While many common laboratory tests are commercial tests, manufactured and marketed to multiple labs, some tests are designed, manufactured, and used within a single laboratory. These tests, called “laboratory-developed tests” or “LDTs” are supposed to be used solely within that laboratory and are not distributed or sold to any other labs or health care facilities. For decades, this has not been exactly the case and laboratories have stretched the concept of a customized test for a specific user concept. A lab may choose to develop an LDT because a commercial test is not currently available and, while the reason for this varies, it is often because tests are needed for rare diseases or novel uses. Because the LDTs are not marketed to other laboratories, they do not require approval or clearance for marketing from the U.S. Food and Drug Administration (FDA), while commercially developed and marketed tests and In-vitro Diagnostics (IVDs) do.
In the past, the FDA exhibited enforcement discretion around LDTs because they were largely simple lab tests. In trend with the medical device industry, LDTs have gone from simple to complex and are more widely used since the FDA gained regulatory authority of all in vitro diagnostics (IVDs) as devices in 1976. The LDTs of today can be highly complex, with great significance relying on their accuracy. In addition to complexity, several high-risk LDTs have been found to have unsubstantiated claims, lack of appropriate controls leading to inaccurate results, and data falsification. Such problems could result in risks to the patient, such as unnecessary or delayed treatments, or lack of treatment entirely, potentially leading to illness or death. [1, 2] A well-known, real-world example is the company Theranos. Therefore, it is not surprising that FDA has reignited their efforts to oversee LDTs and for a couple of years now have been working with the U.S. Congress to clarify laws around LDTs between FDA laws and Clinical Laboratory Improvement Amendments (CLIA) laws. In this Pilot program FDA has chosen to focus on the critical oncology field. On June 20, 2023 FDA issued a new guidance Oncology Drug Products Used with Certain In Vitro Diagnostic Tests: Pilot Program. It is important to note that the guidance was issued as final and not draft due to the public health importance of IVD tests for determining a patient’s cancer treatment but stakeholders are still able to provide comments.
Why is FDA creating an Oncology Drug Products Used with Certain In Vitro Diagnostic Tests pilot program? FDA aims to provide performance characteristics transparency that certain tests for oncology biomarkers, used for selection of oncology drug products, should meet. The organization hopes the program will bolster the performance of LDTs, resulting in better drug selection and improved care for patients with cancer. The pilot program is applicable to drug product sponsors, primarily for:
- CDER-regulated oncology drug products for which FDA determines that
- use of an IVD test is needed to identify the intended patient population;
- no satisfactory alternative treatment exists; and
- the anticipated benefits from the use of the drug product are so pronounced as to outweigh the anticipated risks from approval of the drug product without an FDA-authorized companion diagnostic. and
- corresponding clinical trial assay(s)
- that use the same technology as a previously FDA-authorized companion diagnostic for any indication; and
- for which there is a well-validated reference method, well-validated comparator method, and/or well-characterized materials that can be used to support test accuracy.
There is an urgent public health need to recommend minimum performance characteristics for tests used to identify patients for oncology treatment to address safety risks posed using LDTs that are not properly validated and/or are unable to identify the appropriate population for the corresponding drug products. FDA believes that the above tests are appropriate to extrapolate clinical validity of the test(s) used in a drug trial to other tests of the same type with similar analytical performance. Kindly, note that the pilot does change marketing authorization oncology drug products approval standards for the corresponding companion in vitro diagnostics.
What are the program requirements? As of June 20, 2023, drug product sponsors may be accepted into the pilot program based on the following evaluation of factors:
- clinical trial assays that use the same technology as a previously FDA-authorized companion diagnostic for any indication or for which there is a well-validated reference method or comparator;
- the oncology drug sponsor willingness to discuss with FDA analytical validation data and performance characteristics prior to enrollment of the pivotal clinical trial(s);
- pivotal clinical study protocol(s) use tests that have specified performance characteristics recommended by FDA for acceptance into the pilot;
- the oncology drug sponsor able to collect the analytical validation data and performance characteristics as recommended in FDA templates for all CTAs used for the enrollment of the pivotal clinical trial(s);
- the data owners supporting the safety and effectiveness of the oncology drug product and clinical trial assays willingness to agree to FDA’s use of such data to recommend minimum analytical performance characteristics for tests used to identify patients for treatment with the oncology drug product. This will be publicly available on FDA’s website.
This evaluation period is the initial phase of the pilot program and expected to last up to one year. FDA may decide to not consider bullet (2), for oncology drug products where the pivotal clinical trial started prior to June 20, 2023. The FDA will follow up with no more than 9 sponsors to request further information concerning acceptance. The anticipated number accepted into the pilot program has yet to be released.
How do I apply for consideration?
For consideration into the pilot program FDA directs interested drug sponsors to submit “a Statement of Interest in Participation in the Oncology Drug Product Used with Certain In Vitro Diagnostic Tests: Pilot Program” with their Investigational New Drug (IND) applications, New Drug Applications (NDA), or Biologic License Applications (BLA). Submitting a statement of interest affirms the sponsor's commitment to provide the following, if requested by FDA:
- Pivot trial enrollment status.
- IND, NDA, or BLA number or a timeline for submission if not already submitted
- List of clinical trial assays that were used or are planned for use for enrollment of the pivotal trial(s). The number of subjects enrolled into the trial by each clinical trial assay, the total number of subjects enrolled into the trial, and the total number of subjects that were evaluated by each clinical trial assay but not enrolled into the trial should also be provided for completed trials.
- Analytical validation and performance characteristics recommended in FDA templates for each clinical trial assay
- Right of reference from the owner(s) of the data supporting the safety and effectiveness of the oncology drug product and the clinical trial assay(s), agreeing that
- FDA may use the provided analytical validation data and performance characteristics to recommend minimum performance characteristics that FDA will make publicly available,
- clinical laboratories may use in developing LDTs, and
- FDA may reference to approve, authorize or clear premarket submissions for in vitro companion diagnostic tests.
So, who benefits from this program? One might call this a win-win-win situation. FDA takes another giant leap into regulating the LDT world, and we happily sit with popcorn in hand and watch it unfold. FDA kicks off what is likely to be a years-long effort to oversee LDTs in a small, controlled pilot group. Drug sponsors get early access to FDA’s thought processes on what is to come with LDT oversight, and most importantly, patients will benefit from improved testing that should point towards the best possible treatment for their conditions. Well, there you have it! Keep your eyes out for an update to this guidance, as based on the initial phase experiences FDA could expand the pilot to increase the number of sponsors and/or add more details.
Melissa Paffenroth – Senior Regulatory Consultant & Jean-Marie Toher – Associate Regulatory Consultant