Pharmaceutical manufacturer's duty to warn of adverse drug interactions.

• Author: McCormick, Richard

Drug products liability law is unprepared to meet the multitude of ADI claims that are likely to be the next wave of litigation

DRUG products liability law is predominated by cases in which the injuries are the result of an adverse drug reaction (ADR), caused by the pharmacological effects of a single drug.(1) Although the term "design defect" generally is not used to describe a drug's propensity to cause harm, it is not improper to say that a drug is unsafe, if unavoidably so. Many drugs, however, are safe for normal use and may pose a danger only if used in a particular way. For example, an ordinarily safe drug may become unsafe if it is used in combination with another drug. The unwanted interaction of two or more drugs used concomitantly is called an adverse drug interaction (ADI), which is simply a class of ADRs.(2)

The pharmaceutical manufacturer's duty to warn users about potential adverse drug reactions has not been the subject of much litigation, and it is almost untouched in academic journals. This duty, particularly the premarketing duty to test for ADIs, should be examined from three aspects--first, that of the Food and Drug Administration because it regulates new drug development and testing performed by the manufacturer; second, the case law as it pertains to ADRs generally; and third, extrapolations from the case law to ascertain the difficulties peculiar to applying the decisions to ADIs and to discover several approaches to distinguish drug interaction products liability from general drug products liability.

DISCOVERING ADIS

As society depends increasingly on medication to assuage and cure, the incidence of polypharmacy increases, as does the attendant risk of ADIs.(3) Commentators have proposed various mathematical progressions of risk with each additional drug prescribed, but they describe only numerical permutations of the manner in which any number of drugs may interact.(4) For example, any six drugs administered simultaneously have the potential of interacting in 1,956 ways. But these impressive numbers belie the true problem individual pharmaceutical manufacturers face during drug development--that is, the possibility that their drug may be ingested with any one of the several thousand prescriptable drugs in existence. The seemingly limitless possibilities of harm and liability motivate manufacturers to discover potential interactions throughout the investigational process.(5) Manufacturers also conduct post-marketing surveillance of physician reports to find previously undiscovered ADIs,(6) which has been held to be a part of their continuing duty to warn.(7)

Although drug development and testing are undertaken by the sponsoring manufacturer, the results at each phase are scrutinized by the FDA, and approval is given only if the manufacturer has demonstrated the drug's safety and effectiveness.(8) A new drug application to the FDA must contain information regarding the "safety of the drug product, including ... clinically significant drug/drug interactions."(9) Occasionally, the FDA will make approval contingent on further premarketing drug interaction studies,(10) or, after approval, it will suggest that the manufacturer undertake certain post-marketing drug interaction studies.(11) In addition, the FDA must approve the labeling of the medication, which should include "practical guidance for the physician on preventing clinically significant drug/drug ... interactions that may occur in vivo in patients taking the drug."(12)

In an effort to harmonize regulatory standards for the international pharmaceutical industry, the FDA recently issued final international guidelines for the testing of drugs for geriatric populations, with some emphasis on the design of specific drug interaction studies.(13) Although geriatric patients are more likely to be comedicated than other patients, the FDA suggested that the guidelines should apply to all age groups, and later it issued similar international guidelines for all age populations.(14)

The relevant part of the geriatric guidelines states:

[I]n cases where the therapeutic range (i.e., range of toxic to therapeutic doses) of the drug or likely concomitant drugs is narrow, and the likelihood of the concomitant therapy is great, that specific drug-drug interaction should be considered. The studies needed must be determined case-by-case, but the following are ordinarily recommended: [1] Digoxin and oral anticoagulant interaction studies, because so many drugs alter serum concentrations of these drugs, they are widely prescribed in the elderly, and they have narrow therapeutic ranges. [2] For drugs that undergo extensive hepatic metabolism, determination of the effects of hepaticenzyme inducers (e.g., phenobarbital) and inhibitors (e.g., cimetidine). [3] For drugs metabolized by cytochrome P-450 enzymes, it is critical to examine the effects of known inhibitors, such as quinidine (for cytochrome P-450 2D6) or ketoconazole and macrolide antibiotics (for drugs metabolized by cytochrome P-450 3A4). There is a rapidly growing list of drugs that can interfere with other drugs that metabolize, and sponsors should remain aware of it. [4] Interaction studies with other drugs that are likely to be used with the test drug.(15) These testing guidelines mirror the fore-seeability of use (coadministration) and the foreseeability of harm (interaction) standards, which are the primary tests for the common law duty to warn.

The guidelines present two scientific bases for testing for ADIs. The first assumes a knowledge of the pharmacodynamic or pharmacokinetic behavior of the drug. Based on how the drug affects the body or how the body metabolizes the drug, manufacturers can uncover potential interactions and include coadministration of these drugs in clinical trials. This determination is a function of scientific knowledge and technical capability. If the pharmacology of either drug is unknown, then an interaction may not be predictable. The second basis for testing under the guidelines is grounded in the foreseeability or likelihood of concomitant use, which is limited only by resources, time, and test-subject sample size.

Drug interactions also may be detected by chance when subjects enter clinical trials while taking other medications. These comedicated subjects may then develop ADRs traceable to the unknown concurrent uses.(16) Similarly, after a drug has been approved and marketed, unknown interactions may come to light because the larger patient base provides a greater likelihood of adverse comedication.(17) The post-marketing discovery falls within the manufacturer's continuing duty to warn.(18)

DRUG PRODUCTS LIABILITY: CASE LAW

The FDA is not alone in regulating the pharmaceutical industry. Courts also review, albeit retrospectively, the adequacy of drug products. Most of the case law in this area concerns ADRs relating to a single drug without regard for its manner of use, but the cases do provide a basis for examining adverse drug interactions.

1. Drug Products Liability

   A majority of jurisdictions recognize that adverse side effects are present in many drugs and are an intrinsic part of the drug's action. These courts have thus dubbed all drugs "unavoidably unsafe products" in accordance with Comment k of Section 402A of the Restatement (Second) of Torts, which states, "There are some products which, in the present state of human knowledge, are quite incapable of being made safe for their intended and ordinary use. These are especially common in the field of drugs."(19)

   In jurisdictions that provide Comment k protection for pharmaceuticals, plaintiffs may not bring a strict liability claim for design defect. Instead, they must make out a claim for failure to warn of the dangerous propensities of which the manufacturer was or should have been aware.(20) This is known as strict liability for failure to warn.(21) It is this lack of warning that makes the product defective. Courts have offered pharmaceutical manufacturers protection from strict liability for design defects because of the beneficial nature of drugs. Keeping pharmaceuticals off the market until all dangerous side effects can be revealed would prolong the pain and suffering of people who are in need of immediate treatment. Subjecting manufacturers to design defect liability also would curb research and development of new drugs.

   In addition to strict liability failure to warn, manufacturers also may be liable for negligent failure to warn. Under this theory, propounded in Section 388 of the Restatement (Second), entitled "Chattel Known to be Dangerous for Intended Use," the manufacturer is liable if it "knows or has reason to know that the chattel is or is likely to be dangerous for the use for which it is supplied" and the manufacturer "fails to exercise reasonable care to inform [users] of its dangerous condition or of the facts which make it likely to be dangerous." Under this theory, the manufacturer is liable if its failure to warn "fell below the acceptable standard of care--that is, what a reasonable product manufacturer...