Global Clinical Research, Quality and Regulatory Consulting Services

FDA clearance or approval for an In Vitro Diagnostic (IVD) device requires several steps leading to submission. The first step is determining the correct regulatory pathway. Medical devices and diagnostics have three primary potential pathways: the 510(k), De Novo, or Premarket Approval (PMA). A Biological License Application (BLA) represents a fourth, less-used regulatory pathway for IVDs for blood screening products.The pathway is determined based on two factors: the device’s associated risk level and the existence of an equivalent product already cleared or approved that can serve as a valid predicate.Once a pathway is determined, a submission package or technical file is prepared for submission. This should include analytical and clinical performance data, a completed design history file, manufacturing information, a risk management file compliant with ISO 14971, and device labeling consistent with the intended use claim.Most IVD submissions also benefit from an FDA pre-submission. This provides a formal opportunity to get regulatory agency feedback on proposed intended use claims, study designs, and proposed predicate or comparator devices before a pre-market authorization submission. Landrich Group supports IVD companies throughout the full process, from regulatory assessment through submission, FDA correspondence, and clearance or approval for U.S. market authorization.Typical design and development timelines for an IVD, depending on the complexity and availability of predicate and comparator devices, are approximately 2 years on average. FDA pre-sub meetings, which have a 70-day turnaround time, are highly recommended.  The FDA’s MDUFA review time for 510(k) submissions is 90 days, but average review times are closer to 150 days based on interactive review, requests for additional information, and deficiency letters.  FDA’s review times for higher-risk Class III PMA devices are 180 days, with the average review time exceeding a year if deficiencies are found or additional amendments are submitted.  De Novo 510(k) devices have MUDFA FDA review times that fall between 510(k) and PMA FDA review times.  Well-planned pre-sub meetings and high-quality submissions can minimize time to market authorization.

A510(k) submission is the most common FDA pathway for IVD market authorization. This requires proof that the new device is substantially equivalent to a product already legally cleared for the market. This pre-existing device is known as the predicate device. It must have similar intended use and technological characteristics. If analytical and clinical performance data support an equivalence claim relative to a legally marketed, valid predicate device, the FDA typically clears a 510(k) without requiring formal clinical trials.The De Novo pathway applies to novel, low- to moderate-risk devices when no predicate exists. This means there is currently no device on the market with the same intended use and technology. De Novo submissions must establish a new device classification as a novel IVD. The FDA will evaluate whether this new device is safe and effective for its intended use based on general controls and special controls. If it is approved, it creates a new regulatory classification that can serve as a predicate for future 510 (k) submissions. De Novo requires a more significant body of clinical and analytical evidence than a typical 510 (k), and this, in turn, leads to a longer duration for review and completion.Determining whether to pursue a 510(k) or De Novo approval is a key decision milestone that influences the entire course of IVD development. That’s why it is essential to get expert regulatory input early on, prior to formulating analytical and clinical study designs.The Landrich Group assisted clients with clearance for meningitis and encephalitis rapid tests by managing usability, analytical, and clinical studies, and preparing a 510(k) pre-market submission.  The Landrich Group is highly experienced in interacting with the FDA on pre-submission, 510(k), De Novo 510(k), and Breakthrough Device Designation regulatory submissions.

The FDA’s official review clock for a standard 510 (k) is 90 days from the acceptance of the submission. In practice, total time from submission to clearance can take longer for a variety of reasons. The FDA may put a submission on hold to request additional information during interactive review or as a deficiency letter. If a deficiency letter is provided, the submission review clock would be paused until a complete response is provided. Most 510(k) submissions for IVDs are processed within 6-12 months of filing when the submission package is thorough and properly organized.The clinical evidence and design history file are two key factors in the time required for preparation and review. It is essential to analyze the complexity of these two artifacts and ensure they are well documented and defined with a clear predicate rationale. This decreases the likelihood of multiple AI requests for missing elements that could delay the timeline.During our 10-year history working with IVD clients, Landrich Group has a 100% clearance rate and deep expertise supporting the pre-submission and FDA review process.

The FDA’s clinical evidence requirements for an IVD submission depend on the device’s risk classification, intended use, and regulatory pathway. For most 510(k) submissions, the FDA expects analytical performance and clinical performance studies. Analytical performance studies include precision, accuracy, and interference/cross-reactivity data. Clinical performance studies demonstrate that the device performs as claimed in the intended use population. Using FDA-recognized consensus standards (e.g., CLSI Guidelines) for analytical and clinical study designs is highly recommended.  Consensus study designs may be modified based on the device’s technological features and intended use, but technical/statistical justifications should be provided for modified study designs.Clinical performance data can often come from studies using clinical specimens archived rather than prospective trials. This is typically appropriate when the specimens represent the intended-use population. For companion diagnostics (CDx) and devices with novel intended use claims, the FDA typically requires prospective clinical evidence with pre-specified statistical analysis plans.  The FDA recently shifted its policies to accept Real-World Evidence or Real-World Data more, depending on the relevance and reliability of the data, which could limit the size and scope of prospective studies.The evidence package is expected to support every aspect of the intended use statement. This includes the patient population, specimen type, clinical setting, and performance thresholds. Evidence that doesn’t map precisely to the labeled claim creates gaps in the FDA review.The best ways to ensure robust evidence packages are to research the FDA’s Establishment Registration & Device Listing database for similar or predicate devices, design analytical and clinical studies, prepare a regulatory strategy or road map, and conduct a pre-sub meeting to obtain FDA feedback.  The pre-sub process is non-binding; however, it is rare for the FDA to change its guidance unless risk profiles for the device have significantly changed.

A pre-submission (Pre-Sub) meeting (or Q-Submission) is a formal FDA program that allows device manufacturers to submit specific questions about their regulatory strategy before filing a submission. The FDA provides written feedback, typically within 70 calendar days, on questions related to proposed study designs, intended use claims, valid predicate, regulatory pathway selection, and the adequacy of planned evidence packages.Pre-Sub meetings are an ideal way to get input on the study design strategy. By soliciting feedback before the design execution and data collection, a manufacturer can avoid lengthy delays and evidence gaps that may result in deficiency letters and require complete response letters after initial submission. The Pre-Sub meeting is particularly important for IVDs with novel biomarker claims, unusual specimen types, or no legal, valid predicates. Landrich Group prepares and manages Pre-Sub meeting requests as one of the highest-value activities in regulatory strategy for U.S. FDA approval.FDA pre-sub meetings can be readily scheduled with the FDA.  It is recommended that in the range of 4-6 provocative questions be submitted to obtain FDA feedback regarding the U.S. regulatory pathway, including intended use statement, predicate or comparator devices, and analytical and clinical study designs. The FDA review time for pre-subs is nominally 70 days.  The FDA will typically provide written feedback on pre-sub questions before the 70-day review cycle, and a meeting with the FDA to discuss the feedback is at the discretion of the sponsor or submitter.