When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action 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 the product is a drug or medical device, 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 almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.
Definition of product liability: The legal responsibility of manufacturers and sellers to buyers, users, and bystanders for damages or injuries suffered because of defects in goods.
There are many FDA approved drugs currently involved in litigation despite the fact that many of these cases are related to warnings and adverse events contained in the product labeling [
1) Design defects―resulting from inherent properties of the drug’s molecular structure, or improper preclinical or clinical development. This is probably the most common type of defect encountered in new drugs introduced to the market.
2) 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.
3) Marketing defects―resulting from 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 to a failure to provide adequate instructions regarding the safe and appropriate use of the drug. Many products, even the most ordinary ones, pose some levels 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. If they do not warn consumers, manufacturers may be found negligent in the following circumstances:
they fail to warn users about recognized risk
the warning is too vague to be adequate
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:
1) a duty owed by the particular defendant to the particular plaintiff to act as a reasonably prudent person under the same or similar circumstance
2) a breach of such a duty (by the defendant) that constitutes a failure to act reasonably
3) injury, including personal injury or property damage
4) 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 number 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.
Based on post-marketing surveillance reports sent to the Food and Drug Administration (FDA), usually in the form of MedWatch reports for drugs or 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 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.
Widespread access to Internet resources has greatly facilitated the ability of individuals and public-interest groups to obtain the most recent available information regarding drug safety and the incidence of adverse reaction reporting. The following government web page is a useful site for both reporting drug adverse events and for accessing drug safety information: https://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, and physicians, as well as other professionals and health care practitioners. As an example of the volume of reports, in 2014 the FDA received nearly 1.3 million adverse event reports (AERs) [
Once a drug is approved for marketing, the total number of people exposed to the product increases markedly. This is why the FDA requires each drug manufacturer to continue to monitor the safety of every drug it has approved 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-to-risk relationship. The FDA requires manufacturers to update each product’s labeling on an ongoing basis as new safety information is received. An additional useful source of information regarding drug safety is The Institute for Safe Medication Practices (ISMP), a nonprofit organization that is a valuable resource at https://www.ismp.org/. There are numerous reports, safety updates and other resources available at no charge to the user.
Insurance companies are increasingly demanding that scientific standards be established for product liability litigation. They argue that litigation can be unfairly biased against defendants if subjective or unreliable information can be introduced, leaving the technical merit to be judged by the jury without a rigorous scientific analysis using agreed-upon standards and procedures. In the 1990’s there were two important landmark Supreme Court rulings in the United States that came to set the standards governing the submission of evidence in lower court testimony. In the first case, Daubert v Merrell Dow (1993) [
It is generally recognized that medicine today is generally practiced by following a set of established guidelines based on evidence-based medicine. This means that all decisions regarding diagnoses, treatment (including surgery and pharmacotherapy) and follow-up procedures are determined by the judicious application of the best-available medical-scientific principles that have been established by various professional and regulatory governing organizations such as The Joint National Committee 8 (JNC8) [
Unfortunately, the fact that an investigator’s experimental (laboratory science) 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 citation. Such factors (variables) can include a journal’s manuscript rejection rate, the number of reviewers the manuscript was submitted to, the average turnaround time from initial receipt of a manuscript to final publication, the journal’s “impact factor”, the composition of journal’s editorial review board, the number of times the 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’s citation. This type of scrutiny exceeds that required by the Daubert decision. 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 for example that an article published in a journal that encourages submissions that provoke thought and propose novel hypotheses, even if not substantiated with overwhelmingly convincing data, is less likely to have a significant scientific (or by extension, litigation) impact compared to an article published in a journal that requires meticulous attention to experimental methods and rigorous use of statistics.
The drug combination fenfluramine/phentermine (“fen-phen”) was an anti-obesity treatment alleged to cause potentially fatal pulmonary hypertension and heart valve problems.
In cases involving drug product-injury, drug manufacturers (defendants) sometimes feel 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. Manufacturers might feel that they cannot conduct new research or clinical trials in an attempt to show that their product is not the cause of the alleged injury. Not only could this be a fruitless attempt to prove a negative, but it might put them at risk of having to deal with an unexplainable or artefactual result, possibly resulting in further damage to the case. An exception to this may be plausible if at the time of drug market withdrawal clinical trials with the product are still 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 in order to determine if it really is exposure to the drug that resulted in an increased incidence or severity of the alleged drug injury, or whether it is inherent in the medical conditions of the patient population. 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®, a sustained-release formulation of dexfenfluramine, withdrawn from the market in September 1997), which was reported to be associated with an increased risk of myocardial valvular regurgitation [
A comprehensive retrospective review of all pre-clinical studies and clinical trials with fenfluramine uncovered no evidence that would suggest that the drug would cause the claimed heart valve abnormalities, and no further studies were conducted. Therefore, the defendant needed to rely on the available data in the medical literature. 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 the alleged cardiac valvular regurgitation. In one follow-up study [
It should be mentioned that plaintiffs are under no obligation to conduct any of their own research to identify further evidence to support their case for a defective drug 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 as part of the Discovery Process. 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 criteria 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 even though their findings were published in peer reviewed journals [
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 and widely 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 organizes epidemiological inpatient and outpatient data that is searchable by disease, keywords or ICD (International Classification of Diseases) coding. Other databases that are made freely 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 the incidence and 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 financial interest (potential 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 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 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, it is sometimes more efficient to first browse through several relevant articles and create a list of keywords, then search more broadly using these pre-specified keywords.
Once the literature is identified and available electronically, all or only the most relevant citations can be downloaded and imported into specialized software for storing literature citations. Two examples of such software applications include EndNote® and Reference Manager®. These software applications allow the user to download reference citations from the Internet and store complete literature citations, Abstracts and even the ability to import pdfs (when available) 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 according to desired formatting requirements.
It is generally a good idea to create separate libraries for different litigation cases in order to avoid mixing up of articles or cluttering the reference library with excessive citations that will slow down the searching process. Articles are automatically assigned reference numbers that 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 such software applications with well-organized search terms makes the organization and management of the large medical literature an easier task.
In the Fen-Phen drug litigation discussed above, the defendants adopted a strategy that consisted of long-term monitoring of all patients who were participating in clinical trials at the time that fenfluramine was withdrawn from the market. The defendants extensively searched the medical literature to gather data on a wide variety of medical conditions, adverse events associated with medical and surgical procedures, and a great deal of cardiovascular epidemiological data. As the clinical trial data and literature information were gathered, the information was organized using the strength of evidence pyramid [
Despite the large body of scientific evidence assembled by the defendants, the court ruled in favor of the plaintiffs, and defendant subsequently agreed to a class action settlement. Even though this was an unfavorable decision for defendant in this litigation, the body of medical and scientific information that was gathered turned out to be useful both in the construction of the language of the settlement and in the detection of fraud uncovered 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 continue to monitor the medical literature throughout the first several years of the administration of the settlement.
In order for the massive amount of literature to be useful for attorneys to present in court to the judge overseeing the litigation, to a court-appointed arbitrator, or to a jury, the information must be condensed and organized in a concise manner so that all critical information is readily accessible and comprehensible. Therefore, the decision about the formatting of the work product should be left to the attorneys, since they are most familiar with, and reliant on, 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 usually 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 chemical reactions to illustrate how a potential toxin or drug is metabolized.
Every fact or statement in the work product must be supported properly, and copies of the original articles must be readily available. When information about drug concentrations is used, it is often helpful to prepare tables that show interconversion of measurement units, 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
In another milestone case involving the same defendants as in the Fen-Phen case, the use of the medical literature led to a more favorable outcome for defendant. One reason this was considered a milestone case was that it involved multiple co-defendants, including all manufacturers of thimerosal-containing vaccines and all manufacturers of thimerosal chemical substance. The case was emotionally charged, and became 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, with the possibility that plaintiffs were seeking financial damages potentially approaching the trillion-dollar (USD) 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 entered into 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 (NIMH) and to autism activist groups. This all put an additional stress on the sources and reliability of the scientific evidence.
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 beginning to become 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. Review of available data showed that maximum exposure to mercury (Hg) in infants less than 7 months old varied from 75 µg in 1990 to a peak of 187.5 µg by 1999 [
In order to provide perspective for the discussion that follows here, a few facts about the chemistry of thimerosal is helpful. Thimerosal is an organic compound that contains 50% ethylmercury by weight, and is an antibacterial compound that has been used effectively for that purpose in multi-dose 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 is 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 [
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. Two 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 the quantities of ethylmercury that are derived from 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 [
To appreciate the role of scientific evidence in the litigation of this particular case, 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 concern (ed/s) the relative toxicity of the various organic and inorganic forms of mercury that can release mercury in different states of valence, that is, either in the mercurous form, with a single positive charge (Hg+), or in the mercuric form, with two positive charges (Hg++). They differ in chemical reactivity and 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 the adversary design of the legal system influenced the interpretation (the opponents might claim manipulation) of the epidemiologic data, and the design of research initiated in an attempt to obtain new data more favorable to their side. In order to bolster their argument that thimerosal was involved, the plaintiffs began by citing the epidemiologic studies that suggested a rapid increase in the incidence of autism from the 1990’s to the early 2000s, which coincides with the increase in exposure to thimerosal secondary to 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 1943 [
The situation led to the development of lay advocacy groups who refused to accept other explanations for the apparent increase in the incidence of autism and sought to blame this first on Measles Mumps Rubella vaccine [
Data obtained from the CDC for autism spectrum disorders shows that the removal of thimerosal from vaccines in 2001 did not result in a decrease in the incidence of autism (see
Surveillance year | Birth year | Number ADDM sites reporting | Prevalence per 1000 [range] | This is about 1 in # children |
---|---|---|---|---|
2000a | 1992 | 6 | 6.7 [4.5 - 9.9] | 1 in 150 |
2002b | 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 |
2010 | 2002 | 11 | 14.7 [5.7 - 21.9] | 1 in 68 |
2012 | 2004 | 11 | 14.6 [8.2 - 24.6] | 1 in 68 |
aThimerosal removed from all childhood vaccines except influenza by 2001. bThimerosal and autism litigation initiated.
followed by the defendant’s use of the literature to challenge the plaintiff’s experimental findings.
As shown in
One of the first arguments made by the plaintiffs was that the well-known neurotoxic properties of methylmercury [
A literature search performed by the defendants showed that the chemical, biochemical, pharmacological and toxicological profiles of methylmercury and ethylmercury are quite different (see
Property | Methyl-Hg | Ethyl-Hg | Propyl-Hg | |
---|---|---|---|---|
Molecular weight | 215 | 229.6 | 243 | |
% Hg content | 93.0 | 87.1 | 82.3 | |
Half-life (days, human) | 50 - 80 [ | 4 - 10 [ | ? | |
Level in brain (ppm, rat) [ | 10.4 | 1.1 | 3.0 | |
Distribution after 2 d (mouse) [ | 10% liver, 10% kidney 0.8% brain, 0.4% spleen | 27% liver, 10% kidney 0.3% brain, 0.2% spleen | 12% liver, 6% kidney 0.6% brain, 0.3% spleen |
The next phase of the plaintiff’s approach involved hiring expert witnesses, including chemists and pharmacologists. Each of these scientists had a clear prior opinion about mercury. One (a chemist) had devoted a significant portion of his career studying the neurotoxic effects of various forms of mercury; another was specifically hired to explore potential new biochemically toxic effects of thimerosal. Potential biases were identified by reviewing the experts’ 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, the 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 and conducted small clinical trials 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 two 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 brain.
In a video titled “How mercury causes brain degeneration”, originally developed by researchers at a university, the toxicity of mercury was demonstrated by using isolated neurons obtained from snail brain tissue grown in tissue culture and then following their growth with time-exposure video photography. Under control conditions, the neurons are shown to be growing normally (sprouting new dendrites and lengthening existing ones). When a solution containing inorganic mercury ions (the specific form was not specified) was added to the tissue culture medium at 10−7 molar (0.1 µmolar, 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 demonstrate that the direct exposure of neurons to mercury can lead to neurodegeneration, and therefore may be associated with certain neurodegenerative conditions such as Alzheimer disease. 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 new title could be viewed as somewhat misleading since no thimerosal was ever used in the experiment. In addition, recall that the purpose of the original video was a demonstration of mercury-induced neurodegeneration. By improperly projecting the findings with mercury to thimerosal, the effect of the remade version was to (intentionally) conflate “neurodegenerative” with “neurodevelopmental”―two very different concepts in neuropathophysiology.
Two additional questionable facets 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 causing autism. One questionable assertion arose from the way they predicted brain concentrations resulting from thimerosal exposure. By assuming 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. Mathematical equations have been developed to predict tissue concentrations for multi-compartment models, and these were not utilized by plaintiff scientists in 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 with infants vaccinated using thimerosal-free vaccines [
As the litigation progressed, a cynical view is that the plaintiffs modified their hypotheses and approaches when the experimental findings failed to support the original hypothesis of mercury accumulation in the brain. Thus, they were forced to develop “the mercury retention hypothesis” when studies conducted on autistic children showed that they had little or no more mercury in their hair than did non-autistic controls (at the beginning of the litigation, they postulated that autistics should have much higher levels of mercury in their hair than normal subjects) [
Defendants thought that the plaintiff science was flawed at various levels, and thus that it would not be a difficult task to assemble medical and scientific data of a 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 the model, the expert showed that predicted blood and brain concentrations of mercury were far lower than those that were proposed by the plaintiffs.
The defendants also performed literature searches and compiled a large body of data that was able to convince the courts that the plaintiff evidence was in fact 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 the neuroanatomy and physiology associated with autism, however based on pathological findings from autistic brain tissue, autism may be defined in one way as a disorder of neuronal organization. But at the time of this litigation, there were no studies that specifically studied the role of the microtubule system in the development of autism. Additional literature evidence provided by defendants showed that numerous cellular and biochemical mechanisms protect the body 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 handled by these protective mechanisms [
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 in the New England Journal of Medicine [
In contrast, in the few cases related to thimerosal that were litigated 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 [
The effects of drug product-injury litigation on the financial status of a 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. Short- or long-term consequences are likely to result, contingent on the extent of the financial damage. Depending on one’s point of view, the company may have to cut back its research and development budget, its appetite for innovative research might be diminished, the cost of drug discovery and development might rise significantly, and patients might be deprived of potentially beneficial medications. On the other side, drug-product litigation―whether won or lost―drives the system toward safer drugs.
The fallout from drug product-injury litigation can have a significant financial impact on the manufacturing company, and may disincentivize innovation and possibly discovery of more effective medications. On the other hand, because of the potential for devastating financial damage, large 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 clinical trials, and ideally decrease the extent of drug-product liability litigation. It is recommended that the decision of individual cases will rely on the appropriate use of the medical literature, clinical trial data, and experimental research (as well as additional factors). The significance is that in the long run, this should provide an impetus for―and marketing of―the safest drugs possible.
J.K. is a former employee of Wyeth Pharmaceuticals (Pfizer, Inc) and was actively involved in various cases of drug product-injury litigation from 1997-2005. He has no financial interest associated with any of the information presented in this manuscript. J.P. has acted as a consultant, researcher, and/or speaker for Inspirion, Mallinckrodt, DSI, Grünenthal, BDSI, Depomed, Adapt Pharma and Salix. He is also and partner in CaRafe and cofounder of Neumentum. R.T. has nothing to declare. R.R. was a previous employee of Johnson & Johnson and has received research support and honoraria from several other pharmaceutical companies involved in analgesics research and development―but he receives no remuneration based on sales of any product. He is a cofounder of CaRafe Drug Innovation (involved in the discovery of non-opioid analgesics) and advisor/investor with Neumentum (non-opioid analgesics). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Kitzen, J.M., Pergolizzi Jr., J.V., Taylor Jr., R. and Raffa, R.B. (2018) The Role of Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Primer with Two Examples. Pharmacology & Pharmacy, 9, 208-227. https://doi.org/10.4236/pp.2018.96016