October 16, 2014

FDA Seeks Public Comment on Framework for Regulation of Laboratory-Derived Tests (LDTs)

The FDA is now seeking public comment on a guidance document, Framework for Oversight of Laboratory Tests, that will launch the agency’s entry into a new role regulating a sector of laboratory testing, known as laboratory-derived tests, or LDTs. These tests are offered as services from commercial laboratories, and are developed by the company itself. With respect to the field of genetic testing, LTDs are the predominant form of testing available to the public, where a consumer can send a biological sample to a lab for testing (direct to consumer tests), or provide a sample to a health care provider who mediates the testing process (see here). For years, the FDA has declared that while it has the legal authority to regulated such tests, it has exercised “enforcement discretion" – deciding not to require premarket approval from labs seeking to offer such services. As this marketplace has grown, the agency has moved closer to establishing a more formal role over the quality of these tests, and now has done so with its announcement of how it will require the industry to engage with the FDA in order to offer these tests (see here for the agency's new notification requirements for laboratories). The new proposed framework contains the following observations from the FDA as to why it needs to step up now: 
LDT’s are important to the continued development of personalized medicine, but it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies. 
The FDA has generally not enforced premarket review and other applicable FDA requirements because LDTs were relatively simple lab tests and generally available on a limited basis. But, due to advances in technology and business models, LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976. Some LDTs are now more complex, have a nation-wide reach and present higher risks, such as detection of risk for breast cancer and Alzheimer’s disease, which are similar to those of other IVDs that have undergone premarket review. 
The FDA has identified problems with several high-risk LDTs including: claims that are not adequately supported with evidence; lack of appropriate controls yielding erroneous results; and falsification of data. The FDA is concerned that people could initiate unnecessary treatment or delay or forego treatment altogether for a health condition, which could result in illness or death. The FDA is aware of faulty LDTs that could have led to: patients being over- or undertreated for heart disease; cancer patients being exposed to inappropriate therapies or not getting effective therapies; incorrect diagnosis of autism; unnecessary antibiotic treatments; and exposure to unnecessary, harmful treatments for certain diseases such as Lyme disease. 
The House Energy and Commerce Committee Subcommittee on Health held a hearing on the proposed framework last month. The agency has the guidance document open for 120-day public comment period, which will last until February 2, 2015.

October 2, 2014

Ebola Virus Disease Update: Lags in Drug and Vaccine Development Accelerate Crisis

The urgency of calls for reliable and scaled public health responses to the magnitude of the international Ebola virus disease (EVD) outbreak is increasing; a media frenzy over the apparent emergence of Ebola in Dallas, TX is underway. At the present time, over 7,000 cases and over 3,300 deaths are attributed to the outbreak concentrated in West Africa, where the virus emerged earlier this year. The crisis requires a combination of public health resources (personnel, facilities, diagnostic capabilities) and effective countermeasures (vaccines, drugs). To date, the most effective drug against the  virus appears to be ZMapp, an antibody-based treatment developed by Mapp Biotherapeutical. However, ZMapp supplies are limited, and efforts to scale up production, while necessary, will still not produce enough to meet demand. An expert consultation called by the World Health Organization this week to review vaccine candidates has identified two Ebola vaccines that are ready for Phase I clinical trials. Scheduled milestones for the testing and evaluation of these potential vaccines are now published. Even in a best case scenario, in which a vaccine candidate performs well enough to justify scaleup and distribution, WHO does not anticipate that a significant number of vaccines to be ready before around March, 2015. The WHO meeting participants noted the unprecedented severity and spread of this viral disease relative to other public health crises: 
Participants also drew heavily on lessons learned, in the African setting, during trials for candidate malaria, HIV/AIDS, cholera, epidemic meningitis, hepatitis B, and other vaccines. As some experts noted, never again can the international community allow what boils down to “market failure” to create such catastrophic suffering for humanity in any country, in any region of the world. The sense of urgency and need for speed, without compromising the integrity of studies or the quality of their data, are fully justified by the dire situation in affected countries and the risk that other countries may soon experience their first imported cases. The Ebola outbreak currently ravaging parts of West Africa is the most severe acute public health emergency in modern times. Never before in recent history has a biosafety level 4 pathogen infected so many people so quickly, over such a wide geographical area, for so long.
The CDC has already estimated that 1.4 million cases of EVD could emerge by January next year. Case projections from WHO are smaller, but both agencies point out that a near-term ability to reverse the course of EVD will depend on successful public health efforts, including patient isolation and contact avoidance measures. Drugs and vaccines will not be produced fast enough in the short term to meet demand, but the efforts described above are good starts. More generally, as the WHO acknowledged with its reference to “market failure,” it is clear that government expenditures for research on countermeasures need to continue, but the development of a true pipeline from lab to clinic is still lacking. That is a translational failure here: the emergence of rare but deadly outbreaks of diseases like Ebola are not met with stockpiles of drugs. The U.S. Strategic National Stockpile maintains supplies of drugs for use in viral epidemics, but these are directed to the more familiar diseases such as influenza and anthrax. The current Ebola outbreak illustrates the consequences of focusing national resources too narrowly on the usual suspects in bioterrorism or pandemic crises, with the consequence that new or remote pathogens emerging in the U.S. are not met immediately with effective countermeasures that would contain disease outbreaks.

September 7, 2014

Ebola Virus Disease Response: Public Health Insfrastructure and Experimental Drugs

Ebola virus disease (EVD) has appeared in several West African nations over the last several months, and is now spreading with increasing speed. The international public health response has involved World Health Organization (WHO), Centers for Disease Control (CDC), Doctors Without Borders (MSF), and local public health authorities, among others. WHO has now formulated an Ebola response roadmap for the crisis.The history of Ebola virus outbreaks shows the first recognition of the pathogen in 1976, followed by several decades of periodic outbreaks with various virus subtypes. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), placed the current EVD outbreak in historical context
In most instances, the virus emerged in geographically restricted, rural regions, and outbreaks were contained through routine public health measures such as case identification, contact tracing, patient isolation, and quarantine to break the chain of virus transmission. In early 2014, EVD emerged in a remote region of Guinea near its borders with Sierra Leone and Liberia. Since then, the epidemic has grown dramatically, fueled by several factors. First, Guinea, Sierra Leone, and Liberia are resource-poor countries already coping with major health challenges, such as malaria and other endemic diseases, some of which may be confused with EVD. Next, their borders are porous, and movement between countries is constant. Health care infrastructure is inadequate, and health workers and essential supplies including personal protective equipment are scarce. Traditional practices, such as bathing of corpses before burial, have facilitated transmission. The epidemic has spread to cities, which complicates tracing of contacts. Finally, decades of conflict have left the populations distrustful of governing officials and authority figures such as health professionals. Add to these problems a rapidly spreading virus with a high mortality rate, and the scope of the challenge becomes clear. 
To date, at least 3,000 cases and over 1800 deaths have been reported in the West Africa nations of Sierra Leone, Guinea, and Liberia, with numbers rising. Isolated cases are also observed in Nigeria and Senegal. To date, the case fatality rate is estimated at around 60%. No vaccine or effective antiviral is currently available against the virus. An unapproved cocktail of monoclonal antibodies produced by Mapp Biopharmaceutical of San Diego, called ZMapp, was administered to several health workers from the U.S.; their recovery may be partially explained by the use of this drug (although their access raises ethical questions regarding how to allocate scarce countermeasures). That drug essentially transfers an immune response to the patient (passive immunity). The other modalities for EVD treatment and prevention are the more commonly known avenues of vaccines that elicit the patient’s own immune response and/or antiviral drugs which interfere with virus replication. The availability of vaccines and antivirals for “emerging or reemerging diseases” illustrates the deficiencies in matching market realities to public health demands. The research that led to ZMapp was partially funded by the U.S. government as part of its program to establish medical countermeasures against a bioterrorist attack (resources that greatly expanded after 9/11). The supply of ZMapp is limited; HHS is now funding expanded production and formal clinical trials of the drug. In addition, several Ebola vaccines will enter clinical trials soon. But the availability of countermeasures, while necessary, is not the only determinant of how soon the outbreak (not yet called a pandemic) will be contained. The international public health infrastructure, ideally coordinated by WHO, is dependent on funding from national governments, and mandated funding has declined over the years, undercutting WHO's capabilities. WHO did not declare a public health emergency until August,  despite the fact that cases began to spread in March. While more vaccines and antivirals can make a difference in any viral disease outbreak, the spread of EBV could have been managed with a more robust public health emergency response earlier this year. MSF has called for countries with biological disaster response teams (e.g., U.S.) to send these personnel to the regions to augment field hospitals, diagnostic laboratories, and other facilities needed to manage the crisis.

August 7, 2014

FDA to Formally Regulate Laboratory-Derived Tests; Genetic Tests to be Classified by Risk

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.

July 31, 2014

Scientists for Science Call for Continued Research on Potentially Dangerous Pathogens

In a climate where concerns over experiments that create new potentially dangerous pathogens are now amplified due to recent biosafety lapses in high-profile labs, a new group of scientists, Scientists for Science (SFS), emerged this week to assert that research on dangerous pathogens can be (and generally is) conducted safely, that it is adequately regulated, and that such work is critical for public health (the current Ebola virus public health crisis contributes to public attention on these issues). This statement and organization contrasts with and follows the recent statement from the recently formed  Cambridge Working Group (CWG) (see here) that called for curtailing certain high-risk pathogen experiments until a thorough cost-benefit analysis is conducted by the scientific community, along the lines of work done by the 1975 Asilomar conference on the risks of recombinant DNA research. The SFS rejects the Asilomar comparison and does not call for limiting such experiments now, but it does call for a more formal review of risks and benefits conducted by an outside expert body, such as the National Academy of Sciences (NAS).  From the SFS statement

Scientists for Science are confident that biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment. The results of such research are often unanticipated and accrue over time; therefore, risk-benefit analyses are difficult to assess accurately. 

If we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens. In recognition of this need, significant resources have been invested globally to build and operate BSL-3 and BSL-4 facilities, and to mitigate risk in a variety of ways, involving regulatory requirements, facility engineering and training. Ensuring that these facilities operate safely and are staffed effectively so that risk is minimized is our most important line of defense, as opposed to limiting the types of experiments that are done. 

In contrast to recombinant DNA research at the time of Asilomar in 1975, studies on dangerous pathogens are already subject to extensive regulations. In addition to regulations associated with Select Agent research, experimental plans on other pathogens are peer reviewed by scientists and funding agencies, and the associated risk assessments are considered by biosafety experts and safety committees. Risk mitigation plans are proposed and then considered and either approved or improved by safety committees. 

If there is going to be further discussion about these issues, we must have input from outside experts with the background and skills to conduct actual risk assessments based on specific experiments and existing laboratories. Such conversations are best facilitated under the auspices of a neutral party, such as the International Union of Microbiological Societies or the American Society for Microbiology, or national academies, such as the National Academy of Sciences, USA. We suggest they should organize a meeting to discuss these issues. 

The CWG and SFS clearly do not agree on the need to halt certain experiments while a more thorough review of cost-benefit parameters for high-risk pathogen research is conducted. However, a consensus is clearly emerging on both sides that public confidence in the need for such experiments as well as continued funding support does require more thorough, expert assessment from outside experts. Neither statement references the National Science Advisory Board for Biosecurity (NSABB), the federal advisory committee that most recently was called on during to assess the publication of gain-of function influenza H5N1 research in 2011. That panel has been recently reshuffled by NIH. A high-level study by the NAS on these issues, therefore, appears welcome to all sides of the current debate. The NAS (through its National Research Council) did undertake a general review of bioterrorism research post-9/11, entitled Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma (2004) (the Fink Report), which called for the establishment of the NSABB, so there is a certain circularity here.