In 2013, FDA Commissioner Margaret Hamburg announced that the agency was looking to establish a risk-based framework for regulating lab-developed tests (LDTs) and released a draft guidance document to the public in October 2014. This set off a deluge of commentaries, petitions, and debate within the LDT community, labs, and beyond about the legality of the proposed regulation and broader questions about how in vitro diagnostics (IVDs) are regulated in the U.S. and abroad.
Yet two years later, the FDA took a step back from pursuing the risk-based regulatory framework, indicating the agency would not seek to finalize the draft guidance document. While many in the industry praised this decision, the FDA has clearly not abandoned the issue entirely. Just a few months after that announcement, the agency published a discussion paper on the topic which highlighted the lack of uniformity between LDTs and IVDs, noting currently not all assays are subjected to the same premarket oversight. Additionally, the paper describes a potential regulatory framework that is jointly administered by the FDA and the Centers for Medicare and Medicaid Services (CMS), which oversees the Clinical Laboratory Improvement Amendments (CLIA) Program.
Although the scheme outlined in the discussion paper is not enforceable, the risk-based framework remains. Existing LDTs on the market would be “grandfathered” in, subject only to serious adverse event and malfunction reporting. New LDTs would follow a similar premarket review as IVDs with the same intended use. In short, despite holding off on finalizing LDT regulations, the agency (along with CMS) appears to be holding fast to the risk-based framework, at least for some devices. The recently-released final guidance of Software as a Medical Device (SaMD) is one example that may impact some IVD/LDT developers, which classifies SaMD by severity of the clinical condition and its intended medical purpose.
While a risk-based framework for LDTs is novel, FDA has used such a system for IVDs for years. Class I IVDs are those which don’t support or sustain human life and have a safe and effective profile. Class I IVDs are typically exempt from 510(k) clearance premarket review. Class II IVDs are those with a higher level of risk which require special controls and most undergo 510(k) clearance premarket review. IVDs carrying the highest level of risk, such as those that support or sustain life or have a high risk of injury, require premarket approval and are subject to general, special, and ad-hoc controls as necessary.
Other countries similarly have embraced risk-based regulatory frameworks for IVDs. The European Union’s (EU) IVD Directive on In Vitro Diagnostic Medical Devices 98/79/EC has been replaced in May 2017 by the In Vitro Diagnostic Device Regulation (EU) 2017/746. This new regulation takes into consideration patient impact and classifies devices using a four-tiered, risk-based system that will require approximately 80 percent of IVDs undergo a conformity assessment by a Notified Body. Class A devices represent those with the least risk, whereas Class D is reserved for those with the highest risk. This is a substantial departure from the IVD Directive, under which the vast majority of IVDs were self-declared. Notably, safety and performance data from high-risk class C and D devices are to be made publicly available.
Most other countries have a similar risk-based system in place for IVDs. In Japan, China, and some Central and South American countries, IVDs are classified by risk, with Class III representing those devices with the highest risk, such as genetic testing, allergen testing, and blood and tissue typing, while Class I represents those with little risk to patients. Specific country requirements exist that may require additional levels of scrutiny for some devices or different means of regulatory management. For example, the regulatory management for IVDs in China further depends on the origin of the device: imported devices are regulated through the central China Food and Drug Administration (CFDA) regardless of class, while domestic devices (Chinese) are managed based on their class, with only high-risk Class III devices regulated at the central CFDA and Class I and Class II devices managed at the local or regional offices.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
While the U.S. IVD market is substantial, global markets are expanding. IVD manufacturers looking to enter foreign markets need to consider their market planning strategy carefully to account for evolving regulatory requirements and should work with regulatory experts in those countries to ensure their device is in compliance. Correct classification of a device is essential.
IVDs, particularly LDTs, designed for precision medicine may be among those impacted the most by risk-based frameworks, both overseas and in the U.S., due to their intended use and often, their highest-risk status. Despite the FDA’s current reticence to impose risk-based classification requirements on LTDs, doing so would bring the U.S. into line with other countries’ systems for IVDs. It also may more accurately reflect the potential risk of the device for patients, and assure patients and healthcare providers that the product has undergone sufficient review prior to reaching the market.
Harry is the author of two related books: Commercializing Novel IVD’s; A Comprehensive Manual for Success and MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.
Photo: Pixtum, Getty Images
