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Ensuring FDA Regulatory Success for Biomedical Companies -- Key Lessons for Start-Ups

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Supporting Materials for Michael Swit's Panel remarks at the Workshop Co-sponsored by the Orange County Regulatory Affairs (OCRA) Discussion Group and the Small Business Development Center (SBDC) @ UCI Applied Innovation

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Ensuring FDA Regulatory Success for Biomedical Companies -- Key Lessons for Start-Ups

  1. 1. Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Ensuring FDA Regulatory Success for Biomedical Companies Key Lessons for Start-Ups Michael A. Swit, Esq. Vice President, Life Sciences Supporting Materials for Michael Swit’s Panel Remarks at Workshop Co-sponsored by the Orange County Regulatory Affairs (OCRA) Discussion Group and the Small Business Development Center @ UCI Applied Innovation (SBDC) October 25, 2018 Irvine, California
  2. 2. Solving FDA Legal Challenges for the Life of a Life Sciences Company -2- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Standard Disclaimers • Views expressed here are solely mine and do not reflect those of my firm or any of its clients. • This presentation supports an oral briefing and should not be relied upon solely on its own to support any conclusion of law or fact. • These slides are intended to provide general educational information and are not intended to convey legal advice.
  3. 3. Solving FDA Legal Challenges for the Life of a Life Sciences Company -3- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT FDA's Three Key Development Roles ▪ "Gatekeeper" to the marketplace -- the new drug and device approval/clearance processes ▪ "Cop on the beat" or "Enforcer" -- ensuring quality compliance via inspection and enforcement actions (e.g. criminal charges) ▪ "Sentinel" of Safety Concerns -- during development and post-approval
  4. 4. Solving FDA Legal Challenges for the Life of a Life Sciences Company -4- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 4 Where The Pitfalls Lie • Overall Planning • Working With FDA • Clinical Trial Execution • CMC and Design History Issues • Safety Issues • Labeling • Ingredients – Active And Inactive; Components for Medical Devices • Final Sermons
  5. 5. Solving FDA Legal Challenges for the Life of a Life Sciences Company -5- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 5 Overall Planning • Create A Project Plan With Well-defined Go/No- go Decision Points – – Difficult, But Vital To Know When To Shift Gears. – Plan With The End In Mind – your ultimate labeling will drive what you need to do – create a “Product Profile” early and try to stick to it. – Clinical Regulatory Integrated Strategic Plan (CRISP)
  6. 6. Solving FDA Legal Challenges for the Life of a Life Sciences Company -6- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 6 Overall Planning … • Understand What Your Product Is (yes, sometimes, it is not clear): – Drug – Biologic (but regulated as a drug in U.S.) – Device – Combination Product – Cosmetic – Dietary Supplement – Food • And, remember, often it is what you say about a product that determines what it is … – For example, contrast: • Water – labeled to drink = food • Water – labeled to cure cancer = drug
  7. 7. Solving FDA Legal Challenges for the Life of a Life Sciences Company -7- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 7 Overall Planning … • Make Sure You Are Ready To Go From “R" to “D" – Internally - people and systems; change in mindset from research to development. – Formulation or Design -- Rigorously Reviewed -- so as to optimize your chances when going into humans. – Once Clinical Evaluation With A Compound or Prototype Begins, Preclinical Efficacy Experiments -- should be limited or undergo rigorous review and oversight. – Educate Scientists And Researchers – on the realities of the demands of development, especially documentation • Example -- report writing -- may be a weakness in research, but is important in development. Start early in the process. • Medical device design controls SOPs – when they apply; what to do before hand
  8. 8. Solving FDA Legal Challenges for the Life of a Life Sciences Company -8- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 8 Overall Planning … • Make Sure Regulatory, Clinical, And Sales & Marketing Are All Talking Early On – – Ensure Indication or Intended Use (thus, Endpoints) Being Studied Is One You Want To Sell (and can get reimbursed for) – Some Considerations • Study Design –while marketing may want superiority if you go for that sort of study and fail, the FDA won’t let you reanalyze the study for non-inferiority -- hence failed development program… • Indication or Intended Use Choice – consider limited initial indication that can be the starting point for subsequent bigger indications – can be key to optimal product lifecycle management
  9. 9. Solving FDA Legal Challenges for the Life of a Life Sciences Company -9- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 9 Overall Planning … • Beware of "Divergent Evolution" between Product Development and Intellectual Property Efforts! – How Patents Can Evolve • Attaining patent protection for a novel chemical entity or formulation – or a device design -- is a multiyear process, • In process, claims often become more limited in number and in scope due to prior art, Patent Examiner concerns, etc. – Ensure A Strategic Linkage Between The Product Development And Patenting Efforts -- to best assure: • Patent(s) granted actually cover critical features of the product being studied in clinicals • Clinicals actually cover patented/able claims
  10. 10. Solving FDA Legal Challenges for the Life of a Life Sciences Company -10- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 10 Overall Planning … • Understand Approval Is Not Enough, Somebody Has to Pay for It!! - coverage (on formulary) and reimbursement (at a reasonable copay tier). – Some keys: • Label claims -- Is there anything novel you can say? • Comparative effectiveness: – future of reimbursement – future for competitive/comparative claims – clinicals will be needed (FDA/FTC) • Embed outcomes measures in your clinical studies at the front end – thus need to work with payers before clinicals to ensure that you include those measures – Going back later to get that data will be expensive and delaying
  11. 11. Solving FDA Legal Challenges for the Life of a Life Sciences Company -11- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 11 Overall Planning … • Other Key Planning Efforts – Product Name – • Globalize the product name (be careful with different meanings) • Seek regulatory agency concurrence early. – Find Collateral Support; e.g., Patient Groups, Thought Leaders (aka “Key Opinion Leaders” or “KOLs”) • can help with identifying investigators • can help with patient recruitment – Identify Enemies -- commercial and otherwise (e.g., special interest groups) • Anticipate their moves (e.g., Citizen Petitions) – Pediatric Assessments -- need a plan to address pediatric usage for drugs; may emerge for devices
  12. 12. Solving FDA Legal Challenges for the Life of a Life Sciences Company -12- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 12 Overall Planning … • Management – Must Understand Process. – Must Support Company's Quality System, Especially As A Company Matures. • Device companies – affirmative duty under QSR regulations – Don’t Let Financial Milestones Drive Development – recipe for disaster (e.g., Refuse To Files, Clinical Holds). – Contrast: “What is the minimum we need to do to get approval?" vs. "What is necessary for us to provide in order to get a first cycle review approval". [if your CEO thinks first option is OK, time to update your CV]
  13. 13. Solving FDA Legal Challenges for the Life of a Life Sciences Company -13- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 13 Coordinating with EU • Start planning early for simultaneous efforts • Drug approvals – systems in EU are somewhat similar, but not identical – Complex considerations on scientific advice – Need to ensure you understand if must co via Centralized Procedure or can go Mutual or Individual Member states • Devices – CE Marking Process is quite different from FDA – Generally seen as less onerous than U.S. – But, choose your Notified Body with care • Other regions – also require careful coordination and expertise
  14. 14. Solving FDA Legal Challenges for the Life of a Life Sciences Company -14- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 14 Working With FDA • Early interaction -- essential to understanding your path and what you need for the journey – FDA encourages and appreciates (usually) being consulted early in the development stage -- helps build a relationship with agency that can pay off during the approval process. – Take advantage of all Regulatory “value-added” initiatives – e.g., • Drugs -- Breakthrough, Fast Track, Accelerated Approval, Orphan Drug, Special Protocol Assessments (but be careful on this) • Devices – Abbreviated 510k, Special 510(k), HDE, etc.
  15. 15. Solving FDA Legal Challenges for the Life of a Life Sciences Company -15- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 15 Working With FDA … • Seek to Ensure You Get Agency Agreement On Exactly What Is The Indication – will drive related labeling language, especially if related to disease, treatment or metrics – Example: “Chronic sinusitis” • Not in DSM or accepted text books -- really a term of art among ENTs. • Company – started clinical trials, – Then, went to FDA – “we’re treating chronic sinusitis!!” • FDA -- “what’s that?” -- leading to a rather lengthy debate about symptomatology of “chronic sinusitis”. • Result – company had already studied something not entirely covered by the now agreed upon definition of “chronic sinusitis” both as to: – outcomes – method of measuring • Consequence – also can end up proving a labeled indication that does not jibe with original marketing projections
  16. 16. Solving FDA Legal Challenges for the Life of a Life Sciences Company -16- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 16 Working With FDA … • Safety is Lynchpin Today – – Focus On Signals/AE’s Early • Ensure personnel evaluating are qualified – “REMS” – • “Risk Evaluation and Mitigation Strategies” • Can be required due to Food & Drug Administration Amendments Act of 2007 • You Need to control REMS process; don’t let FDA – Example: anticipate Phase IV, Post-Approval Study, but drive its design – Device approvals –consider similar risk management issues
  17. 17. Solving FDA Legal Challenges for the Life of a Life Sciences Company -17- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 17 Working With FDA … • Logistics: – Understand IND and IDE Regulations – especially on changes: • Amendments • Annual reports – Use the Pre-IND (drugs/biologics) and Pre-Submission (devices) processes – and later meetings such as End of Phase 2 and pre-NDA/PMA filing meetings -- educates FDA and gain clarity on requirements – Keep Detailed Records Of All Interactions between the sponsor and the regulatory agencies. – After Submission -- Be Very Diligent with Follow-Up. • Ensure mandatory review milestones are achieved by the reviewer. • “Force” dialogue if necessary.
  18. 18. Solving FDA Legal Challenges for the Life of a Life Sciences Company -18- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 18 Working With FDA … • Logistics … – Respond To FDA Deficiency Letters and Other Comments During Review Promptly, Fully, And Honestly • Know how the system works - if you don't agree with a reviewer's decision, work up the chain of command • In responding to a deficiency letter: – Respond to FDA's comment in the first sentence. – Give clear and concise responses -- do not ramble and do not discuss other topics. • In interacting with an FDA official, if you do not know the answer to a query, do not guess. – Refer to a colleague who could provide the response. or tell reviewer you will get back with correct reply
  19. 19. Solving FDA Legal Challenges for the Life of a Life Sciences Company -19- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 19 Working With FDA … • Formal Meetings – Don’t Guess Who’s Coming to Dinner -- • FDA: learn as much as possible about the regulatory agency meeting attendees – background (full CVs, hot buttons, past publications) • Company: carefully pick who you will be taking to the meetings to represent your company – internal people, consultants – Rehearse, Rehearse, Rehearse: a well-rehearsed meeting = productive meeting • Anticipate questions -- have a plan of how and who will respond • Use outsiders to prepare – otherwise, you lose perspective
  20. 20. Solving FDA Legal Challenges for the Life of a Life Sciences Company -20- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 20 Working With FDA … • Formal Meetings – Consider technology assistance -- for advisory meetings – Hide your lawyers!! • unless there is a clear legal issue -- and, if you do bring, FDA will bring in theirs • SCIENCE should drive meetings – Outside Experts – • Use judiciously • Ensure qualified – and review their publications and other statements to make sure they have not said something that undermines your position
  21. 21. Solving FDA Legal Challenges for the Life of a Life Sciences Company -21- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 21 Working With FDA … • Late in Review Process– a tip: – Prepare For An Advisory Committee/Panel Meeting, Even If One Is Not Likely – • Helps you to know your arguments on key issues before they arise (as they often do) should the regulatory agencies signal a need to negotiate on your submission
  22. 22. Solving FDA Legal Challenges for the Life of a Life Sciences Company -22- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 22 Working With FDA … • Listen!! – If You Get Regulatory Agency Advice -- Do It! (well, almost all the time) • Failure to adhere to any given advice may only subsequently antagonize the reviewer. • Caveat -- If you don’t want to do it or think it’s wrong, engage FDA promptly to gain its buy-in to your position – Don’t just ignore FDA and go down your own path • Keep your Promises!! – A sure way to lose credibility – fail to deliver what you promised
  23. 23. Solving FDA Legal Challenges for the Life of a Life Sciences Company -23- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 23 Clinical Trial Execution • Unfortunate, But Often Accurate Generalization -- failure to design and execute study properly too often characterizes clinical studies at both small and even large companies • Inadequate Toxicology Review Prior to Phase I – use an outside set of eyes if you can
  24. 24. Solving FDA Legal Challenges for the Life of a Life Sciences Company -24- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 24 Clinical Trials … • Poor Design Issues: – Result -- leads to protocol violations, deviations, and half effective amendments. – Consequence of deviations, violations -- study “mutates” – • progress and treatment of first patient barely resembles last patient -- study population no longer homogeneous • Final Mutation -- heterogeneous population defies statistical analysis`
  25. 25. Solving FDA Legal Challenges for the Life of a Life Sciences Company -25- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 25 Clinical Trials … • Primary Efficacy Endpoints – Must do adequate Phase 2 studies…dose, dosing regimens, etc. so that you aren’t second guessing the appropriate dose in Phase 3 – Be Sure Endpoint Is Validated And Acceptable to FDA • this includes Phase 2b studies • Involve Statisticians In Clinical Design – Don’t Delay Until Problem Occurs – Can Help Define The Study Design At The Correct Stage -- speeds clinical development process
  26. 26. Solving FDA Legal Challenges for the Life of a Life Sciences Company -26- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 26 Clinical Trials … • Key Opinion Leaders: – Include KOL’s In Clinical Program – But, don’t blindly let them design the protocol – But, don’t let Sales/Marketing drive this, as can lead to: • Stark Act issues – distinguish KOL’s from big ‘scribers • Financial disclosure challenges – cost of studies vs. consulting fees – FDA Financial Disclosure rules – 21 CFR Part 54 – Sunshine Act requirements
  27. 27. Solving FDA Legal Challenges for the Life of a Life Sciences Company -27- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 27 CMC/Design Specification Issues • Design Product Physical Characteristics To Be As Robust As Possible – Validate And Qualify – • Drugs -- e.g., dosage form, stability, content uniformity • Devices – choice of biomaterials; design changes – Drugs -- keep A Lot History/Change Control System At The Earliest Stage -- even if very rudimentary form (such as memos to file) – it may be important later to track back to what was done even at early stages • Ideally just as soon as something in "R" starts to show potential of interest to those in "D"! • Do even if project is still under "Research" control -- don't wait for a refined QA system to be implemented or for the researchers to be trained in drug development concepts. – Devices – Design History File is key – make sure it is well-kept
  28. 28. Solving FDA Legal Challenges for the Life of a Life Sciences Company -28- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 28 CMC/Design Specification Issues • Plan For Commercial Scale Production Early – – pre-NDA meeting is no time to learn that you need additional stability or a bioequivalence study to qualify your commercial product (e.g., larger scale, imprinting/debossing etc.) against the one studied in development. • Track And Validate Changes In Processing And Formulations/Designs – ensure studied process/formulation will support commercial process/formulation
  29. 29. Solving FDA Legal Challenges for the Life of a Life Sciences Company -29- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 29 Safety • Detect Issues As Early As Possible – Use Newer In Vitro Approaches to predict potential safety problems (if possible) – Cardiovascular Signals – Key Driver (e.g., HERG) • Dose-Response Data -- – Seek Early On In Animal Studies (if possible) – Vital To Ensure Proper Dose for Phase II
  30. 30. Solving FDA Legal Challenges for the Life of a Life Sciences Company -30- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 30 Labeling • FDA Concurrence On Main Indication/Intended Use -- NOT Enough -- Must Get Sign-off on Other Key Label Claims – – Example -- secondary endpoints • TIP -- Prepare optimal labeling and at least three defensible fallback positions for each key statement.
  31. 31. Solving FDA Legal Challenges for the Life of a Life Sciences Company -31- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 31 Outside Vendors • Audit Aggressively – Prequalification – key – have a robust SOP for doing so • Use outside auditors if you can – more objective; not subject to the “heat” or “dance” of the deal – Types: CROs, clinical investigators, contract manufacturers, API and component makers, nonclinical testing facilities – Don’t Miss Any • Joint venture partners - e.g., Cialis® - Lilly manufacturing plant problems - delayed approval about one year • Contract Lab (e.g., MDS) problems – analytical testing – delayed approvals • IRBs - have been shut down in past • Quality Agreements – essential – must be detailed, robust
  32. 32. Solving FDA Legal Challenges for the Life of a Life Sciences Company -32- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 32 Outside Vendors … • How To Handle: – Audit SOPs, Training, Documentation & Follow-Up – keys to auditing • If don’t have internal expertise, hire qualified consultants (of course, you have to qualify them also) – Insist Contractors Include Sponsor On Document Reviews, such as • Clinical Protocols • Manufacturing-related [master and production batch records, analytical data, stability protocols/data, deviations, etc.] • Nonclinical [draft protocols and reports] documents.
  33. 33. Solving FDA Legal Challenges for the Life of a Life Sciences Company -33- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 33 Outside Vendors … • How To Handle: – Keep Control -- do not let a contractor direct your project – Avoid “CRO Creep” – use stringent and explicit contract language – Liability - even when you outsource, you are ultimately liable for what happens -- you still need to have systems and people in place to ensure your vendors are working correctly
  34. 34. Solving FDA Legal Challenges for the Life of a Life Sciences Company -34- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 34 Ingredients – Active And Inactive • Assure Adequate Supplies -- of all components of the product, packaging, etc. • Naturally-Derived Products – Supply Chain And Cost-of-goods – key issues down the road as well as with potential investors – – Investigate Alternative (e.g., synthetic) Sources • Challenge or Opportunity? – – synthetic source may require new clinicals – may delay or bar generic competition
  35. 35. Solving FDA Legal Challenges for the Life of a Life Sciences Company -35- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Final Sermons • Don't Bury Your Head To Problems -- investigate and disclose promptly • Don't Fall Madly In Love With Your Technology – – You Have To Prove Safety And Effectiveness – – "I just know it works" -- not the standard in the Federal Food, Drug, and Cosmetic Act – … your baby may have some warts
  36. 36. Solving FDA Legal Challenges for the Life of a Life Sciences Company -36- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Questions? • Call or e-mail: Michael A. Swit, Esq. LAW OFFICES OF MICHAEL A. SWIT San Diego, California m: 760-815-4762 e: mswit@fdacounsel.com web: www.fdacounsel.com • Follow me on: – LinkedIn: http://www.linkedin.com/in/michaelswit – Twitter: https://twitter.com/FDACounsel LAW OFFICES OF MICHAEL A. SWIT
  37. 37. Solving FDA Legal Challenges for the Life of a Life Sciences Company -37- www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT About Your Speaker Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30 years. Before returning to his private law practice in late 2017, he served for 3 years as the chief regulatory counsel at Illumina, Inc., the world’s leading developer of gene sequencing technologies. Prior to that, Swit was a special counsel in the FDA Law Practice at the global law firm of Duane Morris LLP, in its San Diego office. Before joining Duane Morris in March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes product development, compliance and enforcement, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics, therapeutic biotech products, medical devices, and IVDs. His FDA legal and regulatory work also has included tenures in private practice with McKenna & Cuneo and Heller Ehrman, and as vice president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty drug firm, where he helped spearhead the company’s emergence from the Generic Drug Scandal. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of regulatory newsletters and other specialty information products for FDA-regulated firms. He has taught and written on many topics relating to FDA regulation and associated commercial activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at Emory University.

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