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Securing an Adequate Drug Supply for each TB Patient Jennifer Flood MD, MPH University of California, San Francisco [email protected] 1 Essential Components of a National TB Program International Standards for TB Control programs – An uninterrupted supply of good quality anti-TB drugs Essential Components of a Tuberculosis Prevention and Control Program, ACET • Ensure patients who have TB receive appropriate treatment until they are cured • Treat patients without consideration of their ability to pay 2 Background Why are we discussing in 2012? • TB patients and U.S. programs have experienced recurring difficulty accessing MDR TB drugs Issues: • Drug shortages • Climbing costs • Multi-step processes for procurement • Out-of-reach for uncovered patients 3 2010 NTCA Survey: Interruptions in TB Drug Supply • 21 of 33 (64%) faced challenges obtaining MDR drugs in the United States • 95% experienced barriers due to a nationwide shortage • 62% indicated drugs too expensive fro program 4 TB Drug Shortages since 2005 • • • • • • • 5 INH Rifabutin Rifapentine Amikacin Capreomycin Kanamycin Streptomycin cycloserine ethionamide cycloserine What factors impede MDR TB drug access? 6 The Short List: • Single manufacturer for most TB drugs • Drug not profitable and not prioritized for production • FDA inspection overseas pending • Materials to make drug in short supply • Not FDA approved, requires lengthy IRB investigational drug (IND) process • Drugs have very short time to expiration • Cost of drugs puts drug out of reach Which drugs have a tenuous supply? Drugs Amikacin Capreomycin 7 Reason for supply barriers materials short for production overseas FDA inspection pending company change huge cost increase Cycloserine company changecost increase Clofazimine manufacturing halted; restricted to Hansen’s disease requires IND /IRB for each patient How much does an MDR TB treatment regimen cost? Drug Capreomycin Linezolid Levofloxacin Cycloserine Ethionamide • • • Cost per dose No. doses $136.00* $50.30 $29.9 $14.76 $10.38 137** 790 790 790 790 $18,632 $39,737 $23,621 $11,661 $8,200 8 months of above multidrug regimen with injectable Followed by regimen without injectable X 18 months Assumes culture conversion at 3 months (treatment: 24 mos. post conversion) TOTAL MDR TB DRUG COSTS: $ 56,049 (340 B clinic) or $101,851 (common hospital) ____________________________________________________________ Pricing Source: 2011 California and Nevada local health departments *Cost varies : $136.00 per 1 gram vial to $350 for 1 gram vial **Injectable given 5 days/week X3.5 months; 3 days/week X 4.5 months 8 Total cost Less expensive regimen* Amikacin $630 Levofloxacin $15,721 Ethionamoide $6,952 Ethambutol $2048 PZA $2212 _______________________________ TOTAL: $27,490 *No linezolid or capreomycin; common hospital cost 9 Who cannot afford TB treatment? Patients with MDR TB • Working with co-pay or limit • Not covered: students, temp workers, undocumented • Indigent, not Medi-caid eligible Programs • Drug costs larger than TB programs’ budget 10 Procedure to obtain Clofazimine • • • • • Patients to fill out a “simple form “ Provider completes application through hospital IRB Submits individual IND to FDA for patient requiring drug Required Documents FDA Forms: – – – – • • • • Doctor's CV Current lab results for patient (CBC, chem, sensitivity data) Signed informed consent document IRB approval letter – • • • • 11 Form FDA 1571 (PDF) Ι Form FDA 1571 Instructions Form FDA 1572 (PDF) Ι Form FDA 1572 Instructions Form FDA HFD-590 (DOC) Download forms from the FDA's Official Website For your information - Clofazimine Treatment Protocol Once IRB approved send forms to FDA Once approved, clofazamine provided to patient through Hansen's Division/Novartis free of cost Usually takes about 10-14 days from time FDA receives fax to arrival of clofazimine Do TB drug shortages affect patient outcomes? National TB Controllers survey: • 58% of respondents reported that drug shortages led to treatment delays • 32% reported treatment lapses • 26% reported changing to less optimal regimen 12 Who pays? Impact of interrupted supply of MDR TB Drugs • Impact felt by patient, programs, providers • Lack of access to optimal drug regimen can lead to further drug resistance • Prolonged infectiousness • Increased spread • Poorer outcomes for patients 13 Example 1 • 26 yo on work visa from European country with high MDR/XDR incidence • Smear negative, culture-positive cavitary MDR TB diagnosed 2 wks prior to travel • Given 10 day supply of medications through Green Light Committee • Told by physician- not to worry because “TB medications are free everywhere in the world” 14 Example 1 -continued • On arrival smear positive • Patient had employer insurance but payment disallowed given pre-existing condition • Prescribed initial regimen but capreomycin cost to program = $140.00/dose • Unable to afford drug regimen, in addition to MD, nurse care, DOT, isolation • Patient on MDR drugs without injectable ~ 2 weeks • Receiving jurisdiction reports ~10 TB cases/year • Through diplomatic channels, arranged delivery of GLC medications from originating country 15 Example 2: The perfect storm • County X reports ~6-10 MDR TB cases/year • All MDR TB patients need injectable agent • Given price of capreomycin, this county changed regimen and pharmacy contract to amikacin • When amikacin had protracted shortage, TB controller became concerned 16 Steps for TB programs: Securing drugs for your patient 1) Ask pharmacy to check with other distribution centers/wholesalers 2) Call manufacturer directly 1) Is drug in stock? 2) How can it be obtained? – through wholesalers or directly from manufacturer 3) If drug is on allocation (requires special request ) 4) Is drug short-dated? 5) If out of stock, anticipated date available? 3) Contact local hospitals to share supply 17 Requirement: Lot’s of time 1)Maintain contacts • Distributers and manufacturers • Customer service and hospital team 2)Staff time Hands-on, time-intensive, shoe-leather telephone/email investigation 3)Track and maintain Up-to-date information on drug availability 18 How to Maintain a Strong Regimen when drug supply is interrupted? Injectable: • Replace with alternate injectable, if can Quinolone: • Use less expensive of levoflox or moxiflox Add to oral agents: • linezolid, clofazamine, cycloserine, PAS, ethionamide 19 Response to Drug Shortages • Not a new problem (ref. 1994 IUATLD) • Multiple agencies, programs, individuals exert effort to resolve • Response has been case by case • Time from shortage detection to drug reaching patient is long 20 FDA Drug Shortage Website http://www.fda.gov/drugs/drugsafety/drugsh ortages/ucm050792 [email protected] 21 2011 President’s Executive Order President Obama issued Executive Order directing FDA and Dept. of Justice to: – Broaden reporting of manufacturing discontinuations – Expedite FDA regulatory review if help avoid a shortage – Report to Department of Justice if FDA finds price gauging or illegal stockpiling 22 Possible Solutions • Central mechanism for accessing drugs – Federal drug stockpile (eg. Botulism anti-toxin) – Centralized IRB mechanism for old drugs – Streamlined process to obtain investigational drugs for compassionate use • Remove cost as barrier for all patients/programs – Remove copays 23 Expedite Investigational Drug Process • Secure centralized IRB – National (CDC – In place in some states (eg California,Texas) • Reduce burden of stepwise process and secure more rapidly for individual patients 24 More Direct Solutions Access • Direct support of TB and MDR TB drug production • Distribute drugs • Track supply, demand, and distribution Cost • Expand entitlement and adopt model of HRSA HIV drug access (eg TB medi-caid for all TB patients) 25 Advisory Council on Elimination of TB • MDR Workgroup charged to describe extent of problem and potential interventions – Survey conducted – Problem statement and fact sheet created • ACET Resolution – Identify interventions that ensure each TB patient has uninterrupted supply of TB treatment in U.S. 26 Acknowledgements • • • • 27 ACET MDR TB Working Group California MDR TB Service Lee Reichman MD Ann Cronin When Drugs are Hard to Come By: Obstacles for Patients Receiving TB Treatment in the United States 28 Drug Shortages in the United States • The number of drug shortages annually has tripled from 61 in 2005 to 178 in 2010. • Many drugs in short supplyare sterile injectables • More than 90% of US hopsitals in June 2011 reported drug shortage in previous 6 months 29 Manufacturer Contacts: Injectable agents CAPREOMYCIN Akorn: 800-932-5676 ask for hospital team, drug is on allocation, must complete request form 30 Injectable Access continued STREPTOMYCIN X-Gen 607-562-2700 • Available by wholesalers and distribution centers AMIKACIN Teva(short supply) and Bedford(none) Teva: 800-545-8800 • For drop shipment 31 Tuberculosis and Drug Shortages Medications June 2011 July 2011 Sept 2011 Oct 2011 Kanamycin Streptomycin Amikacin Capreomycin Levofloxacin Moxifloxacin Cycoloserine PAS Ethionamide Linezolid Clofazamine Red = Unavailable, Orange = Allocation on emergency basis only, Yellow = Short dated or not available at wholesalers, Green = Available, Purple = Investigation Drug requires prior authorization What are the challenges to an uninterrupted supply of anti-TB medications? Medications Challenges to an uninterrupted supply Kanamycin No US manufacturer Streptomycin Sole US manufacturer; increased demand cause for Aug/Sept 2011 shortage. Amikacin Materials short for production overseas FDA inspection pending Capreomycin PAS Sole US manufacturer. Price increase x 10 since change in manufacturer (2007: $11.7/1 gram vial; 2010: $137/1 gram vial after the manufacturer changed from Eli Lily to Akorn; 2011: New report of ~$300/1 gram vial) Sole US manufacturer; price doubled when license transferred from Eli Lily Sole US manufacturer Ethionamide Not immediately available via wholesaler Linezolid Very expensive Clofazamine Requires IND and local IRB approval, process takes 8-10 wks Cycoloserine