Pharmaceutical Shortages: Impact on Patients, Professionals and the Public

1. Pharmaceutical Shortages: Impact on Patients, Professionals and the Public Bernadette Belgado, Pharm.D. – UF Health at Jacksonville West Paul, M.D., Ph.D. – Wake Med Health

2. Drug Shortages: causes & solutions Bernadette Belgado, Pharm.D. Director, Drug Information Center Manager, Department of Pharmacy Shands Jacksonville Department of Pharmacy Clinical Assistant Professor UF College of Pharmacy

3. Objectives • Explain the reasons for medication shortages • Discuss drug shortage legislation • No disclosures

5. New Drug Shortages by Year Keuhn BM. JAMA. 2013;309(6):532-533

6. Reported reasons for sterile injectable drug shortages in 2011 Woodcock J, Wosinska M. Clin Pharmacol Ther 2013;92:170-6.

7. Drug Supply Chain Raw materials http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277626.htm

8. Raw Materials 2008 – heparin recall Over 200 patients died as a result of contaminated heparin with over-sulfated chondroitin Raw materials plant in China was never inspected by the FDA Foreign markets supply 80% of raw materials Increased quality awareness and regular inspection of foreign raw materials plants mandated by FDA

9. This family-owned workshop in Xinwangzhuang, a village in Juangsu Province, China, processes pig intestinesfor heparin http://www.nytimes.com/2008/03/30/weekinreview/30bogdanich.html?ref=heparindrug&_r=0

10. Drug Supply Chain http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277626.htm

11. Drug Manufacturers • Generic injectable drugs (73%) • Lack of redundancy in manufacturing processes • 71% of market controlled by 3 manufacturers • Routine facility maintenance • Business decisions to discontinue drug • Unable to support demand Woodcock J, Wosinska M. Clin Pharmacol Ther 2013;92:170-6.

12. Drug Manufacturers Lack of sterility Particulates of foreign matter Crystallization of the active ingredient Precipitates New/unintended impurities or degradation Equipment breakdown Woodcock J, Wosinska M. Clin Pharmacol Ther 2013;92:170-6

13. Drug Supply Chain http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277626.htm

14. Regulatory Issues • New FDA Commissioner in 2009 • Enforcement and regulatory activities spiked from 2009-2011 • Warning letters to pharmaceutical manufacturers regarding quality increased 42% in 2009 and up 156% in 2010. • Simultaneously shutting down 4 major generic manufacturers of generic medications • 30% of decrease in manufacturing capacity 112th Congress 2012. http://oversight.house.gov/report/fdas-contribution-to-the-drug-shortage-crisis.

15. FDA Warning letters 2004-2011 Number of letters FDA Fiscal Year 2011 Enforcement Statistics

16. Regulatory Issues • FDA increased enforcement of Unapproved Drugs • Drug Evaluation & Safety Initiative (DESI) • Drugs approved or deemed identical, related, or similar (IRS) between 1938 – 1962 • Pre-1938 drugs grandfathered • No change to the formulation, dosage form, potency, route of administration, indication, or intended patient population • FDA requests NDA for any unapproved drug http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf http://www.ashp.org/DrugShortages/NotAvailable/Bulletin.aspx?id=602

18. Regulatory Issues - MMA Medicare Modernization Act (MMA) 2003 • Changed pricing formula for reimbursement in outpatient setting • Originally average wholesale price (AWP) • Generic availability erodes selling prices by ~ 85-90% after a year • Average selling price (ASP) + 6% • MMA limits - Manufacturers only allowed to increase prices by 6% biannually Cabner BA. N Engl J Med 2011 365:2147-49

19. 340B Pricing Program • Provides nominal pricing for outpatient medications • One-third of all hospitals are eligible for 340B prices • Unintended consequence of MMA and 340B • New manufacturers are not entering the marketplace to produce generic medications • Only 7 generic companies make sterile injectables

20. Drug Supply Chain http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277626.htm

21. Group Purchasing Organizations • GPOs – 98% of hospitals • Negotiate price and volume contracts with drug manufacturers • Six GPOs control about 90% of drugs purchased • Contract awarded on multiple factors • lowest cost, returns, rebates, stipulations for “failure to supply” • Speculation that fewer generic manufacturers are a direct result of the GPO structure Nelson R. Medscape. http://www.medscape.com/viewarticle/778146

22. Drug Supply Chain http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277626.htm

23. Health Systems • “Just in time” inventory practices • Pharmacy inventory turns short • 30 days • Hoarding and stockpiling

24. Medicare Modernization Act Heparin recall Unapproved drugs initiative New FDA Commissioner Keuhn BM. JAMA. 2013;309(6):532-533

25. FDA Solutions • Allow temporary importation of foreign equivalent • Propoven from UK for propofol shortage • Phenylephrine from UK • Sodium Bicarbonate from Australia • Allow affected drug with conditions – safety considered • Potassium Phosphate – double filtration required • Mannitol – heat medication to dissolve crystals • Alteplase – rubber stopper particles – filtering required

26. FDA Safety & Innovation Act (FDASIA) • Executive presidential order – October 2011 • FDASIA – July 2012 • Requires at least 6 month notification to FDA and other manufacturers of potential shortages or ASAP • No civil or monetary penalties for industry noncompliance • FDA required to keep updated list of drugs and reasons • Expedited review of new generics

27. Presidential Executive order Medicare Modernization Act Heparin recall Unapproved drugs initiative FDASIA New FDA Commissioner Keuhn BM. JAMA. 2013;309(6):532-533

28. Keuhn BM. JAMA. 2013;309(6):532-533