Premarket Review Research Articles

Growing Calls in United States, Europe to Improve Regulation of Genetic Testing

ALTHOUGH THE NUMBER OF GEnetic tests available has exploded in the past decade and a half, clinicians and patients are often on their own to try to assess whether such tests might help improve care. Tests were available for only about 100 genetic diseases in 1993, a number that soared to more than 1700 in 2008, according to GeneTests, a resource operatedby theUniversityofWashingtonand funded by the National Institutes of Health that includes information on genetic tests (http://www.ncbi.nlm.nih.gov /sites/GeneTests/). But governments in the United States and Europe provide limited oversight of such tests, and there is inadequate evidence on the extent to which genetic tests improve patient care. Suchconcernshave led tocalls for enhancedregulationofgenetic tests,andrecent actions suggest growing consensus amongsomegovernmentalagencies,nonprofitorganizations,andcommercialclinical laboratories that action is needed. The current regulatory framework is complex. The US Food and Drug Administration (FDA) requires a premarket review of test kits sold to outside laboratories, but so far it has not required such premarket review for tests that are made by a laboratory for its own use. The Centers for Medicare & Medicaid Services (CMS) provides some oversight for quality of clinical laboratory testing under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. There are also some voluntary certification and oversight programs operated by professional organizations. The American College of Medical Genetics (ACMG) offers both technical and clinical guidelines, which laboratories may choose to follow. InanApril2008reportbyanadvisory committee to theSecretaryof theUSDepartment of Health and Human Services (DHHS)reviewedandpointedoutmany flaws in this system of oversight (http: //oba.od.nih.gov/oba/SACGHS/reports /SACGHS_oversight _report.pdf). The committee identified gaps in the regulation of laboratory quality and test validity, inadequate transparency about testing, insufficient knowledge about the whether the tests are clinically useful, and a lack of education among clinicians and consumers about such tests. It also outlined recommendations for improvement. Now there is a growing chorus of individuals, advocacygroups,government agencies,andcommercialgroupswhosay thatthispatchworkofoversightdoesadisservicetoall stakeholdersandmustberevamped.ManyofthecallsurgeimplementationofstepsrecommendedintheDHHS committee’s report. In April, the Genetics and Public Policy Center at Johns Hopkins University, the Coalition for 21st Century Medicine—a group that represents genetic testing companies and other groups—and more than 100 patient advocacy groups, genetic test manufacturers, and other interested parties sent a letter to the newly appointed DHHS Secretary, Kathleen Sebelius, calling on her to revamp regulation of genetic tests. “Accurate, reliable, and timely advanced diagnostics offer enormous promise, but poor quality testing can harm patients and waste scarce resources,” according to the letter. The letter calls for government oversight of all genetic tests, including those created and used by the same laboratory, prioritized according to the potential risk associated with a test. It also urged establishment of a mandatory national registry of laboratory tests and stronger regulation of testing laboratories, to ensure test accuracy.

Direct to consumer genetic tests

We would like to respond to the editorial published alongside the commentary that we wrote for European Journal of Human Genetics.1, 2 We feel that Professor Brand has missed the point of the commentary and misrepresented its conclusions. This has unnecessarily placed it in an adversarial position with the article by Gurwitz and Bregman.3 Although there may be different policy implications, these two contributions are complementary and contribute constructively to an informed dialogue. Both call for partnership working between the various stakeholders, which include industry, health service providers and purchasers, the medical and genetics community and the general consumer. As the following quote illustrates, Gurwitz and Bregman3 are, like we do, recommending a sensible control of the processes involved in bringing personal genomics to market, which includes self-regulation by code of practice. Although ‘free-market forces' will be among the decisive factors about the success or failure of such DTC personal genomics and health databasing services, we call upon national regulators and international organizations such as the OECD to consider carefully through which means undesired effects including privacy risks could best be avoided. Yet, as this young industry is rapidly evolving and the spectrum of its societal impact is still unclear, meaning that such regulation may take several years to implement, urgent interim steps must meanwhile be taken. These include self-regulation and the establishment of best practices guidelines, potentially coordinated through a dedicated association of the DTC personal genomics providers. Our commentary described current initiatives in this area and did not, as Professor Brand presents it, make an argument for prohibition and statutory regulation of all aspects of test provision. Instead, it lists some concerns and also the various points at which some control might be applied to tests for health-care purposes. These include premarket review, which is subject to regulation, review by purchaser, which for health-care provision does require evidence of efficacy, and issues of concern to the consumer for those tests that are supplied without medical intervention. We consider the proposals of Gurwitz and Bregman3 entirely complementary to ours. We would furthermore like to add that the OECD has already included issues of validity and utility in its guidelines. Rather than polarising these issues, as might be the effect of Professor Brand's contrasting presentation of the two contributions, like Gurwitz and Bregman3, we propose to work with the various partners to ensure that the delivery of effective technologies within health-care settings is facilitated and the companies and investors are able to bring effective products to market efficiently. This is happening with the work of the UK Human Genetics Commission (HGC), which is attempting to develop a common framework of principles in relation to DTC. The Professional and Public Policy Committee of the European Society of Human Genetics (ESHG) was represented at an expert workshop in March 2009 at the European Parliament organised by the Science and Technology Options Assessment panel, together with The European Technology Assessment Group, where a variety of experts from industry, ESHG, HGC, the European Commission and the public interest groups discussed these issues. These discussions are also supported by the industry partners who seem to want clear processes to ensure that effective products are distinguished from ineffective ones. In addition, other issues relating to the evaluation of evidence for diagnostics are being actively considered at the policy level with health-care providers and purchasers. These initiatives are, as mentioned before, being developed with constructive partnerships at the policy level rather than being rooted in a historical adversarial position.

Gun Control after Heller: Threats and Sideshows from a Social Welfare Perspective

What will happen after Heller? We know that the Supreme Court will no longer tolerate comprehensive federal prohibitions on home handgun possession by some class of trustworthy homeowners for the purpose of, and perhaps only at the time of, self-defense. But the judiciary could push further, if nothing else by incorporating Heller's holding into the Fourteenth Amendment and enforcing it against states and municipalities. In fact, the majority opinion offered little guidance for future cases. It presented neither a purely originalist method of constitutional interpretation nor a constraining doctrinal framework for evaluating other regulation - even while it gratuitously suggested that much existing gun control is acceptable. In the absence of more information from the Court, we identify plausible legal arguments for the next few rounds of litigation and assess the stakes for social welfare. We conclude that some of the most salient legal arguments after Heller have little or no likely consequence for social welfare based on available data. For example, the looming fight over local handgun bans - an issue on which we present original empirical data - seems largely inconsequential. The same can be said for a right to carry a firearm in public with a permit. On the other hand, less prominent legal arguments could be quite threatening. Taxation and regulation targeted especially at firearms might be presumptively disfavored by judges in the future, along the lines of free speech doctrine. This could have serious consequences. In addition, Second Amendment doctrine might generally dampen enthusiasm for innovative regulatory responses to the problem of gun violence. The threat of litigation may inhibit policy experimentation ranging from micro-stamping on shell casings, to pre-market review of gun design, to so-called personalized firearms, and beyond.

PATENT-MEDIATED STANDARDS IN GENETIC TESTING

Genetic testing can be used to identify disease susceptibility, establish diagnostic status, and design therapeutic regimens in medical care. Two legal realities shape the genetic testing environment in the United States. First, most genetic tests are not subject to premarket review by the Food and Drug Administration (FDA). Second, many DNA sequences and genetic testing methods are patented. The lack of FDA oversight of most genetic testing has consequences for patent-related aspects of genetic testing, and patent management, conversely, has consequences for the peer evaluation that compensates for minimal official oversight. Where exclusive control of the relevant patent portfolio for a particular disease field is used to frustrate a competitive genetic testing environment, the patent holder is able to set de facto clinical testing standards, rather than the professional community. The clinical standard then becomes a function of the marketplace, rather than the laboratory. Restrictive management of gene patents with critical diagnostic significance limits peer assessment, and lessens the available testing options for patients. If the sole commercial provider of a particular genetic test does not offer a comprehensive genetic analysis, the test will not provide the most accurate assessment of genetic status, and compensatory genetic testing to correct deficiencies may be prohibited by the patent holder. The actual genetic testing field will then be defined by a divergence between the theoretically optimal and the commercially available. An artificially constrained genetic testing climate can result in patients receiving incomplete test results that cannot be relied on for medical decision making. As an example, limitations on commercial genetic testing for the BRCA1 and BRCA2 genes to determine the risk of hereditary breast and ovarian cancer have been maintained by the dominant patent holder in the field, and similar circumstances could develop for other genetic tests. There are potential patent infringement conflicts that could arise if compensatory genetic testing is offered to patients who are underserved by the patent-mediated limitations in genetic tests. This article identifies doctrinal strategies in patent law to address scenarios where patent management poses risks to public health. It analyzes the prospects for compensatory genetic testing in view of the scope of dominant patents, the infringement evaluation, and the remedies determination, noting that future oversight of genetic testing by the FDA might also allow researchers to invoke a statutory research exemption to improve peer assessment. From the perspective of public health, it is necessary to consider all of these available mechanisms to relieve the patent-imposed obstacles to full exploitation of genetic testing for predictive, diagnostic, and therapeutic applications in medical care.

Trialing plasma protein therapies for rare disorders: Thinking outside the box

The application of evidence-based medicine to the indications addressed by plasma protein therapies is problematic. So-called Level 1 evidence in the form of randomized clinical trials using classical designs to demonstrate efficacy is seldom possible, because the small numbers of patients denies the appropriate level of power from being built in the trial design. In addition, patient accrual is difficult because of understandable patient resistance and “fatigue” at the number of trials. Efforts to address this by regulating agencies over the past years have yielded promising policies in some areas, which recognize the inherent problems and outline practical solutions. The use of patient registries to accrue safety and efficacy data, while rapidly becoming accepting an accepted component as a basis for pre-market review and approval, is also promising as a basis for the incorporation of post-market data, through Phase 4 surveys, of approved therapies. As such, innovative thinking to address the problem of rare disorders may also lead to desirable reform in all aspects of regulation, with a shift from pre- to post-market review.

Future Perspectives for Pharmacovigilance in Japan

Drugs are sophisticated intellectual products that have been evolving and specializing. For the efficient use of a drug, while enhancement of pre-marketing review is important, post-marketing monitoring is also essential, since it has been demonstrated that pre-marketing data provide only a limited understanding of the risks involved in the use of drugs. From the perspective of identifying concerns for future pharmacovigilance in Japan, safety measures for recent Adverse Drug Reactions (ADRs) are compared between Japan and the United States of America (U.S.A.) and are classified into the following three main categories: category one for cases in which ADR problems have not become apparent due to “drug lag” in Japan, category two for cases in which Japanese idiosyncrasies have become apparent, and category three for adverse events for which assessment of the causal relationship is difficult. Particularly, category one and category two are peculiar to Japan, and category three is also on the increase in Western countries. Regarding trends in international pharmacovigilance, the results of analysis of trends in safety measures indicated that there is an active movement, mainly in Japan and Western countries, for adoption of the Data Mining method using the databases of ADR reports (spontaneous reports) submitted by medical institutions or companies, and epidemiological studies have been conducted to improve assessment of risk, to facilitate development of a more active safety-monitoring system. In conclusion, as simultaneous, global developments and approvals have been realized in Japan, safety measures should also be implemented simultaneously, efficiently, quickly, and accurately with internationally harmonized approaches in the future.

Search for Shortcuts on the Critical Path to Market: US FDA Perspectives from the Diagnostic Side

The US FDA has been regulating medical devices (including laboratory tests) since 1976. Premarket review is well defined and may include requirements for both analytical and clinical information. In 2004, the US FDA initiated the Critical Path initiative to help foster development of new medical products. Biomarkers were seen as an important part of this new program for both traditional diagnostic purposes and to aid in drug development. The US FDA has created programs to foster use of biomarkers both for routine diagnostic and for drug development purposes. There is growing methodology to serve as road maps for efficient and scientifically sound development in this area. The US FDA has a flexible regulatory tool box to apply to biomarker development, and has the clear aim of working as a partner to bring these important medical devices quickly to the medical marketplace.

Allen Denver Russell Memorial Lecture, 2006.

Microbial pathogens continue as major threats to health. Indeed, many ongoing societal changes are enhancing our vulnerability and exposure to several frank and opportunistic pathogens. This, together with rampant antimicrobial resistance and reduced prospects for newer drugs and vaccines, is forcing a higher reliance on microbiocides in infection prevention and control. That this reliance may not be well-founded becomes apparent from a closer look at current ways of testing and registering microbiocides, their label claims as well as human and environmental safety of certain widely used microbicidal chemicals. Many methods to test microbiocides for registration are flawed and/or entail test conditions irrelevant to field use. Pathogens listed on product labels may not be among those amenable to interruption through microbiocide use. The wide variations and discrepancies in existing national/regional regulations for registering microbiocides for sale stifle innovation. This is a critical look at the above-mentioned issues with emphasis on chemicals meant for use on environmental surfaces and medical devices. It highlights better ways to test microbiocides and to attain global harmonization of testing and product registration. It also details the known and potential dangers of microbiocide use and what to consider in choosing such formulations for optimal safety and effectiveness. End users are advised to be more critical and prudent in the selection and application of microbicidal chemicals, manufacturers are encouraged to explore infection control products and technologies that are safer in the workplace and for the environment, and regulators are urged to review and update the requirements and procedures for premarket review of microbiocide efficacy data and label claims. Independent investigations are also urgently needed to document the proportion of nosocomial infections that would be amenable to prevention through chemical disinfection of environmental surfaces.

A Formal Methods Approach to Medical Device Review

With software playing an increasingly important role in medical devices, regulatory agencies such as the US Food and Drug Administration need effective means for assuring that this software is safe and reliable. The FDA has been striving for a more rigorous engineering-based review strategy to provide this assurance. The use of mathematics-based techniques in the development of software might help accomplish this. However, the lack of standard architectures for medical device software and integrated engineering-tool support for software analysis make a science-based software review process more difficult. The research presented here applies formal modeling methods and static analysis techniques to improve the review process. Regulation of medical device software encompasses reviews of device designs (premarket review) and device performance (postmarket surveillance). The FDA's Center for Devices and Radiological Health performs the premarket review on a device to evaluate its safety and effectiveness. As part of this process, the agency reviews software development life-cycle artifacts for appropriate quality-assurance attributes, which tend to reveal little about the device software integrity.

FDA Marketing Claims, and the Practitioner

The Food and Drug Administration (FDA) is the federal agency that is tasked with regulating market entry for medical devices. The laws that govern this process are codified in the Federal Food Drug and Cosmetic Act (the Act) and the regulations are based on this law. The medical device amendments to the Act were instituted in 1976, instituting the methods for classification of medical devices and the format for the premarket review of devices. Information for practitioners on how medical devices come to market, what data are required, how specific claims are cleared, and how the practitioner can give input to the system are critical for the further development of safe and effective medical devices.

Introduction to the Food and Drug Administration (FDA) Regulatory Process

FDA oversight of medical devices, including in vitro diagnostic devices (IVDs or laboratory tests), in the United States was a direct result of the passage of the Medical Device Amendments of 1976. This law introduced a series of general controls for medical devices including registration and listing, requirements for production using good manufacturing practices, and requirements for post-market reporting of device failures. This produced for the first time a menu of laboratory tests on the market, a system to ensure these were produced consistently over time, and a mechanism for FDA to identify problems with device use and to work with companies to ensure corrective action. This law also introduced the requirement for premarket review of new versions of old devices and of fundamentally new medical devices.

Dietary Supplements: A Definition That is Black, White, and Gray

The Dietary Supplement Health and Education Act of 1994 (“DSHEA” or “the Act”) was a seminal event in the world of food and drug law. The Act took a controversial category of product traditionally regulated by FDA as either a food or a drug, depending upon the product claims and formulation, and created a new regulatory category called “dietary supplement” that was placed within the “food” definition. As such, products meeting the “dietary supplement” definition benefited in two significant ways, (1) dietary supplements could make “structure/function” claims traditionally within the realm of drug products; and (2) unlike food ingredients, dietary ingredients could be used in dietary supplements without being either approved food additives or generally recognized as safe (“GRAS”) ingredients. These legislative provisions significantly changed the legal, corporate, and consumer landscape, allowing products to enter the marketplace with broadbased claims without FDA premarket review or approval of the ingredients, formulation, or product claims.

A comparative analysis of drug safety withdrawals in the UK and the US (1971–1992): Implications for current regulatory thinking and policy

By going beyond individual case studies and solely quantitative surveys, this paper systematically examines why there were over twice as many new prescription drugs withdrawn from the market on grounds of safety in the UK as there were in the US between 1971 and 1992. Drawing on interviews with regulators, industry scientists and others involved, and on regulatory data never before accessed outside governments and companies, five key hypotheses which might explain this difference in drug safety withdrawals are analysed. These are: (1) simply because the UK approved more new drugs than the US; (2) because of an industrial corporate strategy to seek approval of ‘less safe’ drugs in the UK earlier; (3) because British regulators were more vigilant at spotting post-marketing safety problems than their US counterparts; (4) because the slowness of the US in approving new drugs enabled regulators there to learn from, and avoid, safety problems that had already emerged in the UK or European market; and (5) because more stringent regulation in the US meant that they approved fewer unsafe drugs on to the market in the first place. It is concluded that the main explanation for fewer drug safety withdrawals in the US is that the regulatory agency there applied more stringent pre-market review and/or standards, which took longer than UK regulatory checks, but prevented unsafe drugs marketed in the UK from entering the US market. Contrary to the claims frequently made by the pharmaceutical industry and regulatory agencies on both sides of the Atlantic, these results imply that it is likely that acceleration of regulatory review times in the US and the UK since the early 1990s is compromising drug safety.

Some Legal Implications of the Precautionary Principle: Improving Information-Generation and Legal Protections

ABSTRACT In creating a legal agenda in service of the Precautionary Principle, the idea of precaution requires more inventories and better monitoring of the condition of public and workforce health than at present. Rectifying problems of the past to better serve the aims of precaution will require more affirmative pre-market and much more post-market knowledge-generation by those who create and use potentially toxic substances, improved pre-market review of substances, better responses to early warnings, and quicker protective post-market responses to evidence of toxicity. This paper conceptualizes a model pre-market screening law to highlight the need for primary prevention measures and to provide philosophic ideas for improving post-market laws and addressing a large universe of existing substances that have been poorly characterized. Although retrospective personal injury law does not have good mechanisms for precaution, even this can be more protective than it is at present by enhancing causes of action for reasonable fear of disease and medical monitoring, and moving to create new causes of action for failure to develop and disseminate information needed to assess the toxicity of substances.

Label Claims for Foods and Supplements: A Review of the Regulations

Consumers are confronted with a vast array of food and dietary supplement products claiming to improve health, manage conditions, and reduce disease risks. Most consumers are unaware of the legal requirements, regulatory processes, and scientific evaluation that underlie these label statements. Labeling for foods and dietary supplements is regulated by the US Food and Drug Administration (FDA). Regulations cover 3 main types of health-related statements: health claims, structure/function claims, and nutrient content claims. Health claims must be supported by "significant scientific agreement" among experts that the claimed benefit of a food or food component on a disease or health-related condition is true. When significant scientific agreement is lacking, qualifying statements may be required on the label to describe the strength of the evidence that supports the claim. Structure/function claims describe an effect of a product on body structure or function, and whereas these claims must be truthful and not misleading, they are not subject to premarket scientific review and approval. Nutrient content claims describe the level of a nutrient in a food or supplement and require FDA approval. By understanding the regulatory framework behind label statements and claims, health care professionals can better assist their patients and clients in making informed decisions.

Food and Drug Administration Regulation of in Vitro Diagnostic Devices

The Food and Drug Administration regulates the sale and distribution of laboratory devices under a statutory and regulatory framework that is unfamiliar to most clinical laboratory scientists. In this article we briefly describe the criteria that are used to classify and review in vitro diagnostic devices. We discuss the similarities and differences between devices that are not subject to premarket review, and those that are required to undergo either a premarket application or premarket notification [510(k)] pathway. We then discuss the methods that the Food and Drug Administration uses to assess the performance of in vitro diagnostic devices in the marketplace as a component of the total life cycle approach to medical device regulation.

The US FDA has proposed a rule designed to simplify premarket review and regulation of combination products.

The US FDA has proposed a rule designed to simplify premarket review and regulation of combination products.

Under-Over into Fashion

Another recurring theme was a desire for transparency throughout the regulatory process, from premarket submission, screening, review, and decision to postmarket surveillance. At the most recent consultation (June 10 and 11, 2004), Health Canada sought feedback on its Summary Basis of Decision (SBD), a first attempt at enhancing transparency. This document outlines the regulatory, safety, efficacy, and quality considerations that factor into a decision to grant market authorization for a drug or medical device. Templates have been tested, and pilot exercises can be viewed at ht tp ://www.hc-sc .gc .ca/hpfb-dgpsa/ tpd-dpt/ index_drugs_projects_e.html#sbd. However, the SBD may not add very much to the information already available to pharmacists in product monographs. Of note, the disclosure of negative outcomes or withdrawals (i.e., rejection of market authorization or submissions withdrawn by manufacturers before a decision by Health Canada) is not planned until phase 3 of the SBD implementation strategy, at an unspecified date. A timid attempt at transparency, some would argue, and certainly nothing like the situation that led to Louisiana’s bill banning low-slung pants that intentionally expose underwear — or more! Let’s wait and see how much Health Canada will reveal in the future.

Limitations of direct-to-consumer advertising for clinical genetic testing.

Although direct-to-consumer (DTC) advertisements for pharmaceuticals have been appearing in the mass media for 20 years, DTC advertisements for genetic testing have only recently appeared. Advertisements for genetic testing can provide both consumers and physicians with information about test availability in an expanding market. However, 3 factors limit the value and appropriateness of advertisements: complex information, a complicated social context surrounding genetics, and a lack of consensus about the clinical utility of some tests. Consideration of several advertisements suggests that they overstate the value of genetic testing for consumers' clinical care. Furthermore, advertisements may provide misinformation about genetics, exaggerate consumers' risks, endorse a deterministic relationship between genes and disease, and reinforce associations between diseases and ethnic groups. Advertising motivated by factors other than evidence of the clinical value of genetic tests can manipulate consumers' behavior by exploiting their fears and worries. At this time, DTC advertisements are inappropriate, given the public's limited sophistication regarding genetics and the lack of comprehensive premarket review of tests or oversight of advertisement content. Existing Federal Trade Commission and Food and Drug Administration regulations for other types of health-related advertising should be applied to advertisements for genetic tests.

Determining safety criteria

Determining safety criteria