Sticky business—using kits contrary to labeling

November 2006

Feature Story

Jack R. Bierig
Seth Axelrad

Malpractice issues to keep in mind in using diagnostic kits contrary to product labeling

Editor’s note: The legal opinion presented here was requested during the open-discussion phase of the process used to develop guidelines for the management of cervical cytological abnormalities and cervical intraepithelial neoplasia. (Related article: "Real simple—ASCCP guidelines set things straight") The authors were asked to discuss the specific issue of recommending testing for human papillomavirus DNA without cytology, and not as an adjunct to cytology (such use is currently warned against in the FDA labeling of the Digene Hybrid Capture 2 test). The opinion presented in this article should not be construed to discourage the use of well-validated homebrew methods or non-contraindicated off-label procedures, though they are discussed peripherally. For a discussion of liability and off-label use of an assay approved by the FDA for another purpose, see Bierig J. Arch Pathol Lab Med. 2002;126:652-657.

The discovery of the genetic code and subsequent advances in molecular genetics and biotechnology have provided physicians a new set of tools with which to detect and treat human disease. These new tools—drugs, biologics, and medical devices—come with product labeling that has been approved by the Food and Drug Administration. That labeling addresses those uses for which the manufacturer has established the product’s safety and efficacy. It may explicitly warn against use of the product in specified situations for which safety and efficacy have not been established to the satisfaction of the FDA.

In these circumstances, physicians must decide, based on a review of the labeling and other medical data, whether to use the product in a manner contrary to the instructions in the labeling. This decision should, of course, be guided primarily by the physician’s best judgment, in light of the medical literature and the physician’s experience, regarding what is in the best interests of the patient. Unfortunately, however, well-counseled physicians must also factor in the malpractice consequences of their actions.

This article addresses those con-sequences. It does so in the context of a diagnostic test kit that detects the presence of human papillomavirus DNA in cervical specimens. That kit allows physicians to exploit the association between persistent HPV infection and cervical cancer and to identify those HPV-infected women who may be at higher risk for developing cancer.

Questions have arisen as to how use of the HPV DNA test should be integrated with other cervical disease screening methods, such as the Pap test. As reflected in the kit’s current labeling, the FDA has approved the HPV DNA test for use only as an adjunct to the Pap test—and only in specified patient populations. More specifically, the labeling advises that the test is designed "to augment existing diagnostic methods for the detection of cervical disease." It warns that the test results "should not be used as the sole basis for clinical assessment and treatment of patients" (emphasis in original). The labeling further cautions that use of the test "has not been evaluated for the management of women with prior cytologic or histologic abnormalities, hysterectomy, who are postmenopausal, or who have other risk factors (e.g., HIV+, immunocompromised, DES exposure, history of STI)."¹

Despite these warnings, some physicians have apparently decided to use the HPV DNA kit in a manner contrary to the instructions in the labeling. For example, physicians may have concluded that use of the HPV DNA test without cytology for management of women with prior cytological or histological abnormalities is consistent with the medical evidence and in the patient’s best interests. They have determined that such use is the most efficient and cost-effective approach to managing these patients. As discussed here, however, this approach—though well intentioned and grounded in science—may expose the practitioner to serious risk under state malpractice law.

The labeling of a diagnostic kit that has been approved by the FDA includes indications for use, instructions, warnings, and other information. It may also specify uses for which the kit has not been approved. The manufacturer would violate the Food, Drug, and Cosmetic Act if it were to promote the kit for an unintended use. However, the act does not prohibit practitioners from using the kit in a manner not contemplated by the labeling. As the FDA explained in the context of drug regulation nearly a quarter century ago, "Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such ’unapproved’ or, more precisely, ’unlabeled’ uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in the medical literature."²

Even though a physician is free under the Food, Drug, and Cosmetic Act to use a diagnostic kit—or indeed any drug or device—in a manner not contemplated by the labeling, that physician is still subject to the state law of malpractice. In a malpractice action against a physician, the plaintiff will argue that the conduct of the defendant physician failed to meet the standard of care. That standard is determined by the trier of fact—taking into account all relevant evidence. Significantly, the labeling itself is not conclusive evidence of the standard of care, and a physician’s deviation from that labeling does not, ipso facto, constitute negligence.³ Rather, most jurisdictions require the plaintiff to introduce expert testimony establishing the standard of care. Courts in these jurisdictions may refuse to admit the FDA-approved labeling into evidence without such expert testimony.⁴

Underlying this approach is judicial recognition that off-label use of drugs or medical devices is not inevitably risky, novel, or investigative.⁵ Thus, the Supreme Court of Missouri has noted that the use of antibiotics to treat stomach ulcers was initially an off-label use—before such treatment became the standard of care and ultimately was hailed as a medical breakthrough.⁶ Other courts have observed that product labeling serves many functions other than the provision of safety and efficacy data to physicians, such as the compliance with FDA requirements and the protection of manufacturers from product liability lawsuits.⁷ For these reasons, physicians may defend against the malpractice claim by introducing expert testimony that demonstrates that off-label use of a diagnostic device meets the standard of care.

It should be recognized, however, that acting directly contrary to the instructions in a kit is riskier than simply making an off-label use of that kit. It takes no great imagination to realize that plaintiffs’ attorneys will seize upon deviation from the product labeling as strong evidence of failure to meet the standard of care. They will do their best to characterize action directly contrary to explicit instructions in the labeling as a blatant deviation from the standard. In these circumstances, the FDA-approved labeling will be a powerful weapon for the plaintiff in court. That the government agency charged with regulating drugs and medical devices has declared certain uses to be improper will be stressed to the jury as the jurors deliberate the issue of malpractice.

The case of Fournet v. Roule-Graham exemplifies the thinking that a defendant physician who has acted contrary to instructions in the labeling will have to try to overcome.⁸ In that case, a gynecologist was sued for negligence for prescribing the drug Provera to stop abnormal uterine bleeding in a woman with a history of deep vein thrombosis. The use of Provera in patients with histories of such thromboembolic disorders was contraindicated in the labeling. However, the defendant argued that most OB/GYNs nationwide would nonetheless use the drug in such patients. In other words, the physician argued that use of Provera, although contraindicated, met the standard of care.

In affirming a judgment against the gynecologist, the appellate court stated: "There is nothing in the record that persuades us that the [labeling] should be ignored for any reason. It may very well be the case that a majority of those OB/GYNs are simply unaware of this specific contraindication for Provera, or may simply ignore it. Nevertheless, we see nothing in the record that convinces us the OB/GYN community is correct and the [labeling] is wrong.⁹”

The appellate court also quoted the ruling of the trial judge, who had noted with disapproval the defendant physician’s "apparent mechanistic disdain for anything that FDA may have said about this particular drug."¹⁰ In short, contravention of the labeling, or, at the least, failure to articulate a persuasive justification for doing so, resulted in liability for malpractice. That other physicians would have similarly prescribed the contraindicated drug was not enough to shield the defendant from liability.

Although the Fournet case addressed a contraindicated use of a pharmaceutical, its reasoning is equally applicable to contraindicated uses of diagnostic devices. Thus, to confront successfully the sort of skepticism toward contraindicated uses of diagnostic devices that is reflected in Fournet, physicians must be able to justify their decisions to deviate from the terms of the product labeling. This will require at least two steps.

First, any physician who acts contrary to product labeling should make a contemporaneous record that the decision to do so was a conscious one—based on careful thought, not on ignorance of the labeling. To justify the decision, the physician should keep a file that includes as many as possible of the following sorts of material: any medical literature supporting the contraindicated use, published reports of the contraindicated use from other countries, any favorable guidelines or statements by physician organizations, favorable comments in seminars and continuing medical education materials, and documentation of the physician’s own successful experience with the contraindicated use.

With respect to the HPV DNA test and, more specifically, the warnings about use without cytology in the management of women with prior cytological or histological abnormalities, any physician who disregards these warnings should, to try to protect against malpractice liability, validate the warned use of the test. Validation might include documentation supporting the conclusion that any negative HPV test result accurately portrays the patient’s true HPV status—and not simply the physician’s ailure to obtain an adequate sample. Absent such validation, the physician faces enormous exposure for purportedly substituting an unproven diagnostic method specifically warned against in the product labeling in place of a well-established and well-controlled alternative. Even with such validation and with the other kinds of corroborating evidence discussed here, the physician is at risk.

For this reason, we recommend a second safeguard. Specifically, physicians should inform their patients that the proposed use is contrary to the labeling, explain why a contraindicated approach is being taken, and obtain the patient’s consent to the contraindicated use. To be sure, the process of securing informed consent in the context of off-label uses has generally been limited to disclosing the nature of the proposed treatment or procedure, its benefits and risks, and any feasible alternatives. Indeed, the majority of relevant cases have held that the off-label or regulatory status of medical devices need not be disclosed to patients to satisfy the physician’s informed consent obligation."¹¹

This majority view is based on the proposition that off-label status, or any other FDA regulatory status issue, does not necessarily shed light on the nature, risks, or benefits of the proposed use of the medical device.¹² The term off-label, by itself, does not inform the patient of any inherent medical risk associated with a particular use. Accordingly, proponents of the majority view believe that disclosure of a device’s off-label status unnecessarily complicates and confuses the informed consent process, diverting physicians’ and patients’ attention toward the regulatory process and away from the medical benefits and risks of the proposed procedure.

However, the informed consent requirement may turn out to be different where the use is contrary to instructions in the labeling. Although there is no law directly on point, courts may require informed consent by the patient to uses that directly contravene the labeling. If so, the courts would invoke the minority view that holds that the regulatory status of the device—that is, whether it has been approved by the FDA for the proposed medical procedure—is relevant to the patient’s assessment of the procedure’s risks and benefits.¹³

We cannot, of course, predict whether courts will require informed consent to contraindicated uses. However, given the presumption against such uses, we would advise the physician to discuss the contraindicated nature of the proposed diagnostic testing with the patient in advance. At a minimum, securing informed consent to this type of use will help to counter any charge that the physician is using the patient as an uninformed guinea pig to test his or her own theories.

Finally, before making a contraindicated use of a test kit, a physician would be well advised to check the applicable malpractice policy to make sure that practices contrary to the labeling are not the subject of an exclusion from the policy. If there is anything worse than being sued for malpractice, it is being sued and finding out that the underwriter is denying coverage. The appropriate insurance agent or hospital risk manager should be able to assist with this inquiry.

In conclusion, physicians who use the Digene hc2 High-Risk HPV DNA test—or any other diagnostic kit—in a manner contrary to the instructions in the product labeling should recognize that they will face the presumption that they acted negligently. To be in a position to overcome that presumption in a negligence action, such physicians should, at a minimum, take two steps:

• Make a contemporaneous record that the decision to go contrary to the instructions was a conscious decision—and have as much documentation as possible to support the medical soundness of that decision.
• Secure written informed consent in which the patient, after being advised of the contraindicated nature of the use and the reasons therefore, agrees to the contraindicated use.

1. The Digene hc2 High-Risk HPV DNA Test (DNAwithPap) labeling is available from Digene’s Web site (www.Digene.com) (last visited Aug. 28, 2006).
2. 12 FDA Drug Bulletin 4 (April 1982).
3. See, e.g., Morlino v. Medical Center of Ocean County, 706 A.2d 721, 730 (N.J. 1998).
4. See, e.g., Richardson v. Miller, 44 S.W.3d 1, 16 (Tenn. Ct. App. 2000).
5. See, e.g., Blazoski v. Cook, 787 A.2d 910, 920 (N.J. Super. Ct. App. Div. 2002).
6. State Bd. of Registration for Healing Arts v. McDonagh, 123 S.W.3d. 146, 165 (Mo. 2003).
7. See, e.g., Morlino v. Medical Center of Ocean County, 706 A.2d 721, 729 (N.J. 1998).
8. 783 So. 2d 439 (La. App. 2001).
9. Id. at 443.
10. Id. at 444.
11. See, e.g., Southard v. Temple Univ. Hosp., 781 A.2d 101, 107-08 (Pa. 2001).
12. James M. Beck and Elizabeth D. Azari, FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53 Food Drug L.J. 71, 72 (1998).
13. See, e.g., Retkwa v. Orentreich, 584 N.Y.S.2d 710, 712-13 (N.Y. Sup. Ct. 1992).