©2012 Novation Confidential. 1 ©2013 Novation Confidential. 1 Compounding Misadventures and the Legislative Fix (DQSA) L. Ross Day, R.Ph. Director, Novation

©2012 Novation Confidential.1 ©2013 Novation Confidential.1

Compounding Misadventures and the Legislative Fix (DQSA)

L. Ross Day, R.Ph.Director, Novation Pharmacy

©2012 Novation Confidential.2

Salaried employee of Novation

No financial relationship with any pharmaceutical company

Financial Relationships

L. Ross Day, R.Ph. Disclosure


Pharmacy Education Learning Objectives

At the conclusion of this presentation, participants will be able to:

•Articulate the number of newly reported drug shortages through Q2 2014

•List, by therapeutic category, the types of newly reported drug shortages most frequently reported in the last three years

•List reasons that have been provided for drug shortages

•Describe negative economic and clinical outcomes of drug shortages, including drug compounding misadventures, and the new legislation focused on ensuring drug quality and security



Current State of Drug Shortages


The State of Drug Shortages…(As of June 30, 2014)Number of New Drug Shortages Reported by YearNew shortages decreased 24% in 2012 and 31% in 2013 (YOY)

University of Utah Drug Information Service [email protected]


National Drug Shortages Active Shortages by Quarter (through Q2 2014)

University of Utah Drug Information Service [email protected]


Active Shortages (by therapeutic category)Top 5 Drug Categories through Jun 30, 2014

University of Utah Drug Information [email protected]


Most Drug Shortages are Injectables and Multi-Sourced Generics

Bra

nd

-Gen

eric

Typ

e

83% are Multi-Sourced Generics without Patent Protection or Exclusivity

Fo

rm T

ype

82% are SterileInjectables

Source: IMS Institute for Healthcare Informatics, Drug Shortages: A Closer Look, November 2011.


Causes of Drug Shortages


Drug Shortages Caused by Multiple Reasons

Source: IMS Institute for Healthcare Informatics, Drug Shortages: A Closer Look, November 2011.

Manufacturing Issues

Discontinued/ Suspended

Increased Demand

Raw Material Issues

Crystallization/ Particulates

Recall

No Reason Supplied

Import Ban

FDA Review

Major Sites with Manufacturing Issues

WarningLetter

WarningLetter

Warning Letter

Consent Decree

WarningLetter

WarningLetter Fresenius Kabi (APP): at

Kalyani API facility. Known to make Oncolytic APIs

WL

Fresenius Kabi (APP): Grand Island site under warning letter. Failed re-inspection in January

Explosion

Novartis/Sandoz: Boucherville Canada

WLImport Alert

Wockhardt: Waluj

Boehringer Ingelheim: API & FG

Warning Letter

Apotex: Richmond Hill & Toronto

Novartis/Sandoz: EBEWE SITE

Warning

Letter

Teva: Hovav Israel API Plant

WarningLetter

Teva: Irvine Facility

FOR SALE!

Baxter: Jayuya site

Baxter: Marion North Cove Site

Boehringer Ingelheim: Ben Venue Site

Ceasing Operations

483

Wockhardt: Chikalthana

Strides (Mylan): warning letter at Facility #2 (not the oncology site)

WL


Implications of Drug Shortages


Drug Shortage Crisis has Profound Implications

Increased labor expenses2011 survey1 revealed $216 million labor costs and an average time spent of 9 hours per week for pharmacists and 8 hours per week for pharmacy technicians

Increased non-labor expensesUnprecedented generic drug price increasesBillions of remediation mandated re-investments

Potential for patient injury 2010 survey2 revealed current environment of drug shortages has even resulted in patient deaths

Possibility of delayed patient treatmentShortages of several oncology medications have resulted in delayed or deferred chemotherapy treatment regimens with unknown effects on patient outcomes

1. Kaakeh R, Sweet BV, et al. Impact of Drug Shortages on U.S, Health Systems. Am J Health-Syst Pharm. 2011;68:1811-9.

2. ISMP survey on drug shortages. ISMP Medication Safety Alert! 2010;15(15):4.©2012 Novation Confidential.13


– Top five medications in short supply

• Doxorubicin liposomal injection

• Morphine (oral concentrate and injection)

• Fentanyl injection

• Calcium gluconate injection

• Fluorouracil

– Other problematic oncology medications (Cisplatin, Daunorubicin, and Paclitaxel)

– Alternative medication provided, but not drug of choice leading to inadequate treatment (35%)

– Error with an alternative drug or form/strength of drug (27%)

– Omission of vital medication leading to non-treatment of patient (27%)

– Error when hospital pharmacy attempted to compound a product or drug strength no longer available (6%)

Medications most frequently involved in reports of patient harm

Problems associated with a drug shortage that resulted in patient harm

Documenting Patient HarmISMP Survey Published April 2012

2012 Fungal Meningitis Outbreak (NECC)



Compounding Misadventures in 2012

• Franck’s Compounding Pharmacy

– Adverse events during eye surgeries

• Contaminated triamcinolone ophthalmic solutions

• 47 patients developed serious fungal infections p. surgery

– Recall of all products sold since November 2011

– Franck’s closed and re-opened under another name 4 days later

– Franck’s previously implicated in deaths of 21 polo ponies in 2009

• Federal court ruled FDA lacked jurisdiction for pharmacists compounding

• NECC

– Outbreak of fungal meningitis

• Epidural steroid injections (reports began in late August)

• Multi-state outbreak

• Over 750 cases; 64 deaths

• Recall of all products


Pharmacy Sterile Compounding Summit

Observers

•Pew Charitable Trusts (Coukell, Cosell, Despres)

•Federation of American Hospitals (Chambers)

•APhA (Rowe)

•National Community Pharmacists Assoc (Blankenship, Hauser)

•National Patient Advocate Foundation (Lamarca)

Invited Speakers And Stakeholders

•FDA (Axelrad, Sklamberg, Anderson, Ireland, Riley)

•USP (Firschein, Schnatz, Kastango-Clinical IQ)

•ISMP (Cohen)

•CDC (Craig)

•Practitioners (DOP’s from Vanderbilt Univ., Cleveland Clinic and Baptist Montgomery)

•GPO’s (Novation, Premier, Cardinal and HPG)

•NABP (Russell)

•Mass Society of Health-System Pharmacists (Kerr)

•State Boards of Pharmacy (Massachusetts and Minnesota)

•Children’s Hospital Association (Rudisill)

•AMA (Dickinson)

•Compounding Industry- Pharmedium (Kruzynski, Rasnic)

Feb. 6th, 2013, Washington, DC - Convened by ASHP and AHA



After the Summit, More Misadventures

• FDA conducts audits of “specialty pharmacy” compounders all over the US– All four Pharmedium facilities were inspected in 2013– Observations and 483’s found with all compounders, including Pharmedium– cGMP standards were used for the first time as the basis of audits

• Likely that FDA was establishing a baseline in order to make new regulations

• Georgia Compounding Pharmacy widens recall – Clinical Specialties Compounding Pharmacy of Augusta, GA– First recall was for Avastin– Latest recall was for all sterile products compounded at this facility

• Michigan AG (Mar 27th, 2013) Seeks Grand Jury Investigation (ASHP Daily News)– Criminal charges being considered for executives of NECC

• Officers of NECC settle claims with victims– May 7th, 2014, officers and executives of NECC agree to $100 million settlement for

victims


HR 3204 Drug Quality & Security Act

• 180 page bill introduced Sept. 25th, passed Sept. 28th, signed by President

– Compounding Regulations (Title 1 – 30 pages)

– Track and Trace (Title 2 – 150 pages)

• DQSA (Title 1) Section 503A- “Traditional Compounding”

– 503A – Traditional Compounding (Regs already existed in F.D.C. Act)

– State pharmacy license required and USP <797> Based – Ceiling

– Limited, if any, anticipatory compounding – Primarily patient specific

– State Board of Pharmacy Inspections (Must inform FDA of concerns found)

• Quality issues

• Warnings/Sanctions

• 503A Violators (May need to be registered in 503B)

– Compounding in hospital-based pharmacies will fall under 503A

Drug Quality and Security Act (Compromised 2 earlier bills)….

HR 3086- Compounding Clarity Act (April 2013- states empowered)

S.959- HELP Committee Bill (August 2013- FDA empowered)


HR 3204 Drug Quality & Security Act (cont)

• DQSA (Title 1) Section 503B- “Outsourced Compounding” (New)

– Entities are defined as “Outsourcing Facilities” (new)

– Federal registration required – “FDA oversight”

– Registrants will be on FDA website (listing whether they start with sterile or start with API bulk)

– Fees (to cover inspections) will be assessed upon registration

– Inspection frequency determined by risk (higher risk of API bulk to sterile will have more inspections)

– Reporting requirements (e.g. production activity, ADR’s, compounding for drug shortages etc.)

– Labeling to include:

• “This is a compounded drug”

• “Not for resale”

• “Office use only”-- (industry and stakeholders hoping to get this modified)

– Can hold RX license if doing traditional 503A activities (CAPS model)

– Limitations: (“Do not compound” list from FDA; Limitations on bulk substances


Compounding Quality Act (summary)

• Defines 3 distinct classes of producers

– Pharmacy, Outsourcing Facility, Manufacturer

• Explains exemptions

• Requires annual establishment and re-inspection fees

• Places onus on FDA to perform audits for Outsourcing Facilities

• Designates drugs that may not be compounded

• Defines bulk ingredient qualifications

• Places restrictions on wholesaling

• Increases state and FDA communication (two way)


Outlook Beyond 2014

• Fewer new shortages, but number of active shortages will remain high

– Continuing potential to impact patient care, including additional compounding misadventures

• Comprehensive drug management policies and procedures will remain important

– Effective communication remains critical to drug shortage management strategies

• Shortage crisis will continue to be the subject of government review and advocacy efforts

• New Compounding/Track and Trace Legislation passed to ensure quality and security of the pharmaceutical supply chain

• Estimates of 2 to 3 years before substantial improvement due to improved/expanded manufacturing facilities (following billions of dollars worth of remediation)

• New FDA Guidance to be discussed at second Compounding Summit (July 2014)

– cGMP Standards specific for compounding facilities to be defined

– Do Not Compound List to be expanded (25 new ones→ now total > 75)


Do Not Compound List …(Not safe / ineffective)


What is your contracting criteria?

• Registered as FDA outsourcing facility (503-B)- FDA’s Recommendation– Comply with cGMP regulations– Provide procedure for adverse event reporting– Provide list of all medications compounded

• National provider or regional provider- “compounding scale”• Will the compounder provide their most recent 483 observation form?

– Will the compounder provide you a satisfactory 483 resolution document?

• What is your risk appetite? (non-sterile → sterile or sterile → sterile)• Will your compounder determine BUD for all products at least

annually?• Will your compounder perform sterility testing on all batches?• Can your compounder pass a QSR (Quality Site Review)?

– Performed by your facility or a qualified independent auditor

Have you established minimum requirements for a contract?

Discussion

Documents

©2012 Novation Confidential. 1 ©2013 Novation Confidential. 1 Compounding Misadventures and the Legislative Fix (DQSA) L. Ross Day, R.Ph. Director, Novation