Introduction to U.S. Drug Shortages

1. Introduction to U.S. Drug Shortages CDR Emily Thakur, R.Ph. LCDR Helen Saccone, Pharm.D. U.S.Public Health Service Center for Drug Evaluation & Research U.S. Food & Drug Administration

2. Overview U.S. Drug Shortage Trends Reasons for Drug Shortages FDA’s Role View of the Future

3. Drug Shortage Program History Who works on this? Office of New Drugs Office of Chemistry Office of Generic Drugs Office of Compliance Office of Regulatory Affairs Field Inspectors MANY OTHERS! • Center for Drug Evaluation & Research • Drug Shortage Program (DSP) began in 1999 • Today have 11 full time staff • Many others in involved • Mission: address potential and actual drug shortages • Facilitate prevention and resolution of shortages by collaborating with FDA experts, industry, and external stakeholders • Inform the public • Outreach to healthcare professional organizations, patient groups and other stakeholders

4. Growing problem – and FDA response • FDA website updated daily • Staffing and management coordination • Public reports encouraged – industry reports of problems even more so • Public workshop September 26, 2011 • Collaboration on system fixes • American Society of Healthcare Pharmacists (ASHP) • Industry (GPHA, PhRMA, BIO) • Prevent and mitigate individual shortages

6. 2011 Shortage Data • There were 251 shortages reported in 2011 • High percentage are sterile injectable products • Treatments for cancer, anesthesia, serious illness • Highly specialized manufacturing • High risk to patient if not meticulous When there are quality or production problem for a sterile injectable drug, a shortage is almost always results

7. Sterile Injectables:> 75% lapsed product quality & production

8. Reasons for Shortages: Sterile InjectablesReport by Assistant Secretary for Planning & Evaluation 2011 • State of the industry • Seven (7) manufacturers make up most of market • Contract manufacturers – firms contract out manufacturing as well as acting as contract manufacturers • Lack of redundancy • Multiple products made on existing manufacturing lines • 24/7 production with no “cushion” • Complex manufacturing process • No simple fixes • Problems typically affect multiple products • Investment economics question • e.g., propofol 20ml sells for $0.48/vial

9. Quality and Manufacturing Examples • Lack of sterility • Particulates of foreign matter • Crystallization of the active ingredient • Precipitates • New/unintended impurities or degradants • Equipment breakdown • Natural disasters

10. What doesn’t cause shortages • Increased stringency of CGMPs & standards • Increased inspections/enforcement actions • Foreign manufacturing • Unapproved drugs initiatives • Drug approval delays

11. How does FDA fit? • Patient care is our #1 concern • We get involved when we are informed • Seek ways to prevent & mitigate shortages • Secondary response to industry problem • Find root cause and get manufacturer on track • Some shortages can be prevented, but not all • Unforseen breakdown in manufacturing system • Longstanding quality manufacturing problems • Some can be addressed quickly, others not • Risks to the patient always considered

12. FDA’s Role • FDA is responsible for protecting the public health by assuring the safety and efficacy of drugs • FDA facilitates responses to prevent or mitigate a drug shortage when we are aware of it • This is a secondary response to mitigate a problem that has already happened

13. Medical Necessity • A medically necessary drug product is a product that is used to treat or prevent a serious disease or medical condition for which there is no other alternative drug, available in adequate supply, that is judged by medical staff to be an adequate substitute CDER Manual of Policies and Procedures on Drug Shortage Management 6003.1 http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM079936.pdf

14. FDA Tool Box • Regulatory discretion: allow manufacture of medically necessary product(s) to continue • Minor, low risk issues usually best suited for this tool • In some cases require additional safety controls • Request other firms to ramp up manufacturing. • Expedite any review of company proposals • In rare cases, controlled temporary importation from unapproved sources

15. What can’t FDA do • Mandate firms to continue to manufacture products at certain quantities • Require DEA to increase quotas of controlled substances • Publish the exact cause of manufacturing/ quality issues • Be consultants to manufacturers to fix quality problems • Build robust quality management systems (QMS) and build in quality at manufacturing firms

16. What Can Prevent Shortages • Commitment to quality from senior management down to line workers • Proactively identify & promptly correct issues • Design/qualify robust operations • Reinvestment into equipment, facilities and personnel • Investigate problems to identify and fix root cause • Anticipate supply problems • Plan ahead by adding redundancy to manufacturing & raw material supplies • Arrange for additional manufacturing capacity • Develop alternate supplies of components • It is important to consider the root cause of a shortage • If the root cause that leads to a shortage can be prevented, one can get to primary prevention

17. Communication Good agency-industry communication can facilitate resolution of a drug shortage. FDA is committed to working with industry to quickly resolve any quality or manufacturing problems that arise to ensure continued patient access to vital safe and effective medicines • CAPT Valerie Jensen FDA Drug Shortage Program

18. Communication • Problem of drug shortages is complex and multifaceted-requires continued collaborations • Communication and collaboration with groups has become increasingly important- DSP has taken a proactive approach • DSP routinely communicates with manufacturers, health care professionals, stakeholders, organizations, patient advocate groups, and others

19. Communication • Notify FDA Drug Shortage Program (DSP) of potential and actual supply problem • Contact FDA DSP with creative strategies to mitigate shortages • Contingency plans to increase capacity • Interested in coming into the market to alleviate shortages • President’s Executive Order issued 10/31/11 encouraged more voluntary reporting by manufacturers • 6 fold increase in notifications of potential shortages • normally received 10/month on average in 2010 and now receiving over 60 notifications per month

20. 2011 Data Higher – Executive Order President’s Executive Order issued 10/31/11 encouraged more voluntary reporting by manufacturers • 6 fold increase in notifications of potential shortages • normally received 10/month on average in 2010 and now receiving over 60 notifications per month) • Total of 195 shortages prevented in 2011 • 42 shortages prevented as of April 28, 2012

21. DISCONTINUANCE OF A LIFE SAVING PRODUCT SEC. 506C. [ 21 U.S.C. 356c] DISCONTINUANCE OF A LIFE SAVING PRODUCT. (a) IN GENERAL.—A manufacturer that is the sole manufacturer of a drug— (1) that is— (A) life-supporting; (B) life-sustaining; or (C) intended for use in the prevention of a debilitating disease or condition; (2) for which an application has been approved under section 505(b) or 505(j); and (3) that is not a product that was originally derived from human tissue and was replaced by a recombinant product, shall notify the Secretary of a discontinuance of the manufacture of the drug at least 6 months prior to the date of the discontinuance. • See also 21CFR 314.81(b)(3)(iii)

22. 38 Shortages Prevented in 2010 • All due to firms notifying FDA of problems early • 16 through regulatory discretion • Risk of quality/manufacturing issue able to be mitigated and was outweighed by benefit of the drug • 13 through expedited review • New manufacturing sites, suppliers, etc. • 8 through encouraging other firms to ramp up • 1 through communication with DEA regarding firm’s need for controlled substance quota increase

23. 195 Shortages Prevented in 2011 • Most due to firms notifying the FDA of early problems • The main FDA action taken to prevent drug shortage was Expedited Review • Other actions taken include: • Regulatory discretion • Ramping up production • Assistance with release • Extension of expiry of available products • Additional testing

24. Recent Public Outreach • FDA Drug Shortage Website http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default • Public Meeting • FDA Report – Review of FDA’s Approach to Medical Product Shortages • Letter to Industry • Guidance for Industry – Notification to FDA of Issues that May Result in a Prescription Drug or Biological Product Shortage • Interim Final Rule – Revision of Postmarketing Reporting Requirements – Discontinuance • Meetings with stakeholders – PhRMA, ASHP, GPhA, BIO, Eli Lilly, Amgen, and others

25. Shortages can’t always be prevented • Unanticipated problems, such as a manufacturing line breakdown or natural disaster • Manufacturer(s) may not be able to make up production shortfall • Risks are significant and would cause patient harm (e.g. sterility problems) • FDA will work with company to encourage smart distribution • No easy answers on how to do this well

26. The Future • FDA Drug Shortage work will continue • Multidisciplinary: clinicians, pharmacists, chemists, biotechnology, regulatory and manufacturing • We can only prevent shortages if problems are reported • Public communication of existing shortages • Congress discussing new legislation • Would REQUIRE broader reporting by industry to FDA • Public expects and deserves high quality drugs • Must have industry commitment to culture of quality manufacturing • Many firms are building new plants today • Need better methods and redundancy • Promptly report and correct even small problems

27. Thank You • FDA drug shortage website is: http://www.fda.gov/Drugs/DrugSafety/default.htm • To report shortages our e-mail account is Drugshortages@fda.hhs.gov • FDA Webinar on Prescription Drug Shortages Sept. 30, 2011, http://www.fda.gov/AboutFDA/Transparency/Basics/ucm272223.htm