Letters to the Editor

May 1, 2012

Letters discuss the many issues surrounding compounding pharmacy and 17P with a response from the Joe Cabaliero and cancer biomarkers

Manufacturer takes issue with 17P article

The central tenet of Mr. Cabaleiro's article ("17P: Choosing a quality compounding pharmacy," May 2012) is that the quality of compounding pharmacies is variable, as has been demonstrated in many published studies.1-3 As the former owner of a compounding pharmacy and the current Executive Director of an accrediting body (Pharmacy Compounding Accreditation Board [PCAB]), Mr. Cabaleiro has firsthand experience with these challenges. If accreditation by PCAB addresses these quality issues, why are obstetricians being asked to perform such detailed evaluations before prescribing compounded 17P?

The answer in part is that while the responsibility for the quality and safety of FDA-approved drugs rests upon the pharmaceutical manufacturer and the FDA, for a compounded formulation, this burden shifts to the compounding pharmacy and the prescribing physician, who may be unaware of their liability.4

FDA meticulously reviews applications before granting approval for commercial use of a medication, ensuring that raw materials and finished goods meet rigorous quality standards.5 The controls for potency, purity, and reproducibility are far more extensive than those proposed by Mr. Cabaleiro. In their November 2011 statement on Makena and compounded 17P, FDA reminded physicians and patients that a greater assurance of safety and effectiveness is generally provided with the approved product.6

In addition, ACOG has stated that physicians should understand the inherent differences between an FDA-approved manufactured product and a compounded preparation.7 Compounding pharmacies making 17P may use ingredients purchased from FDA-registered chemical re-packagers, but these re-packagers often obtain ingredients from uncontrolled foreign manufacturers. Prescribers should be concerned about the potential for contamination of ingredients produced and compounded in non-GMP (Good Manufacturing Practices)-controlled environments.8-10 The USP testing monograph for hydroxyprogesterone caproate injection (17P) cited by Mr. Cabaleiro is over 40 years old and has been designated by USP as "in need of modernization," since it lacks an impurity control and employs an outdated nonspecific assay method.11

Manufacturing copies of commercial drugs on a large scale under the guise of pharmacy compounding without FDA oversight poses special risks to patients.8 Hence, the National Association of Boards of Pharmacy (NABP) and the American Pharmacists Association (APhA) state that it is only appropriate to continue to compound medicines after FDA approval and commercial availability if there is a documented medical need to change the formulation.12,13 PCAB's own website states: "PCAB does not support or condone pharmacies creating copies of FDA-approved products solely for the economic, competitive gain of the pharmacy."14 Mr. Cabaleiro's article thus advocates doing precisely what PCAB publicly claims to oppose.

We agree that compounding is appropriate when there is no approved drug or the approved drug is not medically appropriate for a patient. However, when an FDA-approved drug is available and appropriate for the patient, the situation is vastly different. Circumventing FDA for cost savings would not be viewed as appropriate for oncology or cardiovascular medicines, so why should less-than-optimal quality be acceptable for high-risk pregnant women?

JENNIFER GUDEMAN, PHARMD

DIRECTOR, MEDICAL AFFAIRS

THER-RX CORPORATION, ST. LOUIS, MISSOURI

MICHAEL JOZWIAKOWSKI, PHD

VICE PRESIDENT, SCIENTIFIC AFFAIRS

THER-RX CORPORATION, ST. LOUIS, MISSOURI

JOHN CHOLLET, BS

DIRECTOR, ANALYTICAL RESEARCH AND DEVELOPMENT

THER-RX CORPORATION, MARYLAND HEIGHTS, MISSOURI

REFERENCES

1. US Food and Drug Administration. Pharmacy compounding. 2006 Limited FDA Survey of Compounded Drug Products. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm. Accessed April 16, 2012.

2. Chollet JL, Jozwiakowski MJ. Quality investigation of hydroxyprogesterone caproate active pharmaceutical ingredient and injection. Drug Dev Ind Pharm. May 2012;38(5):540-549.

3. Mahaguna V, McDermott JM, Zhang F, Ochoa F. Investigation of product quality between extemporaneously compounded progesterone vaginal suppositories and an approved progesterone vaginal gel. Drug Dev Ind Pharm.. 2004;30(10):1069-1078.

4. McKenna KJ. Compounded sclerosing agents: risks and consequences. Vein Magazine. 2008;1(2). http://www.veindirectory.org/magazine/article/compounded_sclerosing_agents_risks_and_consequences.. March 19, 2011. Accessed April 16, 2012.

5. US Food and Drug Administration. Food and drugs. 21CFR210; 21CFR211. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=210&showFR=1. And http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211. Updated April 1, 2011. Accessed April 16, 2012.

6.  FDA statement on Makena [press release]. Silver Spring, MD: US Food and Drug Administration.. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm?utm_source=fdaSearch&utm_medium=website&utm_term=makena&utm_content=1..March 30, 2011. Updated January 24, 2012. Accessed April 16, 2012.

7. Information update on 17a-hydroxyprogesterone caproate (17P) from The American College of Obstetricians and Gynecologists and The Society for Maternal-Fetal Medicine [press release]. Washington, DC: American College of Obstetricians and Gynecologists. http://www.acog.org/~/media/Announcements/20111013MakenaLtr.pdf.  October 13, 2011. Accessed April 16, 2012.

8.. US Food and Drug Administration.  The special risks of pharmacy compounding.. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm107836.htm. Updated April 16, 2012. Accessed April 16, 2012.

9. From the Centers for Disease Control and Prevention. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy-United States, July-November 2002. JAMA. 2003;289(3):291-293.

10. Civen R, Vugia DJ, Alexander R, et al. Outbreak of Serratia marcescens infections following injection of betamethasone compounded at a community pharmacy. Clin Infect Dis. 2006;43(7):831-837.

11. USP seeks submission of proposals for monograph modernization [press release].  Rockville, MD: US Pharmacopeal Convention. http://www.usp.org/usp-nf/development-process/monograph-modernization. Updated November28, 2011. Accessed April 16, 2012.

12. Government Affairs Issue Brief: Pharmacy Compounding.  Washington, DC: American Pharmacists Association. http://www.pharmacist.com/AM/Template.cfm?Section=Practice_Resources&CONTENTID=20004&TEMPLATE=/CM/ContentDisplay.cfm. Published March 2009.  Accessed April 16, 2012.

13. National Association of Boards of Pharmacy. Model Pharmacy Act/Rules Page 207.  http://www.nabp.net/government-affairs/model-actrules/. Accessed April 16, 2012.

14.Statement: PCAB Applauds Continued Access to Compounded Access to 17-hydroxyprogesterone [press release].  Washington, DC: Pharmacy Compounding Accreditation Board. http://www.pcab.info/press-17.shtml. March 31, 2011.  Accessed April 16, 2012.

Mr. Cabaleiro responds

The purpose of my paper was not to revisit the various issues related to manufactured versus compounded 17P. These issues have been covered exhaustively in the literature and lay media over the past year. The paper was intended to give prescribers the important information they need to select a quality compounding pharmacy for 17P if, in their professional judgment, it is in their patient's best interest.

In closing their letter, the authors state that "Circumventing FDA for cost savings would not be viewed as appropriate for oncology or cardiovascular medicines, so why should less-than-optimal quality be acceptable for high-risk pregnant women?" As noted in my paper, it is legal for a pharmacy to fill a prescription for compounded 17P. In its press release dated March 30, 2011, the FDA affirmed that compounding pharmacies may legally fill prescriptions for compounded 17P.1 Prescribers and compounders of 17P are not circumventing the FDA.

The authors also imply that compounded medications are not acceptable for use in oncology and cardiology patients. In fact, compounded medications are used in both of these practices. Practitioners are familiar with "magic mouthwash," which has been a staple of oncology pharmaceutical care for years, and for which there is no manufactured equivalent. Compounded injectable and intrathecal pain medications are used every day to treat severe cancer pain. More recently, several injectable oncology and cardiac drugs-including cytarabine, epinephrine, and nitroglycerin-have been in short supply because of manufacturing outages and for other reasons. Pharmacies in both community and hospital practice settings have stepped in to compound versions of all 3 of those drugs and others. These pharmacies are not circumventing the FDA; they are providing life-saving drugs for patients who otherwise would not have them. In fact, due to the current national drug shortages, compounding pharmacies are currently providing dozens of vital drugs for use in hospitals, community settings, and even for EMS systems.

Practitioners have always had to use their professional judgment in choosing the most beneficial therapy for their patients, based upon the patient's particular needs. Whether selecting a manufactured drug product or a compounded medication, providers should strive to work with those providers who have a documented history of providing quality medications.

JOE CABALEIRO, RPH

EXECUTIVE DIRECTOR

PHARMACY COMPOUNDING ACCREDITATION BOARD WASHINGTON, DC

REFERENCE

1. FDA statement on Makena [press release]. SilverSpring, MD: US Food and Drug Administration.. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm?utm_source=fdaSearch&utm_medium=website&utm_term=makena&utm_content=1..March 30, 2011. Updated January 24, 2012. Accessed April 16, 2012.

Disagreement with cancer biomarkers article

We read with interest the article by Andrew John Li, MD, in the April 2012 issue of Contemporary OB/GYN ("New biomarkers for ovarian cancer: OVA1 and ROMA in diagnosis") regarding the use of biomarkers for pre-operative management of women with pelvic masses. We did, however, want to make note of a few clarifying points, given the rapid pace of events in this field.

The article indicates online calculators and smartphone applications are available to calculatethe ROMA score. As of the writing of this letter, it appears as though none have been FDA-cleared, nor are they available for use by physicians in the US.

The article suggests ROMA "may be performed by any laboratory via multiple FDA-approved assays". This appears to contradict the FDA clearance, which limits ROMA to the CA125-II assay run on the Abbott Architect and Fujirebio's HE4 manual EIA assay. Using other assays for ROMA may add an unknown risk of erroneous results, since immunoassays often differ in performance and standardization.

The article suggests the differential cost of OVA1 and ROMA is of concern, citing the HE4 and CA125 assays cost approximately $100 compared to approximately $600 for OVA1. As of the writing of this letter, the only major clinical lab offering ROMA is LabCorp, with a listed retail price ranging from $460 to $540.

One differential advantage of OVA1 is its high sensitivity across a broad range of ovarian malignancy subtypes. In the article, the discussion of sensitivity for OVA1 and ROMA was not consistent with respect to histological subtypes. The 94% sensitivity referenced for OVA1 is for a wide spectrum of ovarian cancers including EOC, non-EOC and LMP disease, whereas the reported sensitivity for ROMA was limited to EOC.

We appreciate Dr. Li's addressing this topic and drawing attention to these new tests. We are hopeful that this forward-thinking article will result in improved standards of care and patient outcomes.

DONALD G. MUNROE, PHD

CHIEF SCIENTIFIC OFFICER AND VP RESEARCH AND DEVELOPMENT

VERMILLION INC, AUSTIN, TEXAS