For years the FDA have been concerned with the safety risks of poorly performing Laboratory Developed Tests (LDTs). Despite multiple attempts to regulate the space including the ‘FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)’ in 2014 and the recent ‘Verifying Accurate Leading-edge IVCT Development Act’ (VALID Act) from 2022, the concerns have not provided the desired outcome.
In November 2022 FDA oncology chief Richard Pazdur announced that the agency’s medical device regulators were working on a pilot program to introduce a concept of minimum performance criteria with the objective to move past the ‘one-drug-one-test’ situation.
The new initiative and pilot program was intended to allow doctors to use any test that meets a set of minimum criteria, regardless of if specifically approved for therapy. The objective announced was to avoid patients undergoing multiple tests and using unnecessary amounts of valuable tissue which is increasingly becoming a limiting factor in timely and efficient diagnostic work up.
The FDA also hopes the new initiative will lead to the laboratory community delivering more reliable tests and finally finding a path to better management of LDT performance.
Pilot Program launched and open for entries
Since then, there hasn't been much communication or mention of the initiative or how the program would be detailed. Until now. On June 20th the FDA issued a guidance document: ‘Oncology Drug Products Used with Certain In Vitro Diagnostic Tests: Pilot Program Guidance for Industry, Clinical Laboratories, and Food and Drug Administration Staff’.
The program is intended for oncology drugs where the use of an in vitro diagnostic test is needed to identify an intended patient population. Entry criteria includes 'no satisfactory alternative treatment exists' and 'the anticipated benefits from the use of the drug must outweigh the anticipated risks from approval of the drug product without an FDA authorized companion diagnostic'. In addition, the clinical trial assay(s) must use the same technology as a previously FDA-authorized companion diagnostic (regardless of indication). There must be a well-validated reference and comparator method, and/or well-characterized materials that can be used to support test accuracy.
The FDA is expecting to run a pilot for approximately 1 year. Based on the findings, a permanent guidance could come into force in the next 3 years.
30% of all FDA approvals (2018-2021) were for therapies dependent upon patients pretested to determine their eligibility. While the focus in precision medicine brings promise to patients it has significantly increased the complexity in the patient diagnostic and treatment pathway.
Diaceutics conducted a study, in collaboration with the Personalized Medicine Coalition and a broad steering committee comprising of stakeholders across the pharma and diagnostic industry, laboratories and patient organization, which found that approximately 63% of newly diagnosed NSCLC in the US did not receive the optimal treatment based on their genomic profile.
The suboptimal practice was shown to comprise of practice gaps across the patient’s diagnostic and treatment journey with just above 40% of patients being lost in steps related to test ordering, test performance and test reporting. (The results were published in JCO Precision Oncology: Impact of Clinical Practice Gaps on the Implementation of Personalized Medicine in Advanced Non–Small-Cell Lung Cancer).
As previously commented upon, when the pilot was first mentioned in November, we believe the FDA initiative will support the ambition of allowing all patients access to a treatment optimal to them. The ‘one-drug-one-test’ paradigm made sense in the early days of precision medicine but is now surpassed by the complexity in the market.
The new guidance document is aimed at drug sponsors, reducing the role of Dx developers in Companion Diagnostic products and endorsing LDT in the lab setting. Essentially the FDA is suggesting to allow patient testing in clinical routine, both Companion Diagnostics (CDx) or Laboratory Developed Tests (LDT) to be based on the clinical trial assay (CTA) developed during drug trials.
To evaluate the concept of the Minimal Performance Characteristics, the FDA is inviting up to 9 entries to participate in the pilot. A key requirement to enter the pilot program is to share data for analytical and clinical validation and allowing data to be published on the FDA’s website. The FDA has developed very detailed templates for what data is to be shared and the need to allow for scoring and cut offs to be made publicly available. Templates are available for the technologies: IHC, NGS, FISH, and PCR on FDA’s website.
We believe FDA’s pilot program of a ‘Minimum Performance Characteristics’ will:
- Allow more flexibility for labs to choose test/instrumentation applicable for them.
- Remove the need for determining specific therapy option before test (e.g. deciding and communicating if a HCP is considering Exkivity or Rybrevant)
- Support the labs performing LDT, whether this is chosen due to financial reasons (insufficient reimbursement, no incentive to stock multiple assays for 1 biomarker) or practical reasons (lack of space for multiple instruments, lack of resources to educate and train on multiple assays for 1 biomarker)
- Ease communication between treating HCP and Lab, directly or in MDT
Though, this will be dependent on the program being broadly accepted and implemented. If not, the labs and HCP’s might find themselves having to navigate even more complexity than today in checking the testing requirements to make informed decisions on which tests to order and apply.
Areas to be aware of and Diaceutics' recommendations
Dx vendor contracting
For pharma/drug sponsors it will be critical to think about these new criteria when contracting and partnering with Dx developers. The current practice for partnership in developing and commercializing a CDx linked to a specific therapy is based on the current ‘one-drug-one-test’ model and limits the drug sponsors ability to both participate and be successful in meeting the requirements for FDA’s Minimal Performance Characteristics. Designing the contract with enough freedom to operate and rights to publish validation and verification data of the CTA is a critical change to how contracts are set up today.
Diaceutics recommends: Our industry experts with experience from both pharma and the diagnostics industry have guided our clients in all aspects of Rx-Dx partnership contracting. It is critical to think through the entire lifecycle from early development to commercialization and post-launch management when negotiating and contracting to ensure rights, freedom to operate and the best cost efficiency model. The new FDA guidance will make this work even more critical for a drug sponsor.
IP rights and transparency
The requirement set out by the FDA to enter the pilot program, and likely later the established regulations, for Minimal Performance Characteristics includes sharing what today is considered sensitive and competitive information and something both pharma and Dx developers have been reluctant to share pre drug and CDx approval. Critical for the success of the new FDA program is the willingness to share data related to verification and validation data including cut-off values, scoring and interpretation guidance at the stage of CTA.
Diaceutics recommends: The FDA guidance puts new requirements on data sharing and reconsidering competitive sensitive data. Considering whether to enter this new approach to CDx regulations or to follow the traditional path needs to be evaluated based on market insights and be founded in the specific drug and biomarker strategy. Diaceutics can support strategizing options based on relevant market intel and industry expertise.
LDT usage and test validation requirements
The FDA intends to recommend minimum analytical performance characteristics for other tests that, when established through properly conducted validation studies, the FDA believes would support extrapolation of the clinical validity of the CTA(s) to additional tests of the same type. This sets out requirements for the individual lab to be able to perform sufficient internal validation to document the accurate use of LDTs.
Diaceutics recommends: Test validation and ongoing test performance monitoring is key to successful implementation of LDTs. Verification and validation of test characteristics is not trivial and requires specialized knowledge, test materials etc., often adding stress to an already pressured laboratory setting. Diaceutics has years of experience developing and conducting validation studies such as individual lab validation, ring trials, proficiency testing etc.
Our extensive lab data allows us to identify and segment the most efficient approach and our scientific experts to develop and execute relevant programs.
Even if the new FDA guidance and pilot program comes with specific recommendations and templates, it also leaves several areas open for interpretation. No doubt it is going to raise questions and uncertainty for all parties involved as we move to implementation.
Diaceutics recommends: It is important to not let uncertainty establish barriers for success. It will be key to drive the needed education of all stakeholders involved to remove barriers formed from lack of clarity and knowledge, both in the lab setting, who will have to comply with the new regulations for CDx and LDTs, and also for HCPs understanding how this impacts requesting the appropriate test and interpreting lab reporting.
Diaceutics operates an omnichannel lab and physician outreach and education model. Using our proprietary Diaceutics Data repository we can support our clients in efficiently and targeted outreach to relevant labs and HCPs with tailored education and messaging.
Questions still remain
The newly announced initiative from the FDA, managed and implemented with the right support, is a step in the direction of bringing the right treatment to the right patient, realizing the potential of precision medicine short term, and laying the foundation for an even more complex future.
Even with more clarity provided by the FDA guidance document, several areas are still to be addressed and better understood. Especially if the Pilot moves into broad regulation:
- How will this impact what today is seen as critical proprietary IP, for both Rx and Dx?
- Will this remove the Dx industries incentive to bring CDx assays to market? And the drug sponsors willingness to financially support CDx? The Dx providers today have an attractive business model catering for pharma’s need to develop a CDx in parallel with Rx development and FDA submission.
- Who and how will the quality of LDTs and broader use of CDx assays be monitored?
- How will labs be guided, and supported, in conducting sufficient validation studies?
A scenario where the current ‘traditional’ regulatory pathway co-exists with a new ‘Minimal Performance Characteristic’ approach leaves additional questions related to which tests are applicable and suited for patient selection for certain treatments, potentially adding complexity instead of the intention of removing it.
Unlocking the potential of precision medicine
Diaceutics believe a multi-stakeholder approach is needed to change the clinical practice and fulfilling the promise of precision medicine.
With a focus on every patient getting the opportunity to receive the right test and the right drug to positively impact their disease, Diaceutics are dedicated to supporting the stakeholders in precision medicine via our services and solutions. With our unrivalled data repository and implementation services enabled by DXRX – The Diagnostic Network® and our team of precision medicine experts we are uniquely positioned to solve commercialization challenges and drive solutions to unlock superior value from your precision medicine strategy.
We predict other enablers for success will be:
- New technologies continuing to impact and drive precision medicine
- Finding patients earlier and referring them faster
- Meaningfully involving patients into treatment choices available
- Appropriate reimbursement levels to be proportionate with the clinical value delivered
- Prioritized investment in diagnostic pathway
- Data to increasingly automate treatment decision support
- Labs increasingly partnering with physicians to inform their testing and treatment choices
- Platform business models accelerating the pace of change as networks combine forces
Automation, simplification and communication will be critical to ensuring these new technology arrivals find their rightful place and do not instead make the diagnostic pathway more complex than it already is.