Compounding Problems: 17-Hydroxprogesterone Caproate (17Pc)

Transcription

1 Compounding Problems: 17-Hydroxprogesterone Caproate (17Pc) C Andrew Combs MD PhD Obstetrix Medical Group, San Jose, California Disclosure of Grant Support: I am the PI of an Obstetrix trial of 17Pc for PROM Ther-Rx donated Makena & placebo for this trial No money was involved in this grant

2 Policy Recommendations Drug Compounding Favor draft legislation before the Senate FDA oversight of compounding manufacturers Uniform quality standards Adverse event reporting Medicaid Formulary Timely evidence-based approval of drugs Uniform nationwide approval standards Favor FDA-approved drugs, not compounded drugs

3 Preterm Birth 12% of all births in USA are preterm USA rate is the highest among developed nations 500,000 preterm babies annually Leading cause of infant mortality Economic burden: $26.2 billion annually $16.9 billion for medical costs of newborn $ 1.9 billion for maternity services $ 1.9 billion for early intervention and special education $ 5.7 billion for lost labor productivity & household productivity Half of all pregnancy & newborn care dollars Berhman & Butler, 2007 National Academy of Sciences

4 Preterm Birth (%) - USA Source: National Vital Statistics Reports

5 Recurrent Preterm Birth If PTB in previous pregnancy, 30-50% chance of PTB in the next pregnancy

6 Preventing Recurrent PTB 2003 (February) NIH-sponsored trial Women with prior PTB 17-hydroxyprogesterone caproate (17Pc) vs placebo Recurrent PTB reduced from 54% to 36% Early PTB reduced from 20% to 11% 2003 (November) Committee Opinion ACOG (Am College Ob/Gyn): 17Pc reduces risk in selected women But no ready source of drug Meis et al, New Engl J Med Vol 348, pp , 2003

7 Compounding The combining or altering of the ingredients of a drug to produce a drug tailored to a patient s particular medical needs FDA

8 Brand-Name, Generic, Compounded Brand- Name Generic Compounded FDA-Approved Yes Yes No Mandatory Testing for: Potency Yes Yes No Impurities Yes Yes No Sterility Yes Yes No Stability Yes Yes No Jurisdiction Over: Maker of API FDA FDA Country of Origin Distributor of API FDA FDA FDA Maker of Final Product FDA FDA State Board of Pharmacy

9 FDA Quality Surveys compounded drugs from 12 pharmacies Sample included Progesterone capsules, not 17Pc 34% failed potency standards (all subpotent) None failed identity or sterility tests compounded drugs from across USA Included various Progesterones, not 17Pc 33% failed standards (subpotent or superpotent) Poor quality compounded drugs are a serious public health concern Source: FDA.gov

10 2007 Consumer Health Information Hundreds of adverse events Details of patient deaths, most caused by sepsis, bacterial contamination

11 Physicians & patients should exercise caution in prescribing and using products that are largely untested for safety and efficacy.

12 FDA-Approved 17Pc February, 2011 FDA Approval given to Makena Manufactured by K-V Pharmaceutical Labeled indication: Reduction of Risk of PTB Current singleton pregnancy History of spontaneous PTB in a prior pregnancy Weekly injection 250 mg Start at 16 wks to 21wk6d Continue until 36wk6d

13 Makena Controversy, 2011 February FDA Approval List Price $1500 per dose (versus $10-30 for compounded 17Pc) March ACOG, SMFM leaders outraged Letters to editor, threat of Congressional hearings FDA announces enforcement discretion FDA: greater assurance of safety with approved product Price reduced to $690 per dose April Joint ACOG, SMFM statement: Physicians can prescribe either Makena or compounded with consent October Amended ACOG, SMFM statement, not identical drugs November KV sends analytic testing results to FDA

14 Analytic Testing of Compounded 17Pc Sponsor: KV Pharmaceutical Testing done by 2 independent analytic labs API 10 samples 1 - no progestin at all, only glucose! 8 - unspecified impurities exceeding 0.10% FDA limit 7 unregistered foreign manufacturers 3 repackaged by USA resellers, unclear source 7 no certificate of analysis Final compounded product - 30 samples, 15 states 4 superpotent ( mg/ml) 3 subpotent ( mg/ml) 16 unspecified impurities exceeding 0.20% 1 visible particulates Chollet & Jozwiakowski Drug Devel Ind Pharm Vol 38 pp , 2012

15 Analytic Testing of Compounded 17Pc Sponsor: API 16 samples 0 problems with potency or identity 16 failed limit for unidentified impurities 4 distinct identified impurities, do not raise safety concerns Final compounded product 13 samples 1 subpotent (200 mg/ml) 2 failed standard for unidentified impurities Source: FDA.gov, June 2012

16 Updates June 2012 FDA no more enforcement discretion for compounding 17Pc July 2012 FDA warning letter to Wedgewood Pharmacy Georgia court order: Medicaid must cover Makena October 2012 CAC presentation to Pacific Coast Ob/Gyn Society New England Compounding Center methylprednisolone news Fungal meningitis from infected injectable compounded drug Sources: FDA.gov, CDC.gov/mmwr

17 Mass Casualty Events, New England Deaths Non-Fatal Injuries Boston Massacre, NECC Fungal Meningitis, Sandy Hook Elementary, Boston Marathon Bombing,

18 Updates January through April 17, 2013 FDA inspects dozens of compounding pharmacies 483 notices issued to 41 compounding firms Several announce voluntary recalls of sterile injectables Ongoing Enforcement actions against those making identical drug Compounders consider alternative formulations Source: FDA.gov, May 2013 Pharmacy Compounding: FDA Actions

19 Updates April 16, 2013 Margaret Hamburg MD testifies before House subcommittee Calls for FDA oversight of large-scale compounders April 26, 2013 Draft legislation by Sen Harkin, Alexander, Roberts, Franken Differentiates compounding manufacturers vs. traditional Gives FDA oversight over compounding manufacturers Sources: FDA.gov/NewsEvents and Help.Senate.gov

20 Medicaid Coverage for Makena Fee-for-service plans only, not HMOs Source: Ther-Rx Corp, April 2013

21 Why It Matters What to Prescribe for Patients Makena is more likely to be the right drug at the right dose The only advantage of compounded 17Pc is potential lower cost Patients who cannot afford Makena must choose: Compounded 17Pc - Identical to Makena - Different oil No progestin treatment at all Micronized progesterone (vaginal or oral) Internet pharmacy, get 17Pc from foreign country

22 One Obstetrician s Love-Hate Relationship with Drug Compounding I Love Compounding Before Makena, no other way to get 17Pc After Makena, compounding is an affordable alternative if health plan does not cover Makena No adverse events reported (yet) I Hate Compounding No way to know if there are adverse events (no mandatory reporting) No way to know if the drug is sugar water (no mandatory testing)

23 Policy Recommendations Drug Compounding Favor draft legislation before the Senate FDA oversight of compounding manufacturers Uniform quality standards Adverse event reporting Medicaid Formulary Timely evidence-based approval of drugs Uniform nationwide approval standards Favor FDA-approved drugs, not compounded drugs