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Melanie S. Bailey Burg Simpson Eldredge Hersh & Jardine, P.C. Cincinnati, Ohio
What is heparin?
Heparin is one of a class of medications called anticoagulants that are commonly referred to as blood thinners. Heparin makes an anti-clotting protein in your body work better, thus decreasing the clotting ability of the blood. Heparin is made from pig intestines. Has been marketed in the United States since the 1930s.
Prophylaxis purposes to prevent blood clots. Coronary artery bypass surgery. Kidney dialysis to prevent clotting in dialysis lines and prevent blood clots when blood returned to body. Medically coated stents, catheters, etc.
Heparin Administration
Heparin is a liquid solution. Intravenous injections; i.e. bolus dose. Injection subcutaneously under the skin; usually abdomen. Intravenous drip; usually mixed with another solution such as dextrose sodium.
Baxter Heparin
Overdose of heparin, led to extensive bleeding in infant twins. Received 10,000 u/mL of heparin instead of 10 u/mL of heparin lock flush. Inadequate labeling of heparin vials similar labeling with blue background.
Three premature infants at an Indiana Hospital died as a result of an accidental overdose of heparin. In December 2007, Baxter changed the labeling for its heparin products. The label features an increase of 20 percent font size, a unique color combination, and a large red cautionary tear-off label.
Baxter press release, Dec. 3, 2007
Heparin Manufacturing
Pig farmers / slaughter houses use pig intestines to obtain the crude heparin. Crude heparin is processed to remove impurities and results in the active pharmaceutical ingredient (API). API is then used in the final production of heparin sodium drug.
NY Times photo
NY Times photo
Scientific Protein Laboratories located in Wisconsin manufactured & distributed heparin API. In 1999, SPL entered into joint venture with Changzhou SPL in China to operate a heparin API manufacturing facility in China Why China?
Heparin Contamination
Heparin API from Changzhou SPL in China is shipped back to SPL in Wisconsin. SPL distributes heparin API to various manufacturers of heparin sodium, including Baxter. Baxter uses heparin API in their finished heparin sodium vials and sells to end users.
Heparin Contamination
February 6, 2004, Baxter submitted NDA Prior Approval Supplement to have Changzhou SPL approved as its supplier of API for its heparin. June 8, 2004, Baxter received letter from FDA that Changzhou SPL is approved as alternate supplier.
In 2007, Baxter was one of the largest producers of heparin in the United States and owned 50% of the marketplace. In 2007, Baxter sold an estimated 35 million units of Heparin per year, with annual sales of ~ $30 million.
In November 2007, pediatric dialysis facility in Missouri identified allergic type reactions during dialysis. Late December 2007, Baxter received first adverse event reports associated with use of heparin multi-dose vial products. January 7, 2008, CDC was notified of allergic type reactions by Missouri Dept of Health.
January 2008, CDC investigated allergic type reactions occurring at dialysis centers and concludes that it may be a result of heparin. January 9, 2008, CDC notified FDA of association between allergic type reactions and heparin. January 9, 2008, Baxter placed a hold on their heparin inventory.
January 17, 2008, Baxter issued a recall of nine lots of its multi-dose heparin vials. February 2008, Baxter continued receiving reports of adverse reactions to its heparin products. February 29, 2008, Baxter recalled all of its heparin single dose, multi-dose and heparin flush products.
March 19, 2008, FDA identified the heparin contaminate as oversulfated chondroitin sulfate (OSCS).
FDA determined that OSCS originated from the source product that came from China. Levels of OSCS contaminate in Baxter and SPLs heparin ranged from 3% - 30%.
In January 2008, FDA learned that it had mistakenly approved the use of the Changzhou China plant for the manufacturing of heparin API.
FDA staff entering information in a database confused the name of the Changzhou plant with another plant that had previously been inspected.
Baxter heparin distributed in marketplace from Sept 19, 2008 Feb. 29, 2008 (recall). Recall was not immediate. Several weeks for Baxter to send out recall notices to all customers; i.e., hospital, doctors, dialysis clinics, pharmacies, etc. Concern about shortage of heparin supply.
CDC epidemiology study published in NEJM Dec. 2008. Looked at adverse events from 21 dialysis facilities in 11 different states Conclusion: strongest association with the adverse reactions was Baxter heparin Conclusion: no safe level of OSCS contaminate
Adverse Reactions
Hypotension Facial edema Loss of consciousness Sensation of burning, warmth, or flushing Numbness or tingling Difficulty swallowing Shortness of breath, audible wheezing, chest tightness Tachycardia Nausea, vomiting, diarrhea
Heparin Litigation
February 14, 2008 first lawsuit was filed in N.D. Ohio May 29, 2008 argument at MDL Panel June 6, 2008 cases consolidated and sent to Judge Carr in N.D. Ohio.
Heparin Litigation
First bellwether case was scheduled to go to trial in March 2011; postponed. Daubert hearing April 19 & 20, 2011 Daubert opinion issued by Court July 21, 2011.
Cases limited to those with symptoms occurring within 60 minutes of administration of contaminated heparin; HIT; excessive bleeding/clotting cases
Heparin Litigation
Problems:
Heparin Contamination
Baxter has never been approved by the FDA to sell heparin since the contamination. FDA has never been able to identify who was responsible for the contamination or whether it was intentional. FDA has implemented new testing standards for heparin to specifically test for OSCS.
Heparin Contamination
As of June 2011, the U.S. House Energy and Commerce Committee is still investigating the contamination incident. July 2011 FDA published Pathway to Global Product Safety and Quality.
FDA does not nor will it have the resources to adequately keep pace with the pressures of globalization. FDA is developing international plans and operating models in order to provide safety and quality assurance.
Heparin Contamination
Sept 14, 2011 Senate hearings Deborah Autor, Deputy Commissioner for Global Regulatory Operations and Policy at FDA
40% of drugs Americans take are made elsewhere. 80% of API used in drugs manufactured in US come from outside the U.S. - from more than 150 countries; many with less sophisticated manufacturing and regulatory systems that U.S.
60 minutes video