The recent appropriations bill passed by Congress this week has some good news for NIH and the biomedical research community. The Trump administration had proposed cutting the NIH budget by about 18% for the upcoming year, and stripping $1.8 billion from the current year, compounding more than a decade of funding declines. Support for NIH in general has been bipartisan over the years, but that has not shielded the agency from funding volatility over the last decade or so. As reported previously here, the Trump proposal to slash NIH funding was a pillar of the emerging March for Science movement, and a motivator for participation in the April 22 march.
The Congress has now rejected the Trump proposal:
Lawmakers increased the budget for the National Institutes of Health (NIH) in its bipartisan deal to fund the government, effectively ignoring the Trump administration’s proposal.
Congress bolstered funding by $2 billion over the next five months, securing $34.1 billion for the NIH. It's the biggest boost the NIH has received in more than a decade, higher than at any point during the Obama administration.
The explanation for the Congressional resistance is multi-layered, and certainly the visibility of the NIH proposal was very high and the resistance was very public. In addition, Democratic strategizing in the budget process negotiations played a key role. The recent 21st Century Cures Act (see here) which focuses on breakthrough projects (but was not explicitly funded; see here) is now specifically funded in this new bill. More funding fights loom, however, as the 2017-2018 fiscal year is not far away, and the future proposed cuts to NIH are not resolved. But it's fair to say that the collective resistance to this year's NIH cuts (followed by its success) demonstrated significant political muscle, likely to be exercised in the next round of annual negotiations.
The March for Science on April 22, 2017 focused national attention on a number of science-impacting developments under the Trump administration. The march heralds more of developing movement than a single event. For the biomedical research community, the immediate concern is a proposed cut to the National Institutes of Health (NIH) budget of about 18% which is quite radical, and is a sharp departure from the recent Congressional efforts to restore the NIH funding decline over the last decade (see factsheet). A commentary by Harold Varmus, Nobel Prize winner and former director of NIH, notes the national effects of reductions to the NIH budget:
To understand just how devastating a cut of less than 20 percent of an agency’s budget would be requires some understanding of how the N.I.H. operates. Very little of its typical annual budget is spent on the agency’s administration: The industrious, underpaid government scientists who manage the funding of the N.I.H.’s research programs consume less than 5 percent of its budget. Only a bit more, about 10 percent, supports the work of government scientists. In sharp contrast, over 80 percent of its resources are devoted to competitively reviewed biomedical research projects, training programs and science centers, affecting nearly every district in the country.
Ironically, at the close of the Obama administration, Congress passed the 21st Century Cures Act, which would add a new $6 billion to medical research; it received widespread bipartisan support. It was particularly welcomed by the NIH leadership as promoting several new frontier initiatives: Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the Precision Medicine Initiative (PMI).
So the NIH funding climate remains turbulent, which is not optimal for a funding agency that makes multi-year grants to researchers. The NIH budget proposal was a motivating factor for many march participants, including research scientists. The disconnect between the vitality of American biomedical science and the political vulnerability of federal support is readily apparent. Decades of investment in life science research has had a cumulative effect of integrating molecular biology into medical practice, with many prospects for precise and targeted interventions in disease processes. But it's more than that at stake; the generation of scientific knowledge as a public good is an enterprise worth funding and protecting.
It may not be widely known that the federal government retains a specific legal authority to expand the use of a patented invention that was developed using federal research grants, under a federal statute that was enacted in 1980 to remedy the underutilization of American inventive efforts. The Bayh-Dole Act accelerated the transfer of federally funded research into practical real world use; toward that end, the law allows federal grantees (such as universities) to pursue patent rights for any inventions developed in the course of the federally funded work. In addition, a little-known provision in the Bayh-Dole Act gave authority to any federal agency that funds research, such as the National Institutes of Health (NIH) (the major source of federal biomedical funding), to order a “march-in” of patent rights (35 U.S.C. 203) where the funding agency determines such action is necessary to achieve the goals of the statute. This authority is held by any federal granting agency/department (e.g., NASA, DOE, DOD). Effectively, then, NIH (or others) can compel a patent owner to allow third parties to make and use the patented invention. The patent owner is to be reasonably compensated for the use. According to the statute, march-in authority is justified when "action is necessary to alleviate health or safety needs which are not reasonably satisfied by the contractor, assignee, or their licensees" or "action is necessary to meet requirements for public use." To date, the NIH has refused to exercise this authority; five requests have been submitted since 1980. Most recently, in 2012, NIH was asked by Knowledge Ecology International (KEI) to use march-in rights for the AIDS drug Norvir due to excessive price raises (Abbott Pharmaceuticals held the patents); a previous KEI petition on Norvir had been filed in 2004. The NIH declined both requests (see earlier post). In its 2012 rejection, the NIH rejected the contention that price disparities between the price of drugs in the U.S. drugs compared to other high-income justified a march-in maneuver:
The NIH continues to agree with the public testimony in 2004 that the extraordinary remedy of march-in is not an appropriate means of controlling prices of drugs broadly available to physicians and patients.
In 2010, the NIH also declined to implement a march-in when a KEI petition was filed to remedy the manufacturing shortage of Fabryzyme by Genzyme, Inc. Now, KEI has filed a march-in petition with NIH over the high pricing of the prostate cancer drug Xtandi (patents granted to the University of California; now assigned to Astellas Pharma):
This letter is a request that the U.S. federal government use its rights in patents for the prostate cancer drug (enzalutamide), marketed under the brand name of Xtandi by Japan-based Astellas Pharma. This is a product that has an average wholesale price (AWP) of $129,269 per year, and which is far more expensive in the United States than in other countries. Specifically, we ask the Department of Health and Human Services (DHHS), National Institutes of Health (NIH), and/or the Department of Defense (DoD) to use its royalty free rights in the relevant patents, or to grant this request for march in rights. The relevant patents include, but are not limited to, the three patents listed in the FDA Orange Book for Xtandi (7,709,517, 8,183,274, and 9,126,941), all of which were granted to the Regents of the University of California, a public institution. All three inventions were made with the support of the United States government under National Institutes of Health SP ORE grant number 5P50CA092131 and Department of Defense (Army) grant number W81XWH0410129.
What can be expected with this most recent march-in petition to the NIH? In an environment where drug pricing is high on the radar screen for patients and for physicians (see earlier post on "financial toxicity"), and where the U.S. generally does not subscribe to price controls in health care, the high cost of drugs – especially new, targeted drugs – is causing politicians and bureaucrats to pay more attention. In January, prior to the filing of the new KEI petition, 50 members of Congress wrote a letter to NIH, asking that the agency set true guidelines for when the exercise of march-in rights would be reasonable. Then, in a hearing in the House Ways and Means Committee last week, Department of Health and Human Services (HHS) Secretary Burwell stated that HHS would consider the request for march-in guidance from the legislators. In the current campaign season, efforts to control drug prices are already part of political platforms and discourse (see here, for example). But with respect to the dormant march-in authority granted to the federal government, it may be that HHS and/or NIH are more willing to consider all measures and now actually welcome the existence of a statutory authority long ignored. At the least, NIH could begin to clarify how the march-in provisions are to be interpreted. However, that is not to say that march-in rights are a wholesale solution to drug pricing (see here for one study on the limits of such authority). For example, the ability of the federal government to negotiate drug prices for Medicare is often proposed as a leavening force; Congress has explicitly banned that option but it could be rescinded (or possibly by executive order?). Because some of the new “precision medicine” drugs are the most expensive (especially cancer drugs), the disconnect between the promise of genetically-informed medical care and actual access to biotech drugs is growing. That asymmetry will only add to the pressure on both legislative and executive branches to incorporate drug pricing realities into the overarching project of health care access as exemplified by the Affordable Care Act (Obamacare).
In an unusual foray into advocacy involving the pharmaceutical marketplace, a coalition of oncologists has published a call to action in the Mayo Clinic Proceedings regarding the high price of cancer drugs; the physicians advocate for a number of regulatory and legislative measures to reduce the cost of cancer drugs, increase market competition, and ultimately improve patient access. It has been evident for a while that while molecular research has resulted in the development of new therapeutic approaches to cancer – especially targeted biotech drugs – the price of some of these drugs has well exceeded both patient and physician expectations; hence, the term "financial toxicity." In just one example, the Amgen drug Blincyto, an immunotherapy for leukemia, can cost about $178,000 for a course of treatment. The recent attention to funding research on "precision medicine" from the NIH and the White House focused on how cancer treatment (new drugs) is one of the chief beneficiaries of these efforts. In the published commentary, the oncologists make several points:
In 2014, all new US Food and Drug Administration (FDA) approved cancer drugs were priced above $120,000 per year of use.
For a patient with cancer who needs one cancer drug that costs $120,000 per year, the out-of-pocket expenses could be as high as $25,000 to $30,000—more than half the average household income and possibly more than the median take-home pay for a year. Patients with cancer then have to make difficult choices between spending their incomes (and liquidating assets) on potentially lifesaving therapies or foregoing treatment to provide for family necessities (food, housing, education).
The commentary specifically calls for the following measures:
(1) Creating a post-FDA drug approval review mechanism to propose a fair price for new treatments, based on the value to patients and heath care.
(2) Allowing Medicare to negotiate drug prices.
(3) Allowing the Patient-Centered Outcomes Research Institute, created through the Affordable Care Act initiatives to evaluate the benefits of new treatments, and similar organizations to include drug prices in their assessments of the treatment value.
(4) Allowing importation of cancer drugs across borders for personal use (e.g., prices in Canada are about half of prices in the United States).
(5) Passing legislation to prevent drug companies from delaying access to generic drugs (pay-for-delay).
(6) Reforming the patent system to make it more difficult to prolong product exclusivity unnecessarily (patent “evergreening”).
(7) Encouraging organizations that represent cancer specialists and patients (e.g., American Society of Clinical Oncology, American Society of Hematology, American Association for Cancer Research, American Cancer Society, National Comprehensive Cancer Network) to consider the overall value of drugs and treatments in formulating treatment guidelines.
A number of the suggested measures are familiar tactics, although not all in force. For example, the patent recommendations overlap with ongoing efforts to improve either patent quality or forestall dubious attempts to extend the term of lucrative patents (the “evergreening” phenomenon, for example, has been countered using patent law theories of double patenting). The phenomenon of “pay for delay” in which brand name companies pay would-be generic competitors to stay out of the market has encountered the Supreme Court’s Federal Trade Commission (FTC) v. Actavis decision in 2013 which endorsed antitrust inquiries into such arrangements; the Federal Trade Commission actively monitors such agreements. The call for the FDA to incorporate a pricing determinant in the drug approval process runs counter to any agency mandate to consider such questions in its regulatory work. Federal legislation to allow patients to import prescription drugs from Canada has been introduced, but not enacted. The call for the government to allow Medicare to negotiate bulk pricing with drug companies has been a political football for more than a decade since the enactment of Medicare Part D prohibited that option; the Obama administration has endorsed such negotiations, but the realities of Congress today make that unlikely. With respect for the calls to professional organization, the American Society for Clinical Oncology (ASCO) is actively pursuing methods for drug valuation that incorporate pricing. Despite these particulars, the Mayo commentary lines up with other public acts of priced-based resistance from the oncology community, such prescribing refusals based on cost (e.g., Sloan-Kettering oncologist practices) or cost-consciousness in prescribing practices. The article further endorses a consumer petition drive which seeks patient support for these efforts. A critical mass of attention is developing to the high pricing of new biotech cancer drugs; the British medical journal Lancet published a recent editorial:
It therefore seems depressingly clear that industry's inflated pricing of new cancer drugs is contributing to a failure of health systems to offer promising new therapies to the very people for whom the drugs are created—cancer patients worldwide.
It should be noted that despite the Lancet's pessimism, the U.K. did actually establish a Cancer Drugs Fund under the National Health Service to target assistance to those needing expensive cancer drugs; however, as just announced, the fund is over-budget and now restricting which drugs will be covered.
President Obama announced during the recent State of the Union address that his administration would initiate an enhanced funding and policy focus on the field of precision medicine. Precision medicine is informed by the collection of genetic, proteomic, microbial and other biological data of a patient – and the end result is to more sharply define disease states and allow for treatment that is more personalized, with a higher likelihood of success. In the specific case of cancer, for example, a patient’s tumor cells can be analyzed genetically to develop a precise molecular characterization – and treatments can be customized accordingly. According to the White House release:
Launched with a $215 million investment in the President’s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.
The proposed funding is directed to the National Institutes of Health (NIH), the NIH’s National Cancer Institute and the Food and Drug Administration (FDA), and the National Coordinator for Health Information Technology (ONC). The initiative will focus on oncology-related objectives as a starting point:
The cancer-focused component of this initiative will be designed to address some of the obstacles that have already been encountered in “precision oncology”: unexplained drug resistance, genomic heterogeneity of tumors, insufficient means for monitoring responses and tumor recurrence, and limited knowledge about the use of drug combinations. Precision medicine's more individualized, molecular approach to cancer will enrich and modify, but not replace, the successful staples of oncology - prevention, diagnostics, some screening methods, and effective treatments - while providing a strong framework for accelerating the adoption of precision medicine in other spheres. The most obvious of those spheres are inherited genetic disorders and infectious diseases, but there is promise for many other diseases and environmental responses.
The breakdown of this investment is as follows:
$130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.
$70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.
$10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.
$5 million to ONC to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems.
The proposed investment of $215 million is actually quite small, when compared to an annual NIH budget of around $30 billion, and further still when it is divided among the target agencies. Congressional approval will also be needed, but that is probably likely, given ongoing bipartisan advocacy efforts in Congress to increase funding for “21st Century Cures.” However, apart from the financial aspects, the announcement does tie various policy architects together in the federal ecosystem of personalized medicine – imagining newly developed data from the NIH research cohort that is used to identify a new genetic marker for cancer diagnosis or susceptibility, leading to a new test devised by the NCI, which then enters the marketplace under a regulatory regime supervised by the FDA, and all emerging data points accountable in a more standardized electronic environment that the ONC has helped to develop. There are several regulatory sinkholes in this announcement, of course - what will it mean to launch a volunteer-sourced bio-database under government oversight, given a current minimalist privacy regime for genetic information (e.g., GINA). What regulatory scheme will prevail at the FDA with respect to LDTs and next-generation sequencing technologies (see recent post)?
The FDA advisory committee that recently considered the first U.S. application for a biosimilar drug filed pursuant to the Biologics Price Competition and Innovation Act of 2009 (BPCIA) concluded that the application should proceed (see here). The FDA’s Oncologic Drugs Advisory Committee (ODAC) was asked to consider the following question regarding the Sandoz submission of EP2006 as a biosimilar to Amgen’s blockbuster biologic drug Neupogen, which is used to boost the immune system for cancer and other patients:
Does the committee agree that based on the totality of the evidence, EP2006 should receive licensure for each of the 5 indications for which US-licensed Neupogen is currently licensed?
Following a day-long public meeting that heard from diverse stakeholders, the ODAC unanimously approved the submission. This meeting and its vote shows that the pathway for biosimilar approval has officially been activated in the U.S., but these initial questions of biosimilarity for approval are not the only hurdles in the regulatory scheme. Left for another day is the key question of whether an approved biosimilar will be greenlighted as “interchangeable” with the approved brand name product, thus making it available for substitution when filling prescriptions. The FDA defines interchangeability:
An “interchangeable” biological product is biosimilar to the reference product, and can be expected to produce the same clinical result as the reference product in any given patient. If administered more than once to an individual (as many biological products are), the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product will not be greater than the risk of using the reference product without such alternation or switch. Once determined “interchangeable” two biological products will thus be able to be substituted for each other (i.e., interchanged) by a pharmacist without the intervention of the health care provider. Pharmacists will be responsible for knowing which biological products are interchangeable and which will require prescriber prescription before substitution.
Substitution laws for pharmaceuticals are state laws, and because biosimlar substitution is now on the radar screen, some states have already seen legislative action which is quite early considering that no biosimilars have completed regulatory review and will not for some time. Obviously, the standards for substitution will govern whether any approved biosimilar can compete for distribution with an already approved and well-known original biologic. The logic of any generic drug marketplace is to offer lower-cost options to high-priced brand-name drugs; for the scheme to work, a proposed substitute must provide the same therapeutic benefit to a consumer. In contrast to traditional chemically-based pharmaceutical synthesis, biologic drugs are produced in biological systems, which can introduce some differences in various cycles of production; any differences in a biosimilar must not degrade the overall clinical benefit in order to replace the existing pioneer biologic. That requirement and its implementation will surely test how well the BPCIA was designed to establish a true biosimilar approval process that results in a more competitive marketplace for biologics.
This is a watershed week for biotech drugs (more formally known as biologics). Biotech drugs represent the culmination of molecular investigations into disease processes in order to identify when the use of a natural molecule (e.g., an antibody) offers a targeted treatment to specifically selected patients (e.g, Herceptin for breast cancer, Gleevec for leukemias). In 2014, the FDA issued 41 new drug approvals, a relatively high volume as compared to previous years. Biologics comprise a significant sector of drug approvals: these biotech drugs are often developed as targeted therapies and generally produced with biological processes, rather than chemical synthesis. Biologics have been available for several decades and often command significant (and sometimes unaffordable) prices; in general, there has been no "generic" market competition for a pioneer biologic in the U.S. (reproducing a biologic with high fidelity is more challenging than for standard chemically synthesized pharmaceuticals because the biologic is produced by biological processes). However, 2014 was the year in which the U.S. saw the opening moves in the efforts to bring biosimilars (or follow-on biologics) to the market. With the passage of the Affordable Care Act (ACA), the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as part of that legislation, took effect in 2010. The BPCIA designed an abbreviated approval pathway for products shown to be biosimilar to or interchangeable with the original reference biologic product:
Under the BPCI Act, a sponsor may seek approval of a “biosimilar” product under new section 351(k) of the PHS Act. A biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency.
In order to meet the higher standard of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider.
The recent law is somewhat similar in concept (if not exact details) to the Hatch-Waxman Act of 1984, which designed a generic drug approval process for standard pharmaceuticals. The BPCIA contains the kind of tradeoffs that were seen in Hatch-Waxman, where the generic follower can rely on clinical data developed by the first manufacturer and thus avoid de novo clinical trials, while the first company is rewarded with one or more periods of market exclusivity. From the date of first licensure of the licensed biologic referenced in the biosimilar application, there is a 12-year market exclusivity period accorded to the first biologic. This period is independent of any patent rights that may pertain to the product. Several key developments related to the BPCIA occurred in 2014. In July of last year, the FDA received its first biologics license application (BLA) for a biosimilar version of Amgen's biologic Neupogen, filed by Novartis. The Oncologic Drugs Advisory Committee of the FDA will meet this week to take up the Novartis application. Today's release of a preliminary approval by the FDA staff of the proposed biosimilar ("there are no clinically meaningful differences in the effectiveness") is a watershed development that precedes the meeting this week.
In another recent legal development, the BPCIA lays out a complicated set of patent-related information exchanges between the first biologic manufacturer and the biosimilar follower. In the recent opinion from the Federal Circuit, Sandoz v. Amgen, the court affirmed a district court’s refusal to entertain allegations of irregularities in the patent information scheme by the biosimilar entrant (Sandoz) against the pioneer manufacturer (Amgen). The Federal Circuit did not find declaratory judgment jurisdiction where Sandoz had not yet made a formal biosimilar application to the FDA, and would not consider its allegations out of turn from the sequence of events dictated by the BPCIA. With these recent moves from the FDA and the Federal Circuit, the age of biosimilars in the U.S. - anticipated for some years - will begin to take concrete shape in 2015.
In a move that will significantly impact the field of genetic testing, the FDA has notified Congress that it intends to issue a formal draft guidance that will detail the agency’s plan for formal regulation of laboratory-derived tests (LDTs). LDTs are biochemical or genetic tests that are offered as services by commercial laboratories, whether to medical personnel or directly to consumers (DTC). Over the years, the FDA has sent mixed signals over its regulatory posture for these tests, which constitute the majority of commercially available genetic tests offered in the U.S. (an estimated 11,000 tests offered by 2,000 laboratories). Now, in letters sent to the Senate Committee on Health, Education, Labor and Pensions and the House Committee on Energy and Commerce, the FDA announced that the draft guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), will be published within 60 days. The FDA defines LDTs as medical devices, falling within the subset of devices known as in vitro diagnostics (IVDs). As medical devices, the LDTs are subject to the agency’s existing authority under the 1976 Medical Device Amendments (MDA) to regulate such items. To date, the FDA has asserted that it exercised “enforcement discretion” for LDTs – which generally meant no regulation. That will now change. The FDA will design a risk-based classification system for LDTs (Class I-III), which parallels the existing medical device regulatory structure. For the highest-risk LDTs (Class III), the FDA will require premarket approval, phasing that requirement in over four years, while existing tests stay on the market. Moderate-risk LDTs (Class II) will be subject to registration, listing and adverse reporting requirements. The FDA will regard companion diagnostic tests, genetic tests that are used in tandem with an approved therapeutic drug to assess patient suitabiltity (e.g., the genetic test for the HER-2 gene that determines whether Herceptin should be administered to breast cancer patients) as high-risk Class III devices. The FDA describes the factors that will be used to assess LDT risk and classification:
FDA will rely upon the existing medical device classification system to evaluate the risk of a category of LDTs and, informed by the industry’s expressed interest in participating in the discussion of the classification process, will use expert advisory panels to help classify devices not previously classified by FDA, as appropriate. In determining the risk an LDT poses to the patient and/or the user, FDA will consider several factors including whether the device is intended for use in high risk disease/conditions or patient populations, whether the device is used for screening or diagnosis, the nature of the clinical decision that will be made based on the test result, whether a physician/pathologist would have other information about the patient to assist in making a clinical decision (in addition to the LDT result), alternative diagnostic and treatment options available to the patient, the potential consequences/impact of erroneous results, number and type of adverse events associated with the device, etc.
Risk will correlate with the likelihood that a genetic test result will deliver information that will be used by a patient to make significant medical decisions (e.g., as illustrated by a BRCA1/2 genetic test result that some patients rely on to elect prophylactic mastectomy based on breast cancer risk). Although the FDA’s move is not a complete surprise, it will significantly alter the business landscape for the LDT genetic testing industry as it contends with formal approvals and regulatory compliance measures for lab tests that have been or will be developed. Not all stakeholders are pleased with the FDA decision. The American Clinical Laboratory Association (ACLA) represents the nation's leading providers of clinical laboratory services and filed a citizen petition in 2013 with the FDA, asking it to refrain from imposing new regulations on LDTs, asserting that existing regulations are adequate; the FDA denied the request. Just last month, a coalition of academic lab directors filed a statement of opposition with the Office of Management and Budget (OMB), disputing the FDA’s jurisdiction and alleging that new regulations on LDTs would stifle the innovate environment that has produced the thousands of LDTs already available. The FDA will proceed on its schedule, as announced, and public comments will be sought and public hearings will be held. The industry was braced for the FDA's action: a leading genetic test provider, 23andMe, had already anticipated the FDA moves and initiated its own regulatory relationship with the agency.
The regulation of genetic tests is uneven, with the FDA exercising enforcement discretion of this field within its general authority to regulate medical devices. To date, the FDA requires approval of genetic testing kits, considered to be in vitro diagnostics (IVD). The FDA has paid specific attention to one subset of genetic test kits, known as companion diagnostics. The FDA describes companion diagnostics:
A companion diagnostic device can be in vitro diagnostic device or an imaging tool that provides information that is essential for the safe and effective use of a corresponding therapeutic product. The use of an IVD companion diagnostic device with a particular therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents of the therapeutic product.
Companion diagnostics illustrate the use of pharmacogenetics to refine pharmaceutical treatment of cancers or other illnesses. The FDA has just approved a new companion diagnostic test for use in the treatment of non small cell lung cancer, the cobas EGFR Mutation Test that refines the optimal use for Tarceva, a biotech drug approved by the FDA in 2004 (a monoclonal antibody). This approval scenario illustrates how the optimal treatment profile for an already approved drug is being refined by subsequent genetic research, where new understandings of the relationship between particular genes and the specific cancers is allowing for more refinement in treatment decisions. The FDA published a guidance document for the approval of companion diagnostics in 2011:
An IVD companion diagnostic device could be essential for the safe and effective use of a corresponding therapeutic product to identify patients who are most likely to benefit from a particular therapeutic product; identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic product; or monitor response to treatment for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness.
The FDA also recognizes a scenario of co-development between a drug manufacturer and a test developer, such that both products are approved simultaneously, as illustrated by the FDA's co-approval of Xalkori and the Vysis ALK Break Apart FISH Probe Kit in 2011. The list of approved companion diagnostics continues to grow. As a general matter, the FDA regulates genetic tests sold as kits to laboratories or consumers. In the general genetic testing market, however, most genetic tests are offered as laboratory-derived tests (LDTs), available as services, rather than products. The FDA does not regulate LDTs, although it has stated that some LDTs are considered medical devices, subject to its oversight. However, despite issuing a statement of intention for possible oversight in 2010, the FDA to date has not taken on LDTs in general, or even the genetic LDTs. Laboratories providing LDTs are regulated under the Clinical Laboratory Improvement Amendments (CLIA), administered by the Centers for Medicare and Medicaid Services (CMS), which requires that laboratories meet specified standards, and that individual tests are scientifically accurate, but which does not evaluate the clinical validity or clinical utility of LDTs. Calls for the FDA to increase its involvement in the regulation of LDTs have come from many sources, including the Secretary's Advisory Committee for Genetics, Health and Society in 2008. More recently, the American College of Medical Genetics published a risk-classification framework for the regulation of LDT genetic tests, calling for FDA pre-market approval of high-risk LDTs, where "the consequence of an incorrect result or interpretation could lead to serious mortality or morbidity."
The era of defining the human patient as a data repository continues; this recharacterization represents the convergence of massive molecular (including genetic) data with digital information capacities (electronic medical records), creating an era of “precision medicine.” At the request of the National Institutes of Health, the National Academy of Sciences was tasked to develop an entirely new view of human disease, less informed by a collection of symptoms and a general description of malfunction and centered instead on a molecular-driven profile of a patient. They have issued a report, Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease that proposes a new disease classification system that is informed by the collection of genetic, proteomic, microbial and other biological states – the end result is to more sharply define disease states and allow for treatment that is more personalized, with a higher likelihood of success. As part of this effort, the report calls for the use of existing patient data to build an information commons which provides the intellectual foundation for reunderstanding human medical processes. But how to get there?
The evolving imperative is to integrate patient care and data collection into a giant information commons, where every patient, if you will, is part of the ongoing “clinical trial” that becomes the modern medical enterprise. Of course, actual clinical trials, in which an individual agrees to become a research subject for scientific/medical investigation, are a well-established pillar of medical science and they are conducted using norms of consent, transparency, and privacy; an overview here). What does this mean for the law? The report does note a need to "initiate a process within appropriate federal agencies to assess the privacy issues." Existing legal privacy protections are several (HIPAA, regarding the privacy of medical records, GINA, regarding does provide some assistance as Title I addresses unfair uses of genetic information by health insurers regarding premiums, etc.).The upshot is that rewriting human disease in molecular language is intellectually appealing, but the conversion of patients into information subjects has obvious privacy implications. Treatment consequences include a kind of adverse typecasting with consequences for receiving medical care (or insurance for). The proposed federal initiative is now new. An example of a private effort to integrate patient records into a genetics research program is underway by Kaiser Permanente in California, in which insured patients can consent to having their deidentified patient records entered into their genetic research program. The program provides formal privacy guarantees, and has its own internal Institutional Review Board (IRB) which reviews protocols. As the era of molecular medicine redefines the patient as a data repository, the law must supply the requisite human norms of privacy, risk, and choice to accompany such a transformation.
