Food and Drug Administration Approval of Laboratory Tests (2012)

The United States Food and Drug Administration (FDA) recently granted accelerated approval to crizotinib (Xalkori; Pfizer, New York, New York) to treat patients with advanced-stage non–small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK) fusion genes.1 Concurrently, the FDA granted accelerated approval for a companion diagnostic test, the Xysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc, Chicago, Illinois), designed to detect rearrangements of the ALK gene, which are found in about 5% of patients with NSCLC.1 Crizotinib comes with “a hefty price tag”—$9600 per month, or $115 000 per year; however, “[w]e are going to be treating patients more effectively and avoiding treatments that don't work.” 1 “This is the first targeted agent to be developed with an accompanying diagnostic test, said Mace Rothenberg, MD, senior vice president of Pfizer's Oncology Business Unit.” 1 “‘The Abbott ALK FISH test was developed in conjunction with Pfizer and the clinical trials for crizotinib,’ said Kathryn B. Becker, PhD, director of Abbott Molecular Oncology. ‘It was configured to work specifically in NSCLC patients . . .’” 1 (emphasis added).The launch of crizotinib and the companion Abbott ALK FISH test has made FDA-approved laboratory tests a hot topic among pathologists. Food and Drug Administration approval of laboratory tests is new, and raises many questions. How did FDA approval of laboratory tests come about? What laboratory tests, if any, should require FDA approval? What is FDA approval meant to accomplish? What does this change mean to the pathologist? To the patient? Is FDA approval desirable? Political? Inevitable?The vast majority of biomarker tests generally become available as laboratory-developed tests (LDTs; also called “home brews”—a term that, although widespread, should be abandoned because of its obvious negative connotation); however, some biomarker laboratory tests have been termed “medical devices.” The difference is important because the regulation of LDTs, which are considered laboratory services rather than medical devices, is less stringent for test developers, although laboratories are still thoroughly regulated, for example, by the College of American Pathologists (CAP) accreditation process.2 The distinction between laboratory test kits and LDTs also has an impact on the level of regulation required. The FDA regulates genetic test kits developed for sale to laboratories (or directly to consumers) as medical devices.2 “In contrast, LDTs developed and used by a single laboratory ‘in-house’ are considered medical services and do not need to be approved by FDA, but are instead regulated by the Centers for Medicare and Medicaid Services (CMS) and the Center[s] for Disease Control [and Prevention] (CDC).” 2 This state of affairs changed in July 2010, however, when the FDA announced that it would exercise its authority over LDTs as well.2The FDA classifies medical devices in keeping with their level of risk (Class I to Class III), varying its control over safety and effectiveness accordingly.2 Through its Center for Device and Radiological Health, the FDA regulates genetic laboratory test kits as in vitro diagnostic devices. It considers biomarker tests to pose little physical risk; however, it recognizes the possibility that inaccurate results may lead to mistakes causing inappropriate drug treatment or incorrect dosage. The FDA also recognizes that there is some degree of psychosocial concern about genetic discrimination associated with genetic tests generally.2 It therefore generally classifies biomarker tests as Class II, the moderate risk classification level that requires special controls. Nonetheless, a biomarker test that “cannot be classified as a class II device because insufficient information exists to determine that the special controls . . . would provide reasonable assurance of its safety and effectiveness”—and therefore requires additional oversight to reasonably ensure safety and effectiveness—may be categorized as Class III, requiring submission for premarket approval.2Because the vast majority of biomarker tests are offered as LDTs, the cost and time delay of FDA review is avoided; however, a laboratory's ability to offer its services is limited, making mass production and marketing of LDTs difficult.2 Nonetheless, the ability of a laboratory to offer biomarker tests without FDA approval is an extremely attractive way of providing biomarker testing services. A 2008 estimate showed that only about a dozen of the more than 1200 genetic tests had FDA approval, of which only a few are biomarker tests. As noted above,Although not required by CLIA, most genetic testing laboratories perform proficiency testing voluntarily, for example, through the CAP accreditation process.To understand the FDA's motivations in labeling laboratory tests as medical devices, and demanding increased oversight of laboratory tests, one must first understand the FDA's origin and subsequent growth as a federal agency.Prior to 1906, there was no federal regulation of drugs. In 1906, because of the growing concern about “snake oil salesmen” peddling harmful chemicals, Congress passed the Pure Food and Drug Act, making it illegal to distribute an “adulterated” or “misbranded” drug.3In response to the sulfanilamide tragedy, Congress passed the Food, Drug, and Cosmetic Act (FDCA), “giving the FDA the role of ‘gatekeeper’ for approving ‘new drugs’ for distribution. Here we see the balance changing towards some (but not unlimited) government control over access, up to the point when safety (but not efficacy) was established.” 3 The implementation in the 1950s of statutory regulation of prescription drugs gave physicians, in the name of patient protection, primary responsibility for regulating access to drugs.3Thalidomide was prescribed in the 1950s and early 1960s as a sedative for the treatment of morning sickness in pregnant women; however, it was withdrawn from the market in 1961 after being shown to be teratogenic. The thalidomide tragedy, “one of the biggest medical tragedies of modern times,” prompted Congress to create in 1962 the current overall premarket approval structure that requires the FDA to review a new drug for both safety and efficacy— further shifting the balance of power away from personal autonomy and toward government control.3,4Public attention in the 1970s focused on cancer treatments, and access issues became important policy issues.AIDS activists and cancer activists in the 1980s influenced the FDA's ability to limit access to drugs for life-threatening conditions, resulting in a number of regulatory adjustments designed to speed access. “Congress also eased the regulatory pathway for drugs and devices intended to treat small populations (so-called orphan drugs) in an effort to increase product development and access. This provided somewhat faster access for certain products, but did not eliminate much of the FDA's role as the gatekeeper.” 3In the new millennium, the Abigail Burroughs case has been a “lightning rod in the ongoing battle to balance access with patient protection.” 3 Abigail Burroughs, who died of cancer at age 21, attempted and failed to gain access to an investigational cancer drug, Erbitux. “The FDA was unmoved by her life-and-death situation. Abigail died on June 9, 2001. Less than 3 years later, on February 12, 2004, the FDA approved Erbitux ‘to treat patients with advanced colorectal cancer that had spread to other parts of the body.’” 5 Her father formed the Abigail Alliance, which filed suit and argued that there is a substantive due process right for terminally ill patients, armed with a physician prescription, to be given access to experimental drugs that had completed Phase I testing.3 A 3-judge panel held in favor of the Abigail Alliance; however, on appeal, the District of Columbia Court of Appeals overturned the panel, rejecting the substantive due process argument. That is where the current state of the case law stands. However, the case's negative press put enormous political pressure on the FDA, forcing it to institute regulatory changes allowing expanded access to experimental drugs in limited circumstances.3Since 1998, U.S. government committees, expressing concerns about lack of LDT oversight, particularly the lack of evidence of clinical validity, and the desire to advance the field of personalized medicine, have demanded increased regulation of LDTs.2 The Department of Health and Human Services Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) recommended stringent oversight over “home brews” in 2008, stressing that the advancement of personalized health care depends upon tests that are accurate (analytically valid), predictive (clinically valid), and therapeutically beneficial while taking into account the test's risks (clinically useful).2 “Because, in the case of LDTs, CLIA only reviews analytical validity and does not authorize CMS to assess clinical validity, and due to concerns over the extent of oversight over laboratories, the [SACGHS] report suggested that increased oversight would help . . . improve health care delivery.” 2For several years, the FDA has claimed jurisdiction over LDTs, stating that it considers laboratories to be “manufacturing medical devices”; however, it chose not to enforce its jurisdiction, while retaining the option to reevaluate its position in the future.2 In 2010, the FDA reevaluated its position, and declared its intention to “exercise its authority over LDTs.” The FDA began by clamping down on direct-to-consumer genetic tests (DTC-GTs), sending letters to companies notifying them that FDA approval was required for continued marketing of these devices.2 “[C]oncerns over the safety and effectiveness of both DTC-GTs and LDTs, with some DTC-GTs considered to be LDTs, [had] combined to suggest the need for increased regulation. [The] FDA's proposal [was] also in line with the view that the regulation of [biomarker] tests, particularly with respect to clinical validity, is important . . .” 2 Test accuracy is undoubtedly a valid concern, especially where these results are used to guide expensive and potentially harmful therapy; however, there is significant concern that the FDA's proposed regulation of LDTs could hinder the rapid development of biomarker tests, as well as increase the cost of drug development by adding costs associated with regulatory approval.Further,“[The] FDA's jurisdiction over LDTs depends on two assumptions: [1] that LDTs are devices and [2] that they are sold in interstate commerce . . . “These assumptions are extremely arguable, and indeed “[t]he inclusion of LDTs as medical devices could be the subject of a constitutional challenge.” 2 Also ripe for constitutional challenge is the FDA's position regarding off-label advertising. Directly germane to the discussion of FDA regulation of laboratory tests, the off-label issue is a fascinating illustration of the purposes behind the FDA's actions, and why constitutional challenge of FDA control of LDTs may be appropriate.The off-label conundrum is as follows: to protect the public from harmful or worthless drugs and medical devices, the FDA, as noted above, is legislatively authorized to restrict the sale of prescription drugs or medical devices to those for which it has approved the safety and efficacy.6Therefore, off-label uses may potentially allow worthless or dangerous alternative uses; however, physicians are freely using drugs for those off-label purposes. Further, off-label use of drugs undermines FDA authority and provides no incentive for manufacturers to seek “on-label” FDA approval, no matter how widespread the off-label use.6Also, manufacturers may decide FDA approval is not worth the cost. In any case, the FDA currently asserts that it lacks the authority to restrict physicians' prescribing drugs or devices for off-label uses.6“The FDA has sought to resolve this dilemma by effectively swimming half way across a river—thereby pleasing no one and avoiding none of its quite legitimate concerns. It has resolved its dilemma by leaving off-label uses essentially unregulated, but to make a manufacturer's promotion of an off-label use categorically illegal.” 6 Therefore, off-label drug benefits remain, along with any accompanying dangers. Additionally, the ban on off-label promotion by manufacturers, preventing false or misleading advertising, is all-inclusive, thereby simultaneously preventing promotion of valuable off-label uses of which doctors otherwise may be unaware.6 Anyone other than the manufacturer may freely discuss the relative merits of off-label uses, and even manufacturers are authorized to speak about certain circumstances surrounding off-label use, such as accompanying dangers; however, the FDA clearly and categorically prohibits manufacturers from advocating off-label uses in any manner.6The FDA's ban on off-label promotion is very arguably a clear violation of the First Amendment right of free expression.6 “[The] governmental imposition of a categorical ban of truthful promotion of lawful commercial activity contravenes both established commercial speech doctrine and core notions of free speech theory.” 6 And the FDA's regulation of speech is not its actual objective. “Instead, the purpose of the off-label promotion ban is to regulate indirectly, through enforcement aimed at manufacturers, what the FDA has decided it cannot, for essentially political reasons, accomplish directly—that is, the regulation of the physician's decision to prescribe a drug for a particular off-label use.” 6The question remains: should the FDA regulate laboratory tests? Leaving aside arguments based on financial bias (“. . . but we make money off our lab test”) and emotional bias (“. . . the government's got no right to . . .”), promotion or opposition to FDA regulation of laboratory tests turns on the question of which better serves the public interest: a government regulatory system, or regulations self-imposed by physicians or physician groups concerning patient and physician access to laboratory tests. Although the medical literature has been generally silent on the issue, this question has been debated in the legal literature recently.3,5 It is not a simple question, nor is it one to be taken lightly. Indeed, “[o]ne of the thorniest questions in legal analysis concerns the longstanding tension between individual autonomy and social control.”5The protection of the vulnerable from fraudulent cancer cures and other quack remedies is one basic and compelling argument proponents of strong FDA control express. In the realm of laboratory testing, this argues for strong FDA regulation of laboratory tests in order to better protect uninformed patients from being subjected to inappropriate or unhelpful (though not particularly physically injurious) laboratory tests, from which serious and expensive therapeutic decisions are based.3 Even though LDTs undergo strict evidence-based examination and review, proponents argue that the home-brew nature of these tests strongly implies inferiority. A second argument voiced by proponents is that the FDA, as a federal agency, has significantly greater access to information than any individual laboratory, physician group, or medical specialty group, and, as such, is much better positioned to make appropriate risk-benefit analyses.3 A third argument put forth by proponents is that the FDA, as a government agency, is more and provides more and for public than individual laboratories, physician or specialty groups are of Further, the public nature of the FDA's decisions some degree of for those decisions through the political question is any be to process this the of in other of the that serious be by the FDA on 5 that the FDA is not argue that instead of the FDA's of decisions regarding medical devices, and LDTs should be made by medical specialty and the FDA's to those it had in 1962 that the FDA reviews drug safety but does not assess product which is to the medical a would the of in the of specialty such as the point of strong FDA control desire to the FDA's to those it held with responsibility for safety but not as the 3 that are of the and question over the FDA's regulatory oversight to these 3 that medical have a of or even valid and that the FDA has better and faster access to that lack the structure and to do the and the . . . for some individual medical there is no that a medical access that the FDA 3 also argue that the FDA has and access to and that FDA and medical from across the government and to the panel 3 further that medical not only significant of but also lack and some point the of FDA approval of LDTs must be LDTs be FDA laboratory tests have some in their use, but FDA approval of tests is arguably Therefore, should only genetic tests, for which the FDA has shown concern, be required to have FDA approval? genetic tests do not in drug for which the of a companion test would come into should only genetic tests potentially resulting in the use of expensive drugs require FDA approval? should only biomarker companion the FDA is clearly and for which a new drug is approved in required to have FDA of the arguments by proponents and of strong FDA oversight to LDTs as much as they do to drugs and medical devices. to more understand the it is to how the off-label conundrum changes or to the in FDA approval of What if the Xysis ALK FISH test, FDA approved only for advanced NSCLC patients, is used on a patient with or or and uses the of off-label use, and therefore based on its the FDA very would allow while at the time not allowing the the Pfizer, to or otherwise the test for use in patients with or and This is potentially a dangerous What if an treating a patient with a cancer other than NSCLC considers treating the patient with Is the required to use only the FDA-approved FISH test off or could the use approved ALK test and not FDA FDA the could do however, using that ALK test to test an NSCLC patient would FDA the of FDA approval of laboratory tests as a even physicians, of FDA approval for drugs and physically devices such as may not FDA approval of laboratory tests to be in and therefore not especially Indeed, physicians may the of FDA approval of laboratory tests as example, a a test to test in patients using this has been approved by the U.S. Food and Drug Administration for of . .” there is of the of FDA control in CAP and other specialty medical have for a response to the FDA in an to guide the FDA in its approval of laboratory specialty medical to the FDA have been and in some a strong regarding FDA however, they do not the of FDA This position by specialty medical is and with the FDA in its to control LDTs some level of oversight of the and there are to that the FDA and from these This also that any case for specialty medical control of laboratory a of the FDA's have to be made by groups other than the specialty medical and their much responsibility for the of drugs and medical devices has been from medical to the are the of laboratory test safety and to the FDA as there is a strong argument that medical such as the CAP and indeed to a role in and the of LDTs, of or not such tests are of a The role by the CAP and other medical strongly however, on the medical ability to and evidence-based and accreditation use eliminate or at of and ensure the even as the and of the level of FDA control over LDTs, the CAP and other should improve their of laboratory tests to ensure that LDTs tests. FDA approval of laboratory tests to be there be political pressure to laboratories better tests, those laboratories work to those tests approved by the tests FDA approval by the that is an but social cost. the of the one could a such as a of FDA approval of laboratory tests that is limited, only to biomarker tests for which the cost of treatment based on those test results is extremely expanded FDA regulatory power has been both and one or not with FDA approval of laboratory tests, the legal arguments to the of for FDA approval of laboratory tests is or requires that one do no less than the tension between individual autonomy and social and thoroughly about the role of