Shortages of

Report
International Summit on
Medicines Shortages
Toronto, Canada
June 20-21, 2013
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.
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 lifethreatening illness (off-label or labeled)
•
No reasonable alternatives exist (single-source)
.
Drug Shortage Data & Trends
National Drug Shortages
January 2001 to May 31, 2013
300
267
250
211
200
150
100
204
149166
129
120
88
73
58
74 70
Shortage
60
50
0
01 02 03 04 05 06 07 08 09 10 11 12 13
Note: Each column represents the # of new shortages
identified during that year
National Drug Shortages—Quarterly
Active Shortages
350
300
239
250
200
150
152
188
176
167
246 256
282
273 260
299 295 302
211
Shortages
100
50
0
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
Active Shortages 5/31/13
60
50
40
30
20
10
0
52
38
29
27
University of Utah Drug Information
Service
32
Active Shortages
Common Drug Classes
in Short Supply – 2010, 2011, 2012
50
45
40
35
30
25
20
15
10
5
0
46
35
29
2426
23
1517
11
10
34 35
23
15 17
University of Utah Drug
Information Service
23
16 14 16
1515 13
910 711
9
2010
2011
2012
National Shortages vs. Chemotherapy Shortages
January 2001 to December 31, 2012
300
267
250
211
204
200
129
120
58
74
70
2002
2003
2004
2005
0
3
5
4
2009
7
2008
2
12
2007
4
2006
3
10
2001
50
University of Utah Drug Information
Service
24
26
11
2012
73
2011
88
100
National
Chemo
2010
150
149
166
Shortages – Dosage Forms 2012
3%
4%
3%
1%
10%
45%
34%
University of Utah Drug Information
Service
Injectable
Oral solid
Oral liquid
Topical
Inhalation
Ophthalmic
Device
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
Source – FDA Drug Shortages
4%
Quality - Delays /
Capacity
Quality - GMP
5%
7%
7%
42%
Increased demand
Discontinuation
Raw materials
35%
Loss of manufacturing
site
Quality Problems
Limited
Lines
GMP
Violations
Few
Plants
Raw
Materials
Drug
shortages
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
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
22
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
300
250
200
Injectables
Total
150
100
50
0
2010
2011
Source: CDER Drug Shortages
2012
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
Emergency
Cardiovascular
Hematology
Respiratory
Pediatric
Other
70.6%
43.8%
35.1%
22.2%
18.9%
18.9%
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
Hours Per Week Spent Managing Drug Shortages
10
9
8
7
6
5
4
3
2
1
0
Pharmacists
AJHP. 2011;68:1811-9.
Pharmacy
Technicians
Physicians
Nurses
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 treatment was delayed
17%
Patient received a less effective drug
11%
Patient did not receive recommended
treatment
10%
Patient experienced an adverse outcome
3%
Always
62%
82%
58%
52%
32%
35%
Frequently
Rarely
Source: AHA analysis of survey data from 820 non-federal, short-term acute care hospitals.
Survey completed in June 2011
69%
63%
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 Summit
Bethesda, 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 shortages
2010
38
2011
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 Countryto-Country, But there are also Likely Similarities
•
Communication is key between stakeholders
(providers, government, manufacturers, and patients)
Thank You

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