David L. Rosen, B.S. Pharm., J.D. Partner, Adv. and FDA Regulatory Practice Co-chair, Life Sciences Industry Team Washington, DC

Transcription

1 SUCCESSFULLY DEALING WITH BUSINESS, REGULATORY AND IP CHALLENGES IN ISRAELI BIOMED COMPANIES: Current FDA Issues Impacting the Regulation of BioMed Companies David L. Rosen, B.S. Pharm., J.D. Partner, Adv. and FDA Regulatory Practice Co-chair, Life Sciences Industry Team Washington, DC June 2007 Attorney Advertising Prior results do not guarantee a similar outcome Models used are not clients but may be representative of clients 321 N. Clark Street, Suite 2800, Chicago, IL

2 The View from Downtown DC

3 The President and Cabinet Send Their Regards

4 Department of Health and Human Services

5 Food and Drug Administration

6 Topics for Discussion Five Mistakes That Can Kill Your Chances of an FDA Expeditious Drug Approval or Medical Device Clearance/Approval Some Practical Advice Questions and Answers

7 Hot FDA Topics Increased focus on drug/device safety Response to IOM critique FDA pilot re-evaluation of New Molecular Entity safety Separate safety center for drug post marketing issues Strengthen science to improve device safety over product lifecycle Reauthorization of the Prescription Drug User Fee Act User fees for ANDAs Increased resources for drug safety New proposed legislation Block authorized generics Follow on Protein Products Marketing unapproved new drugs FDA is trying to clean up the marketplace Improve export certification program Consolidation of FDA to White Oak campus Strengthen food safety

8 High Priority Areas for CDRH Safety both pre-approval and post-market surveillance FDA is significantly concerned about any association of a device with patient deaths or serious injuries Patient deaths as a % of treatments does not ameliorate FDA concerns Complaint/MDR investigation processes and reporting Failure to investigate and report as required Root cause analysis and remediation Many companies are experiencing similar problems Result - a heightened level of FDA concern Good Manufacturing Practices/ Quality System Requirements Is the company in control over the manufacturing process Change Control are changes well documented and approved Software Validation Software Changes made without verification and validation

9 Five Significant Mistakes Mistake 1 - Failure to understand FDA s expectations for data necessary to obtain drug approval or PMA approval or 510(k) clearance Mistake 2 Repeated attempts to force FDA to base approval or clearance on questionable data safety effectiveness physical testing

10 Five Significant Mistakes (cont.) Mistake 3 - Failure to have necessary infrastructure in place to comply with FDA requirements Quality Systems Requirements Good manufacturing Practices Design Control Post Marketing Surveillance Mistake 4 Failure to conduct clinical trials in compliance with good clinical practices Investigators not chosen wisely Not regularly monitoring the conduct of investigations

11 Five Significant Mistakes (cont.) Mistake 5 Failure to maintain credibility and integrity with FDA staff Response to patient safety issues Conducting timely investigations Implementing corrective and preventative action plan

12 Five Significant Mistakes Mistake 1 Failure to understand FDA s expectations for data necessary to obtain drug approval or PMA approval or 510(k) clearance

13 Take Advantage of Resources Review available guidance documents Review disclosable public information available at or in PMAs and cleared 510(k)s Review advisory committee/panel transcripts Talk to the experts Clinical PK CMC Design Physical testing mechanical. software Regulatory/Legal Request to meet with FDA staff to discuss development program pre-ind or pre-ide meeting Informal discussions to discuss approach

14 Five Significant Mistakes Mistake 2 Repeated attempts to force FDA to base approval or clearance on questionable data safety effectiveness physical testing (mechanical, software)

15 Understand the Current Climate at FDA Significant safety issues have surfaced with a number of drugs and devices There has been a challenge to the fundamental integrity and the ability of the medical device approval/clearance process to safeguard the public health Increased Congressional scrutiny Public awareness and criticism FDA s response: More conservative decision making Greater scrutiny of the data Seeking consensus review Increased focus on FDA field inspections User fee time pressure for completing reviews

16 Understand the Current Climate at FDA Recommendation Understand FDA s expectations Seek guidance from FDA and outside experts Companies often understand their products more thoroughly than FDA Educate Hear FDA s concerns Attempt to respond Remember FDA does not get it right every time Can challenge FDA decision making

17 Five Significant Mistakes (cont.) Mistake 3 Failure to have necessary infrastructure in place to comply with FDA requirements Quality Systems Requirements Good Manufacturing Practices Design Control Post Marketing Surveillance

18 Be Ready for FDA Inspection FDA inspectors will visit when there is a safety issue, recall, consumer complaint or when there is a potential data integrity issue To prep they will evaluate the company s compliance history What are the first items they want to see: Product Complaints Adverse Event / Medical Device Reports Rejected Lots Trending of issues Thorough and complete investigations Communication with FDA headquarters staff about the issues and how they are going to be further investigated and addressed Corrective and preventative action plans Revised SOPs and staff training Be prepared

19 Five Significant Mistakes (cont.) Mistake 4 Failure to conduct clinical trials in compliance with good clinical practices Investigators not chosen wisely Not regularly monitoring the conduct of investigations

20 Summary of Cited Violations by Study Investigators/CROs Failure to retain complete, current, and accurate records E.g., missing or incomplete case histories or device disposition records; discrepancies between source documents and CRFs); Failure to ensure informed consent obtained as required E.g., forms missing, not currently approved by IRB, incompletely documented); failure to meet/documents requirements for emergency use exemption from informed consent) Failure to conduct the investigation in accordance with the signed agreement, investigational plan/protocol, and/or applicable FDA regulations E.g., enrolling subjects counter to inclusion/exclusion criteria; failure to perform/document required follow-up; failure to document IRB consent/correspondence; unapproved deviations from protocol)

21 Summary of Cited Violations by Study Investigators/CROs (cont.) Failure to timely report/adequately evaluate adverse events Failure of Principal Investigator or CRO to adequately supervise conduct/ensure monitoring of trial Failure to obtain required IND / IDE Failure to make required records available for inspection Other failure to protect patient safety/exposure to serious risk Failure to submit/late submission of scheduled reports to Sponsor, Monitor, IRB Failure to submit/update conflict of interest information

22 Summary of IRB Cited Violations Failure to prepare, maintain, and follow adequate written procedures for initial and continuing review of clinical investigations Failure to review proposed research/amendments at convened meetings including a majority of IRB members and at least one member whose primary concerns are in nonscientific areas Failure to conduct continuing review at appropriate intervals Failure to prepare and maintain adequate documentation of review activities Failure to require adequate informed consent

23 Other Issues Cited in Warning Letters Failure to follow the protocol Falsification Informed Consent Issues Failure to report adverse events Qualifications of persons performing physicals Inadequate Records Failure to get IRB approval, report changes in research Failure to follow FDA regulations Charging for the test article without permission Device accountability No active IND Violations of GLP regs Misleading advertisements Blinding issues Investigator Bias Monitoring practices IRB shopping

24 Five Significant Mistakes (cont.) Mistake 5 Failure to maintain credibility and integrity with FDA staff Response to patient safety issues Conducting timely investigations Implementing corrective and preventative action plan

25 Maintaining Your Credibility and Tips for Influencing the FDA Scientific issues Policy matters Legal battles

26 Maintaining Your Credibility and Tips for Influencing the FDA (cont.) Good science is critical to success In today s environment safety and effectiveness are paramount Examine your company s responses are changes needed? Meet with FDA staff early on in the development process Take advantage of pre-ind / pre-ide meetings Try to reach agreement on key development parameters Understand FDA s expectations for clearance/approval Best opportunity to present and get feedback on your development pathway Build an administrative record If the science is questionable Are additional studies necessary pre-or post marketing Were issues discussed during the development process

27 Maintaining Your Credibility and Tips for Influencing the FDA (cont.) Sound public policy Are the data being requested or issues being raised by CDRH consistent with sound public policy? Is is consistent with the Federal, Food Drug and Cosmetic Act, FDA regulations, published guidance, or precedents If not have you appealed? Up the supervisory chain Have you utilized the informal and/or formal dispute resolution process Do you have any support inside FDA for your position? Have you spoken with the CDER / CDRH or FDA Ombudsman? Is it time (and wise) to seek Congressional intervention

28 Maintaining Your Credibility and Tips for Influencing the FDA (cont.) Is it time for legal action? Have you exhausted all administrative procedures? Has there been a final agency action? Has FDA acted in an arbitrary or capricious manner? Has FDA abused it s discretionary authority? What is the legal relief that you are seeking? Stay of a decision or action or injunctive relief An overturning of a scientific determination or finding Judicial review of FDA s application or reading of the law, regulations, guidance Does the relief sought make practical sense in light of the legal principles or economics of the specific situation

29 Maintaining Your Credibility and Tips for Influencing the FDA (cont.) What price do you pay when you challenge the system? Do you win the battle but lose the war? Will FDA retaliate? What other products are pending at FDA? What is the company s compliance profile? How much disruption will there be around the company if there is a protracted legal action?

30 Managing Your Company s Relationship with FDA Understand FDA s expectations and try to meet them Try to educate reviewers about your product and justify your development plans based on solid science There are often many ways to achieve the same outcome You can disagree with FDA decisions Work your way up the leadership chain Strong scientific support Sound policy reasons Legal arguments as necessary and appropriate Find applicable precedents Advocate your position, listen to FDA s arguments, Be respectful and professional

31 Contact David Rosen Foley & Lardner LLP 3000 K Street N.W. Suite 500 Washington, DC Telephone: Fax: drosen@foley.com