Regulatory Boot Camp: Bringing a Product to Market and Avoiding Regulatory Pitfalls

1. Regulatory Boot Camp: Bringing a Product to Market and Avoiding Regulatory Pitfalls MassMEDICDecember 13, 2007Mass Medical SocietyWaltham, MA Robert Yocher, M.H.Sc., RAC VP RA/CQC Genzyme Corp.

2. Wide Variety of Devices Medical devices vary in terms of the risks that they present: Permanent implant or short term patient contact Circulating blood contacting or patient fluid contact Patient contacting or non-patient contacting Energy emitting or passive Diagnostic or Therapeutic Tool or treatment

3. Risk Based Classification Provides Flexibility Class III devices: Most complex, highest risk Breakthrough technology or high risk (life sustaining,life supporting) Premarket review and approval required through a Premarket Approval Application (PMA) or Humanitarian Device Exemption (HDE) Submitter required to demonstrate reasonable assurance of safety and effectiveness Clinical trials necessary ($$$$$$!) Examples: High intensity focused ultrasound devices, drug eluting coronary stents, photodynamic therapy devices, deep brain stimulators A PMA application is the most stringent type of device marketing application that FDA requires. The requirements for the content and submission of a PMA are stipulated in US Title 21 Code of Federal Regulations (CFR) Part 814. A PMA application involves many volumes that cover device description and intended use, nonclinical and clinical studies, case report forms, manufacturing methods, labelling, and other information and data. To facilitate the regulatory review process, FDA has developed extensive guidance on the submission of PMA applications and on the type of information and data that should be included for specific types of products . It is important that companies review all relevant guidance documents at the beginning of the PMA development process to ensure that FDA expectations are understood. Under the PMA process, FDA conducts a scientific and regulatory review of information and data submitted by the PMA applicant to determine whether or not the PMA contains sufficient valid scientific evidence to ensure that the device is safe and effective for its intended use(s). CLINICAL TRIALS. Clinical trials are almost always required to support an FDA premarket application. In the United States, these trials generally require submission of an application for an Investigational Device Exemption, or IDE, to FDA. The IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound. The IDE must be approved in advance by FDA for a specific number of patients unless the product is deemed a non-significant risk device eligible for more abbreviated IDE requirements. Clinical trials for significant risk devices may not begin until the IDE application is approved by FDA and the appropriate institutional review boards, or IRBs, at the clinical trial sites. Our clinical trials must be conducted under the oversight of an IRB at the relevant clinical trial sites and in accordance with FDA regulations, including but not limited to those relating to good clinical practices. We are also required to obtain patients' informed consent that complies with both FDA requirements and state and federal privacy regulations. We, FDA or the IRB at each site at which a clinical trial is being performed may suspend a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the benefits. Even if a trial is completed, the results of clinical testing may not demonstrate the safety and efficacy of the device, may not be equivocal or may otherwise not be sufficient to obtain approval of the product. Similarly, in Europe the clinical study must be approved by the local ethics committee and in some cases, including studies with high-risk devices, by the Ministry of Health in the applicable country. A PMA application is the most stringent type of device marketing application that FDA requires. The requirements for the content and submission of a PMA are stipulated in US Title 21 Code of Federal Regulations (CFR) Part 814. A PMA application involves many volumes that cover device description and intended use, nonclinical and clinical studies, case report forms, manufacturing methods, labelling, and other information and data. To facilitate the regulatory review process, FDA has developed extensive guidance on the submission of PMA applications and on the type of information and data that should be included for specific types of products . It is important that companies review all relevant guidance documents at the beginning of the PMA development process to ensure that FDA expectations are understood. Under the PMA process, FDA conducts a scientific and regulatory review of information and data submitted by the PMA applicant to determine whether or not the PMA contains sufficient valid scientific evidence to ensure that the device is safe and effective for its intended use(s). CLINICAL TRIALS. Clinical trials are almost always required to support an FDA premarket application. In the United States, these trials generally require submission of an application for an Investigational Device Exemption, or IDE, to FDA. The IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound. The IDE must be approved in advance by FDA for a specific number of patients unless the product is deemed a non-significant risk device eligible for more abbreviated IDE requirements. Clinical trials for significant risk devices may not begin until the IDE application is approved by FDA and the appropriate institutional review boards, or IRBs, at the clinical trial sites. Our clinical trials must be conducted under the oversight of an IRB at the relevant clinical trial sites and in accordance with FDA regulations, including but not limited to those relating to good clinical practices. We are also required to obtain patients' informed consent that complies with both FDA requirements and state and federal privacy regulations. We, FDA or the IRB at each site at which a clinical trial is being performed may suspend a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the benefits. Even if a trial is completed, the results of clinical testing may not demonstrate the safety and efficacy of the device, may not be equivocal or may otherwise not be sufficient to obtain approval of the product. Similarly, in Europe the clinical study must be approved by the local ethics committee and in some cases, including studies with high-risk devices, by the Ministry of Health in the applicable country.

4. Expect Two Submissions Investigational Device Exemption and PreMarket Approval Application Most stringent most lengthy of Device pathways (typically 1-3 yrs. or more) Contains sufficient �valid scientific evidence� that provides �reasonable assurance� that the device is safe and effective for its intended use or uses.

5. Premarket Approval Options Expedited PMA Streamlined PMA Standard PMA Modular PMA An applicant can request Expedited Review for Standard or Modular PMAs Reality �doesn�t make much difference!

6. Expedited PMA Review Geared toward devices that have a major public health impact Device that is intended to treat or diagnose life-threatening or irreversibly debilitating diseases or conditions; and Meets one of the following criteria:

7. Expedited PMA Review Criteria Represents a breakthrough technology with a clear clinically meaningful advantage over existing technology;or� Has no approved alternative;or� Offers significant advantages over approved alternatives; or� Is in the best interest of patients.

8. Expedited PMA Review Expedited review entitles the marketing application to review before other pending applications

9. Streamlined PMA Process Designed for devices using well-known technologies with well known disease processes PMAs may qualify as Streamlined if: the device has a review guidance; or two or more previous PMAs have been approved for the same type of device; or the device has a study protocol jointly developed by the manufacturer and FDA Contact FDA to determine eligibility. Submit study protocol to FDA for review Use abbreviated Summary of Safety and Effectiveness by attaching Executive Summary to labeling Manufacturing inspection may be deferred if FDA completed a GMP inspection within past 2 yrs Final Review within 180 day cycle

10. Standard and Modular PMAs Standard IDE submitted and approved Complete PMA submitted Modular PMA shell developed during IDE process IDE submitted and approved Modules are submitted to FDA as they are completed FDA reviews modules over time Both have the same content requirements

11. Content of a PMA A PMA application must contain: General information (name and address of applicant, Table of Contents) Summary of Safety and Effectiveness Description of the device and its manufacturing process Reference to performance standards Environmental assessment

12. Content of a PMA(continued) Non-Clinical studies Clinical Investigations Financial certification and/ or disclosure statements Labeling Literature review/bibliography other information requested by FDA Sample device, if requested

13. PMA �FDA regulations provide 180 days to review the PMA and make a determination. In reality, the review time is normally longer. Before approving or denying a PMA, the appropriate FDA advisory committee may review the PMA at a public meeting and provide FDA with the committee's recommendation on whether FDA should approve the submission. After FDA notifies the applicant that the PMA has been approved or denied, a notice is published on the Internet (1) announcing the data on which the decision is based, and (2) providing interested persons an opportunity to petition FDA within 30 days for reconsideration of the decision.� http://www.fda.gov/cdrh/devadvice/pma/ accessed 12/10/07

14. Timeline & Milestones Filing review 45 days BIMO inspections 70-90 days Manufacturing Inspection 90 -120 days Day 100 meeting Prep for panel 2-4 weeks Panel hearing Labeling negotiations Final determination Post market responsibilities

15. User Fees FY 2008 Device Review User Fees (U.S. Dollars) Type of ApplicationStandard Fee/Small Business Fee (<$100 million sales) Premarket Application (PMA, PDP, BLA, PMR) *NOTE: The fee is waived for the first premarket application from firms with gross receipts or sales <$30 million. $185,000/$46,250 PMA/BLA/PDP $185,000/$46,250�Premarket Report (PMR) - premarket approval application for a reprocessed device $185,000/$46,250 Efficacy Supplement (for BLA) $138,750/$34,688 Panel-track Supplement $ 27,750/$6,938 180-day Supplement $ 12,950/$3,237 Real-time Supplement $ 2,960/$1,480 30-Day Notice/135-Day PMA Supplement** $ $6,475/$1,619 Annual Fee for Periodic Reporting on a Class III Device** * PMA=Premarket Approval; PDP=Product Development Protocol; BLA=Biologics License Application; PMR=Premarket Report (for a reprocessed device)**New for FY08

16. Fees and Exemptions Exemptions and Waivers The following types of applications require no fee. Special PMA Supplements-Changes Being Affected Express PMA Supplements Humanitarian Device Exemption (HDE) BLA for a product licensed for further manufacturing use only. The following exemptions or waivers apply. Fee Exemptions and Waivers (No Fee for These) Category Exemption or Waiver First premarket application (PMA, PDP, BLA, or premarket report) from a small business with gross receipts or sales <$30 million . One-time waiver of the fee that would otherwise apply. Any application for a device intended solely for pediatric use. Exempt from any fee. If an applicant obtains an exemption under this provision, and later submits a supplement for adult use, that supplement is subject to the fee then in effect for an original premarket application. Any application from a State or Federal Government entity. Exempt from any fee unless the device is to be distributed commercially. 

17. PMA PROs ? High regulatory bar means fewer competitors Competitors cannot use your data Competitors must spend the time and money Liability protection? CONs ? Expensive Time consuming Restrictive Manufacturing Restricted device Labeling, advertising & promotion restrictions

18. Suggestions Try to de novo classify to Class II (510k) Limit your claims Hire an experienced RA professional Hire experienced consultants Look for partners Resist changes by assessing risks Expect to take longer and be more expensive than you planned.

19. Questions??