Drug Shortages: Experiences in the U.S. and Abroad Kasey K. Thompson, Pharm.D., M.S. Vice President,...
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Transcript of Drug Shortages: Experiences in the U.S. and Abroad Kasey K. Thompson, Pharm.D., M.S. Vice President,...
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)
.
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
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)
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
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%
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
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
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)