1. Medicine shortages 1 |1 | P ROGRESS AND FUTURE AGENDA M EDICINES SHORTAGES IN MANUFACTURING " GLOBAL STOCK OUTS " Department of Essential Medicines and Health Products Lisa Hedman

2. Medicine shortages 2 |2 | Defined as shortages or stock outs caused by manufacturing insufficiency Similar incidence between branded versus generics Higher incidence in older g enerics, sterile injectables, oncology medicines Affects countries of all income levels Can be confused with supply chain stock outs in some situations Overview of global stock outs

3. Medicine shortages 3 |3 | Increasing trend United States Food and Drug Administration accessed 22 October 2013 http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtm l Example of trends from USA

4. Medicine shortages 4 |4 | Deferoxamine Mesylate for Injection (Desferal) (Discontinuation) Deferoxamine Mesylate for Injection (Desferal) Denileukin Diftitox (Ontak) Injection (Discontinuation) Denileukin Diftitox (Ontak) Injection Doxorubicin (Adriamycin) Injection (Shortage) Doxorubicin (Adriamycin) Injection Ethiodized Oil (Lipiodol) Injection (Shortage) Ethiodized Oil (Lipiodol) Injection Leucovorin Calcium Lyophilized Powder for Injection (Shortage) Leucovorin Calcium Lyophilized Powder for Injection Leuprolide Acetate Injection (Shortage) Leuprolide Acetate Injection Mesna Injection (Discontinuation) Mesna Injection Ondansetron (Zofran) Injection (Discontinuation) Ondansetron (Zofran) Injection Thiotepa (Thioplex) for Injection (Shortage) Thiotepa (Thioplex) for Injection Tositumomab and Iodine I 131 Tositumomab (Bexxar) (Discontinuation) Tositumomab and Iodine I 131 Tositumomab (Bexxar) Current oncology medicines shortages USFDA 28 October 2015: http://www.accessdata.fda.gov/scripts/ drugshortages/default.cfm

5. Medicine shortages 5 |5 | Ammonium Chloride InjectionAmmonium Chloride Injection (Shortage) Atropine Sulfate InjectionAtropine Sulfate Injection (Shortage) Atropine Sulfate InjectionAtropine Sulfate Injection (Discontinuation) alcium Chloride Injection, USPalcium Chloride Injection, USP (Shortage) Calcium Gluconate InjectionCalcium Gluconate Injection (Shortage) Cefazolin InjectionCefazolin Injection (Shortage) Cefepime InjectionCefepime Injection (Shortage) Cefotaxime Sodium (Claforan) Injection Cefotaxime Sodium (Claforan) Injection (Shortage) Chloramphenicol Sodium Succinate Injection Chloramphenicol Sodium Succinate Injection (Shortage) Chloroquine Phosphate TabletsChloroquine Phosphate Tablets (Shortage) Cidofovir InjectionCidofovir Injection (Discontinuation) Dexamethasone Sodium Phosphate Injection Dexamethasone Sodium Phosphate Injection (Shortage) Dextrose 5% Injection BagsDextrose 5% Injection Bags (Shortage) Doxorubicin (Adriamycin) Injection Doxorubicin (Adriamycin) Injection (Shortage) Epinephrine 1mg/mL (Preservative Free) Epinephrine 1mg/mL (Preservative Free) 23 (Shortage) Epinephrine InjectionEpinephrine Injection (Shortage) Current shortages: Dosage forms for children Fentanyl Citrate (Sublimaze) Injection Fentanyl Citrate (Sublimaze) Injection (Shortage) Leucovorin Calcium Lyophilized Powder for InjectionLeucovorin Calcium Lyophilized Powder for Injection (Shortage) Leuprolide Acetate InjectionLeuprolide Acetate Injection (Shortage) Levetiracetam (Keppra) InjectionLevetiracetam (Keppra) Injection (Shortage) Lidocaine Hydrochloride (Xylocaine) Injection Lidocaine Hydrochloride (Xylocaine) Injection (Shortage) Liotrix (Thyrolar) TabletsLiotrix (Thyrolar) Tablets (Shortage) Lorazepam (Ativan) Injection Lorazepam (Ativan) Injection (Discontinuation) Magnesium Sulfate InjectionMagnesium Sulfate Injection (Shortage) Mecasermin [rDNA origin] (Increlex) Injection Mecasermin [rDNA origin] (Increlex) Injection (Shortage) Meloxicam (Mobic) Oral Suspension Meloxicam (Mobic) Oral Suspension (Discontinuation) Meropenem for Injection, USPMeropenem for Injection, USP (Shortage) Methyldopate Hydrochloride Injection Methyldopate Hydrochloride Injection (Shortage) Methylin Chewable TabletsMethylin Chewable Tablets (Shortage) Methylphenidate Hydrochloride ER Capsules/Tablets Methylphenidate Hydrochloride ER Capsules/Tablets 24 (Shortage) Ondansetron (Zofran) Injection Ondansetron (Zofran) Injection (Discontinuation) Pancuronium Bromide InjectionPancuronium Bromide Injection (Shortage) Peritoneal Dialysis SolutionsPeritoneal Dialysis Solutions (Shortage) Piperacillin and Tazobactam (Zosyn) InjectionPiperacillin and Tazobactam (Zosyn) Injection (Shortage) Potassium Chloride InjectionPotassium Chloride Injection (Shortage) Reserpine TabletsReserpine Tablets (Shortage) Sodium Chloride 0.9% Injection Bags Sodium Chloride 0.9% Injection Bags (Shortage) Sodium Chloride 23.4% Injection Sodium Chloride 23.4% Injection (Shortage) Sodium Chloride 23.4% Injection Sodium Chloride 23.4% Injection (Discontinuation) Sufentanil Citrate (Sufenta) Injection Sufentanil Citrate (Sufenta) Injection (Shortage) Thiotepa (Thioplex) for InjectionThiotepa (Thioplex) for Injection (Shortage) Tiopronin (Thiola)Tiopronin (Thiola) (Shortage) Tobramycin InjectionTobramycin Injection (Shortage) Trace ElementsTrace Elements (Shortage) Vancomycin Hydrochloride for Injection, USPVancomycin Hydrochloride for Injection, USP (Shortage) USFDA 28 October 2015: http://www.accessdata.fda.gov/scripts/ drugshortages/default.cfm

6. Medicine shortages 6 |6 | Regulatory decisions e.g., plant closures Insufficient manufacturing base (3 or fewer manufacturers) Market failures, including unaffordability and low-margins Competition for production capacity with higher margin products Poor visibility into demand cycles Less than full batch order quantities Poor procurement practices, eg payment and other terms Most commonly cited causes

7. Medicine shortages 7 |7 | Advance reporting to regulatory agencies from manufacturers Fast track regulatory assessments to manage risk of substitution Programmatic and association based reporting Compulsory licenses (eg for ARVs) Contract penalties in procurement Solutions in use for national level management

8. Medicine shortages 8 |8 | Who benefits from early warning systems of stringent regulatory authorities

9. Medicine shortages 9 |9 | Case study: global shortage of benzathine penicillin (PenG) WHO quantification in 20 countries with highest syphilis burden –4 million doses (in 2.4 MU) for adult men and women with early stage syphilis 1 and for pregnant women with active syphilis –90,000 doses of 3.8 MU for infants with premature delivery due to syphilis and infants with congenital syphilis Pen G and rheumatic heart disease –Up to 20 million doses needed for acute RH disease and continuing treatment –figures unreliable due to poor Dx, Rx and medicine consumption data Global supply is insufficient with 3 producers and repeated non- availability reports by major procurers 1 Assumptions and calculations are preliminary data from pending WHO analysis

10. Medicine shortages 10 | Global advance reporting systems for medicines at high risk ie manufacturers report in advance Fast track options to manage risk of substitutions along with communication approaches Harmonization of fast track regulatory reviews with information sharing Forums to identify and monitor highest risk products Model policy and legislation to promote effective management Solutions and conclusions of the meeting on managing and preventing global stock outs

11. Medicine shortages 11 | Regularize pricing policy to ensure that production can be realistically sustained Engage in prioritization and include models used by industry in the discussion Paradigm shifts needed in supply chain, motivation to report, and transparency In supply chain, development and exchange of quality information will take major changes –Implementation of GS1 bar coding systems as a starting point Solutions and conclusions of the meeting on managing and preventing global stock outs

12. Medicine shortages 12 | Photo: Dr Charles Senessie, SwissmedIc Thank you to all Thank you