Characterizing Drug Shortages and Their Causes: Anticipating Future Trends

Richard Dolinar, MD

Chairman The Alliance for Safe Biologic Medicines

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Impact of Drug Shortages

According to the 2011 American Hospital Association’s Survey on Drug Shortages, of 820 hospitals surveyed :

Quality of Care:

82% of respondents reported delays in treatments 69% said patients received less effective drugs 35% reported adverse outcomes

Access:

78% reported rationing or restricting drugs

Cost:

92% reported increased drug costs due to shortages 3

How Shortages Affect Patients

A University of Pennsylvania survey of

245 oncologists surveyed between March 2012 and March 2013 found: •

83% of oncologists had experienced drug shortages

—including potentially life-saving drugs for breast, prostate, and ovarian cancers —in the past six months.

• 79% of oncologists treated patients with another drug or regimen • 43% delayed a patient's treatment • 37% had to choose which patients would receive treatments and which would wait • 29% had to ask patients to skip doses.

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Where Are Shortages Occurring?

80% of shortages occurred among Sterile Injectables:

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28% oncology drugs

•

13% antibiotics

•

11% Electrolyte/nutrition drugs

•

9% neuromodulators

•

6% hormonal Source: A Review of FDA’s Approach to Medical Product Shortages, FDA Oct. 2011

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Why Are Shortages Occurring?

One factor: the complex manufacturing process.

The Manufacturing process must be sterile, free of particulate matter, and often requires dedicated production lines.

•

43% of shortages are due to problems in manufacturing process.

•

15% of shortages are due to delays in manufacturing and/or

shipping.

Source: A Review of FDA’s Approach to Medical Product Shortages, FDA Oct. 2011

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Why Are Shortages Occurring?

•

Another factor: market forces

Market concentration

: few manufacturers of a given product lead to supply chain vulnerability. (342 out of 569 (60%) sterile injectable molecules in 2010 were virtually sole ‐ sourced), even among products with generic competitors.

1 • • Wholesaler and GPO purchasers often put additional downward pressure on prices.

2 When downward price pressure makes the margins too thin, manufacturers respond to GMP violations by terminating production, which leads to shortages because the low margin has pushed back-up producers out of the market.

1 The top three generic injectable manufacturers hold 71% market share of sterile injectables 3 , consequently, there are few, if any, suppliers to step in if one manufactures has a problem that will create a shortage.

1 A Review of FDA’s Approach to Medical Product Shortages, FDA Oct. 2011 2 General Purchasing Organizations

aggregate the purchasing volume of its members, typically provide contracted discounts on medical supplies, nutrition, pharmacy and laboratory.

3 IMS Health, IMS National Sales Perspectives?™, Extracted September 2011. Based on 569 sterile injectable molecules.

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FDA Approach to Reducing Shortages

• • • FDA prevented 195 shortages in 2011 and almost 100 shortages during the first half of 2012.

1 Several key FDA authorities facilitated this: Expediting review of manufacturing sites Identifying other suppliers that could increase production to fill gap Working with manufacturers to identify and mitigate quality issues in production (such as filtration of contaminants) to prevent shortages.

• •

July 2012: Food and Drug Administration Safety and Innovation Act (FDASIA) signed into law:

Requires all manufacturers of covered drugs to notify FDA of potential discontinuances, temporary or permanent. (The prior law applied only to sole manufacturers.) Expands notification requirement to biologic products, which were previously exempt.

1 http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstot heFDCAct/FDASIA/ucm313121.htm

Accessed June 2013

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Medical Concerns Regarding Potential Biologic Shortages

• No two biologic medicines are identical and patients may respond to the differences. • Switching a patient between biological products – whether biosimilar or simply biologics in the same class – could have unwanted and unintended consequences, including an unwanted immune response. • Therefore, biologic drug shortages could create additional risk for patients. 9

What Makes Biologics a Drug Shortage Risk?

• Biologic medicines are generally sterile injectables, the drug class historically most prone to shortages.

• The manufacturing process of biologic therapies is far more complex than that of small-molecule drugs, including sterile injectables.

• The proteins used in biologics are often highly sensitive to light, heat, turbulence and container closure systems, among other things. • Shortages occur frequently among those who manufacture copies; the first biosimilars are expected to be approved in 2013 – 2014, when the factors that lead to traditional drug shortages may come into force soon.

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Pharmacovigilance: Naming

Thailand has a substantial spike in Pure Red Cell Aplasia, > 30 RBC stimulating products. Which is the culprit?

Unique non-proprietary names are essential to distinguish these medicines from one another, to track and trace adverse effects. • Patient response must be traced to the correct manufacturer’s product. • Unique naming provides transparency and helps differentiate

products for observing and reporting adverse events.

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ASBM/FDLI Whitepaper, Nov. 2012

1. All biologics should receive

distinct non proprietary names.

2. United States Pharmacopeia (USP) should work with FDA to adapt the product monograph system to accommodate the unique attributes of structurally related, but distinct, biologic medicines. 3. The non-proprietary name of a reference product and product/s biosimilar to it should have a

common, shared root but have distinct and differentiating suffixes.

4. Products designated interchangeable should have a distinct name from the reference product for which they are considered interchangeable to

facilitate accurate attribution of adverse events.

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Medicine Naming Conventions

The same drugs…

should have the same non-proprietary name.

Levothyroxine / levothyroxine Synthroid ® / Levothroid®

Similar drugs...

should have similar non-proprietary names.

Different drugs…

should have different non-proprietary names.

pravastatin / fluvastatin Pravachol ® / Lescol ® aspirin / acetaminophen Bayer ® / Tylenol® 13

Distinguishing Prefixes in Biosimilar Naming

FDA, 2012:

“The nonproprietary name tbo-filgrastim is intended to differentiate this product from Neupogen to minimize medication errors and facilitate postmarket safety monitoring.” ZALTRAP® (ziv-aflibercept),was also approved by FDA in 2012 using a distinguishing prefix to differentiate from its reference biologic (aflibercept).

• • •

However, confusion between similar biologic medicines may still occur:

For example, the new medicine KADCYLA® (ado-trastuzumab) is dosed differently than the reference biologic HERCEPTIN ® (trastuzumab). Cases have occurred wherein a prescribing physician has mistakenly omitted the distinguishing prefix, resulting in a patient receiving the wrong medication, at the wrong dose. (Confusion could also occur with suffixes).

Prefixes, unlike suffixes, prevent similar medicines from appearing together in alphabetized lists, but potentially may allow the similarity to be missed.

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Global Standards Being Discussed

However, FDA’s use of distinguishing prefixes does not align globally.

On April 15-17, WHO held the 56th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances.

ASBM Letter to WHO:

“Product naming is an important element of biologic safety. We firmly advocate that all biologics should receive distinct non-proprietary names to ensure products will be distinctly identified to facilitate accurate attribution of adverse events.

The non-proprietary name of a reference product and product/s biosimilar to it, should have a common, shared root but have distinct and differentiating suffixes as a means of facilitating clear adverse event reporting .” 15

Pharmacovigilance: Testing

Clinical testing of a biosimilar medicine is vital for gaining real-world data on how these medicines actually function in a therapeutic setting.

Pre-approval and post-market clinical studies should be required to demonstrate:

• Similar therapeutic response profile- that is, the biosimilar is as safe and effective as the original medicine • Similar known side effects, not new ones • Study should be long enough and large enough sample size 16

Pharmacovigilance: Labeling

Clarity during prescription, dispensing, and monitoring is essential.

Biosimilars should be

clearly labeled with distiguishable product name, name of the manufacturer, and the product lot number

to enable physicians, pharmacists, and patients to quickly identify the source of any adverse effects.

This provides multiple means of product identification (unique names, NDC, lot numbers) avoid a single point of information failure.

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Summary: Ensuring Access to Safe Biologics

• Hold manufacturers accountable for the quality of their products. • Transparency = Accountability. – FDA can facilitate accountability by making information about companies’ history of manufacturing quality [available to purchasers, physicians, consumers / publicly available].

– Implementation of unique naming, and a robust track/trace system including clear labeling will facilitate accurate identification of biologic manufacturers. • Rigorous testing of biosimilars – hold copies to the same standard of quality as the reference biologics 18

Questions?

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