Drug Shortages:Experiences in the U.S. and Abroad

Kasey K. Thompson, Pharm.D., M.S.Vice President, Office of Policy, Planning and Communications

American Society of Health-System Pharmacists

Bethesda, Maryland, U.S.A.

International Summit on Medicines ShortagesToronto, CanadaJune 20-21, 2013

Objectives

• Define causes and current trends in drug shortages

• Discuss implications of drug shortages

• Describe lessons learned from efforts in the United States to address drug shortages.

Drug Shortages in the United States: A Historical Perspective

• Not a new issue

• ASHP and others have been addressing drug shortages for almost 14 years

• ASHP web resource center—Updated Daily (www.ashp.org/drugshortages)

• Current challenge is the extent, duration, and type of drug shortages

• Has a major impact on patient safety and pharmacy practice

Drug Shortage Definition

• A drug supply issue requiring a change

• Impacts patient care

• Requires use of an alternative agent

American Society of Health-System Pharmacists. ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. AJHP. 2009;66:1399-1406.

U.S. Food and Drug Administration (FDA)

• Policy is to “prevent or alleviate shortages of medically necessary products”

• Shortages of “medically necessary” drugs are listed on FDA’s website

Jensen V, Kimzey LM, Goldberger MJ. AJHP. 2002;59:1423-1425.

FDA - Medical Necessity

• Product treats or prevents a serious or life-threatening illness (off-label or labeled)

• No reasonable alternatives exist (single-source)

.

Drug Shortage Data & Trends

National Drug Shortages January 2001 to May 31, 2013

01 02 03 04 05 06 07 08 09 10 11 12 130

50

100

150

200

250

300

120

8873 58

74 70

129149 166

211

267

204

60

Shortage

Note: Each column represents the # of new shortages identified during that year

National Drug Shortages—Quarterly

Q1-10

Q2-10

Q3-10

Q4-10

Q1-11

Q2-11

Q3-11

Q4-11

Q1-12

Q2-12

Q3-12

Q4-12

Q1-13

Q2-13

0

50

100

150

200

250

300

350

152167 176 188

239 246 256273 260

211

282299 295 302

Active Shortages

Shortages

Note: Each column represents the # of active shortages at the end of each quarter. Q2-13 are data through 5/31/13. University of Utah Drug Information Service

Active Shortages Top 5 Drug Classes

Antim

icrob

ials

Chem

othe

rapy

Cardio

vasc

ular

CNS

E-Lyt

es, N

utrit

ion0

102030405060

3829 27

52

32

Active Shortages 5/31/13

Active Shortages

University of Utah Drug Information Service

Common Drug Classes in Short Supply – 2010, 2011, 2012

Antibi

otics

Chem

othe

rapy

Auton

omic

Cardio

vasc

ular

CNS

Electro

lytes

EENT GI

Horm

one

0

10

20

30

40

50

23 24

15 15

34

23

137

14

35

26

1723

46

159 11 9

29

11 10

17

35

1510

16 16 201020112012

University of Utah Drug Information Service

National Shortages vs. Chemotherapy ShortagesJanuary 2001 to December 31, 2012

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

0

50

100

150

200

250

300

120

8873

5874 70

129149

166

211

267

204

3 4 2 7 10 3 5 12 424 26

11

NationalChemo

University of Utah Drug Information Service

Shortages – Dosage Forms 2012

45%

34%

10%

4%

3% 3%1%

InjectableOral solidOral liquidTopicalInhalationOphthalmicDevice

University of Utah Drug Information Service

Reasons for Shortages – 2012

Reason Determined by University of Utah Drug Information During Shortage Investigation

Unknown 44%Manufacturing 36%Supply/Demand 8.3%Discontinued 7.8%Raw Material 3.9%

Reasons for Injectable Shortages – 2012

42%

35%

7%

7%

5% 4%

Source – FDA Drug Shortages

Quality - Delays / CapacityQuality - GMPIncreased demandDiscontinuationRaw materialsLoss of manufacturing site

Quality Problems

Drug shortages

Raw Materials

Few Plants

Limited Lines

GMP Violations

Unknown

Supply Chain Issues

• Manufacturers and wholesalers typically have a 15 to 40 day inventory on hand

• Pharmacies - 10 to 16 annual inventory turns

The Pink Sheet. May 6, 2002:17-18

ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. AJHP. 2009;66:1399-1406.

Manufacturing Problems

• Sources• Sole source raw materials

• Time to establish new source

• Capacity• Few manufacturers of sterile injections

• Same production lines for multiple items

• Limited lyophilization capacity

Provisional observations on drug product shortages: effects, causes, and potential solutions. AJHP. 2002;59:2173-2182

Complex Manufacturing

• Over 23 steps to manufacture meropenem• Starting materials (Italy, Japan)• Crude meropenem (Japan)• Purified meropenem (Italy, Japan)• Bulk Meropenem (Italy, Japan)• Vial Filling (Switzerland, US)• Packaged in boxes (US)• Biologic products

• Take longer to produce• Any problems take longer to resolve

Multifactorial Reasons

• Multiple reasons can play a role in any particular shortage

• A product may be recalled due to concern for microbial contamination or particulate matter in the vials (propofol)

• 3 manufacturers of propofol, 2 had recalls, and the 3rd could not keep up with demand—U.S. imported product from Europe.

• A product may be recalled and the manufacturer may have difficulty accessing raw materials (lipid emulsion)

Business Decisions

• Profitability

• Manufacturing fixes

• Capacity – most factories running 24/7

22

Fragile Supply Chain Sterile Injectables

• Few suppliers– Majority of the market supplied by 7 manufacturers– Contract manufacturers – the company that supplies the product didn’t

always manufacture

• Lack of redundancy – Multiple products made on existing manufacturing lines – Limited resiliency in manufacturing process

• Complex manufacturing process– No simple fixes for quality problems– Problems typically affect multiple products

http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml

Raw Material Issues

• Raw material availability• 20 years ago – 90% from US and Europe

• Currently, 75 – 80% from China and India

• Some materials are no longer accessible or only available as single source products

Schweitzer SO. N Engl J Med. 2008;358:1773-1777

Provisional observations on drug product shortages: effects, causes, and potential solutions. AJHP. 2002;59:2173-2182

Fox ER, Tyler LS. AJHP. 2009;66:798-800

Example – Fragile Supply Chain

• Manufacturing plant closes April 2010.

• Impacts 49 drugs – 18 are chemotherapy.

• Problems occurred at the same time at other facilities.

• Manufacturing resumed spring of 2011, but still not up to prior capacity for some agents.

FDA’s Strategy

• Prioritize medically necessary agents (determined on a case by case basis)

• Evaluate risks and benefits for patients

• Offer assistance and advice, but up to the manufacturer to fix

• Success hinges on early notification

Jensen V, Kimzey L M, and Goldberger MJ. FDA’s role in responding to drug shortages. AJHP. 2002; 59:1423-5

How Does FDA Prevent Shortages?

• Regulatory discretion• Require filters (products with particulates, glass fragments)

• Ask clinicians to double check volume (overfill)

• Ask others to increase production

• Expedite reviews (new product, longer expiration, new raw material, new manufacturing sites

A Review of FDA’s Approach to Medical Product Shortages. October, 2011. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm275051.htm

Imports

• 12 different agents 2010-2013 • propofol, foscarnet, ethiodol, thiotepa, norepinephrine,

capecitabine, leucovorin, levoleucovorin, methotrexate, doxorubicin liposomal, phentolamine, sodium bicarbonate

• Limited by quantity available to share with US market

• Importation is not a viable long-term solution for U.S. market

Shortages Prevented by FDA 2010 - 2012

2010 2011 20120

50

100

150

200

250

300

InjectablesTotal

Source: CDER Drug Shortages

FDA Can Only Do So Much…

FDA CAN require *notification of supply disruptions (FDASIA)

FDA CANNOT require

*continued production

*increased production

*disclosure of distribution

International Perspective on Drug Shortages

• Drug shortages is a global issue!

• Globalization of the pharmaceutical supply chain:1

• 40 percent of finished drug products are manufactured abroad

• 80 percent of drug components (e.g., active pharmaceutical ingredients) are from foreign countries

• Quality issues in the global supply chain contribute to drug shortages

1. www.prescriptionproject.org/assets/pdfs/Pew_Heparin_Round4b_SinglePgs_b.pdf

European Association of Hospital Pharmacists—Drug Shortages Surveys

• Surveyed 346 hospital pharmacists in 31 countries

• Focus on the prevalence of drug shortages

• Surveyed 266 hospital pharmacists in 29 countries

• Focused on causes and impact on patients

EAHP Survey Results

• 98.8% of respondents had experienced a shortages in the past 12 months

• 63.1% reported that problems associated with shortages occur at least weekly; 27% reported monthly problems.

EAHP Survey Results

Medicines in Short Supply

Oncology 70.6%

Emergency 43.8%

Cardiovascular 35.1%

Hematology 22.2%

Respiratory 18.9%

Pediatric 18.9%

Other 31.4%

EAHP Survey Results

Originator Versus Generic Shortages

Originator/Brand 42.9%

Generic 57.1%

EAHP Survey Results

Root Causes of Shortages

Single or Limited Suppliers 52.4%

Raw Chemical Shortage 43.7%

Manufacturing Quality Problem 43.7%

*Small Country with Limited Market 41.7%

Impact of Drug Shortages

Practice Impact of Drug Shortages

• No advance warning

• Limited or no information

• Significant increase in resources used to manage shortages• Personnel: pharmacists, pharmacy technicians,

nurses, physicians

• Financial: increased cost of alternative products/off-contract purchasing; gray market

• Diverts health care providers from direct patient care activities• The resulting impact on patient safety and

outcomes may be substantial but is difficult to quantify

University of Michigan/ASHP Survey. AJHP. 2011;68:1811-9.

Time Spent by Health Care Practitioners

Pharmacists Pharmacy Technicians Physicians Nurses0123456789

10

Hours Per Week Spent Managing Drug Shortages

AJHP. 2011;68:1811-9.

Patient Care Impact

• Patient care issues

• Delayed or unavailable care

• Safety implications

• Adverse impact on patient outcomes

Percent of Hospitals Reporting the Impact on Patient Care as a Result of a Drug Shortage

Patient experienced an adverse outcome

Patient did not receive recommended treatment

Patient received a less effective drug

Patient treatment was delayed

3%

10%

11%

17%

32%

52%

58%

62%

35%

63%

69%

82%

Frequently Rarely Series 4

Source: AHA analysis of survey data from 820 non-federal, short-term acute care hospitals. Survey completed in June 2011

Cause for Concern: Errors that May Be Caused by Drug Shortages

• Clinicians may be less familiar with dosing, administration, or monitoring of the alternative therapy

• Use of different package sizes can lead to over or under dosing

• Compounding of unavailable therapies can lead to errors or sterility issues

U.S Efforts to Prevent Shortages

ASHP Guidelines on

Managing Drug Shortages

www.ashp.org/DocLibrary/BestPractices/ProcureGdlShortages.aspx

Drug Shortages SummitBethesda, Maryland; November 2010

• Goals

• Define the scope, causes, and potential patient harm from drug shortages

• Discuss potential changes in public policy and stakeholder practices

• Partner Organizations

• ASHP

• American Society of Anesthesiologists

• American Society of Clinical Oncology

• Institute for Safe Medication Practices

• American Hospital Association (joined post summit)

• 21 recommendations to improve communication and remove

barriers faced by the FDA and drug manufacturers

www.ashp.org/drugshortages/summitreport

Addressing Drug Shortages in the U.S.: ASHP Advocacy

• Early notification to FDA by manufacturers for all drugs regulated by FDA

• Civil monetary penalties

• Inter-agency coordination

• Contingency plans

• Generic user fee program

Why Early Notification?

Prevented shortages2010 382011 195

2012 42

Impact of New Law

• A good first step – not a total solution

• Increases scrutiny on shortages

• Strengthens FDA’s Drug Shortages Program

• Expedites approval of additional industry capacity and applications

• Does not directly address capacity and economic factors

Conclusions

• Drug Shortages Remain a Major International Problem

• There is No Single Cause of Shortages

• The Reasons for Shortages May Differ From Country-to-Country, But there are also Likely Similarities

• Communication is key between stakeholders (providers, government, manufacturers, and patients)

Thank You