1. Regulatory Pathway/ Clinical Development of Medical Devices Sudhakar Bangera MBBS, MD, MMedSc Chief Operating Officer & Program Director Clinical Development Services Agency sudhakarbangera.cdsa@thsti.res.in

2. This presentation reflects the views of the author and should not be construed to represent Government of India’s views or policies Disclaimer

3. Introduction ‘Make in India’ campaign of Hon’ble Prime Minister Narendra Modi’s government has a mandate to boost the medical device manufacturing sector in India for all types of medical devices and equipment used in manufacturing of pharmaceuticals To implement the initiative a Task Force was constituted under the chairmanship of the Secretary, Department of Pharmaceuticals (DoP) to address issues relating to the promotion of domestic production of high end medical devices and pharmaceutical manufacturing equipment in the country

4. Recommendations of the Task Force on the Medical Devices Sector In India – 2015 Facilities for efficacy and safety testing 1.Medical device testing centers should be set up preferably in the PPP mode -Common medical device testing facilities can be set up by government in major medical device manufacturing hubs to facilitate testing/ evaluation of medical devices. Recurring expense can be borne by the industry 2.Designate “Centers of Excellence” (CoE) for supporting product development and validation -2.1. These centers having existing requisite facilities and expertise for different categories of medical devices (Example: DeitY, BIS, IIT- M, IIT-D, IISc-B, CIPET, DRDO) -2.2. They would support: Product development – design and prototyping Validation and certification of the medical use of devices Adopt, implement and advocate policies on efficacy and safety testing 3.Strengthen a made in India marking (BIS) specific to Medical devices in line with international standards like CE and FDA Where are the Clinical Development guys? Evaluation means? Device testing for stability, plastic mold, shape, electricity flow? What about Regulators?

5. Recommendations of the Task Force on the Medical Devices Sector In India - 2015 Medical devices should be treated distinctly from drugs and a separate chapter for medical devices should be made in the existing Drugs & Cosmetics Act A distinct regulatory pathway to be created for clinical trials of Medical devices -It should not be same as those for drugs. Formulation of a risk based regulatory system for medical devices based on justified regulatory control mechanisms -A risk based classification of medical devices into different categories based on safety and usage in Humans would permit requisite regulation while avoiding unnecessary hindrance to growth in the sector More stringent regulation for high risk devices, regulation of medium risk devices by notified bodies and self-regulation and conformance to standards for lowest risk category of medical devices What about drug eluding stents? Who decides what is High or Low risk?

6. Recommendations of the Task Force on the Medical Devices Sector In India - 2015 A policy on safety, efficacy and adverse reaction reporting based on international quality standards -Should be defined in consultation with concerned bodies like BIS and National Health Systems Resource Centre (NHSRC) Is BIS for Efficacy testing?

7. Traditional differences between Medical Device and Drug clinical studies

8. Clinical Development Clinical development of a new medical device is normally conducted in two phases: -Pilot Goal is to establish medical device safety and to assist in design of the pivotal trial Generally limited to less than 100 patients at one or two sites -Pivotal studies After establishing that the medical device is safe in this pilot group of patients, the pivotal trial is conducted to generate data to demonstrate that the medical device is safe and effective, for a defined intended use, within a certain patient population

9. US & EU Clinical Data Requirements for Medical Devices – Differences

10. U.S. Clinical Data Requirements for Medical Devices Class I, IIa, and IIb (Low- to medium-risk devices), to rely on a literature review and/or clinical experience to support the device’s intended use Class III (High-risk) medical devices that pose a significant risk of illness or injury will require a premarket approval application (PMA) submission (21 CFR 814), which will include clinical data to support medical device claims.

11. U.S. Clinical Data Requirements for Medical Devices FDA requires clinical data to support intended use statements and marketing claims for some class II medical devices that require a 510(k) premarket notification submission, rather than a PMA In either case, if the FDA determines that your device is not exempt, you will need to apply for and receive an IDE (Investigational Device Exemption) before beginning any clinical studies For first-in-class medical devices, where there is limited data regarding short or long-term outcomes, the FDA pivotal trial would be a prospective, randomized controlled study, adequately powered and involving hundreds of patients at multiple study centers

12. European Medical Device Requirements for Clinical Data EU raising the regulatory bar on clinical evidence requirements The Good Clinical Practice (GCP) standard for medical device investigation is laid down in EN ISO 14155 (2010) European legislation also explicitly requires adherence to the Declaration of Helsinki, which defines the ethical principles to be respected when performing investigations on human subjects As a rule, all clinical investigations need to be approved by Ethics Committees and notified to the competent authorities of involved countries

13. European Medical Device Requirements for Clinical Data A manufacturer must demonstrate that the device is safe, that the level of risk is acceptable when weighed against its medical benefits Clinical data encompasses everything from bench testing to clinical trials in human subjects Show actual clinical benefit (means the positive health impact of a medical device based on clinical and non- clinical data) for patients; no longer be sufficient to demonstrate safety and claimed performance Existing clinical evidence with comparable devices can be used for the clinical evaluation, provided device equivalence can be demonstrated

14. European Medical Device Requirements for Clinical Data For Low- to medium-risk devices (Class I, IIa, and IIb), a compilation of relevant scientific literature to support the device’s intended use and the techniques employed is enough For first-in-class medical devices, a pivotal prospective, randomized controlled study, adequately powered and involving hundreds of patients at multiple study centers is necessary Clinical investigation means verifying the clinical safety and efficacy of the device, including the intended benefits to the patient, when used for the intended purpose, in the target population and in accordance with the instructions of use.

15. Other Traditional Differences The essential documents for a medical device investigation are similar to the ones required for a pharmaceutical study The term Clinical Investigation Plan is generally used to refer to the study protocol in the case of a clinical investigation of a medical device There is a requirement to include a section on risk management in the CIP No legal requirement to demonstrate the efficacy of the device to obtain CE marking

16. Other Traditional Differences Number of patients in a medical device investigation are usually lower than in pharmaceutical studies Since efficacy does not need to be demonstrated, randomized controlled trial designs for medical devices are rarely necessary and therefore proof of statistical significance may not be necessary. However efficiency need to be checked. Interim analysis of study data may be feasible, provided it has been written into the investigation plan Not for every device !

17. Other Traditional Differences In comparative pharmaceutical studies the most robust comparator is a placebo control, which is often applied and generally required by authorities In a medical device investigation, a placebo control is usually not feasible. No standard therapy or comparator may be available. The user (usually a healthcare professional) often cannot be blinded to the study intervention Unlike drug, product performance can be influenced by the user and outcomes improve with experience

18. Other Traditional Differences Adverse device effects, may not only concern the investigation subjects but also third parties, such as users of the device In contrast, adverse events in pharmaceutical studies are only monitored for the trial subjects Due to the wide range of types of device, testing methodologies vary widely Some performance data might simply require user handling feedback; other data might be more analytical

19. Other Traditional Differences Medical devices often create large amounts of data that are transmitted, processed and stored via specific software interfaces. For such data sets, specific monitoring rules have to be established focusing on supervising data processing rather than individual data points. Medical devices are subject to frequent incremental innovation

20. India (CDSCO)

21. FAQ What is a medical device in India? -Such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette, after consultation with the Board What is a “new” medical device? -A “new” medical device is one which does not have a predicate (base/ ground) medical device registered/ approved in India

22. FAQ What is a “predicate” medical device? -One which is registered/ approved in India and has the same indications/ intended use, material of construction and design characteristics as the device which is proposed for registration in India Whether medical devices are regulated in India? -Yes, import, manufacture, sale and distribution of medical devices are regulated in India under the provisions of the Drugs & Cosmetic Act 1940 & Rules 1945 - Medical Device & Diagnostics Division, CDSCO HQ

23. FAQ Whether all medical devices are regulated in India? -No, however only notified medical devices are regulated in India. The following medical devices are notified under the DCA 1.Bone Cements 2.Cardiac Stents 3.Catheters 4.Disposable Hypodermic Needles 5.Disposable Hypodermic Syringes 6.Disposable Perfusion Sets 7.Drug Eluting Stents 8.Heart Valves 9.I.V. Cannula 10.In-vitro Diagnostic Devices for HIV, HbsAg and HCV 11.Internal Prosthetic Replacements 12.Intra Ocular Lenses 13.Orthopaedic Implants 14.Scalp Vein Set

24. FAQ The following devices are regulated as “Drugs” under DCA, hence registration and import license is required for import in to India -Blood/ Blood Component Bags -Blood Grouping Sera -Condoms -Intra Uterine Devices (Cu-T) -Ligatures, Sutures, Staples -Surgical Dressing -Tubal Rings -Umbilical Tapes

25. FAQ What are the requirements for import of medical devices in India? -For the import of medical devices into India, Registration Certificate in Form 41 and Import License in Form 10 are required as per provisions of the DCA -For import of medical device, the manufacturing site and products (medical devices) are required to be registered with CDSCO -Applicant can apply for both Registration Certificate (Form 41) and Import License (Form 10) together -Requirements for grant of import license in Form 10 are available in the CDSCO website under link http://cdsco.nic.in/Medical_div/medical_device_division.htm http://cdsco.nic.in/Medical_div/medical_device_division.htm

26. FAQ Whether Registration and import license is required for import of non-notified medical device in India? -No, registration is not required for import of non-notified medical devices in India Is there any system of prescreening of applications for issue of grant of Registration Certificate/ Import License at the time of submission at CDSCO (HQ) -Yes, application will be prescreened as per checklist available at: http://cdsco.nic.in/Medical_div/medical_device_division.h tm http://cdsco.nic.in/Medical_div/medical_device_division.h tm

27. FAQ What is the time period for Grant, Validity and Renewal of Registration Certificate & Import License? -If the application is complete in all respects and information specified in Schedules D-I and D-II are in order, the licensing authority shall, within 9 months for RC and 3 months for IL from the date of receipt of an application, issue such Registration Certificate in From 41, valid for 3 years and renewal before 9/3 months of expiry

28. FAQ Whether Notified Medical Devices can be imported only for demo purpose into India? -No -Under Test License in Form 11, small quantities of Drugs/ Medical Devices/ Diagnostic kits can be imported for the purpose of examination, test or analysis provided they shall not be used for any commercial purposes Where can I submit my enquiries related to registration, import and manufacture of medical devices? -All enquiries regarding the submission and approvals can be sent to the DCGI (dci@nb.nic.in) - CDSCO, FDA Bhawan, ITO, Kotla Road, New Delhi 110002. Phone: 011-2323 6965 / 2323 6975

29. CDSCO Order on Phase 1 (Med Device) Order dated 3 Jul 2014 -No concept of conducting Phase 1 Clinical Trial -Procedures for the CT approval, Accreditations of Investigators, Sites, EC and such other conditions would be similar to the CT of New Drugs/ Vaccines Order dated 9 Jul 2014 -Any device, other than the notified (14) do NOT require any registration, license, permission or NOC for their import, manufacture, sale or distribution ….

30. CDSCO Requirements for Conducting CT of Medical Devices Guidance Document – Requirements for Conducting Clinical Trial(s) of Medical Devices in India 1.Covering Letter 2.Form 44 3.Requisite Fee (Rs. 50,000 for Phase 1/ Feasibility and Rs. 25,000 for P2 and P3 4.Delegation of Responsibility 5.Study Protocol 6.Global Regulatory Status of the Device 7.Investigator Undertaking 8.Institutional Ethics Committee Approval

31. CDSCO Requirements for Conducting CT of Medical Devices 9.Informed Consent Form 10.Case Record Form 11.Patient Record Form (Hospital File) 12.Relevant Published Literature 13.Investigator’s Brochure 14.Suspected Unexpected Serious Adverse Reaction (SUSAR) from participating countries 15.Affidavit from Sponsor 16.Any Other Specific Relevant Information with regard to Medical Device 17.Clinical Study Report (Annexure X)

32. The Drugs, Cosmetics & Medical Devices (Amendment) Bill, 2013 WHEREAS it is expedient to regulate the import, export, manufacture, distribution and sale of drugs, cosmetics and medical devices to ensure their safety, efficacy, quality and conduct of clinical trials and for matters connected therewith or incidental thereto” Medical Device Technical Advisory Board Medical Device Officer (instead of Drugs Control Officer) appointed by the Central Drugs Authority

33. References Recommendations of the Task Force on the Medical Devices Sector in India – 2015 – DoP, MoC&F, GoI White Paper on Clinical Data For Medical Devices – Mar 2015, CROM Source, USA CDSCO Frequently Asked Questions on Registration and Import of Medical Devices in India (21 Feb 2013) DCGI Order 12-01/14-DC dated 3 July 2014 DCGI Order 29/Misc/5/2014-DC dated 9 July 2014 Draft Guidance Document on Requirements for Conducting Clinical Trial(s) of Medical Devices in India – 4 Aug 2010 GSR 690(E) Notification 25 Sep 2014 The Drugs and Cosmetics (Amendment) Bill, 2013

34. Thank You