The Role of the Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Detailed Analysis of Two Case Studies

Introduction
When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, it is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When a drug or medical device incurs this situation, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will be sure to follow.

Since this article is specifically focused on drug product-injury litigation, no other forms of product liability will be discussed.

Definition of product liability: This term refers to the legal responsibility of manufacturers and sellers to buyers, users, and bystanders for damages or injuries suffered because of defects in goods.

In order to prevail on a product liability claim, the product complained about mustunreasonably threaten the personal safety of a consumer and must be shown to be defective. Manufacturers and suppliers can incur liability through three types of product defects.

Design defects-resulting from inherent properties of the drug's molecular structure, improper preclinical or clinical development. This is probably the most common type of defect encountered in new drugs introduced to the market.
Manufacturing defects - these may occur during the manufacturing process and may result from improper cleaning or maintenance of manufacturing equipment used in the large-scale production of large quantities of drugs. Lack of adherence to current Good Manufacturing Practices (cGMP) may result in manufacturing defects. These are usually more limited in scope than design defects, and the defect may be confined to one or more batches of the manufactured product.
Defects in marketing- These refer to the improper marketing and claims made for specific drug products. This category often involves injuries caused by a failure to provide adequate or accurate warnings regarding a dangerous side effect or a failure to provide adequate instructions regarding the safe and appropriate use of the drug. Many products, even the most ordinary, pose some level of risk, and the law recognizes that it is often not possible to design a totally safe product. However, manufacturers are legally obligated to warn consumers about known dangers. Manufacturers may be found negligent in these circumstances:
1. They fail to warn users about recognized risk.
2. The warning is too vague to be adequate.
3. The warning is not brought to the user's attention.

Defective product lawsuits may include a combination of claims. For example, a claim based on a drug with a dangerous side effect may be coupled with a claim based on the failure to warn of that side effect. There are four elements of a negligent tort as applied to product liability cases as follows:

A duty owed by the particular defendant to the particular plaintiff to act as a reasonably prudent person under the same or similar circumstance
A breach of such a duty (by the defendant) that constitutes a failure to act reasonably
Injury, including personal injury or property damage
A causal link between the defendant's breach of duty and injuries sustained by the plaintiff

Because design and marketing defects are the most serious of liability defects and usually include the largest population of people exposed to the product, the remainder of this article will only be concerned with defects in these categories and will focus specifically on drug-related personal injury.

The Food and Drug Administration (FDA) and decisions regarding severity of liability
Based upon the post-marketing surveillance reports sent to the FDA, usually in the form of MedWatch reports for drugs and reports using the vaccine adverse event reporting system (VAERS) for vaccines, the agency may impose one of three possible decisions on a manufacturer. The most serious decision is the issuance of an order to the manufacturer to immediately recall the product from the market. A less forceful, but equally serious option is for the agency to request that the manufacturer voluntarily remove the product from the market. In either case, the manufacturer issues recall notices to all providers of the product (wholesalers, distributers, pharmacies, physician samples etc.) for them to immediately quarantine the product and prevent any further distribution to customers as soon as possible. When the FDA makes its decision, chances are highly likely that the public-at-large will become aware of this via various news alerts and press releases. The final type of decision that the agency may make regarding a product's safety is to issue a restricted use order that limits the use of a particular product to only a small portion of patients in whom other treatments have been deemed as ineffective. The manufacturer may also be required to expand its post-marketing surveillance activities and monitor closely the now limited population of patients exposed to the drug.

Adverse Drug Reaction Reports and the Internet
The widespread access to Internet resources has greatly facilitated the ability of individuals to obtain the most recent information available regarding drug safety and the incidence of adverse reaction reporting. The following government web page is a useful site for both reporting adverse events and accessing drug safety information: http://www.fda.gov/Safety/MedWatch/default.htm. The FDA monitors all adverse events through its MedWatch reporting system. This database accepts reports from patients, pharmacists, physicians as well as other professionals and health care practitioners. In 2010 the FDA received nearly 760,000 adverse event reports (AERs).¹ Of these 760,000 reports, over 670,000 were actually entered into the MedWatch database. The large number of MedWatch reports increases the probability that drug related adverse events will likely lead to cases of liability litigation. The incidence and magnitude of the litigation cannot be determined solely from the number of AERs reported, as many other factors must be considered, such as the nature of the adverse event(s), whether or not it is reported multiple times for a single product, severity and reversibility of the adverse event, among others. Many of the adverse events reported may have been predicted from the clinical trials of the drug.

However, once a drug is approved for marketing, the total number of people exposed to the product increases markedly. This is why it is necessary for the FDA to require each drug manufacturer to continue to monitor the safety of every drug it has marketed throughout its market life. This is known as post-marketing surveillance. This information must be reported to the manufacturers, and they are responsible for monitoring the data and continuing to evaluate the benefit: risk relationship. The FDA requires manufacturers to update each product's labeling on an ongoing basis as new safety information is received. Another useful source of information regarding drug safety is The Institute for Safe Medication Practices (ISMP), a nonprofit organization that is a very valuable drug safety resource found at http://www.ismp.org/default.asp. There are numerous reports, safety updates and other resources available at no charge to the user.

Evidence-Based Medicine and Drug Liability Litigation
Insurance companies are increasing their demand for scientific standards in product liability litigation. They argue that, without a rigorous, scientific analysis, using preordained standards and procedures, litigation would be unfairly biased against defendants, because unreliable information could be introduced, leaving the scientific merit to be judged by the jury. In the case of Kumho v. Carmichael², the 11th Circuit Court of Appeals distinguished between "scientific" evidence, which must meet standards set by the Supreme Court in Daubert v. Merrell Dow³, and "engineering" evidence, which need not. "Engineering" refers to technical evaluations offered by expert witnesses, without a systematic examination of the specific materials involved in the case. In the oral argument at the Supreme Court for Kumho, this distinction was rigorously questioned. Though the Supreme Court upheld the Circuit Court's verdict in the case, the arguments furthered the debate over scientific standards and seemed to provide insurers with some ammunition.⁴

It is generally recognized that medicine today is practiced according to established guidelines based upon the use of evidence-based medicine. This means that all decisions regarding diagnoses, treatments (including surgery and pharmacotherapy) and follow-up procedures are determined by the judicious application of medical/scientific principles that have been established by various professional and regulatory governing organizations such as The Joint National Committee 7 (JNC7), The American Heart Association, The American Society for Echocardiography, The American Society for Pediatrics, and so forth for each clinical discipline within medical practice. One of the principles involved in evidence-based medicine includes the concept of strength of evidence. This important method of evaluating the quality of medical evidence is essential to both plaintiffs as well as defendants. To be classified as an evidence-based medical practice, a medication or intervention must be thoroughly evaluated using the scientific method. Medical decisions are based on the multiple reviews of several sources of information and focus on a comprehensive assessment of the quality of the information provided.⁵ The safety of each drug is evaluated based on the risks and therapeutic benefits revealed during clinical trials, which must be randomized and placebo-controlled. Experts review data from these studies to determine whether or not the treatment can generally be recognized as safe and effective.

Evaluating the Medical Literature - The fact that an investigator's experimental or clinical findings are published in a peer-reviewed journal is not necessarily an indicator that high quality research was carried out during the research process, which may have lasted for months or years. One must also consider other aspects related to publication that can provide better insight into the quality of a journal. Such factors (variables) include a journal's manuscript rejection rate, number of reviewers manuscript was submitted to, average turnaround time from initial receipt of manuscript to final publication, journal impact factor, composition of journal's editorial review board, number of times journal is cited elsewhere in the literature (science citation index), and other semi-objective factors that contribute to a better understanding of the quality of a journal. This type of scrutiny exceeds that required by the Daubert decision.3

When these variables are factored in, it becomes possible to show that some peer-reviewed journals are of higher quality than others. Therefore, it can be shown that an article published in the journal Medical Hypotheses, which requires little or no data for an article to be published, is less likely to have a significant scientific impact compared to an article published in The American Heart Association journal Circulation, which requires meticulous attention to experimental methods and rigorous use of statistics. It also requires that authors refrain from unjustified speculation about the implications of their findings and confine their discussion solely to what is presented in their data. Both of these journals are peer-reviewed.

Case Study I: The Diet Drug (Fen-Phen) Litigation

Defendants Use of the Medical Literature
In cases involving drug product-injury, drug manufacturers (defendants) are extremely limited in terms of what they can do to produce new evidence in an effort to show that their drug is not culpable as the primary source of alleged injury. Therefore, manufacturers cannot possibly conduct any new research or clinical trials in an attempt to show that their product is not the cause of the alleged injury. Not only would this be a foolish attempt to prove a negative, but to do so would put them at risk of possibly identifying previously unidentified adverse events or preclinical toxicological evidence predictive of human toxicity, possibly resulting in further damage to the case. However, a comprehensive retrospective review of all pre-clinical studies and clinical trials with fenfluramine revealed no evidence suggestive that the drug would cause valvular abnormalities; nevertheless, no further studies were conducted. Since the defendant cannot afford to take this risk, it must rely on available data in the medical literature.

An exception to this may be plausible if, at the time of drug market withdrawal, clinical trials with the product are in progress. In this situation, the manufacturer may decide to continue to follow these patients in the absence of drug, in order to gather additional safety data regarding the adverse event reported to occur in these patients to determine if exposure to the drug has resulted in an increased incidence or severity of the alleged drug injury. This is exemplified in the decision by Wyeth Pharmaceuticals in 1997 to continue to follow patients participating in a clinical trial involving the diet drug fenfluramine (Redux®, withdrawn from the market in September 1997), which was reported to be associated with an increased risk of myocardial valvular regurgitation.^6,7 No further trials, other than follow-up studies, were conducted in an attempt to collect data showing that fenfluramine was not associated with an increase in the incidence of cardiac valvular regurgitation. In one follow-up study⁷ results showed that, in 1142 patients who were followed for up to 26 months after discontinuing the study drug (fenfluramine, fenfluramine/ phentermine or placebo), no further progression of valvular abnormalities was observed compared to the valvular abnormalities observed approximately one month after the drug was discontinued.

It should be mentioned that the plaintiffs are under no obligation to conduct any of their own research to identify further evidence to support their case for a defective product. The burden of proof rests solely with the manufacturer of the product. Accordingly, all new findings from defendant sponsored studies were required to be submitted to the courts and plaintiff counsel. In the event that plaintiffs decide to conduct their own research (see Case Study II), they should be aware that all research they perform should adhere to the Daubert criteria³ in order to be admissible in court. Nevertheless, numerous independent investigators, with no vested interest in the litigation, found this to be a very interesting research subject, and many original research articles were published on the effects of fenfluramine on cardiac valvular tissue. These publications had no effect on the outcome of the litigation^8,9

Conducting Literature Searches and Managing the Literature for Case Analyses
There is an enormous amount of medical information available from various databases that are searchable using a variety of methods. Some of the most commonly used medical literature databases are EMBASE, MedLine and PubMed (made available through the National Institutes for Health), among others. There are also epidemiological databases such as those offered by Timely Data Resources, Inc. This company does an outstanding job of organizing epidemiological inpatient and outpatient data which is searchable by disease, keywords or ICD-9 coding. Other databases such as those made available to the public by the American Heart Association, the Centers for Disease Control (CDC) and many others offer endless possibilities to gather information on most medical conditions, and incidence & prevalence data for essentially any disease or condition. In some cases it is even useful to search the United States Office of Patents and Trademarks as most of the patents are available electronically and can be searched in the usual manner. These can provide insight into whether or not a researcher may have a bias.

Typically, different literature databases may use different keywords or Boolean logic to describe similar conditions, so some knowledge of the appropriate search terms and how they may be combined is necessary. Reference books are available that identify these keywords and their associated medical conditions. Here is a simple example of the use of different keywords to describe similar conditions. In one database the term mitral insufficiency is used to identify all articles related to mitral regurgitation. In another database, the term mitral regurgitation may be used to identify these same articles while the term mitral insufficiency may not. For this reason, when searching simultaneously in multiple databases and results may have identified hundreds or thousands of articles, the manager of the database being used for the litigation case may find it easier to browse through each relevant article and create new keywords for all articles in order that the same articles can be retrieved using the pre-specified keywords.

Once the literature output is available electronically, all or only the most relevant citations should be downloaded and imported into specialized software for storing literature citations. Examples of software applications for storing literature citations include EndNotes® and Reference Manager® These software applications allow the user to download reference citations from the Internet and store complete literature citations and abstracts as identified in literature searches. Numerous fields are available for sorting, adding search terms and organizing the articles, and they usually contain formatting styles that allow the user to export citations for most journals' formatting requirements. EndNotes® is designed to be interactive with Microsoft Word®, and this makes the preparation of documents much easier with the referencing of citations which can be directly exported out of EndNotes® and imported into any Word document. Citations can be added, deleted or moved anywhere in the text without altering the numbering in the bibliography since the software is able to format automatically the entire document when completed.

It is generally a good idea to create separate libraries for different litigation cases to avoid mixing up of articles or cluttering the reference library with excessive citations which will slow down the searching process. Articles are automatically assigned reference numbers which can be manually added to the first page of a hardcopy of the article, making filing and retrieving articles a simple process. The use of these software applications with well organized search terms makes the organization and management of the medical literature an easy task.

In the well known case of the diet drug litigation, the defendants adopted a strategy that consisted of long-term monitoring of all patients who were participating in clinical trials at the time fenfluramine was withdrawn from the market. During this time, defendants extensively searched the medical literature to gather data on a wide variety of medical conditions, adverse events associated with medical and surgical procedures, in addition to a great deal of cardiovascular epidemiological data. As the clinical trial data and literature information were gathered, this information was then organized using the strength of evidence pyramid.¹⁰ According to this approach, medical articles are classified or partitioned into categories based on the strength of evidence. All articles and data were organized in ascending order from those that were considered to contain the weakest supportive evidence to those considered to contain the strongest level of evidence as follows: case reports ≤ case series≤ case controlled studies < cohort studies < randomized controlled trials (including double-blind, placebo controlled trials) < systematic reviews. By performing this rigorous and extensive use of the medical literature, valuable information was obtained that provided insight into the background prevalence of valvular abnormalities in the general population, as well as information on pre-existing confounding medical conditions that can be associated with or exacerbate cardiac valvular abnormalities, such as prior history of rheumatic heart disease or concurrent mitral valve prolapse.

Despite the large body of scientific evidence assembled by the defendants, the court ruled in favor of the plaintiffs, and the defendant was forced into a class action settlement. Even though this was an unfavorable decision for Wyeth Research in this litigation, the accumulated body of medical and scientific information proved useful both in the construction of the language of the settlement and in the detection of fraud after the settlement was in place. Due to the emergence of numerous unexpected medical conditions and geographical patterns associated with many of the settlement cases, it was found necessary to monitor the medical literature continuously throughout the first several years of the administration of the settlement.

Types of Work Products - In order for the massive amount of literature to be useful for counsel to present in court to either the judge overseeing the litigation, a court appointed special master or expert witnesses or juries, the information must be condensed and organized in a concise manner so that all critical information is readily accessible and comprehensible by attorneys. Therefore, the decision about the formatting of the work product should be left to the attorneys since they are most familiar with how the information needs to be utilized. Various types of formats should be offered for each specific need. For example, if a summary of blood pressure data is needed, this is best organized into a table arranged by either year of publication or in order of strength of evidence. All references in the table must be cited, and the original articles should be readily available in case they are needed by the court. Work products may be in the form of data extractions (table format) summaries, white papers for more lengthy analyses or figures when chemical structures are helpful, pharmacokinetic plots showing blood concentration over time, or even in the form of chemical reactions to illustrate how a potential toxin or drug is metabolized.

As with the tables, every fact or statement in the work product must be supported properly, and copies of the original articles must always be readily available. When information about drug concentrations is used, it is often helpful to prepare tables that allow for interconversion of units of measurement since these may be expressed differently in different articles. It is not unusual to find one article expressing blood or tissue concentrations in units of micrograms/milliliter (µg/ml), micromoles/liter (µmoles/l), parts per million (ppm) or as a dilution (1:100) or percentage. A table that includes how all of these units compare to each other is very useful. Occasionally it may be necessary to include conversion equations as part of the work product in order to prepare counsel for unexpected new information. The main point to keep in mind is that the purpose of the work product is to provide attorneys with quick and easy access to the information needed in as comprehensible and useful a form as possible.

Case Study II: Thimerosal and Autism Litigation

Background: In another milestone case involving the same defendants, the use of the medical literature led to a more favorable outcome. The reason this was considered a milestone case was that in actuality, the case involved multiple co-defendants (including all manufacturers of thimerosal-containing vaccines and all chemical manufacturers of thimerosal) The case was politically charged, with members of the United States Congress taking a personal interest in the litigation and attorneys-general from several states taking an active interest, coupled with the possibility that plaintiffs were seeking financial damages possibly approaching the trillion dollar mark. This landmark case received a great deal of attention by the news media, advocacy groups, professional actors, and talk radio hosts. Much of the information was entirely in the public domain throughout the course of litigation since the plaintiffs published numerous articles and also traveled around the USA presenting their findings at various meetings, as well as to the National Institute of Mental Health and autism activist groups.

The case involved the issue of whether the mercury-containing preservative thimerosal was a possible risk factor in contributing to a perceived increase in the incidence of autism spectrum disorders (ASD) in young children who were vaccinated with multiple thimerosal-containing vaccines as infants. At the time this litigation was initiated, the affected children ranged from 4-8 years of age, and signs of autism were becoming evident. Thimerosal was a logical choice as the alleged cause of neuronal injury shortly after birth since the Centers for Disease Control (CDC) had recommended in the early 1990s an increase in the number of vaccinations to be administered within the first 6 months of life. It was then hypothesized by plaintiffs that this extra exposure to thimerosal could have resulted in neuronal injury in the postnatal development of the brain leading to autism. According to the thimerosal-related hypothesis, some genetically susceptible population of children reacted to the thimerosal in vaccines with increased accumulation and decreased excretion of mercury from the body, which can then alter several biochemical pathways critical for normal brain development.^11,12 They also hypothesized at this time that autistic children would show higher levels of mercury in their hair relative to non-autistic children.¹²

In order to provide perspective for the discussion that follows, a few facts about the chemistry of thimerosal need to be described. Thimerosal is an organic compound that contains 50% ethylmercury by weight and is an antibacterial compound that has been used effectively in multidose vaccine preparations for over 50 years. After thimerosal enters the body through vaccination, it is metabolized to ethylmercury and thiosalicylate. Ethylmercury is primarily excreted though biliary excretion and ultimately eliminated from the body through the feces. It is also further metabolized by the oxidative drug metabolizing systems which then facilitate additional excretion in the urine.¹³ A portion of the remaining mercury can be retained in the body as it binds to sulfhydryl groups found in proteins in various tissues, especially skeletal muscle. Mercury-containing compounds were previously used as a variety of medicinal agents in the 1950s and 1960s and were frequently found in antiseptic solutions such as Merthiolate® and Mercurochrome® and were also used as diuretic agents (Mercuhydrin®) for many years.

As awareness of mercury toxicity increased in the 1970s and 1980s, mercury-containing products were gradually phased out from medical use with the exception of thimerosal, which continued to be used as a preservative in vaccines. In 1997, the US Food and Drug Administration Modernization Act mandated identification and quantification of mercury in all food and drugs; 2 years later, the US Food and Drug Administration found that children might be receiving as much as 187.5 µg of mercury within the first 6 months of life. Despite the absence of data suggesting harm from quantities of ethylmercury contained in vaccines, in 1999, the American Academy of Pediatrics and the Public Health Service recommended the immediate removal of mercury from all vaccines given to young infants.¹⁴ It was not until 2001 when this goal was finally achieved.

The Plaintiff Hypothesis and use of Experimental Data and the Medical Literature to Support their Case - To begin, it is important to point out that the toxicity of mercury has never been in dispute by anyone. Mercury is clearly a highly potent toxic substance. The controversy concerns the relative toxicity of the various organic and inorganic forms of mercury which can release mercury in different states of valence (either in the mercurous form with a single positive charge (Hg⁺) or in the mercuric form which has 2 positive charges on the mercury ion, (Hg⁺⁺) which differ in biological activity.

The manner in which the plaintiffs developed their strategy to implicate thimerosal as the likely cause of autism is an extremely interesting example of how bias influenced their manipulation of epidemiologic data and the design of their new original research in their attempt to obtain new data about the neuronal toxicity of thimerosal. In order to create the notion that thimerosal was involved, the plaintiffs began by citing epidemiologic studies that suggested a rapid increase in the incidence of autism from the 1990's to the early 2000s, when the increase in exposure to thimerosal occurred via the increase in the number of vaccinations administered to infants. They cited the following evidence to support their case: For decades after Kanner's original paper on the subject was published in 1943¹⁵, autism was generally considered to be a rare condition with a prevalence of around 0.2-0.4 per 1000 children (1 case per 2500-1 case per 5000 children). Then, studies carried out in the late 1990s and in the early 2000s reported annual rises in incidence^a of autism in pre-school children, based on age of diagnosis, and increases in the age-specific prevalence rates^b in children. Prevalence rates of up to 6.0 per 1,000 (1 case per 166 children) for autism and even more for the entire autistic spectrum were reported. Although the general medical community accepted rational reasons for these increases, including changes in diagnostic criteria, development of the concept of the wide autistic spectrum, recognition of different methods used in studies, growing awareness and knowledge among parents and professional workers and the development of specialist services, as well as the possibility of a true increase in numbers, the lay public disagreed.¹⁶

These findings led to the development of lay advocacy groups who refused to accept these medical explanations for the apparent increase in the incidence of autism and sought to blame this first on Measles Mumps Rubella vaccine¹⁷ and then on thimerosal^11,12 These advocacy groups were comprised primarily of parents of autistic children who appeared to be in search of external environmental factors as a cause for the increased incidence in ASD. The plaintiffs then hired researchers not trained as epidemiologists to perform risk analysis using data provided to them by the CDC. It was later determined by the Institute of Medicine (IOM) that these researchers had misused this data and improperly used the terms "incidence rate" and "attributable risk" in addition to coining a new term "percent association" which is not a recognized epidemiologic measure.¹⁸ If one searches the medical literature on this topic, one would find that the incidence rates vary widely because so many factors and variables, including wide ranging definitions of ASD and an increased awareness that lead to increased reporting of cases, have been used in these incidence calculations.

The following table of overall prevalence (Table 1) was obtained from the National Center for Health Statistics and shows that, in retrospect, the removal of thimerosal from vaccines in 2001 did not result in a decrease in the incidence of autism.¹⁹ Nevertheless, during the years from 2002-2004 plaintiffs mounted a huge multifaceted effort to implicate thimerosal as the cause of this problem. Due to space limitations, only the most important and significant research will be described, followed by the defendant's use of the literature to challenge the plaintiff's experimental findings.

Table 1: Identified Prevalence of Autism Spectrum Disorders ADDM Network 200-2008 Combining Data from All Sites
Surveillance Year	Birth Year	Number of ADDM Sites Reporting	Prevalence/1000 Children	This is about 1 in X children
2000¹	1992	6	6.7 (4.5-9.9)	1 in 150
2002²	1994	14	6.6 (3.3-10.6)	1 in 150
2004	1996	8	8.0 (4.6-9.8)	1 in 125
2006	1998	11	9.0 (4.2-12.1)	1 in 110
2008	2000	14	11.3 (4.8-21.2)	1 in 88
Abbreviations: ADDM= Autism and Developmental Disabilities Monitoring. Footnotes: 1.Thimerosal removed from all childhood vaccines except influenza (2001). 2. Thimerosal and autism litigation initiated (2002)

As shown in Table 1, in 2007, CDC's ADDM Network first reported that about 1 in 150 children had an ASD (based on 2002 data from 14 communities). Then, in 2009, the ADDM Network reported that 1 in 110 children had an ASD (based on 2006 data from 11 communities). This means that the estimated prevalence of ASDs increased 23% during 2006 to 2008 and 78% during 2002 to 2008−long after thimerosal was removed from childhood vaccines. Similar epidemiological data were available in the early 2000s and showed that retrospective studies conducted in children over a 30-year period exposed to thimerosal in vaccines had no increased incidence in autism. This study also showed that the incidence of autism began to increase in the years after thimerosal was removed from vaccines.²⁰

Plaintiff Experimental Approach
One of the first assumptions made by the plaintiffs was that the well known neurotoxic properties of methylmercury^21,22, would be similar for ethylmercury. Accordingly they used the guidelines for the maximum safe limit of methylmercury exposure as issued by the Environmental Protection Agency (EPA) and the FDA. The fallacy of this line of thinking is that it is generally well known that in a heterocyclic series of alkyl congeners, the properties of the shortest alkyl group (methyl) are usually quite different from those of the longer alkyl congeners (ethyl, propyl etc.). This is best exemplified by the properties of methyl and ethyl alcohol. Methyl alcohol is so acutely toxic that ingestion of small quantities can lead to blindness and even death. In contrast, ethyl alcohol, which contains only a single additional carbon atom (as a methylene moiety, CH₂), does not cause blindness, and acute ingestion of large quantities is rarely fatal.

A literature search performed by the defendants showed that the chemical, biochemical, pharmacological and toxicological profiles for methyl and ethylmercury were quite different. One of the most important differences identified was a marked difference in their biological half-lives (time for the plasma concentration to decrease by 50%). The half-life for methylmercury in humans is 50-80 days while that for ethylmercury is 4-10 days, another reason that the guidelines for methylmercury exposure are not applicable to ethylmercury. Another important difference identified is that methylmercury accumulates in the brain nearly 10-fold more than ethylmercury.

The next phase of the plaintiff approach involved the hiring of expert witnesses including chemists and pharmacologists. Each of these scientists had a clear bias about mercury and one (a chemist) had devoted a significant portion of his career studying the neurotoxic effects of various forms of mercury while another scientist was specifically hired to explore new potential biochemically toxic effects of thimerosal. These biases were identified by reviewing their earlier publications and patents. In order to preserve their anonymity, no reference citations will be included in this section.

In the scientific phase of their strategy, plaintiff scientists tried to find novel ways of implicating thimerosal with the neurodevelopmental aspects associated with autism. They also were able to find evidence that supported some new concepts they advanced such as their mercury retention hypothesis. They conducted their own experiments to show that autistic children excreted less mercury into their hair compared to non autistic controls. No attempt was made to adjust for exposure to mercury between the 2 groups. Other approaches they used consisted of illogical extrapolations to neurodegenerative conditions such as Alzheimer's disease, where they claimed that these patients also had higher concentrations of mercury in certain areas of their brains.

In a video originally developed by researchers at a university titled "How mercury causes brain degeneration," the toxicity of mercury was demonstrated by using isolated neurons obtained from snail brain tissue grown in tissue culture and following their growth with time-exposure videophotography. Under control conditions, the neurons are shown to be growing normally-sprouting new dendrites and lengthening of existing ones. When inorganic mercury ions (specific form of mercury not specified) were added to the tissue culture medium at 10-7 molar (0.1 micromolar, a concentration far in excess of what would normally be found in brain tissue following exposure to mercury), the neurons ceased their growth and began to retract their dendrites. The purpose of this video was to show that direct exposure of neurons to mercury can lead to neurodegeneration and, therefore, may be associated with certain neurodegenerative conditions such as Alzheimer's disease. It is generally believed that experiments conducted using tissue culture or isolated tissues (in vitro studies) are not necessarily predictive of actions when the substance is administered to an intact animal or human (in vivo studies).

Sometime after this video was produced (2001) and after the thimerosal litigation was ongoing, a plaintiff law firm used this video to create a new video titled "The dangers of thimerosal." The title is misleading since no thimerosal was ever used in this single experiment. Although the original purpose of the video, as stated above, was to demonstrate mercury's effects on neurodegeneration; by improperly extending these findings with mercury to include thimerosal, the purpose of the remade version of the video was to change the concept of "neurodegenerative" to "neurodevelopmental," two very different concepts in neuropathophysiology.

Two additional major flaws in their approach were the assumption that 100% of the thimerosal was absorbed into the circulatory system and that most, if not all of this was able to reach the developing brain where it interfered with microtubule assembly, one of the mechanisms claimed by the plaintiffs to play a role in autism. They also disregarded the use of pharmacokinetics, which is the study of the absorption, distribution, metabolism and excretion of exogenous substances such as drugs or environmental agents. By avoiding these important principles, plaintiff scientists were basically able to make any assertions they desired. One such assertion that had no basis in science was the way they predicted brain concentrations resulting from thimerosal exposure. By assuming that 100% of the thimerosal was able to reach the brain, the plaintiff scientists were essentially using a one-compartment pharmacokinetic model. Most drugs follow at the very least a two-compartment model (blood + tissue distribution), and some drugs require multiple compartment models in order to understand thoroughly how the drug is handled by the body. Mathematical equations have been developed to predict tissue concentrations for multi-compartment models, and these were never utilized by plaintiff scientists in their calculations of predicted levels of mercury in the brain. Furthermore, at about the time the litigation was initiated, a paper was published showing that blood levels of mercury in infants who had received multiple vaccines containing thimerosal were not significantly elevated compared to infants vaccinated with thimerosal-free vaccines.²³ This information, although acknowledged by plaintiff experts, did not have any impact on their determination to continue with research to implicate thimerosal as the likely cause of autism.

As the litigation progressed, the plaintiffs modified their hypotheses and approaches when their experimental findings failed to support their original hypothesis of mercury accumulation in the brain. Thus, they were forced to develop "the mercury retention hypothesis" when experiments conducted on autistic children showed that they had little or no mercury in their hair compared to non-autistic controls. At the very beginning of the litigation, they postulated that autistics should have much higher levels of mercury in their hair than normal subjects.12 According to the new hypothesis, the reason that little or no mercury was found in the hair of autistic children was due to the fact that they had an impaired ability to excrete the mercury and therefore more of it was retained in their body and brain tissue.

Defendant's Response to Plaintiff Science Given that the plaintiff science appeared to be flawed at various levels, it was not a difficult task to assemble medical and scientific data of a much higher caliber to refute many of their claims. One important action taken by the defendants was to hire a pharmacokineticist to develop a two-compartment model that could be used to estimate more accurately tissue concentrations of mercury from blood samples obtained from a small sample (sample size = 7) of plaintiff children. Using this model, it was possible to show that predicted blood and brain concentrations of mercury were far lower than those proposed by the plaintiffs. The defendants performed exhaustive literature searches and compiled a large body of data that was able to convince the courts that the plaintiff evidence was very weak.

For example, a literature search on microtubules and autism failed to identify a single publication that investigated these two topics together. Therefore, the role of microtubules in the etiology and pathophysiology of autism had to be inferred from a general knowledge of the basic function of the microtubules and how this could possibly relate to the neuroanatomical and neurophysiological changes associated with autism. It is beyond the scope of this article to discuss any of the neuroanatomy and physiology associated with autism. However, it can be stated that based upon pathological findings from autistic brain tissue, autism may be defined in one way as a disorder of neuronal organization. It must be emphasized that at the time of this litigation, there were no studies available that specifically studied the role of microtubule system in the development of autism.

Additional literature evidence provided by the defendants showed that numerous cellular and biochemical mechanisms exist in the body to protect against heavy metal toxicity and specifically against mercury toxicity. Although these mechanisms are insufficient to protect against an exposure to high doses or concentration of mercury, the literature clearly showed that toxic effects from small amounts of mercury exposure could be decreased by these protective mechanisms.^24,25 There were numerous additional efforts made by the plaintiff scientists, and each one was able to be refuted successfully by careful use of published studies by independent researchers who had no connection to the thimerosal litigation.

Conclusions
The two cases of litigation were used here to illustrate how medical and scientific evidence, when properly used, can impact decisions rendered by juries and judges. In the diet drug litigation, the publication of a case report consisting of 24 subjects in the New England Journal of Medicine⁶ was the initial trigger to cause the FDA to request that Wyeth voluntarily withdraw fenfluramine from the market in September 1997. It is interesting to note that, despite Wyeth's ability to generate numerous publications (in what are considered to be high quality journals) demonstrating that the valvular abnormalities were not as severe as originally thought, the overwhelming number of plaintiffs that came forward was sufficient to carry more weight than the clinical follow-up studies, forcing Wyeth into a class action settlement.

In contrast, in the few cases of the thimerosal that were tried in courts, each one was dismissed and class-action status was denied after the presentation of the second Immunization Safety Review by the Institute of Medicine, issued in 2004.¹⁸ Despite this decision, cases continued to be tried in court for an additional several years. In one of the final cases, tried in Circuit Court in Baltimore, MD, in 2008, the judge ruled to preclude the plaintiff's expert witnesses from testifying that exposure to thimerosal-containing vaccines can cause autism. In his ruling, the judge asserted that “plaintiffs had failed to show that the methodologies underlying their expert witnesses' opinions are generally accepted as reliable in the scientific community." He also stated that "plaintiffs' expert witnesses were not qualified by knowledge, skill, experience, training or education . . .to support the causation opinions that plaintiffs wished to present to the jury."

The overall effects of drug product-injury litigation on the financial status of any manufacturer is devastating and has a long-term effect on the business, especially when it is found guilty of marketing a defective product and must pay out large sums of money for many years. Even when the manufacturer is found innocent of the charges, it still has to incur the extra costs associated with its defense, which can easily run into the multimillion dollar range. Given this post-litigation effect on a pharmaceutical company, the following consequences are likely to occur, depending on the extent of the financial damage:

Company may have to cut back in R&D budget
Company may decide to phase out risky areas of research or not market certain new products
Company may decide it is necessary to lengthen the R&D process as "defensive" studies may be added to clinical trials. e.g. Abbott Labs, the developer of another anti-obesity medicine (Meridia^®, sibutramine) added echocardiography studies to Phase III trials in order to proactively identify valvular abnormalities as occurred with fenfluramine
Innovation may be hampered
Cost of drugs may have to be increased
Patients may be deprived of potentially beneficial medications

In conclusion, the overall effects of drug product-injury litigation can not only have a significant financial impact on the manufacturing company, but may also result in depriving patients of innovative and possibly more effective medications for treating many types of medical conditions and disease states. Because of the potential for devastating financial damage, most pharmaceutical manufacturers now routinely develop clinical risk management plans as part of the drug development process. This new aspect of drug development, when combined with the ongoing post-marketing surveillance of newly approved drugs as well as those previously approved for marketing, should decrease the risks associated with long-term use of a drug, help in the early identification of adverse events not previously identified in Phase I to Phase III clinical trials, and ideally decrease the extent of product liability litigation.

References

^a Incidence is defined as the number of new autism cases in a specific population during a specific period of time.

^b Prevalence is defined as the number of people living with autism spectrum disorders in a given year.

¹ http://fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm. Accessed 4/15/12.

² Kumho Tire Company, Ltd. v. Carmichael, U.S. Supreme Court, 131 f.3d 1433, No. 97-1709, 1999.

³ Daubert v. Merrell Dow Pharmaceuticals, Inc, U.S. Supreme Court, 509 U.S. 579, No. 92-102, 1993.

⁴ http://www.referenceforbusiness.com/encyclopedia/Per-Pro/Product-Liability.html. Accessed 4/18/2012.

⁵ Ascione FJ, Principles of scientific literature evaluation: Critiquing clinical trials. American Pharmaceutical Association; Washington, DC, 2001.

⁶ Connolly, H. M., Crary, J. L., McGoon, M. D., Hensrud, D. D., Edwards, B. S., Edwards, W. D., et al. (1997). Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337, 591–98.

⁷ Gardin JM, Weissman NJ, Leung C, Panza JA, Fernicola D, et al. Clinical and echocardiographic follow-up of patients previously treated with dexfenfluramine or phentermine/fenfluramine; J Am Med Assoc 2001 Oct 24-31;286(16):2011-4.

⁸ Steffee, C. H., Singh, H. K., and Chitwood, W. R. (1999). Histologic changes in three explanted native cardiac valves following use of fenfluramines. Cardiovasc Pathol 8, 245–53.

⁹ Rothman, R. B., Baumann, M. H., Savage, J. E., Rauser, L., McBride, A., Hufeisen, F. J., et al. (2000). Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–41.

¹⁰ Sackett DL, Straus SE, Richardson WS, et al. Evidence-based medicine: how to practice and teach EBM. 2nd ed. Edinburgh: Churchill Livingstone, 2000.

¹¹ Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of mercury poisoning. Med Hypotheses. 2001 Apr; 56(4):462-71. Review.

¹² Bernard S, Enayati A, Roger H, Binstock T and Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiat 7: S42-S43, 2002.

¹³ Suzuki T et al, Jap J Exp Med, 33:277-282, 1963.

¹⁴Centers for Disease Control and Prevention. Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service. MMWR Morb Mortal Wkly Rep 1999;48:563–5.

¹⁵ Kanner L, The nervous child, 2:217-250, 1943.

¹⁶ Wing L, Potter D.; Ment Retard Dev Disabil Res Rev 2002; 8(3):151-61.

¹⁷ Wakefield AJ, Murch SH, Linnell AAJ, Casson DM, Malik M, Berelowitz M, et al. Ileallymphoidnodular hyperplasia, nonspecific colitis and pervasive developmental disorder in children. Lancet 1998;351:637--41.[ Note: This article was formally retracted from the literature in 2010 and is no longer available]

¹⁸ Immunization Safety Review: Vaccines and autism, Institute of Medicine, National Academies Press, Washington, DC, 2004.

¹⁹ National Center for Health Statistics, http://www.cdc.gov/nchs/. Accessed 4/23/2012.

²⁰ Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Madsen KM, Lauritsen MB, Pedersen CB, et al. Pediatrics. 2003 Sep;112(3 Pt 1):604-6.

²¹ Methylmercury poisoning in Iraq. Bakir F, Damluji SF, Amin-Zaki L, et al. Science. 1973 Jul 20;181(4096):230-41.

²² Kurland LY, Faro SN, Siedler H: Minamata disease: the outbreak of a neurologic disorder in Minamata, Japan, and its relationship to the ingestion of seafood contaminated by mercurial compounds. World Neurol 1: 370, 1960.

²³Pichichero ME, Cernichiari E, Lopreiato J and Treanor J, Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet 360:1737-41, 2002.

²⁴ Suzuki K, Nakajima K, Otaki N et al., Metallothionein in developing human brain. Biological Signals, 3(4):188-192, 1994.

²⁵ Monks TJ, Ghersi-Egea JF Philbert M et al., Symposium overview: the role of glutathione in neuroprotection and neurotoxicity. Toxicol Sciences, 51(2):161-177, 1999.

This article discusses issues of general interest and does not give any specific legal or business advice pertaining to any specific circumstances. Before acting upon any of its information, you should obtain appropriate advice from a lawyer or other qualified professional.em>

This article may not be duplicated, altered, distributed, saved, incorporated into another document or website, or otherwise modified without the permission of TASA.

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The Role of the Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Detailed Analysis of Two Case Studies

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