If you’re litigating a pharmaceutical case involving alleged adverse drug reactions (ADRs), you’re probably inundated with evidence based on individual cases or collections of cases. The plaintiff will attempt to use this evidence to connect your client’s product to certain ADRs in general (i.e., general causation) or ADRs in the plaintiff (i.e., specific causation).
If you’re litigating a pharmaceutical case involving alleged adverse drug reactions (ADRs), you’re probably inundated with evidence based on individual cases or collections of cases. The plaintiff will attempt to use this evidence to connect your client’s product to certain ADRs in general (i.e., general causation) or ADRs in the plaintiff (i.e., specific causation). Such anecdotal evidence is almost always flawed and can never serve as definitive proof of causation. But to effectively confront these arguments, you need to thoroughly understand them. We provide below a description of the types of arguments involving causal inference that you may confront in pharmaceutical personal injury litigation.
1. Diagnosis by Exclusion
The most common argument leveraging case report evidence is based on the medical concept of differential diagnosis. This means that the physician purports to use his skill and medical knowledge to exclude all other potential causes of a medical condition until he is left with no choice but to assume that the event must be due to product exposure. The problem with this approach is that a differential diagnosis does not equal a causal inference. In many cases, a physician can appropriately evaluate all of the information available to make a reasonable diagnosis, but still fail to uncover the underlying cause for the condition.
Time-to-onset refers to the time between the first exposure to the potentially causal agent and the onset of the ADR. Time-to-onset is usually expressed as chronological time. For example, if the patient received a single dose of the medication, time-to-onset is measured from the time the medication was administered to the onset of the reaction. Time-to-onset can also take into account the number of exposures to a product that is given intermittently. For example, if the patient received multiple doses, time-to-onset is measured from the time of the most recent exposure to the onset of the reaction. A time-to-onset analysis is typically compared to a hazard (or risk) curve. An ADR that corresponds to a hazard curve with a high incidence is more likely to be causal, and an ADR that corresponds to a hazard curve with a low incidence is more likely to be related to something else. For example, an acute allergic reaction that occurs within minutes or days of an exposure is consistent with causality, while one that occurs months or years after the exposure is more likely to be related to something else.
3. Positive Re-challenge
Positive re-challenge means that the ADR recurs after re-introduction of the drug of interest. A period of re-challenge must follow a period of de-challenge. If signs and symptoms reappear after the patient resumes the medication, this serves as good evidence that the relationship is not a coincidence, which is why the FDA and other health agencies have long considered positive re-challenge to be the single most important factor in causal assessments. However, well documented re-challenge results are uncommon because healthcare providers are reluctant to expose a patient to potentially dangerous outcomes. In addition, many ADRs are not amenable to re-challenge because the damage associated with the initial ADR obscures subsequent changes (e.g., pulmonary fibrosis), and re-challenge results may be difficult to interpret in the presence of disease states with high natural variability (e.g., multiple sclerosis).
4. Positive De-challenge
Positive de-challenge means that the ADR subsides after the patient stops taking a medication. However, the value of a positive de-challenge is limited because the patient’s improvement could be attributed to medical treatment administered for the ADR or due to spontaneous remittance.
5. Locational Tests
A positive locational test for causality means that the ADR occurred in the distinct location on or in the body where the drug was applied. A classic example of a positive locational test is an adverse reaction at the site of an injection. Injection reactions are often considered causal because the exposure is focal, not diffuse, and the reaction develops at the injection site. If the same reaction were to occur in the same timeframe but in a different location, a causality argument might still be plausible, but more difficult to prove.
6. Dose-Response Tests
A positive dose-response test for causality means an increase in the dose of a drug is followed by an increase in the frequency or intensity of the ADR. In individual cases, dose-response testing relies on observing an ADR that is known to have occurred in a high-dose environment. The key to a positive case-based dose-response test is to document that the ADR occurred in a setting of excessive exposure. The better the documentation for high-dose exposure, the more convincing the argument in favor of a positive test. Dose-response tests for causality that are based on blood or tissue levels provide the best evidence for a positive test, while those that are supported only by history provide equivocal evidence for a positive test.
7. Immunologic Tests
Many ADRs are related to immunologic reactions to medical products. Immune system testing (e.g., antibody tests, skin tests) that demonstrates a specific immunologic link to a component of a particular medical product can provide good evidence that an immunologically mediated ADR is due to a particular medical product’s antigens. However, although such results are compelling, immunologic tests are not definitive proof of causality. Immunologic phenomena can occur during clinical management that have no predictive value for ADRs. The key is to demonstrate a mechanism that links the immunological phenomenon to the ADR.
8. Physical-Chemical Tests
Although unusual, it is possible for a physical or chemical component of a medical product to be so closely linked mechanistically to an ADR that the physical or chemical moiety is actually incorporated into the ADR lesion. A well-known example of this phenomenon is the precipitation of certain drugs into urinary stones (e.g., ciprofloxacin, triamterene). When stones that are caused by drug precipitation in the urinary tract are sent for analysis, they are shown to be partially or completely formed from the offending drug. This test establishes a direct physical-chemical link between exposure and ADR, making causality virtually certain.
9. Physical-Laboratory Examination Tests
Rarely, the results of a physical or laboratory examination can show that an ADR is causally related to a specific medical product. For example, chronic recipients of amiodarone often present with a distinctive blue-gray coloring of the skin on the face, neck and arms. Aside from amiodarone toxicity, it is extremely uncommon for a patient to experience this kind of skin change.
Although a positive result for any of the above tests may sound convincing, the fact is that none of them establish causality with any degree of certainty. In today’s complex treatment environments, case information is never totally complete, and other potentially causal explanations are always present. This is why case-based information is viewed as a source of safety signals (potentially causal relationships), but is not used to test causal hypotheses.
When attempting to determine causality, there is no substitute for controlled studies (e.g., a body of well-designed, analytical epidemiological studies or randomized controlled trials).
By John A. Clark, MD, MSPH of PCSglobal
About the Author: John A. Clark, MD, MSPH, is president and chief medical officer of PCSglobal, a specialty consulting company that provides adverse event expertise to the pharmaceutical, biotechnology, and medical device industries. Dr. Clark has consulted with corporations and defense counsel on mass tort and complex litigation for the past two decades, and has worked with individual clients and industry groups on management of some of the country’s largest and most prominent pharmaceutical and device litigation issues.
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