ACC February 2015 Quick Hit. FDA Hot Topics. David L. Rosen, B.S. Pharm., J.D. Foley & Lardner LLP (202)

Transcription

1 1 ACC February 2015 Quick Hit FDA Hot Topics David L. Rosen, B.S. Pharm., J.D. Foley & Lardner LLP (202) Foley Foley && Lardner LLP LLP Attorney Advertising Prior Prior results results do do not not guarantee a similar a similar outcome Models Models used used are are not not clients clients but may be representative of clients 321 N. Clark Street, Suite 2800, Chicago, IL but may be representative of clients 321 N. Clark Street, Suite 2800, Chicago, IL

2 2 Greetings from Washington, DC

3 3 The President and Cabinet Send Their Regards Margaret Hamburg, MD

4 4 Bo and Sunny Send Their Greetings Too!

5 5 My Dog Goddard Also Says Hello

6 6 Congressional FDA Initiatives! The 114th Congress has just been sworn! House Energy and Commerce Committee has placed FDA reform issues as a top priority! 21st Century Cures Initiative will be a major focus early this year. discovery, development, and delivery of treatments and cures relaxing how companies communicate off-label information about their products how to increase transparency, such as how to publicly open the agency s significant amount of clinical trial data submitted by companies.! Repeal of the 2.3% medical device excise tax through the Medical Device Access and Innovation Protection Act

7 7 21st Century Cures Act Discussion Draft! TITLE I PUTTING PATIENTS FIRST BY INCORPORATING THEIR PERSPECTIVES INTO THE REGULATORY PROCESS AND ADDRESSING UNMET MEDICAL NEEDS! TITLE II BUILDING THE FOUNDATION FOR 21 ST CENTURY MEDICINE, INCLUDING HELPING YOUNG SCIENTISTS! TITLE III MODERNIZING CLINICAL TRIALS! TITLE IV ACCELERATING THE DISCOVERY, DEVELOPMENT, AND DELIVERY CYCLE AND CONTINUING 21 ST CENTURY INNOVATION AT NIH, FDA, CDC, AND CMS! TITLE V - MODERNIZING MEDICAL PRODUCT REGULATION

8 8 21st Century Cures Act Discussion Draft! Title I proposals intended to incorporate patient perspectives into the regulatory process help address their unmet medical needs Requiring that a structured risk-benefit assessment frame be built into the new drug approval process! that includes the development and use of patient experience data to facilitate a balanced risk-benefit consideration, and the development and implementation of a consistent and systematic approach to the discussion of, regulatory decision making with respect to, and the communication of, the benefits and risks of new drugs

9 9 21st Century Cures Act Discussion Draft! Surrogate endpoint qualification and use! Qualification of other biomarkers! Modify the breakthrough therapy evidentiary standard! Foster the development of new antibiotics! Require greater transparency for expanded access program! Allow for streamlined data review so that the sponsor of an approved prescription drug can submit qualified data summaries in a supplemental application for approval of a qualified indication (i.e., an indication for the detection, diagnosis, prevention, treatment, or cure of cancer, or other types of indications identified by FDA)! New patent and non-patent exclusivity opportunities

10 10 21st Century Cures Act Discussion Draft! Provisions concerning genetically targeted platform technologies for rare diseases! Revisions to human subject research regulations! The requirement that FDA establish and implement a framework through which sponsors of drugs, biological products, or devices may submit to the Secretary a proposal for the incorporation of adaptive trial designs, Bayesian methods, or other alternative statistical methods into proposed clinical protocols and marketing applications for drugs, biological products, or devices! Changes to the Tropical Disease Priority Review Voucher provisions of FDC Act 524 that broaden the voucher program to infectious diseases! Creation of a new precision medicine initiative! FDA succession planning

11 11 FY 2016 Budget Request to implement the FDA Food Safety Modernization Act! Improve the quality and safety of medical products! Implementing a New Food Safety System training of new inspectors; provide the appropriate guidance to industry about the changes the law will bring; strengthen the role of the states in helping to ensure the safety of the country s food supply; and build and implement a new import safety system

12 12 FY 2016 Budget Request to implement the FDA Food Safety Modernization Act! Improving the Safety and Quality of Medical Products! Key priorities include combating the growing threat of antibiotic resistance; facilitating the development and appropriate use of reliable molecular and genetic diagnostics also known as precision medicine tools to personalize the diagnosis and treatment of disease; implementing key requirements of the Food and Drug Administration Safety and Innovation Act; addressing the safety of compounded drugs and medical products; and Implementing the Sunscreen Innovation Act.

13 13 FY 2016 Budget Request to implement the FDA Food Safety Modernization Act! Building a More Modern FDA More scientists, doctors, analysts and inspectors are deemed necessary to fulfill the FDA s evolving mission The FDA is seeking additional funding for rental payments and a feasibility study to update and issue a revised Master Plan for the White Oak campus to address its expanded workforce and the facilities needed to accommodate them.

14 14 FDA Hot Topics! Biosimilars! Generics! Quality of Products Imported Domestic! E-Cigarettes and related articles! Supply Chain Integrity! Pharmacy Compounding! Drug Shortages! Off Label Uses! Use of Social Media! Mobile Medical Device Applications! Conduct of Clinical Investigations

15 15 Device Hot Topics! Guidance on General Wellness Products Exempts products fitting into GW category! Guidance on Device Accessories Provides clarification on definition! Guidance on 510(k) Transfers Clarifies process and coordination with device listing! Final Order: remarket approval for AEDs required

16 16 What are the Key Laws Enforced by the FDA?! The Federal Food, Drug and Cosmetic Act Governs the approval, production, shipping, holding, testing, promotion, distribution, import and export drugs, medical devices, dietary supplements, food and electronic products! The Public Health Service Act Governs the licensing of biologics and provides for the control of communicable diseases spread by food (or other products)

17 17 What are Some of the More Significant Amendments to These Laws! The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman) Allows for generic drugs to be approved by citing confidential safety and efficacy data included in a reference drug s application.! The Biologics Price Competition and Innovation Act of 2009 (BPCIA)! Allows biosimilar and interchangeable biological products to cite confidential safety and efficacy data included in a reference biological product s application

18 18 What are Some of the More Significant Amendments to These Laws? (cont.)! The Family Smoking Prevention and Tobacco Control Act Authorizes FDA to regulate tobacco products, including restrictions on the marketing and sale of tobacco products.

19 19! Biosimilars

20 Biologics Price Competition & Innovation Act of ! The Act amended the Public Health Service Act (PHSA) to create a new pathway for the approval of biological products biosimilar to an approved reference product or biosimilar and interchangeable with an approved product.

21 21 Scope of Biologics Covered! Anything for which a BLA is filed Biologics licensing application ( BLA ) is required for most complex biotech products:! a virus, therapeutic serum, toxin, antitoxin, blood, or blood component or derivative, allergenic product, or analogous product... applicable to the prevention, treatment, or cure of a disease or condition of human beings. PHSA 351(i)! New legislation amends this definition to include protein (except any chemically synthesized polypeptide)

22 Biologics Price Competition & Innovation Act of ! The Act amended the Public Health Service Act (PHSA) to create a new pathway for the approval of biological products biosimilar to an approved reference product or biosimilar and interchangeable with an approved product.

23 23 Lots of Issues Associated with the Development of Biosimilars! What is a biologic product! What is a biosimilar product! Nomenclature! Interchangeability requirements! Data Requirements CMC Indications clinical data Safety immunology data! Use of non US reference product! Non clinical data requirements! Impurity, degradant, cross linkages and related issues! Reference product drift! Requirements for non-heterogenious mixtures! Patent Information Exchange and Litigation! Bio - Betters! European Experience! Foreign market opportunities! Citizen Petitions! Guidances! Opportunities for Combination Products

24 24 Scope of Biologics Covered! Anything for which a BLA is filed Biologics licensing application ( BLA ) is required for most complex biotech products:! a virus, therapeutic serum, toxin, antitoxin, blood, or blood component or derivative, allergenic product, or analogous product... applicable to the prevention, treatment, or cure of a disease or condition of human beings. PHSA 351(i)! New legislation amends this definition to include protein (except any chemically synthesized polypeptide)

25 25 Definitions! A biosimilar product is: (1) highly similar to the reference product notwithstanding minor differences in clinically inactive components and (2) no clinically meaningful differences in terms of safety, purity and potency.! An interchangeable biosimilar is a biological product that may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

26 26 Basic Requirements for US Biosimilar Application (1) Analytical studies showing product is highly similar to a reference despite differences in clinically inactive components; (2) Animal studies (including assessment of toxicity); (3) Clinical study(ies) sufficient to demonstrate safety, purity and potency in 1 or more appropriate conditions for use that parallel an approved use of the reference product; *note: FDA may determine that any of 1-3 is not required in a given case

27 27 Basic Requirements For US Biosimilar Application (4) Requires same mechanism of action as reference product (if known) for approved indication; (5) Label for biosimilar must match approved indication of reference product; (6) Route of administration, dosage form, and strength must match reference product; (7) Must be approved manufacturing facility (safety, purity and potency).

28 28 Standard for Approval of Interchangeable Biosimilar! The FDA will label a biosimilar as interchangeable if: (1) it is found to be biosimilar and (2) expected to produce the same clinical result as the reference product in any given patient (3) for a biological product that is administered more than once the risk of safety or diminished efficacy of switching between the reference product and interchangeable is not greater than using reference product without switch

29 29 Sandoz Biosimilar Filgrastim Clears FDA Advisory Panel In Milestone Vote! FDA advisory panel unanimously (14-0 vote) advised FDA to approve Sandoz s version of Amgen s Neupogen Significant milestone for the first product to use the Affordable Care Act s biosimilars pathway.! FDA staff on Monday Jan 7, 2015 issued a report deeming Sandoz s Zarxio highly similar to Neupogen.! Formal approval is expected to occur in coming months, although pending patent litigation between Sandoz and Amgen could delay actual marketing.

30 30! FDA Quality Concerns

31 31 Ten Common Reasons for FDA 483 Observations and Warning Letter Citations 1. Complaint Handling Procedures are Inadequate 2. Corrective and Preventive Action (CAPA) Procedures are Inadequate 3. Written Adverse Event Reporting (AER) Procedures are Inadequate 4. Corrective and Preventive Actions are Inadequately Documented 5. Process Validation Procedures are Inadequate 6. Quality Audits were not Adequately Conducted 7. Executive Management Failed to Ensure Quality at all Organizational Levels 8. Procedures for Conducting Quality Audits are Inadequate 9. Procedures for Controlling the Manufacturing Process are Inadequate 10. Procedures for Change Control are Inadequate or Weren t followed during the Change Validation/Verification Process

32 Current Top 10 Objectionable Conditions 32! #10 Written procedures are not established followed for the cleaning and maintenance of equipment 21 CFR (b)! #9 Employees are not given training in the particular operations they perform as part of their function and cgmp 21 CFR (a)! #8 Batch production and control records are not prepared for each batch of drug product produced 21 CFR

33 Current Top 10 Objectionable Conditions 33! #7 Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications. 21 CFR (a)! #6 There is a failure to thoroughly review any unexplained discrepancy, the failure of a batch or any of its components to meet any of its specifications 21 CFR ! #5 There is no written procedure for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport to are represented to possess 21 CFR (a)

34 34 Current Top 10 Objectionable Conditions! #4 Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, test procedures designed to assure that components, containers, closures, in-process materials conform to appropriate standard of ISQ&P 21 CFR (b)! #3 Control Procedures are not established which monitor the output validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.21 CFR (a)

35 35 Current Top 10 Objectionable Conditions! #2 Written production and process control procedures are not followed in the execution of production and process control functions, documented at the time of performance 21 CFR (b)! #1 The responsibilities and procedures applicable to the quality control unit are not in writing, such written procedures are not followed. 21 CFR (b)

36 Enforcement Actions Under the Federal Food, Drug and Cosmetic Act! Prohibited Acts Generally some type of activity performed with an adulterated or misbranded product or resulting in an adulterated or misbranded product! Remedies: - Seizure - Injunction - Civil Money Penalties - Civil and Criminal Penalties (strict liability)! Other remedies include Warning Letters, untitled letters and other administrative penalties, import detention! Note that enforcement actions by the FDA may establish important policies 36

37 Enforcement Under the Federal Food, Drug and Cosmetic Act: Key Terms! Adulteration adulterated product generally describes a defect in the product (unsafe for its intended purpose, unacceptable toxicity, contamination with filth, inadequate manufacturing controls) or the lack of approval! Misbranding misbranded product generally describes a defect in the product s labeling or advertising (false, misleading, failure to include required information), or the lack of compliance with FDA requirements other than approval 37

38 38 Use of the Park Doctrine! FDA Commissioner, compliance officials and general counsel have targeted responsible individuals within pharma/biotech and medical devices Seek to hold company management responsible for the actions of the company Seek to impose criminal penalties! In addition to civil monetary penalties Also use to debar individuals from future participation in product development and in other federal programs

39 39 Conducting Investigational Research! To develop and investigate new treatments and products for use in the diagnosis, cure mitigation or treatment of disease! To improve the quality of life of patients

40 40 Important Research Principles! Do not expose subjects to an unreasonable and significant risk of illness or injury! Risks to the subjects are not outweighed by the anticipated benefits and the importance of the knowledge to be gained, or informed consent is inadequate, or the investigation is scientifically unsound, or there is reason to believe that the device as used is ineffective.! Protect the safety of subjects participating in research studies.

41 41 What Can Go Wrong! Breach of Contract! The rejection of the data in a marketing application! A loss of research funds! Inspectional Observations and Warning Letters! Disqualification as an Investigator! Debarment! Civil Penalties! Criminal Penalties

42 Informal Exercise of FDA Authority! Press Releases! Inquiries! Inspections! Recommendations by FDA Staff! Speeches and Testimony 42

43 Engaging the FDA! Participation in the Notice and Comment Rulemaking Process! Pre-IND Meetings and Other Formal and Informal Meetings! Contacting the Ombudsman! Citizen Petitions 43

44 44 Understand the Current Climate at FDA! Periodically significant safety issues surface with a number of drugs and medical devices! There has been challenges to the fundamental integrity and the ability of the drug /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

45 45 Understand the Current Climate at FDA! Recommendation Understand FDA s expectations Try to address requirements in FDA Guidance. Communicated in meetings and approvals of similar products Seek information and 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 responsibly challenge FDA decision making Need good science and legal / regulatory precedents

46 46 Thank You & Questions Contact Information: David L. Rosen, B.S. Pharm., JD (202) Foley & Lardner LLP 3000 K St, NW, 6 th Floor Washington, DC