigation], the informationcollated and processed in the electronic system shall be accessible only to theMember States and to the Commission.• Article 60 (b): Commission can take implementing acts re the functioning of theelectronic system in article 53
  15. 15. Structuring• MDR proposal: “In line with the above-mentioned Commissions Proposal for aRegulation on clinical trials on medicinal products, also this proposal leaves itto the Member States to define the organisational set-up at national level forthe approval of clinical investigations. In other words, it moves away from alegally required dualism of two distinct bodies, i.e. a national competentauthority and an ethics committee.”• Both the rapporteur for the MDR and IVDR proposal comes right back with aseparate Ethical Committee proposal:• “The Commission proposal also mirrors the provisions of the proposedregulation on clinical trials in which the reference to ethics committees hasdisappeared. However, your rapporteur believes that clinical investigationsshould only start after having been granted a positive evaluation result byan independent ethics committee.”• Ethics Committees are also being put back in last Parliament rapporteursproposal for Clinical Trials Regulation
  16. 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 theclinical trials database (access levels)• But, caution:
  17. 17. Thanks for your attentionErik 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.comREAD MY BLOG:http://medicaldeviceslegal.com

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