Scientists have long realized the need to deal with clotting when disturbing blood flow during dialysis or other procedures. In 1913, John Abel, a pharmacologist at Johns Hopkins University, reported the first successful performance of dialysis in a dog using “hirudin,” an anticoagulant extracted from leeches. (Mark J. Acierno, Vera Maeckelbergh “Continuous Renal Replacement Therapy,” Compendium, May 2008, Vol. 30, No. 5; Research Defence Society Website, “Anticoagulants,” (2008)). This early anticoagulant was unsuitable for human use, however, as it was expensive, difficult to extract and purify, and caused severe heart and lung problems, as well as allergic reactions. (Research Defence Society Website, “Anticoagulants.”)

Heparin, one of the oldest drugs currently still in widespread clinical use, was discovered in 1916 by a second-year medical student, Jay McLean (1890-1957), and his Professor of Pharmacology, William Henry Howell (1860-1945) at Johns Hopkins University in Baltimore. (Wikipedia: Heparin; Rutty, Christopher, Health Heritage Research Services, “Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928-1937.”)

Allthough “the first description of heparin has been clouded in controversy,” it is reported that McLean, working under the direction of Howell, was investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anti-coagulant from liver cells from dogs, (hence its name hepar or "ηπαρ," which is Greek for "liver"). (“Practical Haemodialysis Began with Cellophane and Heparin: The Crucial Role of William Thalhimer (1884-1961),” Nephrol. Dial. Transplant (200) 15: 1086-1091; Wikipedia: Heparin.)

Although it appears that “Howell initially seemed not to have welcomed this discovery, perhaps because [he] disagreed with [McLean’s] theories of coagulation,” most historians believe that McLean’s work lead to Howell’s later isolation of a water-soluble polysaccharide anticoagulant in the early 1920s. (“Practical Haemodialysis Began with Cellophane and Heparin: The Crucial Role of William Thalhimer (1884-1961),” Nephrol. Dial. Transplant (200) 15: 1086-1091; Wikipedia: Heparin.)

This early heparin, however, was expensive, toxic and not practically applied by doctors until the early 1930s when a research team lead by Dr. Charles H. Best at Connaught Medical Research Laboratories, (then part of the University of Toronoto), developed a method to make it into a “purified, plentiful and inexpensive supply safe for human use.” (Rutty, Christopher, Health Heritage Research Services, “Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928-1937;” Wikipedia: Heparin.)

In 1928, Best, the head of University of Toronto’s Physiology Department and an Associate Director of Connaught, “decided to break the heparin stalemate and explore its practical value.” (Rutty, Christopher, Health Heritage Research Services, “Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928-1937.”) Best then expanded his team in 1929 to include Drs. Arthur F. Charles (1905-1972), an organic chemist, David A. Scott (1892-1971), a scientist closely involved with insulin production, and Dr. Gordon Murray (1896-1976), a prominent surgeon at Toronto General Hospital. (Id.)

Charles and Scott turned to beef liver because it was cheaper than dog liver and readily available from local slaughterhouses. (Id.) When the price of beef liver increased, they turned to beef lung and intestines. (Id.) In conjunction with Murray’s experimental surgeries on animals using the more potent heparin, the team succeeded in purifying and then crystallizing heparin into a standardized dry form that could be administered in a salt solution. (Id.)

In May of 1935, the first human trials began and “by 1937, it was clear that Connaught's heparin was a safe, easily-available, and effective blood anticoagulant.” (Wikipedia: Heparin.)

FDA first approved heparin drug products for sale within the U.S. in the 1940s. (04/14/08 USP Press Release.)

On June 26, 2008, Congressman and Chairman of the House of Representatives’ Committee on Oversight and Government Reform, Henry A. Waxman, sent a letter to the FDA Commissioner demanding production of documents that explain why under the Bush Administration, the FDA changed its position regarding whether FDA regulation should bar liability claims. (To view this letter, click here.)

Prior to the Bush Administration, the FDA had a long-standing position that despite its regulation of medical drugs and devices, “product liability lawsuits in state court complement the agency’s regulation of drugs and medical devices, providing an important additional layer of consumer protection against unsafe products.” (See 06/26/08 Letter to Eschenbach.) As such, the FDA did not interfere or challenge the constitutional right of innocent Americans injured by defective products to hold the drug companies responsible in a court of law.

On May 14, 2008, the House of Representatives Committee on Oversight and Government Reform, held a hearing on the issue of preemption of state liability claims related to FDA-approved drugs and medical devices. (We have previously blogged on this hearing and the problem with preemption. See prior blogs, “Should FDA Drug and Medical Device Regulation Bar State Liability Claims?” (05/14/08); “FDA Needs Subpoena Power” (05/21/08); “The Preemption Problem” (06/04/08); “Draft Bill Regarding Preemption To Be Introduced” (06/13/08)).

Despite the FDA’s long-standing position regarding preemption, the current FDA Deputy Commissioner for Policy, Randall Lutter, testified at the hearing that under the Bush Administration the FDA reversed its position and calls such suits a “challenge” to the agency that have “detrimental effects on the public health.” (For a transcript of this hearing, click here. For a video, click here.) As such, under the Bush Administration, the FDA now sides with drug manufacturers. They argue that regardless of any misconduct or failures on behalf of the drug companies, Americans injured by defective drugs should be stripped of their constitutional right to a trial by jury for most, if not all, legal claims, where the drugs are regulated or approved by the FDA, giving negligent drug companies almost complete immunity.

Ironically, this position comes amidst the heparin disaster, wherein the FDA has admitted that it does not have the resources, authority and capability to ensure product safety. (See 04/29/08 Video of House of Representatives’ Subcommittee on Oversight and Investigations Hearing, “The Heparin Disaster: Chinese Counterfeits and American Failures; 04/22/08 Video of House of Representatives’ Subcommittee on Oversight and Investigations Hearing, “FDA’s Foreign Drug Inspection Program: Weaknesses Place Americans at Risk.”) Indeed, the FDA currently does not even have subpoena power, which would allow the FDA to demand certain documents from companies who have sold contaminated drugs. Without this ability, the agency is powerless to obtain internal company documents that a company itself chooses to withhold. (See prior blog, “FDA Needs Subpoena Power” (05/21/08)).

The June 26, 2008 letter asks that the requested information/documents be produced by July 11, 2008.

Much is yet to be learned regarding the contaminate found in the recalled heparin, oversulfated chondroitin sulfate (“OSCS”). However, the first and only study published to date since the January 2008 heparin recall does shed some light on the relationship between the contaminate and the severe reactions, sometimes fatal, experienced by many Americans. (“Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System,” N. Engl. J. Med. 358:23, pgs. 2457-2467, June 5, 2008, available for a charge on the New England Journal of Medicine Website.) One of the issues addressed in this article is a question that we are often asked by our clients, why weren’t all patients who received tainted heparin from a particular lot affected?

In order to investigate this and related issues concerning the biologic link between the contaminant and the reported reactions, the researchers conducted animal testing. (6/5/08 N. Engl. J. Med. article, pg. 2464.) Pigs were chosen because unlike rabbits, horses and rats, only the pig plasma supported an appropriate level of response to the OSCS contaminated heparin, but not the uncontaminated control heparin. (This also may explain why early attempts by Baxter to provoke an allergic response with suspect lots of heparin failed. See Baxter 03/19/08 Press Update and 6/5/08 N. Engl. J. Med. article, pg. 2464.)

The pigs were given a single intravenous dose (5 mg per kilogram) of OSCS-contaminated heparin, uncontaminated heparin, or other substances. (06/05/08 N. Engl. J. Med. article, pg. 2466.) They were then monitored for 60 minutes. Two of six pigs treated with OSCS-contaminated heparin had at least a 30% drop in blood pressure over the first 30 minutes after infusion. One animal remained in a hypotensive state for more than 15 minutes. In contrast, none of the four animals treated with uncontaminated heparin showed any substantive changes in blood pressure. (Additionally, three pigs were given pure synthetic OSCS. All three of these pigs “showed a profound drop in blood pressure [maximal decrease, 45 to 59%] and a concurrent increase in heart rate within minutes after infusion.”)

Interestingly, while not all pigs who received OSCS-contaminated heparin exhibited clinical signs, the researchers found that “induction of kallikrein activity [kallikrein is an enzyme present in blood plasma and other body fluids which can lead to the generation of bradykinin that in turn, impacts the blood vessels leading to hypotension and other symptoms] was evident in all animals that received OSCS-contaminated heparin, even when no substantive changes in blood pressure were observed.” (06/05/08 N. Engl. J. Med. article, pg. 2466, with explanation and emphasis added by Zoll, Kranz & Borgess, LLC.) Based on these findings, the researchers concluded as follows:

“These findings suggest that activation of kallikrein does not always manifest as clinical symptoms, perhaps because of individual variations in control mechanism that regulate bradykinin activity…. The finding that hypotension did not develop in all animals treated with OSCS-contaminated heparin, even at a relatively high dose, is consistent with the observation that the majority of patients who received contaminated heparin did not experience an adverse event. However, it is important to note that all animals treated with OSCS-contaminated heparin showed evidence of kallikrein activation in vivo, even in the absence of clinical signs. Patients undergoing dialysis who are also receiving heparin therapy are already at high risk for hypotension because of their exposure to the dialysis membrane, which can also activate the contact system, and their treatment with angiotensin-converting-enzyme inhibitors, which inhibit bradykinin degradation. Exposure to OSCS-contaminated heparin may further increase the risk and could potentially trigger an adverse event.” (06/05/08 N. Engl. J. Med. article, pg. 2467.)

Thus, the scientific evidence to date suggests that while some patients may not exhibit clinical signs after receiving OSCS, this does not necessarily lead to the conclusion that those patients were “unaffected” by the OSCS, particularly those patients, including dialysis patients, who are already at greater risk.

Hopefully, researchers will continue to investigate the relationship between OSCS and the reported reactions, so that the families of those who have lost loved ones can understand how and why this happened, and continue to hope that it can and will be prevented in the future.

The FDA issued an updated report yeseterday on the number of deaths reported after heparin administration that occurred and were submitted to the FDA from January 1, 2007 through May 31, 2008. (See FDA 06/17/08 “Information on Adverse Event Reports and Heparin.”)

According to the FDA, as of May 31, 2008, there have been 246 reports of death in patients receiving heparin since January 1, 2007. Out of the 246 reported deaths, 149 of the reports included one or more allergic symptoms or symptoms of hypotension. This report is nearly double the FDA's earlier report in April 2008, which advised of 131 reported deaths, with 81 of those reports including one or more allergic symptoms or symptoms of hypotension.

The FDA's Center for Devices and Radiological Health (CDRH) has also recently reported 11 deaths and 86 injuries since January 1, 2008, which have been linked to use of medical devices containing heparin. (06/03/08 FDA web update: "Questions and Answers on Heparin, Medical Devices and In-vitro Diagnostic Assays.") The heparin in the majority of these medical devices was found to be contaminated with OSCS.

On May 29, 2008, Zoll, Kranz & Borgess, LLC argued before the United States Judicial Panel on Multi-District Litigation that the Heparin Products Liability Litigation be transferred to the Northern District of Ohio, before the Honorable Chief Judge James G. Carr. Other districts, including the Southern District of Illinois, District of New Jersey, Southern District of Florida, the District of Puerto Rico, and the Northern District of California, were suggested by Baxter Healthcare Corp., Scientific Protein Laboratories, LLC, and other parties.

Today the United States Judicial Panel on Multi-District Litigation issued a transfer order, transferring the Heparin Multi-District Litigation MDL No. 1953 to the Northern District of Ohio, before the Honorable Chief Judge James G. Carr.

A copy of the decision is available by clicking here.

Any inquiry regarding this or any other Heparin matter may be directed to either David Zoll or Pamela Borgess at (419) 841-9623.

We have invited all Plaintiff attorneys from across the nation to meet with us and organize for this important litigation. We are committed to working for the common benefit of all Plaintiffs in this action.

Update: Link to story in Toledo Blade

Baxter, along with other drug manufacturers, continues to advocate for complete immunity from the majority of suits involving unsafe medical drugs under a legal concept called “federal preemption.” (See Baxter’s “Response to Preemption Discussion to Quaid’s Lawsuit.” See also testimony of Dennis and Kimberly Quaid at the Committee on Oversight and Government Reform’s 5/14/08 hearing, “Should FDA Drug and Medical Device Regulation Bar State Liability Claims?” The full transcript and video of this hearing is available by clicking here.) Baxter and other drug manufacturers argue that regardless of misconduct or failures on their part, Americans injured by defective drugs should be stripped of their constitutional right to a trial by jury for most, if not all, legal claims, where the drugs are regulated or approved by the FDA.

This argument is not only legally and ethically problematic, but is based on the flawed assumption that the FDA has the resources, authority, and capability to ensure product safety. Unfortunately, as the heparin debacle as reminded us, such is not the case. Since the contaminated heparin recall, the significant shortcomings in the FDA’s ability to protect this county against unsafe drugs and medical devices, has been on the forefront of the news media, as well as the agenda of Congress. Reports exposing the depth of the problem continue. This week USA Today published an article entitled “Drug Companies Drain Scientific Brains from FDA,” which reports that the FDA continues to lose its most experienced scientific minds to major drug companies with more financial resources. This has led to staffing problems for the agency, which has a turnover rate twice that of other agencies.

A previous study conducted by USA Today and reported in an article entitled “FDA Advisers Tied to Industry,” found that “more than half of the experts hired to advise the government on the safety and effectiveness of medicine had financial relationships with the pharmaceutical companies that will be helped or hurt by their decisions.”

With their undeniable influence at this and other levels of our government, it is no wonder that drug companies have gained support for federal preemption of medical drug and device lawsuits. It is also no wonder that Americans continue to die from unsafe drugs and medical devices.

Yet, our constitution gives every-day Americans injured through no fault of their own, a powerful weapon against corporate corruption and greed, the right to a jury trial. In a United States court of law, a regular American can hold even the wealthiest and most powerful corporation accountable. Attempts by Baxter and others to sacrifice that constitutional right for protection of its corporate profits, should be not be permitted.