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Extra-Label Usage: Open Secret

April 1990 (edition of) Medical Device and Diagnostic Industry

By Jonathan S. Kahan

(Jonathan S. Kahan is a partner in the Washington, DC-based law firm of Hogan and Hartson. He is co-chairman of the DC Bar Administrative Law and Agency Practice Section and a member of the editorial advisory board of the Food, Drug and Cosmetic Law Journal.)

A question subtly pervading the entire medical device regulatory are is: To what extent will FDA intervene in the use of an approved (applicable to devices subject to premarket approval) or cleared (applicable to devices subject to 510[k] clearance) device for an unapproved or uncleared use? While FDA unquestionably has jurisdiction over a manufacturer’s or distributor’s promotion of a device for an unlabeled indication, it typically makes no attempt to regulate the practice of medicine, or restrict physicians to prescribing drugs or devices only for approval or cleared indications.

In many instances, however, physicians use medical devices widely for unapproved or uncleared indications. This extra-label use raises many issues for the device manufacturer, FDA, and the physician. Three of the most important issues are the FDA regulatory implications, product liability exposure of the medical device manufacturer, and medical malpractice risk to the physician.

FDA REGULATION OF THE PRACTICE OF MEDICINE

Generally, the Federal Food, Drug and Cosmetic Act (FD&C Act) neither addresses the practice of medicine nor attempts to regulate how physicians use marketed drugs or devices.¹ At one time, FDA did propose to regulate physicians’ practices in prescribing approved drugs for unlabeled uses. However, the proposed regulation faced massive resistance by the medical profession and others and was never promulgated.² FDA has essentially abandoned efforts to restrict physicians to prescribing products only for approved or cleared indications. In fact, several court decisions have implied that FDA recognizes the legality of using approved drugs or devices for purposes other than those for which they have specifically been found to be safe and effective by the agency.³

The FD&C Act does not require a physician to file an investigational new drug (IND) or investigational device exemption (IDE) application before prescribing an approved drug or device for an unapproved or uncleared use. ⁴ FDA may, however, take action against a physician when it has evidence that he or she is involved in commercializing a product for an extra-label use. ⁵ Once a treating physician becomes a doctor promoting a product for a specific uncleared use, FDA may act, even though, typically, it does not regulate the practice of medicine.

The policy behind FDA’s reluctance to intervene in the practice of medicine seems reasonable. First, the agency has a full-time job exercising its present jurisdiction over medical device and drug manufacturers. Extending its regulatory efforts into physician utilization of drugs and devices would likely overextend FDA’s present limited resources. Second, FDA recognizes that many advances in medicine have come from physicians utilizing devices and drugs for unapproved or uncleared uses. An example in the pharmaceutical area is propranolol. This drug became widely used for angina pectoris and hypertension many years before it received FDA approval for these indications. Clinical experience showed the drug was safe and effective for those purposes. Thus, and advancement in medicine was made through physician initiative in utilizing a drug for an extra-label use.

FDA Regulatory Implications

What are the implications, however, when a medical device manufacturer learns its product is being widely used for a purpose never delineated in the labeling approved under a premarket approval (PMA) application, or for an intended use not covered by 510(k) premarket clearance? This question is not simply academic. FDA regulations provide if a company knows its device is being widely employed for a use never reviewed by FDA (and review is legally required), the company must label the product for that use. When labeled for a use never cleared by FDA, the product becomes misbranded and subject to FDA enforcement action. This is what some companies call the "Catch 22" regulation enunciated in 21 CFR 801.4 and relating to meaning of intended uses:

The words "intended uses" or words of similar import…refer to the objective intent of the persons legally responsible for the labeling devices. The intent is determined by such persons’ expressions or may be shown by circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral and written statements made by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. The intended uses of an article may change after it has been introduce into interstate commerce by its manufacturer. If, for example, a packer, distributor or seller intends an article for different uses that those intended by the person from whom he received the devices, such packer, distributor or seller is required to supply adequate labeling in accordance with the new intended uses. But if a manufacturer knows, or has knowledge of facts that would give him notice that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the one for which he offers it, he is required to provide adequate labeling for such a device which accords with such other uses to which the article is to be put.

Upon a strict reading of this regulation, a manufacturer must relabel its device to accord with extra-label uses if the manufacturer knows or has knowledge of facts that would lead it to know, that a device introduced into interstate commerce by the company is to be used for conditions, purposes, or uses other than those for which the company offers it. The key questions are: How will FDA interpret and enforce this regulation? And, What should manufacturers do when they learn of widespread extra-label use?

In response to the first question, FDA has never instituted litigation against a medical device manufacturer solely for failing to relabel a product upon learning of its extra-label use. Further, FDA would be unlikely to do so unless the unlabeled use was very widespread. Moreover, before taking enforcement action, FDA would probably first send a notice of adverse findings (NAF) or a regulatory letter giving the company an opportunity to remedy the problem.

FDA has, however, either threatened or taken regulatory action against companies that have had some role in promoting the extra-label use. In only one case has FDA ever sued a company for commercializing an investigational device for an uncleared use. That case resulted in a consent decree that Centocor, Inc., in an instance where the FDA believed the company egregiously promoted an uncleared device. Whether FDA will take regulatory action in connection with extra-label uses of a medical device has relied, in practice, primarily upon the company’s role in promoting the product for the extra-label use and the economic and health implications if such is widespread.

There is, of course, a financial incentive for medical device manufacturers to explicitly or implicitly promoted their products for extra-label uses and to commercialize investigational devices. By doing so, a company can expand the use of its medical device prior to FDA premarket clearance, possibly resulting in the sale of a greater number of devices. A classic example has been reported in the spinal fixation device area. FDA has ruled that spinal fixation devices designed to fix the position of certain vertebrae to allow spinal fusion are subject to 510(k) premarket clearance when attached by sacral screws. FDA has found that when the same device is to be attached to the pedicle, a PMA application is required. Allegedly, some companies have tried to avoid PMA requirement by explicitly or implicitly promoting their devices for pedicle screw fixation wile selling under the cover of a sacral screw fixation 510(k) acceptance. Once the physician has the device in his or her hands, it can then be utilized for whatever purpose. It is the physician’s prerogative to fix the device to the pedicle, even though this procedure has never been subject to PMA. FDA exercises its authority only over the device manufacturer. It may take months or years for the Office of Compliance or Surveillance (OCS) or CDRH to take action against companies promoting devices for extra-label use.

Manufacturers learning of widespread extra-label use and promotion for uncleared indications of competitor’s devices have several options. They can report this widespread extra-label use and, if appropriate, illegal promotion by the competitors to the OCS. Some action may be forthcoming. Alternatively, the company can play the same game as its competitors and act in violation of the law by promoting its own device for unapproved uses. This is discouraged for obvious reasons, including the possibility that the company could be subject to FDA seizure, or injunctive or criminal sanctions. Lastly, the company can play by the rules, hope its device gets approved quickly, then promote it as the only one legally authorized for that indication.

Another question arises: What are the companies to do when they learn that, contrary to their wishes, their own device is being used for an extra-label indication? Companies may fear FDA regulatory sanctions or product liability problems if their device becomes widely used for extra-label purposes. Upon learning of extra-label use of their device, companies can advise physicians or hospitals that they are neither selling nor promoting the device for such use. A company can then recommend that the physician or hospital discontinue using the device for that specific purpose. By attempting to limit wide-spread extra-label use of the device, the company can validly claim to FDA, should the issue arise, that it is doing everything within its power to keep utilization of the device within the labeling cleared by the agency.

Product Liability

A device can be found defective according to the product liability laws of most states when directions or warnings regarding its use are inadequate. If a manufacturer knows of the widespread use of its device for extra-label indications and has not provided labeling or directions for physician use of the device for such purpose, a putative plaintiff could argue that the manufacturer placed a "defective" device into commerce. Further, the manufacturer’s position could be weakened if the company can, in any way, be linked to promotion of the device for its extra-label use. In such a case, an injured patient’s assertion that the manufacturer illegally promoted the device for the uncleared use and did not provide adequate directions to the physician for such used would be more persuasive.

Very little case law exists in this area. However, some examples can be examined that raise issues of general relevance to the product liability exposure inherent in extra-label use.

Many disposable devices are labeled for "single use only." Nevertheless, their manufacturer often know that such devices are being reprocessed by hospitals or clinics. One survey showed that roughly 90% of all hospitals were using at least some devices not labeled for reuse. A common example is the now prevalent use of hemodialyzers. FDA and CDC are presently investigating reports of acute allergic reactions among patients in at least seven dialysis centers involving reprocessed dialyzers.

A patient injured by an improperly reprocessed disposable device could argue that both the hospital that inadequately reprocessed the device and the manufacturer that knew the product was going to be reprocessed but failed to provide adequate directions for such a procedure should be held liable. If, during the discovery process, a plaintiff’s attorney comes across documents showing the company knew its products were being widely reused and took no action to prevent such reuse, the plaintiff could have a stronger case for holding the disposable device manufacturer liable for failing to provide adequate reprocessing instructions.

What should a manufacturer do? Again, it could, upon learning that its produce has been reprocessed or has an extra-label use, attach a warning label to the product stating that the device is not to be used for such purposes. By taking such a step, the company could shift liability to the physician or the hospital utilizing the device contrary to its writings and labeling.

The company could go further and seek to design the product so that it could not be used contrary to its labeling. For example, a company might attempt to manufacture a disposable device that reprocessing would permanently damage.

In sum, a manufacturer must balance benefits of increase sales of its device through extra-label uses against the product liability and regulatory implications of such uses. For certain low-risk devices, chance of product liability suits or regulatory action may be so minimal that a device manufacturer may wish to take no action preventing physicians or hospitals from utilizing its device for extra-label purposes. On the other hand, for certain critical devices, liability and regulatory risks may far outweigh any profit potential. The best course is to promote a medical device for cleared indications only and to discourage any extra-label use by hospitals, physicians, clinics or caregivers.

Medical Malpractice Risk

The physician also takes some risk by using a medical device for an extra-label purpose. He or she must consider several factors, the foremost being potential malpractice exposure, in determining whether to go forward with the extra-label use.

Informed consent must be of utmost concern when prescribing a device for extra-label use. Is the physician obligated to inform his or her patient that the device is being used for an indication not cleared by FDA? A patient who has not been informed may subsequently argue that the doctor breached his or her duty to secure informed consent. The law on this issue is diverse.⁶ Some states will find a doctor negligent only if other physicians would customarily have provided information concerning extra-label use.⁷ Although generalizing on this issue is impossible, many believe that physicians probably tend not to disclose that a device is being used for extra-label indication. Thus, widespread nondisclosure would preclude recovery in many states there the "customary practice test" is law.

In addition to the risks associate with informed consent, a physician’s chances of being found negligent can be markedly greater when an injury occurs as a result of the use of a device for an extra-label indication, rather than from a product prescribed or used in accordance with its label. Since FDA has neither approved or cleared the device for extra-label use, nor received data to determine the safety or efficacy of the device for such use, a physician must rely more heavily on his or her independent analysis of risk/benefit to justify the extra-label use. This does not mean, of course, that a physician will automatically be held liable for an extra-label use. No court has held that a physician has committed malpractice due solely to prescribing a drug or device for an extra-label use. Deviation from labeling indications is not evidence per se of negligence.

What are the factors determining if use of a device for an unlabeled indication constitutes malpractice? The key is whether or not the physician exercised a reasonable level of skill and care in his or her treatment of the patient.¹⁰ To make this determination, a court will first consider whether there is scientific support (for example, in published studies) for the extra-label use of a device Another important factor is the availability of alternative therapies for the same condition. If no acceptable approved approach can be expected to achieve the same effect, the extra-label use of a device may well be reasonable and justifiable under the circumstances.¹¹ Finally, widespread used of the device for extra-label indication, even if unsupported by scientific publications, provides some evidence demonstrating reasonable professional judgment on the part of the physician.¹²

Conclusion

Based on case law and FDA’s past policies, it is evident the agency does not regulate medical practice, provide a physician does not attempt to commercialize a drug or device for an extra-label indication. However, when a physician crosses the line from treating physician to device distributor or manufacturer, FDA could institute enforcement proceedings.

The device manufacturer is the party under FDA scrutiny. If a device manufacturer understands that its device is being widely distributed for an extra-label use, the company must serious consider its obligations under the "Catch 22" regulation. 21 CFR 801.4. If, contrary to the company’s wishes, use of the product for indications not cleared or approved by FDA is widespread, the device manufacturer may seek to curtail it. Each company must judge, based upon the nature of the device and its extra-label use, whether or not to take such action.

The device manufacturer must always keep in mind that it could be subject to attack under the product liability laws if it is perceived as either promoting or acquiescing to the widespread extra-label use of a device without providing warnings or adequate directions for use. Similarly, a physician who has unilaterally determined to use a device for an extra-label purpose must consider the attendant medical malpractice implications.

Physicians’ extra-label use of devices is an open secret in the medical device industry. Both FDA and the device manufacturers realize that one a product is on the market, the physician’s use of it in any fashion is restricted only by state medical boards of licensure and medical malpractice concerns. Medical device manufacturers must realize, however, that they have certain responsibilities and obligations, which, if ignored, could lead to FDA regulatory action or product liability judgments.

References;
1. 21 USC 301 et seq., 1982

2. Federal Register. 37 FR: 16503, 1972

3. See.e.g., FTC v Simeon Management Corp. 532 F.2^nd 708 (9^th Cir.) 1976

4. 37 FR: 16504: 21 CFR 312.2(d)