FDA Update. Objectives. Overview. Self-assessment questions 1. Generic drugs represent 88% of all prescriptions dispensed in the U.S.

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1 FDA Update Ilisa B.G. Bernstein, Pharm.D., J.D. Deputy Director Office of Compliance Center for Drug Evaluation and Research U.S. Food and Drug Administration American Pharmacists Association Annual Meeting Baltimore, Maryland March 6, 2016 CAPT Mary Kremzner, Pharm.D., MPH Division Director Division of Drug Information Center for Drug Evaluation and Research U.S. Food and Drug Administration Objectives At the completion of this activity, participants will be able to: Describe FDA activities during the last year Describe FDA direction and focus in the coming year State how changes in FDA regulations and actions will affect participant s practice 2 Overview Introduction Approvals and performance Recalls Drug shortages Compounding Drug supply chain security Innovation in drug development Biosimilars Risk management activities Safety initiatives Compliance and enforcement actions What s next 3 Self-assessment questions 1. Generic drugs represent 88% of all prescriptions dispensed in the U.S. a) True b) False 2. Breakthrough Therapy Designation is a process designed to expedite the development and review of certain drugs that meet which two statutory criteria? a) Drugs must be intended to treat a serious condition and preliminary clinical evidence must indicate that drug may demonstrate substantial improvement over available therapies on at least one clinically significant endpoint b) Drugs must be intended to treat a serious condition and there is no clinical evidence indicating that drug may demonstrate substantial improvement over available therapies on at least one clinical significant endpoint c) Drugs must be intended to treat a serious unmet medical condition and a substantial body of clinical evidence must indicate that drug demonstrates substantial improvement over available therapies d) None of the above 3. The Pregnancy and Lactation Labeling Rule does which of the following? a) Allows women/mothers to make informed and educated decisions for themselves and their children b) Adds additional pregnancy letter categories to define risk in labeling c) Removes pregnancy letter categories A, B, C, D, and X 4 d) A and C FDA: What we do Mission: Promote and protect the public health FDA s primary responsibility is to protect the American people from unsafe or mislabeled food, drugs, and other medical products and to make sure consumers have access to accurate, science based information about the products they need and rely on every day. FDA/CDER (Center for Drug Evaluation and Research) ensures that safe, effective and high quality drugs are available for U.S. consumers. 5 FDA around the globe 300,000 foreign facilities from more than 150 countries export FDA-regulated products to the United States 40 percent of listed finished drugs are imported Imported medical devices constitute over 35 percent of the U.S. medical equipment market There are myriad opportunities for drug products to be improperly formulated or packaged, contaminated, diverted, counterfeited or adulterated 6 1

2 FDA around the globe CDER/Office of Compliance Center for Drug Evaluation and Research Office of Compliance Office of Drug Security, Integrity and Response Office of Manufacturing Quality Office of Scientific Investigations Office of Unapproved Drugs and Labeling Compliance Office of Program and Regulatory Operations CDER/Office of Communications Center for Drug Evaluation and Research Office of Communications Approvals and performance Division of Online Communications Division of Health Communications Division of Drug Information 9 Novel new drugs rovalprocess/druginnovation/ucm pdf Novel drug report 2015 In 2015, CDER approved 45 novel drugs Approvals were significantly more than the average of 28 approved during the previous nine years 64% of CDER s novel drug approvals were approved in the United States first - before any other country vation/ucm htm

3 Notable novel new drugs of 2015 Expedited development and review pathways Generic drugs Generic drugs represent 88% of all prescriptions dispensed in the U.S.* Generic drugs are responsible for $254 billion in health system savings in 2014** Use of generic drugs is increasing domestically and internationally** 15 *Dr. Woodcock s Testimony on January 28, 2016 ** GPhA Generic Drug User Fee Act (GDUFA) Ten-month review cycle for 90% in year 5 Review goals began on October 1, 2014 for newly filed applications Risk-adjusted, biennial surveillance inspections Parity of foreign and domestic inspection frequency in year 5 1 ST generics create competition & drive down costs FDA expedites the review of potential first generics because they are public health priorities If a generic drug application can mitigate a drug 16 shortage, its review is expedited ANDA Submissions ANDA approvals and tentative approvals Since FY2012 FDA received more ANDA submissions than expected Projected received 1473 in FY

4 Recall definitions Recalls Class I recall: a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death Class II recall: a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. Class III recall: a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences Event vs Product Recalls FY 08-16* * 21 * = Quarter Events Products Product Recalls by Type FY 08-16* OTC Rx DS Major Reasons for Recalls FY 13-16* 2013 Lack of Assurance of Sterility Impurities/Degradation Products Presence of Particulate Matter 2014 Marketed without an Approved NDA/ANDA Presence of Particulate Matter Lack of Assurance of Sterility Drug shortages 2015 Lack of Assurance of Sterility Presence of Particulate Matter Impurities/Degradation Products 2016* Lack of Assurance of Sterility Impurities/Degradation Products Failed USP Dissolution Test Requirements Labeling: Ingredient Mix-up Due to Mislabeling 23 4

5 26 Drug shortage data Drug Shortages: New vs Prevented Number of Drug Shortages PREVENTED 350 NEW FY 2010 FY 2011 FY 2012 FY 2013 FY 2014 FY 2015 A high percentage of shortages involve sterile injectables Drug shortages mobile app

6 FDA toolbox Regulatory Discretion Allows for manufacture of medically necessary products to continue May require additional safety controls Filters with product; extra testing at plant; 3 rd party oversight of production; special instructions for safe use Request other firms to raise production Expedite reviews New manufacturing sites, longer expiry date, new raw material source, changes in specifications, etc. In rare cases, temporary importation from unapproved sources 31 Is the drug product information listed on the FDA s Drug Shortage website the same as on the American Society of Health-System Pharmacists (ASHP) Drug Shortage website? Contrasting the websites FDA receives information provided by manufacturers ASHP receives information from practitioners unable to get product FDA does not consider a product to be in shortage if one or more manufacturers are able to supply the full market demand for the product ASHP s Drug Shortage website provides information about which manufacturers have the drug available and which ones do not, since supply chain disruptions may occur when all previous manufacturers are not yet back on the market FDA and ASHP work closely to share information and provide the most updated information possible on our websites 32 Compounding Section 503A Describes conditions under which certain compounded human drug products are entitled to exemptions from three sections of the FDCA requiring: FDA approval prior to marketing (section 505) Compliance with current good manufacturing practice (CGMP) (section 501(a)(2)(B)); and Labeling with adequate directions for use (section 502(f)(1)) Pharmacies that qualify for the exemptions are primarily regulated by the states, although some Federal requirements still apply (e.g., no insanitary conditions) 34 Compounding Quality Act of the Drug Quality and Security Act Removes certain provisions from section 503A related to solicitation of prescriptions and advertising and promotion that were found to be unconstitutional by the U.S. Supreme Court in 2002 Clarifies that section 503A is applicable to compounders nationwide Adds new section 503B: Outsourcing Facilities 35 Section 503B Describes conditions under which certain human drug products compounded at a facility registered as an outsourcing facility are entitled to exemptions from certain sections of the FDCA, including those requiring: FDA approval prior to marketing (section 505); and Labeling with adequate directions for use (section 502(f)(1)) Outsourcing facilities are not exempt from Current Good Manufacturing Practice (CGMP) requirements and will be inspected by FDA according to a riskbased schedule 36 6

7 Outsourcing facilities Section 503B defines outsourcing facility as a facility that: Is engaged in the compounding of STERILE drugs Has elected to register as an outsourcing facility Complies with all of the requirements in section 503B In addition, an outsourcing facility: Is NOT required to be a licensed pharmacy, but compounding must be by or under the direct supervision of a licensed pharmacist May or may not obtain prescriptions for identified individual patients Inspections Since enactment of the DQSA, FDA has: Conducted over 230 inspections of compounders including approximately 60 inspections of compounders registered as outsourcing facilities Approximately 80 of these inspections have been forcause, generally based on reports of serious adverse events or product quality issues such as drug contamination 39 Inspections and resulting actions Since enactment of the DQSA, FDA has: Overseen over 85 recalls by compounders, and requested numerous compounders to cease operations Issued over 75 warning letters; one addressed violations identified at four facilities Issued 20 letters referring findings from inspections of pharmacies that compounded their drugs in accordance with the conditions of section 503A to the state Obtained 3 civil consent decrees of permanent injunction Sought several criminal prosecutions 40 Guidances issued since DQSA Draft and Final Guidances: 503A Outsourcing Facility Fees Registration of Outsourcing Facilities Guidance For Entities Considering Whether to Register as Outsourcing Facilities Adverse Event Reporting for Outsourcing Facilities Draft Guidances: Interim CGMPs for Outsourcing Facilities Draft and Revised Draft Product Reporting Guidance for Outsourcing Facilities Repackaging Non-biologics Mixing, Diluting, and Repackaging Biologics Interim Policies on Compounding Using Bulk Drug Substances Under Sections 503A and 503B (two separate draft guidances) Animal drug compounding from bulk drug substances 41 Other actions Issued draft Standard Memorandum of Understanding (MOU) under 503A Issued proposed rule describing additions and modifications to the Withdrawn or Removed List (503A and 503B) Solicited nominations for 503A and 503B bulks lists and for drugs that are difficult to compound under sections 503A and 503B Announced membership of Pharmacy Compounding Advisory Committee and held three meeting covering drugs proposed for withdrawn or removed list, nominations for the 503A bulks list, and criteria for the difficult to compound list 42 7

8 Some of the other policy issues under consideration Anticipatory compounding and compounding without a prescription for office use Compounding radiopharmaceuticals Definition of facility under section 503B Description of under the supervision of a licensed pharmacist under section 503B Prohibition on resale under section 503B State interactions Three intergovernmental meetings with representatives of the states since DQSA Summaries of the meetings and action items posted on the Web Robust communications with the states on specific cases Close coordination with NABP Drug supply chain security

9 Know your source ( Protect your patients from unsafe drugs Beware of offers too good to be true Check for signs that a prescription drug may be unsafe, ineffective or fake Ensure you receive FDA-approved prescription drugs Buy only from wholesale drug distributors licensed in your state Pay close attention to patient feedback 49 Drug Quality and Security Act (DQSA) Track and trace law Title I: The Compounding Quality Act Title II: Drug Supply Chain Security Act (DSCSA) FDA DSCSA web page: ainsecurity/drugsupplychainsecurityact/default.htm 51 Product Tracing Wholesale Distributor and 3PL Licensing and Standards 52 ARE YOU READY FOR DSCSA? 54 9

10 DSCSA major provisions Product tracing (by 2015 lot-level, by 2023 packagelevel) Product verification Quarantine and investigation (steps for detection and response) Notification, recordkeeping Product identification (applied to product beginning 2017) Wholesale distributor and Third-party logistics provider standards for licensure Enhanced system (electronic, interoperable system to trace products at the package-level by 2023) Penalties 55 National uniform policy Product What s covered: Prescription drug in finished dosage form for administration to a patient without further manufacturing (such as capsules, tablets, lyophilized products before reconstitution) What s not covered: Blood or blood components intended for transfusion Radioactive drugs or biologics Imaging drugs Certain IV products Medical gas Homeopathic drugs Lawfully compounded drugs Scope of the law* Transaction Transfer of product where a change of ownership occurs Exempt Intracompany distributions Distribution among hospitals under common control Public health emergencies Dispensed pursuant to a prescription Product sample distribution Blood and blood components for transfusion Minimal quantities by a licensed pharmacy to a licensed practitioner Certain activities by charitable organizations Distributions pursuant to a merger or sale Certain combination products Certain medical kits Certain IV products Medical gas distribution Approved animal drugs *Refer to definitions in Section 581(13) for product and 581(24) for transaction for specific information regarding exclusions or exemptions. 56 Product tracing information: TI/TH/TS Transaction Information (TI): Proprietary or established name or names of the product; Strength and dosage form of the product; National Drug Code number of the product; Container size; Number of containers; Lot number of the product; Date of the transaction; Date of the shipment, if more than 24 hours after the date of the transaction; and Business name and address of the person from whom and to whom ownership is being transferred. Transaction History (TH): A statement in paper or electronic form, including the transaction information for each prior transaction going back to the manufacturer of the product. Transaction Statement (TS): A statement, in paper or electronic form, that the entity transferring ownership in a transaction Is authorized as required under DSCSA; Received the product from a person that is authorized as required under DSCSA; Received transaction information and a transaction statement from the prior owner of the product, as required under the law; Did not knowingly ship a suspect or illegitimate product; Had systems and processes in place to comply with verification requirements under the law; Did not knowingly provide false transaction information; and Did not knowingly alter the transaction history. 57 Verification Must have systems and processes to be able to comply with the verification requirements: Must be able to respond to verification requests from Secretary about suspect product Quarantine and investigate suspect product to determine if illegitimate product (includes validating applicable TI and TH) Notify trading partners and FDA of illegitimate product (within 24 hours of determination) Respond to notifications of illegitimate product Recordkeeping Verification requirements change once product is serialized. 58 Authorized trading partners are: WD and 3PL Reporting Database Manufacturers and repackagers with valid registration with FDA Wholesale distributors with valid State or Federal license and compliance with reporting requirements; considered authorized before federal licensing regulations effective if possesses valid license under State law Third-party logistic providers with valid State or Federal license and compliance with reporting requirements; considered authorized before federal licensing regulations effective, unless FDA makes certain findings and gives notice Dispensers with valid State license

11 What s new? Frequently asked questions: 1. Is the pedigree provision of the Prescription Drug Marketing Act still in effect? 2. Do the DSCSA requirements related to transaction information, transaction history and transaction statements apply to all prescription drugs? 3. Does FDA have standardized forms of transaction information, transaction history and transaction statements that I can use? 4. Do the DSCSA product tracing requirements related to transaction information, transaction history and transaction statements apply when pharmacies transfer/sell product to another pharmacy? 5. What if I meet the definition of more than one trading partner? 6. Can FDA advise me on my specific obligations under the DSCSA? Requirements for Transactions with First Responders ormation/guidances/ucm pdf Enhanced System 2023 Establishes package level requirements for the interoperable, electronic tracing of products that shall go into effect 10 years after enactment of this Act, including those relating to: Electronic exchange of transaction information for each sale of certain prescription drugs Verification of product identifiers at the package level Prompt response to suspect and illegitimate products when found Improved efficiency of recalls 62 Innovation in drug development Breakthrough therapy designation (BTD) Breakthrough Therapy designation is a process designed to expedite the development and review of certain drugs that meet two statutory criteria 1. Drugs must be intended to treat a serious condition 2. Preliminary clinical evidence must indicate that drug may demonstrate substantial improvement over available therapies on at least one clinically significant endpoint Year 2015 (as of ) Total Requests Received Breakthrough therapies Granted Denied Rescinded Withdrawn (After Granting) Marketing Application Approvals Biosimilars A biosimilar must demonstrate no clinically meaningful differences in safety, purity & potency from its reference product Potential to lower treatment costs, enabling greater patient access From Breakthrough Therapy Designation (BTD) PPT by Rajesh Venugopal, MPH, MBA, Senior Regulatory Health Project Manager, CDER FDA is undertaking a multi-phase plan to educate health care professionals & consumers to about #biosimilars. CDERLearn course launched in February 2016 (with CE) 11

12 The Purple Book Biosimilars 1 st biosimilar approved in Zarxio (filgrastim-sndz) is a biosimilar of Neupogen Recent advisory committee meeting on possible approval of biosimilar of Remicade. Biosimilar User Fee Act (BsUFA) As of January 21, 2016, 59 proposed biosimilar products were in the Biosimilar Product Development Program (BPD) to 18 different reference products Since program inception and as of December 31, 2015, five companies have publicly announced submission of eight 351(k) BLAs to FDA for proposed products The BPD Program was created as a part of BsUFA to provide a mechanism and structure for the collection of developmentphase user fees to support FDA s biosimilar review program activities 68 Clinical Trials Transformation Initiative (CTTI) Public private partnership Engaging all stakeholders in the clinical trials enterprise Using evidence to issue official recommendations that will improve the quality & efficiency of trials Creating tools to facilitate the adoption of CTTI's Electronic Health Records (EHR) Promote seamless exchange of structured, re-usable information between health care and clinical research systems Data entry once at the point of care and used many times without manual re-entry or manual source data verification Foster collaboration among regulated industry, EHR and Electronic Data Capture (EDC) vendors, academic medical centers, and Standards Development Organizations (SDOs) and other parties June 26, 2015, FRN to elicit projects to test and evaluate performance of end-to-end Electronic Health Record (EHR) -to- Electronic Data Capture (EDC) official recommendations Biomarkers development Measurable biological factors found in blood, body fluids, or tissues that serve as markers of a disease or condition When well-understood, can be used to predict effectiveness, safety Can serve as surrogate endpoints reasonably likely to predict clinical benefits Greatly speed drug development Maintain standards for substantial evidence of safety and effectiveness Clinical Outcome Assessment (COA) Measure a patient s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions COAs can be used to determine whether or not a drug has been demonstrated to provide treatment benefit o Treatment benefit can also be defined in terms of a safety benefit compared to other treatments A conclusion of treatment benefit is described in labeling in terms of the concept of interest, what is measured by the COA

13 Patient-Focused Drug Development (PFDD) Systematic gathering of patient perspectives on specific diseases and their treatments per commitment under PDUFA V Establishing the therapeutic context is an important aspect of the benefit/risk assessment Patients are uniquely positioned to inform understanding Current mechanisms for obtaining patient input are often limited to discussions related to specific applications under review 73 PFDD Meetings for FY Externally-led PFDD Meetings To expand the benefits of FDA s PFDD initiative, the FDA: Welcomes patient organizations to identify and organize patient-focused collaborations to generate public input on other disease areas, using the process established through PFDD as a model Risk management activities Will be open to participating in a well-designed and well-conducted meeting May consider in-person attendance for meetings held in the DC area May also be willing to provide specific recommendations on the planning of the meeting and the development of any meeting outputs Approved Risk Evaluation and Mitigation Strategies (REMS) Get alerts when the site changes Download historic REMS data in CSV format Search by REMS, drug name, and element Sort to find the most recently updated REMS Click for more detailed info on each REMS 77 13

14 Information for Participants Go to application holder s REMS website Find out what you have to do, and when View requirements for each participant 80 Sentinel Timeline Sentinel basics present 81 FDA s postmarket risk identification and analysis system Created from Congressional mandate in FDAAA 2007 Distributed database with 16 data partners* 193 million individuals total 39 million currently enrolled 43 million individuals 3 years of continuous observation time Data access and privacy Data partners retain control over their own data Analytic programs run against a common data model Access to laboratory, pharmacy data, and medical records * (data as of August 2015) 82 Opioids website Opioids action plan Focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief Expand use of advisory committees Develop warnings and safety information for immediate-release (IR) opioid labeling Strengthen postmarket requirements Update Risk Evaluation and Mitigation Strategy (REMS) Program Expand access to abuse-deterrent formulations (ADFs) to discourage abuse Support better treatment Reassess the risk-benefit approval framework for opioid use 83 Feb 4, 2016 Press Release

15 Pregnancy and Lactation Labeling (PLLR) PLLR requires content and format changes for information presented in prescription drug labeling Changes intended to assist health care providers in assessing benefit versus risk, assist with counseling Allows women/mothers to make informed and educated decisions for themselves and their children PLLR removes pregnancy letter categories A, B, C, D and X PLLR requires the label to be updated when information becomes outdated 85 PLLR Comparison of current prescription drug labeling with the PLLR new labeling requirements 86 Medication Errors and Drug Safety Communications (DSC) Other initiatives 87 Patient Medication Information (PMI) Regulation in development to require all prescription drugs have a single Patient Medication Information (PMI) document - Draft rule is still in development Public workshop held July 1, 2014 to explore: (1) lessons learned from health literacy researchers on PMI and (2) role of stakeholders who regularly interface with patient medication information Article published July 10, 2015, Influence of patient medication information format on comprehension and application of medication information * Non-Prescription Safe Use Regulatory Expansion (NSURE) FDA continues to explore how novel technologies or other conditions of safe use for nonprescription drugs may mitigate the under-treatment of common conditions and diseases Why now? Public health need People interested in self-selection Differences between generations Dramatic changes in technology * Available online at:

16 Drug trials snapshots Pharmacists role In drug safety Quality issues and complaints Tablets break apart Scored tablets break unevenly or crumble into powder when split Tablets stick in the throat Precipitates in oral liquids and injectable Patches do not stick Errors in packaging (wrong quantity) Container and/or closure issues Device issues Suspected contamination Abnormal solubility Large size tablet/capsule Dropper issues with Ophthalmologic Products 93 MedWatch reporting MedWatch Reporting - VOLUNTARY Clinician Form 3500 Consumer/Patient Form 3500B 94 Compliance and enforcement actions Consent decrees Import alerts Seizures Warning letters Clinical investigator disqualifications Criminal indictments/convictions Unapproved drugs Health fraud Data integrity CGMP violations GCP violations Compounding More Enforcement Statistics for FY 2015 FDA CDER Seizures Injunctions Seizures Injunctions Warning Letters 76 Recall Events Recalled 303 Products 9,178 Warning Letters 17,232 Recall Recalled Events Products 2,789 1,

17 What s next.top priorities for 2016 New legislation User fee reauthorization coming soon Other? Continue implementation of DQSA (compounding/track and trace) Focus on meeting GDUFA goals Focus on quality/safety More guidances. Resources for Pharmacists List serves and Apps Drug Safety Communications (DSC) GADIS Listserv Orange Book App Drug Shortage App Resources for pharmacists (cont d) CDER Social Media Drug Info Rounds 99 Pharmacists at FDA/CDER How do I get a Job at FDA? Pharmacist Direct Hire Self-assessment questions 1. Generic drugs represent 88% of all prescriptions dispensed in the U.S. a) True b) False 2. Breakthrough Therapy Designation is a process designed to expedite the development and review of certain drugs that meet which two statutory criteria? a) Drugs must be intended to treat a serious condition and preliminary clinical evidence must indicate that drug may demonstrate substantial improvement over available therapies on at least one clinically significant endpoint b) Drugs must be intended to treat a serious condition and there is no clinical evidence indicating that drug may demonstrate substantial improvement over available therapies on at least one clinical significant endpoint c) Drugs must be intended to treat a serious unmet medical condition and a substantial body of clinical evidence must indicate that drug demonstrates substantial improvement over available therapies d) None of the above The Pregnancy and Lactation Labeling Rule does which of the following? a) Allows women/mothers to make informed and educated decisions for themselves and their children b) Adds additional pregnancy letter categories to define risk in labeling c) Removes pregnancy letter categories A, B, C, D, and X 102 d) A and C 17

18 THANKS!! Ilisa B.G. Bernstein, Pharm.D., J.D Deputy Director Office of Compliance Mary Kremzner, Pharm.D., MPH CAPT, USPHS Division Director Division of Drug Information