Introduction to
U.S. Drug Shortages
CDR Emily Thakur, R.Ph.
LCDR Helen Saccone, Pharm.D.
U.S.Public Health Service
Center for Drug Evaluation & Research
U.S. Food & Drug Administration
1
Overview
U.S. Drug Shortage Trends
Reasons for Drug Shortages
FDA’s Role
View of the Future
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Drug Shortage Program History
• Center for Drug Evaluation & Research
– Drug Shortage Program (DSP) began in 1999
– Today have 11 full time staff
– Many others in involved
• Mission: address potential and actual drug
shortages
Who works on this?
Office of New Drugs
Office of Chemistry
Office of Generic Drugs
Office of Compliance
Office of Regulatory Affairs
Field Inspectors
MANY OTHERS!
– Facilitate prevention and resolution of shortages by
collaborating with FDA experts, industry, and external
stakeholders
– Inform the public
– Outreach to healthcare professional organizations,
patient groups and other stakeholders
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Growing problem – and FDA response
• FDA website updated daily
• Staffing and management coordination
• Public reports encouraged – industry reports of
problems even more so
• Public workshop September 26, 2011
• Collaboration on system fixes
– American Society of Healthcare Pharmacists (ASHP)
– Industry (GPHA, PhRMA, BIO)
• Prevent and mitigate individual shortages
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U.S. Drug Shortages
300
251
250
200
157
150
100
50
41
182
110
90
61 51 56
178
All Dosage Forms
Shortages
Sterile Injectable Shortges
74
44
35
46
0
2005 2006 2007
2008 2009 2010 2011
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2011 Shortage Data
• There were 251 shortages reported in 2011
• High percentage are sterile injectable products
– Treatments for cancer, anesthesia, serious illness
– Highly specialized manufacturing
– High risk to patient if not meticulous
When there are quality or production problem
for a sterile injectable drug,
a shortage is almost always results
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Sterile Injectables:
> 75% lapsed product quality & production
Product Quality 54%
Delays, capacity and
loss of manufacturing
site 25%
Discontinuations 11%
Raw Materials 5%
New demand 4%
Other 2%
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Reasons for Shortages: Sterile Injectables
Report by Assistant Secretary for Planning & Evaluation 2011
• State of the industry
– Seven (7) manufacturers make up most of market
– Contract manufacturers – firms contract out manufacturing as
well as acting as contract manufacturers
• Lack of redundancy
– Multiple products made on existing manufacturing lines
– 24/7 production with no “cushion”
• Complex manufacturing process
– No simple fixes
– Problems typically affect multiple products
• Investment economics question
– e.g., propofol 20ml sells for $0.48/vial
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Quality and Manufacturing Examples
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Lack of sterility
Particulates of foreign matter
Crystallization of the active ingredient
Precipitates
New/unintended impurities or degradants
Equipment breakdown
Natural disasters
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What doesn’t cause shortages
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Increased stringency of CGMPs & standards
Increased inspections/enforcement actions
Foreign manufacturing
Unapproved drugs initiatives
Drug approval delays
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How does FDA fit?
• Patient care is our #1 concern
• We get involved when we are informed
• Seek ways to prevent & mitigate shortages
– Secondary response to industry problem
– Find root cause and get manufacturer on track
• Some shortages can be prevented, but not all
– Unforseen breakdown in manufacturing system
– Longstanding quality manufacturing problems
• Some can be addressed quickly, others not
– Risks to the patient always considered
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FDA’s Role
• FDA is responsible for protecting the
public health by assuring the safety and
efficacy of drugs
• FDA facilitates responses to prevent or
mitigate a drug shortage when we are
aware of it
– This is a secondary response to mitigate a
problem that has already happened
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Medical Necessity
• A medically necessary drug product is a
product that is used to treat or prevent a
serious disease or medical condition for
which there is no other alternative drug,
available in adequate supply, that is judged
by medical staff to be an adequate substitute
CDER Manual of Policies and Procedures on Drug
Shortage Management 6003.1
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesPro
cedures/UCM079936.pdf
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FDA Tool Box
• Regulatory discretion: allow manufacture of
medically necessary product(s) to continue
– Minor, low risk issues usually best suited for this tool
– In some cases require additional safety controls
• Request other firms to ramp up manufacturing.
• Expedite any review of company proposals
• In rare cases, controlled temporary importation
from unapproved sources
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What can’t FDA do
• Mandate firms to continue to manufacture products at
certain quantities
• Require DEA to increase quotas of controlled
substances
• Publish the exact cause of manufacturing/ quality
issues
• Be consultants to manufacturers to fix quality
problems
• Build robust quality management systems (QMS) and
build in quality at manufacturing firms
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What Can Prevent Shortages
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Commitment to quality from senior management down to line workers
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Anticipate supply problems
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Proactively identify & promptly correct issues
Design/qualify robust operations
Reinvestment into equipment, facilities and personnel
Investigate problems to identify and fix root cause
Plan ahead by adding redundancy to manufacturing & raw material supplies
Arrange for additional manufacturing capacity
Develop alternate supplies of components
It is important to consider the root cause of a shortage
• If the root cause that leads to a shortage can be prevented, one can get
to primary prevention
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Communication
Good agency-industry communication can
facilitate resolution of a drug shortage.
FDA is committed to working with industry
to quickly resolve any quality or
manufacturing problems that arise to
ensure continued patient access to vital
safe and effective medicines
- CAPT Valerie Jensen
FDA Drug Shortage Program
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Communication
• Problem of drug shortages is complex and
multifaceted-requires continued collaborations
• Communication and collaboration with groups
has become increasingly important- DSP has
taken a proactive approach
• DSP routinely communicates with
manufacturers, health care professionals,
stakeholders, organizations, patient advocate
groups, and others
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Communication
• Notify FDA Drug Shortage Program (DSP) of potential
and actual supply problem
• Contact FDA DSP with creative strategies to mitigate
shortages
– Contingency plans to increase capacity
– Interested in coming into the market to alleviate shortages
• President’s Executive Order issued 10/31/11 encouraged
more voluntary reporting by manufacturers
– 6 fold increase in notifications of potential shortages
• normally received 10/month on average in 2010 and now receiving
over 60 notifications per month
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2011 Data Higher – Executive Order
President’s Executive Order issued 10/31/11
encouraged more voluntary reporting by
manufacturers
• 6 fold increase in notifications of potential shortages
– normally received 10/month on average in 2010 and now
receiving over 60 notifications per month)
• Total of 195 shortages prevented in 2011
• 42 shortages prevented as of April 28, 2012
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DISCONTINUANCE OF A LIFE SAVING
PRODUCT
SEC. 506C. [ 21 U.S.C. 356c] DISCONTINUANCE OF A LIFE SAVING
PRODUCT.
(a) IN GENERAL.—A manufacturer that is the sole manufacturer of a
drug—
(1) that is—
(A) life-supporting;
(B) life-sustaining; or
(C) intended for use in the prevention of a debilitating disease or
condition;
(2) for which an application has been approved under section 505(b) or
505(j); and
(3) that is not a product that was originally derived from human tissue and
was replaced by a recombinant product, shall notify the Secretary of a
discontinuance of the manufacture of the drug at least 6 months prior
to the date of the discontinuance.
•
See also 21CFR 314.81(b)(3)(iii)
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38 Shortages Prevented in 2010
• All due to firms notifying FDA of problems early
• 16 through regulatory discretion
– Risk of quality/manufacturing issue able to be mitigated and was
outweighed by benefit of the drug
• 13 through expedited review
– New manufacturing sites, suppliers, etc.
• 8 through encouraging other firms to ramp up
• 1 through communication with DEA regarding firm’s
need for controlled substance quota increase
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195 Shortages Prevented in 2011
• Most due to firms notifying the FDA of early
problems
• The main FDA action taken to prevent drug
shortage was Expedited Review
• Other actions taken include:
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Regulatory discretion
Ramping up production
Assistance with release
Extension of expiry of available products
Additional testing
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Recent Public Outreach
• FDA Drug Shortage Website
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default
• Public Meeting
• FDA Report – Review of FDA’s Approach to Medical Product
Shortages
• Letter to Industry
• Guidance for Industry – Notification to FDA of Issues that
May Result in a Prescription Drug or Biological Product
Shortage
• Interim Final Rule – Revision of Postmarketing Reporting
Requirements – Discontinuance
• Meetings with stakeholders – PhRMA, ASHP, GPhA, BIO, Eli
Lilly, Amgen, and others
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Shortages can’t always be prevented
• Unanticipated problems, such as a
manufacturing line breakdown or natural
disaster
• Manufacturer(s) may not be able to make up
production shortfall
• Risks are significant and would cause patient
harm (e.g. sterility problems)
• FDA will work with company to encourage smart
distribution
– No easy answers on how to do this well
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The Future
• FDA Drug Shortage work will continue
– Multidisciplinary: clinicians, pharmacists, chemists,
biotechnology, regulatory and manufacturing
– We can only prevent shortages if problems are reported
– Public communication of existing shortages
• Congress discussing new legislation
– Would REQUIRE broader reporting by industry to FDA
• Public expects and deserves high quality drugs
• Must have industry commitment to culture of quality
manufacturing
– Many firms are building new plants today
– Need better methods and redundancy
– Promptly report and correct even small problems
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Thank You
• FDA drug shortage website is:
http://www.fda.gov/Drugs/DrugSafety/default.htm
• To report shortages our e-mail account is
Drugshortages@fda.hhs.gov
• FDA Webinar on Prescription Drug Shortages
Sept. 30, 2011,
http://www.fda.gov/AboutFDA/Transparency/Basics/
ucm272223.htm
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