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]
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
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
- 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.
In addition, such physicians should make sure that nothing in their malpractice
policies permits the insurer to deny coverage based on the deviation from
the instructions. Even then, physicians should engage in the contraindicated
practice only if they are prepared to accept the increased malpractice
risk that will come with such practices.
- 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).
- 12 FDA Drug Bulletin 4 (April 1982).
- See, e.g., Morlino v. Medical Center
of Ocean County, 706 A.2d 721, 730 (N.J. 1998).
- See, e.g., Richardson v. Miller,
44 S.W.3d 1, 16 (Tenn. Ct. App. 2000).
- See, e.g., Blazoski v. Cook, 787
A.2d 910, 920 (N.J. Super. Ct. App. Div. 2002).
- State Bd. of Registration for Healing
Arts v. McDonagh, 123 S.W.3d. 146, 165 (Mo. 2003).
- See, e.g., Morlino v. Medical Center of
Ocean County, 706 A.2d 721, 729 (N.J. 1998).
- 783 So. 2d 439 (La. App. 2001).
- Id. at 443.
- Id. at 444.
- See, e.g., Southard v. Temple Univ. Hosp.,
781 A.2d 101, 107-08 (Pa. 2001).
- 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).
- See, e.g., Retkwa v. Orentreich,
584 N.Y.S.2d 710, 712-13 (N.Y. Sup. Ct. 1992).
Jack R. Bierig and Seth Axelrad are with the
Chicago law firm Sidley Austin LLP.