FDA held a public meeting on blood glucose meters in March of this year; the agency is very pleased with the level of discussion and input that was generated at the meeting. 

Courtney Harper, director of the division of chemistry and toxicology devices at CDRH, the division that hosted the meeting, cited 12,000 measurement errors reported each year by users of blood glucose meters (BGMs) and said that the meeting was “a way for FDA to try to take a new approach to addressing that problem in addition to some other issues we’d been hearing about.”

NIH director Francis Collins’s chief of staff, Kathy Hudson, said the agency will soon publish a notice in the Federal Register posing a series of questions about the project to stakeholders and other interested parties. NIH hopes to elicit plenty of feedback and input from those who have an interest in the database. “We anticipate we’ll have an ongoing consultative process,” Hudson said. NIH is interested in learning the potential opportunities, barriers, and challenges that potential submitters to and users of the registry foresee as the database is constructed. 

Currently, obtaining comprehensive information on genetic tests is difficult. The site GeneTests.com, funded by a contract with the National Institutes of Health, is one source; however, it excludes certain types of tests and is limited in its functionality.

 FDA held a public meeting on blood glucose meters in March of this year; the agency is very pleased with the level of discussion and input that was generated at the meeting. 

 FDA held a public meeting on blood glucose meters in March of this year; the agency is very pleased with the level of discussion and input that was generated at the meeting. 

The National Institutes of Health (NIH) announced in March that it is creating a public database of genetic tests. Researchers, consumers, healthcare providers, and others will have access to the Genetic Testing Registry (GTR) to search for information submitted voluntarily by genetic test providers.

NIH director Francis Collins’s chief of staff, Kathy Hudson, said the agency will soon publish a notice in the Federal Register posing a series of questions about the project to stakeholders and other interested parties. NIH hopes to elicit plenty of feedback and input from those who have an interest in the database. “We anticipate we’ll have an ongoing consultative process,” Hudson said. NIH is interested in learning the potential opportunities, barriers, and challenges that potential submitters to and users of the registry foresee as the database is constructed. 

 AACC has an Industry Division to identify and develop synergies between industry and clinical laboratory members who contribute to the healthcare system, and enhance patient care and focus on issues relevant to industries that serve the clinical laboratory.

Chandra Jain is chair, Industry Division of AACC (Washington, DC). She worked for 33 years for a major IVD manufacturer as senior staff scientist in various capacities. She has been involved in IFCC, CLSI, and the ISO TC 212 committee for the last fifteen years. Currently she is a consultant to the IVD industry on traceabilty and standardization of assays. She can be reached at cpjain@technijian.com.

IVD manufacturers are accustomed to risk. Taking risks is part of their business. Companies develop plans to identify and mitigate risks, from product development to finished product manufacturing. While risks cannot be eliminated, generally they can be recognized and managed.

Jeffrey N. Gibbs is a director at Hyman, Phelps & McNamara, P.C. (Washington, D.C.). He can be reached via e-mail at jgibbs@hpm.com.

Australia's Therapeutic Goods Administration (TGA) is planning to implement a new risk-based regulatory framework for in vitro diagnostic medical devices during 2010. The regulatory framework is based on the recommendations of the Global Harmonisation Task Force (GHTF). Australia will be the first GHTF founding member to implement a GHTF-based system for IVDs.

The proposed framework will regulate IVDs as a subset of medical devices and will amend the current Therapeutic Goods (Medical Devices) Regulations 2002 to include IVDs. The elements of the regulatory system are the same as those for medical devices; Australia adopted the GHTF framework for regulation of medical devices in 2002.

The system covers all IVDs that are used for a therapeutic purpose; i.e., those intended for use in diagnosing a disease or condition, or testing susceptibility to a disease. There will be exemptions only for IVDs used for special or experimental purposes, or developed or stockpiled for use in the case of a national emergency. IVDs for non-therapeutic use, such as those for gender or kinship testing, or use of recreational drugs, are not covered by the framework.

TGA will also introduce regulation of “in house” IVDs—those that are manufactured by a laboratory for use in that laboratory or a related network of laboratories.

All IVDs will be required to comply with the Essential Principles (EPs) for safety and performance. The EPs identify performance levels required, hazards to be addressed, or issues to be considered, but do not necessarily specify how the principles can be satisfied or complied with. This approach provides flexibility for manufacturers and allows for technological advances and future changes in the application of medical devices. In many cases the manufacturer will choose to use recognized standards as a means of demonstrating compliance. The TGA will identify standards that may be used to demonstrate compliance. While the use of standards is not mandatory, compliance with those standards identified by TGA will be considered an acceptable means for demonstrating compliance with the EPs. The manufacturer is expected to consider the EPs at the design phase, and gather the evidence for compliance through the development and production phases. The EPs also include requirements for content of labeling and instructions for use.

IVDs will be regulated in accordance with the risk level assigned to the IVD by the classification rules set out in the regulations. The rules divide IVDs into four risk classes according to the risk posed by an incorrect result:

 • Class 4 (highest risk): These IVDs present a high public health risk and high personal risk (e.g., diagnosis of HIV; IVDs for screening of blood and tissue donations).
• Class 3: These present a moderate public health risk and high personal risk (e.g., diagnosis of infectious diseases; human genetic tests; pharmacogenomics).
• Class 2: These present a low public health risk and a moderate personal risk (most biochemistry tests).
• Class 1: These present no public health risk and low personal risk (e.g., IVD instruments, microbiological culture media, blood collection tubes).

It is the manufacturer’s responsibility to assign and justify the classification of an IVD, although the TGA will check that the risk class assigned is appropriate to the IVD in accordance with the manufacturer’s intended purpose, as defined in the labelling and instructions for use.

The proposed regulations impose on the manufacturer the obligation to apply a conformity assessment procedure (CAP) to demonstrate and document the initial and ongoing compliance of the IVDs manufactured with the EPs and other regulatory requirements, such as postmarket surveillance and incident reporting. The manufacturer has some choice of CAP to be applied, depending on the classification of IVDs manufactured. In general, the CAPs necessitate the implementation of a quality management system (QMS), the requirements for which are aligned with those of ISO 13485:2003: Medical devices – Quality management systems – Requirements for regulatory purposes. This is the standard to which the TGA audits manufacturers of medical devices.

The differences in conformity assessment procedures for different classes of devices relate mainly to the extent to which the QMS covers the design of the IVD. For lower risk (Class 2) IVDs, the manufacturer may choose not to implement clause 7.3 of ISO 13485:2003, which relates to design and development, and instead institute a QMS that relates only to production aspects. For Class 3 and Class 4 IVDs, the manufacturer must implement a QMS covering all the clauses of the standard, or alternatively, implement a QMS that covers production only and demonstrate compliance of the design with the intended design outputs via testing. (This is the European “type testing” option.) Type testing is not supported in the GHTF model, and the TGA does not expect that this option will be routinely utilized, but it has some applicability to large pieces of equipment and IVDs that have been on the market for some time and for which the design aspects were not subject to the QMS approach.

The classification of an IVD determines the level of regulatory oversight. For instance, for a Class 4 IVD, the TGA will assess the level of compliance of the manufacturer’s quality management system through an on-site audit and undertake an in-depth review of the technical documentation for the product (equivalent to a PMA review in the United States), although this process may be abridged if acceptable overseas certification exists. The manufacturer of a Class 1 IVD may “self declare” compliance with the regulatory requirements, although the TGA may choose to review the evidence of compliance at any time. For Class 2 and 3 IVDs, the regulations require the implementation of a quality management system, and a review of evidence of compliance with the regulatory requirements, but for many Class 2 and 3 IVDs manufactured overseas, the TGA will accept evidence that an assessment comparable to that required in the Australian regulations has been performed by an acceptable overseas regulatory body. For the purposes of this regulatory framework, acceptable overseas bodies are considered to be Health Canada, which has a regulatory system similar to the GHTF model, or European Notified Bodies designated under the IVD Directive.

The evidence of conformity is subject to review at any time. If such evidence does not exist, but the manufacturer holds an acceptable ISO 13485 certificate (a Canadian CMDCAS certificate, or an ISO 13485 certificate issued by a body accredited by an IAF member organization), the TGA may undertake a review of the technical file, particularly for Class 3 IVDs, at the time of application. For IVDs manufactured in Australia, the regulations currently require that the TGA undertake the assessment, regardless of any certification issued by an overseas body.

For now, evidence of FDA approval is not accepted, mainly due to the differences in regulatory requirements. However, the data package submitted to the FDA for a 510(k) or the FDA summary of a PMA submission may be submitted to the TGA to support an application requiring a conformity assessment certificate or a technical file review, and the assessment may be abridged on the basis of these documents.

If an overseas manufacturer does not hold acceptable quality systems certification from an overseas body, the manufacturer may apply to the TGA for a conformity assessment certificate, to cover the range of IVDs manufactured. The issue of a TGA conformity assessment certificate, requiring audit by the TGA of the manufacturing premises and a review of the technical documentation for the products manufactured, precludes the need for a technical file review at the time of application.

In-house IVDs must comply with the EPs and be classified in accordance with the classification rules. Class 4 in-house IVDs will be subject to the same regulatory requirements as commercially supplied IVDs, but Class 1, 2, and 3 in-house IVDs will be regulated through the laboratory accreditation system already in place in Australia. Laboratories manufacturing Class 1, 2, or 3 in-house IVDs will be required to comply with the standards for test method validation developed by the National Pathology Accreditation Advisory Council (NPAAC), hold certification through the National Association of Testing Authorities (NATA) to ISO 15189: Medical laboratories – Particular requirements for quality and competence, and notify the TGA of the IVDs manufactured.

Another feature of the regulatory system proposed by the TGA is to prohibit the supply of home-use (self-testing) IVDs for serious diseases, in accordance with Australian government concerns over the supply of these tests without adequate pre- and post-test counselling. The proposed prohibition will cover IVDs used to test for pathogens or diagnose notifiable infectious diseases, tests to determine genetic traits, and IVDs used to test for serious disorders—for example, cancer or myocardial infarction.

As can be gleaned from the outline of the regulatory requirements provided here, the proposed system imposes heavy responsibility on the manufacturer, throughout the life cycle of an IVD. The TGA will assess the manufacturer’s evidence of compliance with the requirements, to an extent determined by the class of the IVD. Penalties, both civil and criminal, apply for noncompliance. The manufacturer is required to prepare a declaration of conformity to Australian requirements and make that document, together with any other evidence of compliance, available to the sponsor for provision to the TGA on request.

As the person responsible for supply in Australia, the sponsor is required to have the product entered into the Australian Register of Therapeutic Goods (ARTG) prior to supply, to undertake recall or other regulatory action in Australia as necessary, and to gather information on performance of the IVD in the market and report issues to the manufacturer, as well as to the TGA. The sponsor signs a declaration at the time of application for ARTG entry, to state that he or she holds, or can obtain from the manufacturer within 20 days, all required evidence of conformity to the regulatory requirements.
Post-market controls currently in place for medical devices will apply also to IVDs. These include the mandatory reporting by sponsors of adverse events related to IVD use or supply, the requirement to comply with advertising restrictions, and the obligation to provide to the TGA samples for laboratory testing, if required. A process for random or targeted post-market reviews will be in place, particularly for low-risk IVDs that undergo limited pre-market assessment.

In implementing the framework, the TGA will encourage and move toward mandating at a later date the use of the GHTF Summary Technical Document (STED) as a format for presentation of technical documentation to support an application for inclusion of an IVD medical device on the ARTG. The GHTF document Summary Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices is currently in draft; it is expected to be finalized later this year. The document defines the type and depth of information to be provided to a regulatory authority for each class of IVD medical device and is intended to promote consistency in the review of applications.

The TGA will also use, as a basis for ARTG entry, the Global Medical Device Nomenclature (GMDN) System for identification of IVD medical devices for purposes of inclusion on the ARTG. Since the GMDN code tables have not previously had a comprehensive, structured set of codes for IVDs, the TGA has worked with Health Canada, FDA, and the GMDN Maintenance Agency to develop a hierarchical code structure for IVDs, which is currently being uploaded into the GMDN code table. IVDs will be included on the ARTG as a “kind of IVD,” defined for Class 1–3 IVDs as those having the same sponsor, same manufacturer, same class, and same GMDN code. The level of GMDN code to be used for each class of IVD is defined in the regulations. Class 4 IVD entries are, in general, defined by the additional requirement of a Unique Product Identifier (UPI), which is specific to the IVD and will normally equate to the trade name or model number.
Once the new framework is implemented, applications may be made on-line, through the TGA’s eBusiness services (eBS). Applications for ARTG inclusion may only be made by sponsors (or their agents) based in Australia. The process requires the sponsor to register for eBusiness and receive a password and log-on, access to which, within a company, is managed by that company. Once registered for eBusiness, the sponsor lodges the “manufacturer’s evidence”—copies of the quality systems certification or conformity assessment certification issued by the TGA and held by the manufacturer. Once the TGA has accepted the manufacturer’s evidence and issued an identification number, the sponsor may make application, again through eBS, for the inclusion of the IVD. The TGA is a 100% cost-recovery organization, and its costs are met by fees and charges imposed for assessment, ARTG entry, and maintenance of that entry. A schedule of fees and charges for the IVD framework can be found at www.tga.gov.au/ivd/regframe.htm.

The transition period for the new regulatory system is four years. Sponsors of IVDs currently on the Australian market have four years to apply under the new framework. There is no automatic transfer of products currently included in the ARTG. If no application is made within the four years, the ARTG entry will lapse and the products can no longer be legally supplied. Once the new regulations commence, new IVDs cannot be supplied until they are included in the ARTG.
It is expected that the new regulatory framework will come into effect July 1 of this year. Further details may be obtained from the TGA Web site, www.tga.gov.au.

Shelley Tang is director, Medical Device Conformity Assessment Section, Office of Devices, Blood and Tissues at the Therapeutic Goods Administration (Australia). She is currently leading the task force that is developing the new framework for regulation of in vitro diagnostic devices in Australia. Tang can be reached at shelley.tang@tga.gov.au.

The recently passed healthcare reform legislation implemented various provisions related to comparative effectiveness research (CER), including a section that created an independent, nonprofit organization, the Patient-Centered Outcomes Research Institute. This institute will be charged with conducting research that informs the public and healthcare providers about the comparative risks and benefits of marketed drugs, devices, and medical products.

According to the legislation, the Patient-Centered Outcomes Research Institute will “assist patients, clinicians, purchasers, and policymakers in making informed health decisions by advancing the quality and relevance of evidence concerning the manner in which diseases, disorders, and other health conditions can effectively and appropriately be prevented, diagnosed, treated, monitored, and managed through research and evidence synthesis that considers variations in patient subpopulations and the dissemination of research findings with respect to the relative health outcomes, clinical effectiveness, and appropriateness of medical treatments, services, and items.”

The legislation also instructs for the establishment of an independent 15-member research methods committee that will be responsible for “developing and improving the science and methods of comparative clinical effectiveness research.” The committee members will be experts from various fields, including genomics, biostatistics, and molecular diagnostics.

But industry analysts believe given that IVDs play a pivotal role in the vast majority of medical decisions and are expected to play an even larger role in the development of effective and cost-efficient personalized medicine strategies, there are many unanswered questions regarding how CER will be applied to IVDs.

“The IVD industry has a great opportunity to work with agencies performing CER to further define the following: appropriate study designs and methods for assessing the value of IVDs; how and when cost-per-test data should or can be appropriately used; the timing of CER assessments relative to market entry; and opportunities for IVD manufacturers to work with users of CER data for funding studies,” says Michele Schoonmaker, PhD, executive director, government affairs at Cepheid (Sunnyvale, CA).

Best practices. What are the best practices for methods of evaluating IVDs in the context of CER? Most IVDs do not undergo randomized clinical trials, so CER will need to recognize other study designs as appropriate for evaluating IVDs.

Use of cost data. Should cost-per-test data be used to measure the value of medical technologies as done in most international technology assessments? If so, how should it be calculated, and how should the cost related to not ordering the test be determined? In other words, would more restricted use of IVDs result in reduced expenditures in the short term, followed by an eventual increase in overall costs as expensive therapeutics are indiscriminately applied to patient care? What costs should be measured and to whom (e.g., patients, healthcare facilities, insurers)? Health insurers should consider working with professionals in health outcomes research (such as the International Society for Pharmacoeconomics and Outcomes Research) to promulgate guidelines for assessing the value of IVDs.

Timing of CER assessments. At which point in the life cycle of an IVD should CER be applied, given the shorter life cycle of IVDs versus therapeutic products? Certainly, FDA and payers (e.g., CMS, private companies) have an interest in CER findings. However, because CER focuses on patient outcomes, such studies may present too high of a hurdle in the premarket phase of IVDs. Rather, innovative post-market activities, with collaboration between IVD manufacturers, the academic medical community, and payers, should be considered. If CER is applied prior to marketing, an IVD may never get to market. Reimbursement conditions may be negotiated to incentivize data collection and/or participation in registries in the post-market setting.

Funding of studies and reimbursement. CER represents large, multicenter trials and registries, and a significant expense to small IVD companies, many of which will not be able to support the effort. In addition to collaborative efforts between IVD manufacturers, medical centers/providers, and payers, payers should consider rewarding manufacturers that meet a threshold of evidence (i.e., being open to value-based reimbursement arrangements rather than resource-based pricing such as current fee schedules).

Other analysts believe that CER should be viewed as an opportunity for data and methods standardization in the IVD industry.

“Molecular sub-stratification of human disease as it relates to clinical management will only be successful in CER if and when IVD manufacturers effectively engage in evidence generation and clinical study protocols that produce sufficient data to warrant systematic review,” says Sharon Terry, president and chief executive officer at Genetic Alliance.

According to Terry, the narrow scope and definition of CER in the healthcare reform legislation “is the conduct and synthesis of systematic research comparing different interventions and strategies to prevent, diagnose, treat, and monitor health conditions.” The immediate limitation of CER is that the entire enterprise will be arranged to look backward at already published data and completed studies that were conducted many years ago. As a result, very few opportunities exist for evidence to emerge supporting quality decision making around IVD testing and its value to an accountable healthcare delivery system. In the absence of such data, there will be no comparators for CER to assess quality and informed decision making in many clinical circumstances.

The Federal District Court for the Southern District of New York ruled that certain claims covering isolated DNA sequences in seven patents on the BRCA genes owned or exclusively licensed to Myriad Genetics Inc. (Salt Lake City) are invalid. The ruling follows a lawsuit that was brought by a group of patients and scientists who were represented by the American Civil Liberties Union and the Public Patent Foundation, a not-for-profit organization affiliated with Benjamin N. Cardozo School of Law. Myriad is appealing the decision to the Court of Appeals for the Federal Circuit.

The following is an analysis of this ruling and its potential impact on the IVD industry by Timothy B. McBride, JD, an attorney at Senniger Powers LLP (St. Louis):

“To say that the District Court’s ruling in the Myriad case is ground-breaking would be an understatement. For approximately 25-30 years, the United States Patent and Trademark Office has been issuing patents directed to genes and nucleic acid sequences. Thus, the ruling in this case comes as what can only be described as a shock to the biotech community.

“With respect to the DNA claims, I think the Federal Circuit will likely overturn, or at the very least curb, the breadth of the district court’s ruling. In particular, the district court refers to the fact that the DNA as claimed does not have ‘markedly different characteristics’ from the natural form of the DNA such that it has ‘a new or distinctive form, quality, or property.’ However, there is no clear indication of what, if anything, with respect to DNA would constitute a modification sufficient to confer ‘markedly different characteristics.’

“Certainly, isolation of DNA and even the isolation or creation of cDNA (which contains only the coding regions of a DNA sequence) does not meet the district court’s assessment of ‘markedly different characteristics.’ But would, for example, a DNA hybridization probe that is labeled and designed to hybridize to a wild-type or even a naturally occurring mutant gene constitute a sufficient difference? If the Federal Circuit decides to affirm the district court’s ruling, what constitutes ‘markedly different characteristics’ is a point on which the Federal Circuit may have to elaborate in order to provide guidance for future patent preparation, prosecution, and litigation.

“How will this ruling affect IVD manufactures and the industry as a whole? In the short term, I do not think it will have any substantial or real effect. In particular, since the decision is going to be appealed and since a majority of those familiar with the decision, particularly those in the legal field, believe the decision will likely be overturned or curtailed in some fashion on appeal, I do not believe that IVD manufacturers or the IVD industry generally will radically change or be affected by the district court’s decision.

“But if the decision were affirmed, the effect on the IVD industry depends heavily on the degree of necessity of the use of DNA for IVD purposes. If IVD manufacturing and the industry as a whole can effectively utilize means other than comparisons of isolated human genes for IVD purposes, then the effect could be minimal. For example, claims directed to methods and kits that utilize antibodies for purposes of diagnosis were not challenged in this litigation and remain valid and patentable subject matter.

“Moreover, claims directed to primers and constructs containing the DNA sequences or gene segments also remain valid and patentable. Thus, to the extent that kits and methods utilize antibodies or to the extent that IVD kits and methods rely on the use of primers or constructs containing human genes, there is no real effect on the manufacturers and industry as a result of this decision.

“However, if the IVD industry were moving more toward methods and manufacturing (e.g., kits) that require the use of human gene sequences (in particular those that do not rely on the use of primers or constructs as described above), then the affirmation of the district court’s decision will likely have a substantial impact. In particular, in the absence of the ability to patent isolated and purified genes, there will likely be an underinvestment in genetic research, as the investments of capital and manpower will come with an almost guaranteed risk of never paying off.

“Thus, IVD companies performing this research in order to develop their own proprietary methods, tests, or kits will likely greatly reduce or cease such research. Moreover, due to the reduction or cessation of genetic research generally, even companies that would typically piggyback on the knowledge obtained by others will suffer. Specifically, while these companies would be able to avoid payment of substantial licensing fees that would generally be related to IVDs based on gene technology patented by others, they will nevertheless suffer as genetic research in general rapidly and substantially declines.

“In a nutshell, if the decision were affirmed, the initial result might be a reduction in medical and IVD costs generally (which it seems was a focus of the ACLU’s suit). However, the industries that provide these technologies will suffer, potentially causing this benefit to dwindle, and ultimately result in long-term detriments.”