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Food and Drug Law November 8, 2010

Food and Drug Law November 8, 2010. Ralph F. Hall. Overview. Current events Hatch Waxman Critical Path Initiative Medical devices Classification 510(k) process Current 510(k) issues PMA process. Hatch-Waxman Act. Or The Let’s Make Patent Lawyers Rich Act. Hatch-Waxman Overview.

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Food and Drug Law November 8, 2010

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  1. Food and Drug LawNovember 8, 2010 Ralph F. Hall

  2. Overview • Current events • Hatch Waxman • Critical Path Initiative • Medical devices • Classification • 510(k) process • Current 510(k) issues • PMA process

  3. Hatch-Waxman Act Or The Let’s Make Patent Lawyers Rich Act

  4. Hatch-Waxman Overview • Major new use of FDCA and FDA • First major FDCA provision designed to regulate industry economics • Adding economics to FDA’s public health role • Ability of FDA to be economic policy maker • Prior “economic” provisions were anti-fraud • Major linkage of two separate regulatory systems • FDA and PTO

  5. Hatch-Waxman • Trade off of two competing policies • Faster access to cheap generics • Loss of patent protection due to FDA review process • Generics got: • ANDA process • No clinical testing • Certainty • Innovators got: • Extended exclusivity

  6. Hatch-Waxman • Clinical data is trade secret • Eroding provision? • New York fraud cases • Clinicaltrials.gov • Orange book listing • Impact • $100 BB in sales “at risk” for big pharma in next 5 years • 70% of all prescriptions are for generics • Generic v. generics

  7. Hatch-WaxmanBasic process • Generic references “pioneer drug” • Active ingredient the same • Same dosage, formulation, etc. or • Bioequivalence or • Same pharmacology/therapeutic class w/ same effects • Same labeling • If so, no clinical testing • “Pioneer” has to list all relevant patents • Patent status included in ANDA • No patent listed • Expired patent • Approval on date of expiration • “Paragraph IV” certification

  8. Hatch-Waxman • Paragraph IV certification process • ANDA application contents • Patent is invalid or not infringed • What about “unenforceable” • Notification to patent holder and NDA holder • Notice specifies factual and legal basis why patent not infringed or invalid • Patent holder has exclusive 45 day period to sue • Application then on hold for up to 30 months

  9. Hatch-Waxman • Market exclusivity • No ANDA for 4 or 5 years post pioneer approval for NCEs (NMEs) • New uses for pioneer NCEs get 3 year protection • No ANDA for 3 years for non-NCEs • 30 month period for litigation • Post 30 months market at own risk

  10. Hatch-Waxman • Approval effective if district court or appellate court finds patent invalid or not infringed • Date of settlement agreement or consent decree finding patent not infringed or invalid • First generic applicant gets 180 exclusivity • What about process patents? • List each patent that “claims the listed drug” • Different formulations (“controlled release formulation”)

  11. Critical Path Initiative http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm204289.htm

  12. Critical Path Initiative • Declining number of innovative new drugs • NCEs or NMEs • Fewer drugs, longer time periods, higher cost • Still have post market issues • CPI intended to accelerate or streamline drug development • Emphasis on new developmental processes

  13. Medical Devices

  14. Historical Development • 1906 • Devices not separate category • 1938 • First consideration of devices • 1976 • Medical Device Amendments • Implemented Cooper Report • Approval process, classification, etc. • 1990 • SMDA • Added post market surveillance and other • 1997 • FDAMA • 2002 • MDUFMA • 2007 • FDAAA

  15. Statutory Definition of a Device21 USC 321 (h) The statutory definition of a device requires that a device be an: • Instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar related article, including any component, part or accessory

  16. Statutory Definition of a DeviceAdditional Requirements Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease in man or other animals Intended to affect the structure or any function of the body of man or other animals

  17. Statutory Definition of a DeviceAdditional Requirements • Not achieve any of its principal intended purposes through chemical action within or on the body of man • Not dependent on being metabolized to achieve any of these purposes • Listed in USP

  18. Types of Medical Devices • Implantable, active, life sustaining • ICD • Implantable, passive, life sustaining • Heart valve • Critical care, acute use • heart lung machine • Acute use, diagnostic • MRI, X-Ray • Remote use, critical care • Home oxygen • Remote use, diagnostic • Blood glucose monitor • Convenience or low risk • bed pan

  19. Device Concepts • Devices present range of risk • Not the view about drugs • Effort to match risk and regulation • Builds on core 1906 concepts • Technology differences • Faster changes • Shorter life cycles • Different clinical trial needs • Total Product Life Cycle (TPLC) approach

  20. Key Regulatory Structure • It is illegal to ship an adulterated or misbranded device in interstate commerce (21 U.S.C. §§ 331, 351, 352) • Introduction into interstate commerce (or receipt) • Manufacture of adulterated or misbranded device • Adulteration and misbranding include: • Failure to get approvals (§351(f)) • Manufacturing/quality problems • Failure to file reports • Improper promotion • False or misleading labeling

  21. Comparison to Other Regulatory Structures

  22. Comparison to Other Regulatory Structures

  23. Device Classification and Approval

  24. Device Classification Overview • Is it a device? • If yes, is it an old device? • If no, what level of control is needed? • General (Class I) • Special (Class II) • Device specific (Class III) • Is it substantially equivalent to a prior device? • Is a clinical trial needed?

  25. Device Classification Purpose • The goal of the classification system is to tailor the level of regulation to the characteristics of the device • Risk • Complexity • History or knowledge • FDA divides all devices into three classes • Classes I, II and III • Consistency requirement

  26. Device Classification • Class I - general controls are sufficient to provide reasonable assurance of safety and effectiveness • General controls include: • FDA’s misbranding and adulteration powers • Registration requirements and reporting obligations • Basic manufacturing controls • Most Class I devices are exempt premarket notification or approval • Class I includes tongue depressors, elastic bandages, ice bags, and bedpans

  27. Device Classification • Class II - general controls are not sufficient and for which special controls will provide the necessary assurance • Special controls can include • Post market surveillance or patient registries • Guidelines (including guidelines for the submission of clinical data and premarket notification submissions) • Other administrative controls (including 510(k)s) • Class II includes such products as syringes, bone plates, hearing aids, and resuscitation devices

  28. Special Controls • Include general controls • Can include • design requirements • Materials • Performance characteristics • Generally product type specific • Infusion pump issues • New special controls proposed • Administrative processes

  29. Device Classification • Class III - devices that cannot be adequately regulated under either Class I or II • General controls are not sufficient, and not enough is known about the device to regulate it adequately with special controls • Class III devices are subject to the requirement of a premarket approval application containing valid scientific evidence of the safety and effectiveness of the device • Class III contains such products as pacemakers, IUDs, and artificialhearts

  30. Device Classification • Grandfathered devices • Pre 1976 • General obligations apply • Adulteration and misbranding • Reporting • “New” devices • Assigned by preexisting rule • Presumption of Class III • Agency determination • Petition, regulation, etc. • Reclassification petition • De novo process

  31. Device Approval Process • Illegal to distribute an “unapproved” device • IDE exemption • Pre 1976 devices • Paths to approval • Class I devices not subject to 510(k) • 510(k) for lower risk devices • Premarket notification • Class II and some Class I devices • PMA for higher risk devices • Class III and some Class II devices

  32. Device classification and approval 510(k) PMA Low risk High Risk Class I Class II Class III

  33. 510(k) Submission for Some Class I and Most Class II Devices • Substantial Equivalence (SE) • The goal of a 510(k) submission is to demonstrate substantial equivalence to a device that is already legally marketed. (see section 510(k) of the FDCA (21 U.S.C. § 360 (k)). • The 510(k) process involves a comparison of one device to another. • The device used for comparison purposes is the “predicate” device.

  34. Recent 510(k) Controversies • 510(k) creep • Lack of clinical data • Technology, not clinical, focus • Number and types of submissions • ReGen • Role of “political” pressure • Current activities • IOM study • FDA study • Data needs

  35. Comparison to Marketed Device NSE No Same Intended Use? New Technological Characteristics and New Questions of Safety and Effectiveness Yes No Data Demonstrates Equivalence Yes SE 510(k) Decision-Making Process

  36. Device Modifications • A new 510(k) notice must be filed for a legally marketed device if it is significantly modified in design, components, method of manufacture, or intended use • Significant modifications include: • Changes that could significantly affect safety or effectiveness, e.g., a significant change in design, material, chemical composition, energy source, or manufacturing process • Major changes in the intended use of the device

  37. Determining Whether a 510(k) Must Be Submitted for a Device Modification • Is the proposed modification “significant”? • Is it a major change in the intended use? • New therapy • New patient population • “Could” it significantly affect safety or effectiveness? • Does it perform in a different manner

  38. 510(k) Special Categories • Certain special categories exist: • Special 510(k)s • Device modification • Design controls/QSR • Declaration of Conformity • Abbreviated 510(k)s • Use of guidance documents/special controls • Declaration of Conformity • Allow faster handling of certain lower risk 510(k) applications

  39. PMA Process • Purpose of PMA is to establish “reasonable assurance” that device is safe and effective • Cannot market or ship without an approved PMA • PMA required for Class III and some Class II devices • PMA filingincludes: • Animal studies • Clinical studies • Indications for use • Contradictions, warnings and adverse events • Manufacturing information • Proposed labeling

  40. NDA/PMA Comparison • Standard for approval • NDA – safe and effective (355 (d) • PMA – “reasonable assurance of safety and efficacy (360e(d)) • Explicit consideration of risk/benefit • Clinical trials not mandatory for PMA

  41. SPMA Process • PMA supplement is required for any change which could affect safety or effectiveness • Includes more changes than 510(k) standard • Examples include: • New indications • Sterilization changes • Labeling changes • Manufacturing changes • All other changes are to be included in an annual report

  42. PMA Process • Special PMA – changes been effected • Certain narrow changes such as enhanced warnings can be made upon submission to FDA • Manufacturing Changes • Certain narrow manufacturing changes can be made upon 30 days notice • 21 CFR 814 and guidance documents set forth processes and requirements

  43. PMA Process • Advisory Panel • FDA can assemble an “expert” panel from outside FDA for input on scientific or clinical questions • Panel conclusions are advisory • Panel meetings are public • Panels used for new or controversial therapies • Panel meetings add significant time to approval process • Regulated by FACA • Conflict of interest issues • Improper delegation of authority issues

  44. PMA Process • 180 day approval clock • Standards for approval • Approve application if no grounds for denying approval exist (360e(d)(1)(A) (i)) • Based on proposed labeling • Reasonable assurance of safety and efficacy • Labeling not false or misleading

  45. PMA Process • Reasons for denial • lack of showing of “reasonable assurance” of safety • lack of showing of “reasonable assurance” of efficacy • Quality system issues • False or misleading labeling • Failure to meet a performance standard

  46. PMA Process • Fast track devices • breakthrough technology • No approved alternative therapies • Significant advantage over existing therapies • “best interest of patients”

  47. Special Categories • Humanitarian devices (360j(m)) • Small population (4,000) • Designation • Exempt from effectiveness review • Safety still required • Custom devices (360j(b)) • Individual specifications • Dentures • Emergency use • Life threatening • No option • Notification

  48. Revising the 510(k) system

  49. Reality Check 510(k) under great pressure Congress, FDA, public advocacy groups Industry has few allies or friends Multiple issues and concerns Product review system (including 510(k)) No data demonstrating systemic safety issues FDA hasn’t identified any FDA feels compelled to act Increasing Congressional interest Something will be done Too much pressure and time investment

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