FDLI s Introduction to Medical Device Law and Regulation: Understanding How FDA Regulates the Medical Device Industry October 28-29, 2002 The Westin Grand Hotel Washington, D.C. Premarket Approval Applications (PMAs), Product Development Protocols (PDPs), and Humanitarian Device Exemptions presented by Suzan Onel, Partner Kirkpatrick & Lockhart, LLP 1800 Massachusetts Ave., N.W. Washington, D.C. 20036 Phone: 202-778-9134 Fax: 202-778-9100 sonel@kl.com DC-537219 v1 0950000-102
PREMARKET APPROVAL APPLICATIONS (PMAs), PRODUCT DEVELOPMENT PROTOCOLS (PDPs), AND HUMANITARIAN DEVICE EXEMPTIONS Suzan Onel, Esq. I. PMA REVIEW (FDCA 515 (21 U.S.C. 360(e)); 21 C.F.R. Part 814) A. Overview. 1. Standard: Reasonable Assurance Of Safety and Effectiveness. 2. Filing Date Is Date FDA Receives Complete PMA. 3. Clock Is 180-Day Review Time. 4. Substantial Changes Will Restart The Clock. 5. Review By FDA Personnel And Possibly Referred To FDA Advisory Committee. 6. FDA Notifies Applicant Of Approval By Letter. 7. Notice Announcing The Decision And Availability Of Summary Of Safety And Effectiveness Data Used To Be Published In Federal Register, Now On Internet. B. Early Collaboration Meetings. 1. Determination Meeting Type Of Scientific Evidence That Will Be Required. FDCA 513(a)(3)(D). 2. Agreement Meeting Pre-IDE Meeting To Agree On Investigational Plan. FDCA 520(g)(7). 3. Binding On The Agency Unless Contrary To Public Health. 4. Early Collaboration Meetings Under the FDA Modernization Act (FDAMA), Guidance for Industry and CDRH Staff (Feb. 19, 1998) [Exhibit 1] C. PMA Application Should Contain (21 C.F.R. 814.20): See PMA Manual at http://www.fda.gov/cdrh/manual/pmamanul.pdf and PMA Elements Used [Exhibit 2] 1. Name And Address Of Applicant. 2
2. Comprehensive Summary. 3. Complete Description Of The Device Including Photographs And Drawings. 4. Full Reports Of Investigations On Safety And Effectiveness. 5. Components. 6. Methods And Controls Used For Manufacturing Or Processing. 7. Reference To Any Performance Standard Under 21 U.S.C. 514. 8. Bibliography Of All Publications. 9. Summary Of Unpublished Information. 10. Statement That Nonclinical Studies Meet FDA Requirements (21 C.F.R. 58). 11. Summary Of Clinical And Nonclinical Investigation. 12. Investigator Financial Disclosure Or Certification 13. Sample (When Reasonable). 14. Labeling, Literature And Installation Instructions. 15. An Environmental Assessment. 16. If Only One Investigator Has Participated, A Justification That A Single Investigator Was Sufficient To Demonstrate Safety And Effectiveness Of Device. D. Filing The PMA Application. 1. Send To: Document Mail Center Food and Drug Administration HFZ-401 9200 Corporate Blvd. Rockville, MD 20850 (301) 594-3027 2. FDA Will Acknowledge Receipt And Provide Unique Application Number. 3. Only Authorized Person Submitting Application Can Obtain Information. 3
4. FDA, By Regulation, May Take 45 Days To Review Application To Determine If Complete. If Filed, FDA Begins Substantive Review. E. FDA Refusal To File PMA. 1. FDA May By Letter Cite Deficiencies In PMA And Refuse To Accept For Filing. 2. Sponsor May Contest Deficiencies. 3. Sponsor May, Within 10 Working Days, Request Informal Conference With Office Of Device Evaluation (ODE). 4. ODE Will Hold An Informal Conference Within 10 Working Days Of Its Receipt Of Sponsor's Request. 5. ODE Will Advise Sponsor Within 5 Working Days After Conference If PMA To Be Filed. 6. Sponsor May Request Reconsideration By Director Of CDRH. 7. Guidance Document -- Center For Devices And Radiological Health s Premarket Approval Application (PMA) Refuse To File Policy (6/30/93). F. Scope Of Review Limited To Conditions Of Use Submitted In Proposed Labeling (FDCA 515(d)(1)(A)). G. Review By Advisory Committee (FDCA 515(c)(2)). 1. FDA May Refer PMA To Advisory Committee On Its Own Initiative Or Upon The Request Of Applicant. 2. Meeting On PMA Is Public Except for Discussion of Confidential Information. 3. Panel Must Provide Report And Recommendation On PMA To FDA. H. Planning For And Meeting With Panel. 1 Obtain From Executive Secretary Copies Of All Material Submitted To Panel -- Pursuant To 21 C.F.R. 14.75. 2 Obtain Information Regarding Panel Consultants. 3 Attend Public Meeting Or Obtain Transcript From Prior Panel Meetings. 4 FDAMA Reforms (FDCA 513(b)(6)(A)). a. Same Access To Data And Information As FDA; 4
b. Same Opportunity To Submit Additional Information As FDA; c. Same Opportunity To Participate As FDA; d. FDA Must Notify Applicant In Writing After Making Decision, Detailed Reasons For Variation From Panel Recommendations. e. Guidance on Amended Procedures for Advisory Panel Meetings (Jan. 26, 1999). I. Day-100 Meeting (FDCA 515(d)(3)). 1. Meeting To Discuss Status Of Review. 2. Must Be Requested Either When The PMA Is Filed Or No Later Than 70 Days After Filing. See Guidance on PMA Interative Procedures for Day- 100 Meetings and Subsequent Deficiencies for Use by CDRH and Industry (Feb. 19, 1998). J. Approval/Denial Of PMA. 1. Approval Order (21 C.F.R. 814.44(d)). 2. Approvable Letter (21 C.F.R. 814.44(e)). 3. Not Approvable Letter (21 C.F.R. 814.44(f)). 4. Denial Order (21 C.F.R. 814.45) With A Finding Of: K. Modular PMAs. a. Lack Of Reasonable Assurance Of Safety Or Effectiveness. b. Lack Of GMP In Manufacturing. c. Labeling False And/Or Misleading. d. Failure To Conform To Performance Standard. e. Sponsor May Appeal Denial Order To Special Panel. f. Special Panel Decision May Be Appealed To Court. 1. Review Of The PMA In Pieces Or Modules. 2. Allows For Closure Of One Or More Modules Before PMA Is Submitted (e.g., manufacturing information). 3. PMA Shell Outline of Sections. 5
4. Guidance for Industry: Guidances for the Medical Device Industry on PMA Shell Development and Modular Review (Nov. 6, 1998) [Exhibit 3]. L. Use And Availability Of PMA Data. 1. FDAMA Repealed "Four-Of-A-Kind" Rule For Release of PMA Data By Which Certain Clinical And Preclinical Test Data Compiled To Prove Safety And Effectiveness Would Become Available For Use By The Agency One Year After The Application For The Fourth Device "Of A Kind" Is Approved. This Rule Is Replaced With A Similar Provision By Which The Data Is Available Six Years After The Approval Of The Application That Is The Source Of The Data. Note: method of manufacture and composition of material remains confidential. Note: FDA has never declared that four devices "of a kind have been approved. 2. PMA Guidances -- FDA Has Published Guidances On Various Devices And Testing Protocols For Devices. M. Dispute Resolution Process. See Guidance: Resolving Scientific Disputes concerning the Regulation of Medical Devices, A Guide to Use of The Medical Devices Dispute Resolution Panel, (7/2/01) [Exhibit 4]. II. MAKING CHANGES TO PMA APPROVED DEVICES PMA SUPPLEMENTS A. Device Changes Affecting Safety Or Effectiveness Require Approval Of A PMA Supplement (21 C.F.R. 814.39). 1. Examples Of Changes That Require A Supplement If Affecting Safety Or Effectiveness: a. New Indications For Use; b. Labeling Changes; c. Change in Manufacturing, Processing, Or Packaging Facility; d. Changes In Sterilization Procedures; e. Changes In Packaging; f. Changes In Specifications, Circuits, Components, Ingredients, Principle Of Operation, Or Physical Layout; or 6
g. Extension Of Expiration Date Based On Data From An Unapproved Stability Protocol. 2. PMA Holder s Obligation To Determine If A Supplement Is Required. Draft Guidance: Guidance for Industry: Modifications To Devices Subject to Premarket Approval The PMA Supplement Decision Making Process (Aug. 6, 1998) [Exhibit 5]. 3. 135-Day Review Period. B. Special PMA Supplement Changes Being Effected Used For Changes That Enhance Safety. 21 C.F.R. 814.39(d) 1. Do Not Have To Wait For FDA Approval, But Must Wait For Acknowledgment. 2. May Be Used For The Following Changes: a. Strengthening Of Warnings, Contraindications, Or Precautions; b. Adding Or Strengthening An Instruction Intended To Enhance The Safe Use Of The Device; c. Deletion Of Misleading, False, Or Unsupported Indications; d. Quality Control Changes That Provide Additional Assurance Of Purity, Identity, Strength, Or Reliability. C. 30-Day Notice Used For Changes In Manufacturing That Affect Safety And Effectiveness. FDCA 515(d)(6); 21 C.F.R. 814.39(f). 1. Notify FDA Of A Modification To The Manufacturing Procedures Made In Accordance With QSRs. 2. May Implement Change 30 Days After FDA Receives The Notice Unless FDA Notifies The Manufacturer That The Notice Is Inadequate. 3. If A PMA Supplement Is Required Time Under Review As A 30-Day Notice Is Subtracted From The 135 Day Review Period. D. Changes That Do Not Affect Safety Or Effectiveness Can Be Documented In File Or, If Required By FDA, Reported In Annual (or Periodic) Reports. III. PRODUCT DEVELOPMENT PROTOCOLS (PDP) A. Alternative To Submission Of PMA. 7
B. FDA And Applicant Reach Pre-Application Agreement As To Data Requirements For Approval Of Device. Completion Of Protocol Results In Approval Of Device. C. FDA Has Not Issued Regulations. D. FDA Draft Guidance, Contents Of A Product Development Protocol (5/14/98) (Full Text Available At [http://www.fda.gov/cdrh/pdp/pdpguide.pdf]. E. Usually Works Best for Devices Already Well Understood By FDA. IV. HUMANITARIAN DEVICE EXEMPTION (HDE) (FDCA 520(m); 21 C.F.R. Part 814, Subpart H) A. Allows Marketing Of A Humanitarian Use Device (HUD) Without Reasonable Assurance Of Effectiveness. B. Limited To Devices Intended To Benefit Patients In The Treatment Or Diagnosis Of Diseases Or Conditions That Affect Or Are Manifested In Fewer Than 4,000 Individuals In The U.S. Per Year. C. Amount Charged For The Device Cannot Exceed The Costs Of the Research, Development, Fabrication, And Distribution. D. After Approval, Must Periodically Provide Detailed Information On Cost, Safety, And Continued Justification For HUD Status. E. Must Be Used Only Under The Review Of An Institutional Review Board ( IRB ). 8