Drug & Device News

The defense proposed to admit three supplemental defense expert reports all asserting that the methodology used in analyzing the 19 Larson study low-dose cases was unreliable because: 1) the patients' reported dose history was inaccurate; 2) the patients' diagnosis of acetaminophen-induced ALF was inaccurate; 3) the patients had reported histories of alcohol and/or illegal drug use; and 4) the patients' cases were mishandled in one way or another.

The court summed up the defense experts' theory as follows:

The defense experts opine that the majority of the 19 cases include an inaccurate dosing history. They support this conclusion by using a two-step methodology, which they claim determines what the patients' dosing history was. First, they determined the “body burden” of the patient at the time their blood sample was taken in the study. This “body burden” formula is a pharmacokinetic calculation to determine how much acetaminophen is in the bloodstream at the time blood was drawn. It is sometimes used in clinical practice to help physicians determine when or how much antidote a patient may need in the event that the acetaminophen has caused liver failure. This formula is more often used in research settings to understand how acetaminophen is processed and metabolized by the body.

After calculating the amount of acetaminophen in the patients' bloodstream using the “body burden,” the defense experts then used a “half-life” formula to calculate backwards how much acetaminophen should have been in the patients' bloodstreams at the time they reported to have taken their last ingestion of acetaminophen. The “half-life” formula is a pharmacokinetic calculation to determine the rate at which a drug is metabolized by the body. In the case of acetaminophen, its half-life may vary depending on how quickly the liver is processing the acetaminophen toxins. If the liver is healthy, acetaminophen should have a half-life of two hours. However, if it is damaged or failing, acetaminophen's half-life can be upwards of 12 to 24 hours.

The “half-life” calculation is also one that may be used to help physicians determine how much antidote a patient experiencing acetaminophen-induced ALF may need to be given. If the half-life takes longer, this often correlates with more liver damage, hence the need for longer treatment of the antidote.

Using the above formula, the defense experts claimed they could show that the dosages taken by the 19 patients in the Larson study were actually higher than they or the study's authors reported.

The plaintiff challenged the admission of the proposed defense experts' testimony, claiming their “body burden half-life” formula was both irrelevant and unreliable under Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 597, 113 S. Ct. 2786, 125 L. Ed. 2D 469 (1993), and that this formula had never been published, tested, or used in clinical practice.

According to Daubert, district courts are tasked with allowing admission only of reliable expert opinions. To do this, courts are to assess the reliability of a scientific method by asking: 1) whether it can be tested; 2) whether the theory or technique has been subjected to peer review and publication; 3) the known or potential rate of error; 4) the existence and maintenance of standards controlling the technique's operation; and 5) whether the methodology is generally accepted in the scientific community. Daubert, 509 U.S. at 592-95. In addition, judges within the U.S. Court of Appeals for the Third Circuit are required to consider how and when the methodology in question is used outside of litigation. See In re Paoli R.R. Yard PCB Litigation , 35 F.3d 717 (3d. Cir. 1994).

Applying Daubert to the defense experts' “body burden half-life” methodology, the court could find no factor that favored admission. The defense offered no evidence that this method had been found reliable by the scientific community, that it had been used in a a clinical setting or that any agency ' like the U.S. Food and Drug Administration (FDA) or National Institutes of Health (NIH) ' had ever used, cited or approved this method for determining dosing. The manufacturers of Tylenol had not used the “body burden half-life” methodology while doing their internal research and the three proposed experts had never used it for anything but this litigation. In addition, no published study had ever addressed the method. “Furthermore,” stated the court, the “plaintiff points out why this methodology has not been used in this way: the assumption of a simple 'half-life' is not appropriate for chronic dosing or multiple doses taken over multiple days. If a person does take too much acetaminophen and liver failure results, the person may not realize that they are experiencing liver failure. The symptoms of liver failure are often similar to those of many common illnesses. As a result, ingested doses taken after the liver has failed may not be processed at all. Since it is not always clear in hindsight when the liver has failed, it is difficult for an accurate 'half-life' calculation to be created for chronic dosing.”

And, finally, one of the 19 patients at issue in the Larson study developed ALF while hospitalized, where that patient's dose of acetaminophen was controlled and monitored by the staff. Despite being administered no greater than the recommended amount of acetaminophen, the patient's liver failed and an emergency liver transplant was required. When faced with this evidence, all three proposed defense experts opined that this patient's dosing history was unreliable based on their “body burden half-life” calculations.

Thus, the court concluded that the defense experts' assumption about body burden half-life was unreliable, and that Daubert required exclusion of their testimony in the case.

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