1. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 PRESENTATION TO: Public Hearing: FDA Regulation of Combination Products November 25, 2002

2. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Angiogene Inc. Angiogene develops unique drug-device combination products that increase the success rate of vascular interventions Guy Chamberland, Ph.D. Vice-President, Regulatory Affairs & Drug Development

3. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Premarket review mechanism; Mixed regulatory approach should be applied; Orphan Designations Topics:

4. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Angiogene’s experience: Product 1: Unapproved stent (PMA) + unapproved drug (NDA) A device to manufacture the combination product on-site (PMA) Combination product = PMA Sold as separate items and combined on-site Primary function: device Product 2: Preamendment device (510(k)) + unapproved drug (NDA) Combination product = PMA Sold as combined product Primary function: device

5. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Outline: Response to FDA questions Premarket regulatory authorities & Benefits Advantage of Orphan Status to drug component of drug-device combination products

6. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Response to FDA questions.

7. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 (a) What are the general scientific and policy principles that should be followed in selecting the premarket regulatory authorities to be applied to combination products? (b) Is one premarket review mechanism (e.g., premarket approval (PMA), premarket notification (510(k)), new drug application (NDA), or biologic licensing application (BLA)) more suitable than another for regulating combination products? Question 3:

8. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3a: 21 CFR § 3.4(a) 'To designate the agency component with primary jurisdiction for the premarket review and regulation of a combination product, the agency shall determine the primary mode of action on the product.' Combination of the two components brings new development issues such as: Drug release from a polymer coating Local safety issues of drug and polymer New drug stability issues Drug-device interactions

9. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3a (contd): The criteria that should be followed in selecting the premarket regulatory authorities should be based on assuring safety to patients and not one purely based on the primary mode of action. FDA should determine through the designation process what are the issues that suggest potential risk to patients. CDER: If the risks of the drug outweigh the risks of the device CDRH: If the risks of the device outweigh the risks of the drug Division with most experience with primary safety issue would have primary review responsibility. Should not impact development Good science should dictate the types of nonclinical studies, device/drug manufacturing requirements, and clinical trials required

10. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3a (contd): For example, some drug-eluting stents may have drugs that represent more safety issues for patients than the device: an approved stent coated with an unapproved drug from a new pharmacological class: – Based on current regulations, the stent would be declared the primary mode of action and CDRH would obtain the primary review responsibility. The stent on its own should not have any unique or potentially complicated issues. –However, a new class of drugs could represent unique safety issues including systemic toxicity. In addition, the molecule could have complex stability and chemistry and manufacturing issues that raise safety concerns. – If FDA developed scientific and policy principles based on potential safety concerns, this type of combination product would be regulated as a drug.

11. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3b: A single file should be applied for combination products even when one or both of the components are not approved. FDA review team must review the application from the point of view that safety and efficacy is entirely dependent on the combination of the two components. Irrespective of the premarket review mechanism, a Drug-Device combination product application would consist of: Preclinical studies Nonclinical safety Biocompatibility Physical testing (Bench testing) Chemistry, Manufacturing & Controls Submission of IND or IDE Clinical Submission of NDA or PMA

12. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3b (contd): The most efficient method for review is the creation of a review team that is composed of scientists and regulatory personnel from more than one division. – The file must be assessed from the point of view of what will be commercialized and administered to patients. – How the two components interact is often pivotal in the assessment of safety.

13. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3b (contd): FDA should develop a Combination Products General Guidance: – Consistency is required between divisions if safety is to be assured to patients. For example: Acceptable preclinical standards (i.e., GLP) for in vivo studies used to demonstrate safety/efficacy in animals Local safety often assessed in model of efficacy Current FDA Guidance documents do not emphasize compliance with GLPs A lot of studies conducted in University facilities. Degree of compliance to GLP?

14. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 3b (contd): FDA should develop a Combination Products General Guidance: – The development phase of a device is regulated (e.g., Design Input, Design Control). Provide a definition/description of when the development phase of a combination product should begin Companies may begin development phase too late

15. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Recognizing the need to ensure product safety and effectiveness, what criteria should FDA use to determine whether a single application or separate applications for the individual components would be most appropriate for regulation of a combination product? For example, FDA may determine that it is necessary to apply elements of different regulatory authorities to a combination product to ensure safety and efficacy (e.g., device postmarketing reporting for the combination product, with drug current good manufacturing practices (CGMPs) applicable to the drug component only). Should the need to apply a mixed regulatory approach influence whether one application or two are more appropriate? Question 4:

16. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 4: FDA should not impose separate applications. It is crucial that FDA review a combination product in a joint effort. The drug alone has issues but the drug-device combination also has issues and these must not be underestimated because of separate applications. For example: – The safety of an approved drug for intravenous administration may be well established. – The delivery of the drug locally in a coronary artery raises new safety issues since the local drug concentration may exceed that achieved by the intravenous product. –Therefore, safety must be assessed from this new route of administration and this requires understanding how the drug is released from the device.

17. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 4 (contd): FDA should develop a mixed regulatory process and determine what elements of different regulatory authorities are required during the designation process. Regulations should permit FDA to modify these elements if data submitted during the review process suggests or demonstrates a potential safety issue. –The guiding criteria must be safety of patients. –Potential to loose efficacy should also be a criteria. –FDA must not develop a strict policy but instead establish criteria to determine the elements.

18. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 What scientific and policy principles should be followed in determining the appropriate manufacturing and quality system regulatory authorities (e.g., Current Good Manufacturing Practices versus Quality System Regulation) applicable to combination products? Question 5:

19. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 5: Both the cGMP (drugs) and QSR (device) regulations were developed with the same philosophy: to control manufacturing and quality in order to minimize risks to patients. In the early phases of development, QSR is more demanding on companies since it regulates Design Control: –Design and development planning; Design Input; Design Output. FDA should develop a Combination Product QSR (CP-QSR) regulation that includes parts of 21CFR211 that would be required for the drug component prior to the merging of both components. –QSR requires that the merge of the drug with the device be part of the Design Control. –In fact, the development of the combination product begins after the merge.

20. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Answer 5 (contd): Both QSR & cGMP require that companies hire qualified employees, provide training, document the training, and require documentation of the manufacturing process through SOPs and a batch record. The CP-QSR regulation should include a section that cross- references to GMP sections that require documentation, in- process and raw materials control, specifications, validation, etc to assure the safety, quality and potency of the drug component.

21. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Premarket regulatory authorities & Benefits Advantage of Orphan Status to drug component of drug-device combination products

22. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Complexity of developing a drug-device combination product Addition of drug to preamendment device Primary function associated with that of the preamendment device Would not be considered Substantially Equivalent Drug introduces new development issues Manufacturing and safety of drug component Drug-device interactions, elution/release of drug from device, or other unique issues Therefore, regulated through the PMA process

23. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Therapeutic advantage of a drug in a device function CYPHER TM Sirolimus-eluting Stent (PMA # P020026) CDRH Designated as primary review center Primary mode of action is a device function Sirolimus added to stent to augment the performance of the stent Therapeutic action of drug is short term Clinical trials demonstrated superior effectiveness to bare stents In-stent restenosis: 35.4% (bare) to 3.2% (DES) In-segment restenosis: 36.3% (bare) to 8.9% (DES)

24. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Development of a drug for a rare disease Drug companies are encouraged to develop products for rare diseases through the FDA’s Orphan Drug Act. Companies will begin to develop drug-device combination products for the treatment of rare diseases.

25. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Drug component of drug-device combination products For combination products regulated through the PMA process: Primary function associated to device Drug added to device to provide additional therapeutic or preventive properties Role of drug should be recognized Drug should be entitled to Orphan Status even when the premarket regulatory authority is CDRH (i.e., PMA)

26. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Orphan Status would encourage the development of promising drug-device combination products for the treatment of rare diseases. Just like the CYPHER TM Sirolimus-eluting Stent has brought to the field of interventional cardiology. Advantage of Orphan Status to drug component of drug-device combination products

27. COPYRIGHT 2002. ALL RIGHTS RESERVED. LEGAL DISCLOSURE. November 25, 2002 Angiogene Inc. would like to thank the FDA for allowing us to communicate our experience with drug-device combination products and how the modification of current regulations could continue to assure the safety and efficacy of these new technologies.