Exports Clinical Trials for Medical Devices Dr Subodh

Exports & Clinical Trials for Medical Devices Dr. Subodh P. Adeshara Executive Director Sahajanand Medical Technologies Pvt. Ltd. & Coordinator – Medical Devices Panel - Pharmexcil

Industry Segments

Global Clinical Trials Permission is required from CDSCO for conducting global clinical trials in the country ¡ Phase I for New Drug substance developed outside India is not permitted ¡ So far, approx. 500 permissions have been granted since 2003 ¡

Costs ¡ Costs – Macro View l Pre-Clinical (estimates) ¡ Chemistry – 30% to 60% of the cost of West ¡ Other Pre-clinical l l Toxicology – 30% of the cost of the West Animal Testing – 30% of the Cost of the West Clinical (estimates) ¡ Phase I – 25% of the cost of the West ¡ Phase II/III – 30% of the cost of the West Time Equals Money ¡ Patient Recruitment ¡ Pre-clinical Regulations

Costs Cont. . ¡ Costs – Micro View Item US Cost India Cost

Conducting Clinical trials With Medical Devices in India Regulatory Aspects (Regulated by the DCGI office under Gazette Notification No. S. O. 1468(E) dated 6 th October 2005 and G. S. R. 627(E) dated 7 th October 2005)

Indian Regulatory Environment – Regulatory Bodies Governing & Controlling Clinical Trials

Drugs Controller General India (DCGI) –Role ¡ ¡ ¡ Permission to conduct clinical trials with New Drugs/Existing Drugs/Medical devices under drugs category Import license / Test License for clinical trial drug supplies – concurrent with main submission Approval for conducting clinical trials with Medical Devices under Drug Category Permission/N. O. C. /Notification for Protocol Amendments/ICF amendments/Safety reports Notification for SAEs observed in ongoing clinical trials

Following Medical Devices have been considered as Drug by DCGI as per Gazette notification no. S. O. 1468(E) dated 6 th October 2005 and G. S. R. 627(E) dated 7 th October 2005 1. Cardiac Stents 2. Drug Eluting Stents 3. Catheters 4. Intra Ocular Lenses 5. I. V. Cannulae 6. Bone Cements 7. Heart Valves 8. Scalp Vein Set 9. Orthopedic Implants 10. Internal Prosthetic Replacements

Medical Devices Contd… A. All devices falling under the category of devices specified by DCGI and containing the drug components will: 1. Be reviewed and approved by the NEW DRUG DIVISION of the DCGI. 2. Approval timelines are 4 -6 weeks for Category A and 8 -12 weeks for Category B applications. a. CATEGORY A: Those Protocols which are approved by recognized and developed countries viz. USA, UK, Switzerland, Australia, Canada, Germany, South Africa, Japan, EMEA. b. CATEGORY B: All other applications not falling under Category A.

Medical Devices Contd… B. All devices falling under the category of devices specified by DCGI and not containing the drug component will: 1. Be reviewed and approved by the MEDICAL DEVICE SECTION of DCGI. 2. Approval timelines are between 6 -8 weeks.

Medical Devices Contd… C. All those devices which do not fall under the category of devices specified by DCGI will : 1. Be submitted ONLY FOR NOTIFICATION at DCGI for conduct of clinical trial. 2. No written approval / NOC is issued / required from DCGI to conduct clinical trial in India. 3. Ethics Committee approvals are required to initiate the clinical trial at the sites.

Timelines Approval Time Frame • Export NOC • Dual use, Rule 37 & Neutral code • Additional indication etc. • Form 10 • Test License • First response to New Drug • FDC first response • Endorsement of additional products on registration • Registration 2 Weeks 3 4 4 4 6 6 8 Weeks Weeks 12 weeks

Checklist of documents for seeking permission to conduct Clinical Trial with Medical Devices under Drug category (With Drug / Without Drug) and Device category 1. Name of the Applicant 2. Transfer of Responsibility letter from the sponsor 3. Name of the Device 4. Regulatory status of the device in other countries (US FDA clearance/approval) 5. Objective of the Study 6. Phase of study 7. Names of the Participating Countries/Investigator sites 8. No. of patients to be included in India 9. Country / IRB approvals from participating countries 10. ISO/CN/CE certification for the manufacturing facility and the list of countries where the device is being marketed.

Checklist of documents contd…. 11. Status of the study in other countries 12. Affidavit from the sponsor regarding non- discontinuation of the study 13. CE certificate from European authority & approval from Australia / Canada / Japan, if available 14. Undertaking of conformity w. r. t product standards, safety & effectiveness requirements and quality systems in the country of origin. 15. Clinical data and published literature on the safety, quality & usefulness of the medical substance used in the medical device (Only for devices containing drug component).

Checklist of documents contd…. 16. Data submitted I. Chemical & Pharmaceutical data § Generic name and chemical name § Dosage Form § Composition II. Animal Pharmacology Data III. Animal Toxicology data IV. Clinical data 17. Documents submitted I. Form 44 & Fee Receipt II. Form 12 and Fee Receipt III. Details of Biological specimens to be exported IV. Protocol V. Informed Consent Form VI. Case Report Form VII. Investigator’s Brochure VIII. Undertakings & CVs by Investigators IX. Ethics Committee approvals (For Category B)

Directorate General of Foreign Trade –Role 1. Issuing Export Permission for exporting Human biological samples for study related analysis to Central Lab • Export Permission valid for a period of 1 year 2. Revalidation of Export Permission

Approval Timelines -Export Permission 1. Devices Containing Drug component 4 -6 Weeks 2. Devices not containing Drug Component 4 -6 Weeks 3. Devices Under notification category Export Permission not issued by DGFT

Joint Directorate General of Foreign Trade –Role 1. Issuing Export License for exporting Human biological samples for study related analysis to central lab • The export license is valid for a period of 2 years 2. Revalidation of Export License

Checklist of documents to be submitted for Export License 1. Cover letter 2. Copy of DCGI approval letter 3. Letters from the Labs 4. Aayat Niryaat Form 5. Copy of IEC Certificate 6. Copy of PAN Number 7. Copy of Registration cum Membership certificate 8. List of Directors 9. Copy of Certificate of Incorporation 10. Copy of Study Protocol 11. Copy of Export Permission

Approval Timelines -Export Licence 1. Devices Containing Drug Component 2 Weeks 2. Devices Not Containing Drug Component 2 Weeks 3. Devices Under Notification Category Export Licence not issued by Jt. DGFT

Role of Pharmaceutical Export Promotion Council - PHARMEXCIL Promote Activity related to export of Medical Devices ¡ Conduit for financial assistance by GOI ¡ Up gradation of medical Device Industry in the country ¡ Vital link between India & Buyer Countries ¡ Conducts buyer seller meets ¡

Activity by Pharmexcil ¡ 50% of expense on Registration of Medical Device in any country for the purpose of Export is Reimbursed by GOI thro’ Pharmexcil upto Rs 50 lacs pa per company. Such registration costs several thousands of USD ¡ Helps exporters to get exposed to buyer’s marke ¡ Promotes export by helping industry to fulfill export procedures ¡ Provides Technical support wherever possible ¡ Activities like seminars, training, cluster development for modernization

Current Trials being Conducted in India – NIH Registered ¡ ¡ Overall Clinical Trials Device based Trials Biotechnology based Trials Stent based Trials 870/68811 25/3544 3/140 13/409 1. 3% 0. 7% 2. 1% 3. 2% Clinical. Trials. gov

Global Trials in India Based on The Boston Consulting Group and Business Communications Co.

Trials in India Based on The Boston Consulting Group and Business Communications Co.

Why India ? ¡ ¡ ¡ ¡ Genetically diverse population : Western disease distribution Low Cost : 40 -60% reduction Large and quick pt. recruitment Over 600 ICH/GCP compatible sites Large number of medical specialists Well developed IT and other infrastructure available English as spoken and technical language Increase in number of CROs [National and International]

On-going Device Based Trials in India

Interventional Cardiology Device based Trials ¡ Indian Trials ¡ Multi-national Trials

Indian Stent Trials - Completed ¡ ¡ ¡ ¡ SIMPLE I : Infinnium stent, FIM, completed (SMT) NOVA FIM : Pronova stent, FIM, completed (Vascular Concepts) RELEASE T : Relisys stent, FIM, completed (Relisys Medical Devices) SIMPLE II & III : Infinnium stent, Pre-market, completed (SMT) EMPIRE : Propass stent, Pre-market, completed (Vascular Concepts) PROSES & INNOVA : Propass stent, Post-market, completed (Vascular Concepts) SERIES I : Supralimus stent, FIM, Completed (SMT) MAXIMUS : Supralimus-Core stent, FIM, Completed (SMT)

Multinational Device based Trials Completed ¡ ¡ ¡ ¡ ¡ COSTAR I : Costar stent, FIM (Conor Medsystems) WISDOM : Taxus stent, Pre-market (Boston Scientific) SPIRIT II : Xience V vs. Taxus stent, Pre-market (Abbott Vascular) TAXUS OLYMPIA : Taxus stent, Post-market (Boston Scientific) E – Cypher : Cypher stent, Post-market (Cordis, J & J) VIVE : Vision stent, Post-market (Abbott Vascular) REALITY : Cypher vs. Taxus stent, Post-market (Cordis, J & J) DECODE : Cypher vs. Bx Velocity stent, Post-market (Cordis, J & J) SPIRIT V : Xience V stent, Post-market (Abbott Vascular)

Multinational Device based Trials On-going ¡ ¡ ¡ ¡ ¡ FRONTIER : Frontier Bifurcation stent, Post-market (Abbott Vascular) PROTECT : Endeavor vs. Cypher stent, Post-market (Medtronic) E – SELECT : Cypher stent, Post-market (Cordis, J & J) CC Flex : CC Flex stent, Post-market (eucatech ) FREEDOM : Cypher vs. CABG, Post-market (Boston) ENDEAVOR 5 : Endeavor stent, Post-market (Medtronic) EXPORT : Export Aspiration Catheter, Post-market (Medtronic) PANORAMA : CRDM Device, Post-market (Medtronic) Bone Marrow aspiration for CLI, Post-market Ci. Top. TM Guidewire for CTO, Post-market (Ovalum)

Issues in India ¡ ¡ ¡ ¡ Informed Consent Issues Truly Independent IRBs Proper documentation Under-reporting by pts. , physicians etc. Proper Follow-up Change in study co-coordinators Regulatory Apparatus

Market Implications [adapted from Sumner K. Attitude Adjustment. Available on www. devicelink. com]

WW Combination Product Market 2009 (est) $10 billion ¡ 88% all Cardiovascular applications ¡ 12% Wound Care, Orthopedics and all other applications ¡ DES will account for 70% of total market [Combination Products: An Impact Analysis on the Convergence of Medical Devices and Therapeutics. Navigant Consulting/Front Line Strategic Market Reports]

Conclusions ¡ ¡ Clinical trial industry in India accounts for ~ 1% of global trials but is likely to increase up to 15% Lower cost and faster recruitment potential is most important reason for it Several Indian and prestigious Multinational device based trials have already been conducted and many more are in pipeline Some regulatory and local IRB Accreditation issues need still to be addressed