The US Food and Drug Administration (FDA) said yesterday, Monday 21st April, that contamination of the blood thinner heparin, used in surgical and dialysis procedures to stop blood clots, is a worldwide problem. The agency stressed while there is still no scientific evidence of a direct link between the contaminant, and dozens of deaths and hundreds of severe allergic reactions in the US, they have established a credible route through which such a link might be possible.

Earlier this year, there was a significant increase in reported deaths and adverse reactions in the US following use of batches of heparin product made by Baxter International.

Baxter implemented a phased recall of its heparin products, and lab tests by the FDA and others showed that the products linked to the adverse reactions and deaths contained a contaminant, a form of chondroitin sulfate, derived from animal cartilage. The contaminant was found in the heparin raw ingredient made by a Chinese subsidiary owned by the Wisconsin based company Scientific Protein Laboratories (SPL). The Chinese subsidiary is called Changzhou SPL.

Dr Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, told the press yesterday that the agency had now “established a mechanism by which we think this contaminant could cause these adverse events”, reported CNN, but she did not go so far as to say there was certain proof, only that the route was possible.

Earlier yesterday, a senior Chinese health official, Jin Shaohong, said that the contaminant that had been found in batches of the Baxter’s blood thinner, thought to be an oversulfated form of chondroitin sulfate, was not to blame for the deaths, because according to China’s own investigations, some of the adverse events followed use of heparin that did not contain the contaminant.

Woodcock disputed this assertion, and told the press that the Chinese tests “did not find contamination, but we are fairly certain because of multiple labs doing the testing that this lot contains contaminants”.

Yesterday the FDA CDER website posted a number of documents updating the heparin situation.

One is a world map highlighting 11 countries where heparin containing the contaminated active ingredient from China has been found. The 11 countries are: Australia, Canada, China, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand and the USA.

Another FDA CDER document posted yesterday updates the US figures on the adverse events and deaths linked to the drug. This details the adverse event reports, including deaths, reported to the FDA between 1st January 2007 to 13th April 2008 (note this is according to date of report and not date of event; some reports came in later, once awareness of the situation increased).

Altogether there have been 131 reports of deaths in the US (from any cause, that is with or without allergic reaction) following use of heparin since 1st January 2007, with 123 of them reported on or after 1st January 2008.

81 of the deaths included one or more symptoms of allergic reaction or high blood pressure. 78 of these were reported after 1st January 2008.

The FDA stressed that the fact allergic reaction or high blood pressure were reported does not mean these caused the deaths.

A third document posted on the FDA CDER website yesterday was a letter to Changzhou SPL, stating that a recent inspection by US FDA officials had found significant deviations between procedures at the plant and US practice in the manufacture of active pharmaceutical ingredients (APIs).

The letter said the company had not adequately evaluated the suppliers of the crude materials, and the crude material itself, and that the manufacturing equipment was not suitable for purpose. It said that tanks to make the API were certified as clean, but “unidentified material” was found clinging to their inside surfaces.

The letter warned that until the irregularities are put right, shipments from the plant will be refused entry into the US.

Woodcock told the press she would not comment on the details of evidence collected so far because the better thing to do is wait until it is published in scientific literature when other scientists have had a chance to review it.

She also said the agency was not “able to rule out the fact that there could be other problems leading to these adverse events”, reported CNN.

This has also been the position maintained by Baxter, which to a certain extent reflects what the Chinese authorities said yesterday, where the possibility that manufacturing problems after the raw ingredient has left China, and the condition of the patients themeselves, could be contributing factors.

Woodcock said she hoped that scientific dialogue will help to overcome some of the skepticism about the FDA suggestions.

While it is not possible to trace a direct link to the adverse events and deaths, since the product recall, the number of deaths and adverse events reported to the FDA has returned to the previous level.

Click here for FDA CDER page on heparin.

Sources: FDA CDER, CNN.

Written by: Catharine Paddock, PhD