by Paula Gray and Sharon Kvistad, Navigant
Many industries, including automotive manufacturers, NASA, information technology systems and countless others, suggest or even require implementation of a Quality Management System (QMS) in order to ensure products are manufactured to a high quality standard. For products like medical devices, QM systems ensure that products are not only of a high quality, or deemed “effective” to perform as they are intended, but are also safe for their intended use. For all laboratory testing, Congress passed the Clinical Laboratory Improvement Amendments (CLIA) in 1988, which established quality standards to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed. The Centers for Disease Control and Prevention (CDC) and the Centers for Medicare & Medicaid Services (CMS) published final CLIA Quality Systems laboratory regulations that became effective April 24, 2003.
Laboratory testing regulations continued to emerge and on Feb. 28, 1992, the Department of Health and Human Services (DHHS) published laboratory standards regulations (57 FR 7002) implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a). The implementing regulations are codified at 42 CFR Part 493. The CLIA regulations promulgated quality standards based on test complexity and established quality requirements for laboratories, similar—yet different—from the quality system requirements established by the FDA for device manufacturers. The more complex the test systems, the more stringent the applicable standards, with tests being categorized as “waived,” “moderate,” or “high” complexity. So, laboratories wishing to perform certain types of tests could comply with CLIA regulations as long as the new standards for quality were met.
Since 1988, clinical laboratories have been developing laboratory tests in accordance with their own procedures, referred to as “laboratory developed tests” or LDTs. These LDTs are typically used by hospitals, academic and clinical laboratories for their own internal use in response to unmet needs, and are commonly used for early and precise diagnosis, monitoring and guiding of patient treatment. The beginning of the 21st Century has seen an explosion of innovation in the personalized medicines movement that is rapidly changing, lending to the development of LDTs, which work to identify or disqualify the use of a specific drug product. These drug-specific LDTs are generally referred to as a “companion diagnostic” (or CDx) in reference to their specific association to one drug. The evolution of companion diagnostics, which are clinical in vitro diagnostics (IVD) have come under much regulatory scrutiny by the FDA in recent years.
While few CDx devices have been developed and/or approved by the FDA, one thing that is becoming significantly clear is that FDA expects manufacturers of such CDx, even if they fall in the LDT bucket, to control such products under the guiding regulations for medical devices and/or drug products. As such, the development of a QMS which is compliant with the FDA regulations for drugs or devices is imminent, and currently required, depending upon the specific test. However, many laboratories which have already achieved CLIA-level compliance with their existing QMS assume that their system is sufficient to comply with the FDA’s QMS regulations. The short answer is no. While QMS systems typically implemented for CLIA laboratories build a QMS foundation which looks like the medical device’s Quality System Regulation (QSR), 21 CFR Part 820; it is “close, but no cigar.” In many ways, CLIA QM systems fall short of the requirement. In addition, recent approval of CDx-type products demonstrates that the expectation for laboratories is to implement a QMS which fully complies with the medical device QSR. Part I will share how these sets of QMS requirements are similar, yet unique. Part II will describe (for those unfamiliar with working with FDA) how best to gain feedback and determine if you are “on the right track” for compliance with these regulations.
Misconception 1: All Quality Management Systems are constructed the same
In general, Quality Management Systems (QMS) are a hierarchical series of responsibilities proceduralized in order to ensure processes and/or manufacturing are carried out in a consistent manner. This includes documentation of roles and responsibilities within the organization, how the QMS processes are monitored and subsequently improved and assurances that unacceptable products or outputs from processes or systems are identified, evaluated and appropriately dispositioned. The key difference between a QMS to comply with CLIA regulations versus an FDA regulation compliant QMS lies in the specifics of the requirements.
Within the current version of the CLIA regulations (42 CFR 493), subpart K covers the expectations for a laboratory’s Quality System for any tests which are non-Waived (for example, either Moderate or High complexity). These regulations focus on the appropriate qualification of personnel and the generation and control of patient results before, during and after test generation, including control over the systems used to generate such patient results. Subpart K includes such activities as assessment of the established quality system activities and processes for taking corrective actions when the laboratory’s testing processes do not perform as expected or patient results are outside the anticipated values during analytical testing. The focus, however, is on the end product during identification and control of handling patient specimens, testing of such specimens and the final reporting of the results related to specific patient specimens.
The medical device QSR (21 CFR 820) applies to manufacturers of medical devices. Quality systems in accordance with the QSR focus on how the medical device is designed, developed, manufactured and distributed for use, including controls and actions taken when the device is deemed to be questionable or unsuitable for use. In similar terms, the QSR QMS’s focus is on not only on how the finished medical device performs, but also on how all of the processes perform—and that no unintended sequelae are experienced by the ultimate user or recipient of the device. While the QSR QMS includes requirements for personnel, continuous improvement of the product and processes and monitoring of the QMS at various stages to ensure proper control and function, this standard also includes requirements for the processes for development of the medical device, expectations for controls put in place during the manufacturing process and how non-conformances for the products or processes are identified, evaluated and dispositioned. The difference between CLIA and the QSR is that the QSR QMS focuses on the results of the product and the processes within the QMS, not just on the product itself.
The differences in these system requirements comes both in the agencies that regulate them as well as what they are focused on regulating. CLIA regulations are put in place by the Centers for Medicare and Medicaid Services (CMS), while the medical device Quality System Regulations are established by the Centers for Devices and Radiological Health (CDRH) of the FDA. While both Agency’s primary focus is patient safety (and, in many cases, the safety of the users of the products or test systems), the QMS under the CDRH regulations in 21 CFR 820, focuses on the product’s ability to function as intended (referred to as “efficacy”). Efficacy can be evident either each time the device is used or, if it is a single use disposable medical device, that each device performs the same as the next. Under 21 CFR820, CDRH holds the manufacturer responsible for the safety and the effectiveness of the medical devices they place on the market.
When a CLIA laboratory takes an LDT and aligns its technology with a specific drug product/biologic or use of a medical device, it has the potential to change the regulatory classification of the product. While LDT’s typically fall under what is referred to as “enforcement discretion” under CDRH regulations, recent promulgation of 21 CFR Part 4 on combination products specifically identifies LDT’s aligned with a drug product, biologic or medical device as a CDx. This removes the LDT from enforcement discretion and places it directly under the pervue of FDA’s regulations. Most typically, LDT’s used with a drug/biologic/medical device are regulated as a type of medical device known as an In Vitro Diagnostic, or IVD. Such medical devices, as clarified in the recent FDA draft guidance “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” issued Oct. 3, 2014, are expected to comply with the QSR QMS model under 21 CFR820. Laboratories originally thought that this might consist of an abbreviated system aligning with most laboratory CLIA certifications, but recent experience by CLIA laboratories finds that such thoughts are incorrect. The guidance document describes a risk-based framework for addressing oversight of LDTs and provides guidance to clinical laboratories that manufacture them. Additionally, it provides insight to those labs about how the FDA intends to apply enforcement relative to them as medical device manufacturers. While the guidance is not an all-inclusive prescriptive structure, it does provide clearer direction and a good frame of reference from which to start.
Again, because the focus of the quality systems is different, the CLIA QMS only covers a small portion of the activities that a lab will be performing when developing and “manufacturing” the LDT for use as a CDx or IVD. Thus, CLIA focuses on the processes associated with how patient results are generated vs. the QSR which focuses on the processes for design and manufacture of the test (for example, the medical device). The caveat here for the CLIA lab lies in the fact that they are now held accountable for the work done to “make” the LDT before it is used to test patient samples. For example, the manufacturing process for an LDT would include the collection of reagents and assembly of materials used during the testing process—such as the creation of an ELISA gel to run and read results. The QSR intent of validation has also been confusing to CLIA laboratories as many times the act of “validating” the laboratory test is closely aligned or even performed within the same process of running the laboratory test and generating the patient’s results. In these cases, the act of generating the patient results immediately consumes what was manufactured leaving nothing to “validate.” However, in the FDA’s eyes, the process of developing reagents, assays, or control of equipment used to perform the tests on patients’ specimens, constitutes “manufacturing” activities and, as such, must have documented procedures and processes and be designed, developed and controlled to function in a predictable way, including taking action when these processes do not perform as predicted.