The evolution of CDx: Navigating regulatory pathways, co-development strategies and future advancements
By: Vinod Nair, Anindita Ghosh, Amit R Kumar, Vikram Sinha, Gargi Arora and Pavan Anné (ZS Precision Medicine Center of Excellence)
Companion diagnostics (CDx) development in the United States has come a long way since the first introduction of INFORM human epidermal growth factor receptor-2 (HER-2/neu) — of Ventana Medical Systems, Inc. — a CDx for trastuzumab, in the late 1990s. Over the past three decades, the number of drugs launched with predictive biomarker assays has risen steadily, paralleled by a growing number of the U.S. Food and Drug Administration (FDA)-approved CDx assays. The U.S. FDA has approved approximately 60 CDx assays so far, with around 25% of these approvals coming in the last two years — 2022 and 2023. The CDx market is projected to increase from $6 billion to almost $14 billion by 2030, fueled by their capacity to guide treatment decisions across a broader range of cancers and chronic diseases. Given the exponential projected rise over the next decade, regulatory processes will play a key role in how the market shapes up and how soon the full promise of precision medicine is realized.
In this article we will discuss:
1. Clinical trial requirements for biomarker-based study and how it can be expedited.
2. Considerations for co-developing CDx with a therapeutic product.
3. Future advancements to regulatory pathways.
1. Clinical trial requirements for biomarker-based study
Clinical trial requirements depend on the current market landscape as well as on the risk profile of the assay.
Expedited approval pathways can be explored based on patient conditions and unmet needs in the market. Table 1 shows the five potential pathways and associated application processes in which the FDA makes an exception and delivers earlier approval in case of a life-threatening condition where alternate therapy isn’t available.
Medical device approval process can range from one month to 30 months depending on risk class and market landscape.
Key Pointers:
- Classification of an IVD determines the appropriate premarket process for approval.
- Most of the Class I IVDs are exempted from the FDA requirements for premarket notification (510k) and PMA.
- For IVDs opting for 510K, the application to FDA at least 90 days and 180 days for PMA before marketing.
- Before a manufacturer obtains marketing authorization for an IVD product, they must label the product in accordance with labeling regulations.
- For approval of a new indication for an already marketed device for use as a CDx with a drug or biological product, the manufacturer must submit an additional premarket submission for the new intended use.
Q-Submission Program, also known as the pre-submission program, is a voluntary initiative that allows medical device manufacturers to obtain feedback from the FDA during various stages of the product lifecycle, including before clinical studies or submission review. There are nine types of Q-Submissions, each with its own feedback mechanisms and timelines. Participating in the Q-Submission program offers significant benefits by enhancing communication with the FDA, providing invaluable insights and increasing the likelihood of a successful and timely regulatory review.
This program allows companies to engage with the FDA early in the product development process, seeking feedback on regulatory strategies, clarifying requirements and addressing potential issues.
Figure 3 below shows a comparison of expedited pathways and designations globally. While the U.S. and Japan enable earlier approvals based on unmet needs and patient conditions, the European Union (EU) takes a more conservatory approach to approvals.
In order to foster global collaboration and to reduce approval timelines the FDA, the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) all allow global data to be used for formal regulatory approvals. In fact, the ‘harmonization by doing (HBD)’ initiative was launched between the U.S. and Japan to foster collaboration between U.S. and Japanese regulators, academia and industry to promote regulatory convergence and overcome barriers for timely access to safe and effective medical devices in both countries. It has been critical in improving timeliness and in saving costs. Established in 2003, HBD has been used for global cardiovascular device clinical trials and pediatric medical device development — the HBD for Children Program — program.
The FDA acknowledges that clinical investigations may be conducted outside of the U.S. especially to secure an adequate number of subjects for specific diseases, conditions or pathogens:
- The premarket approval (PMA) regulation contains information regarding research conducted outside of the US (21 CFR 814.15).
- The FDA can also accept data from foreign studies in support of 510(k).
Use of foreign and international data as the sole support for FDA approval
- PMA regulation (21 CFR Part 814) permits the use of foreign data as the sole support for a marketing application if the data is applicable to the U.S. population or U.S. medical practices, is conducted by recognized competent investigators and deemed valid by the FDA, either through inspection or other means.
- For in vitro diagnostic (IVD) devices, the FDA suggests sponsors consult with the reviewing division before applying solely based on foreign data, considering differences in population demographics, disease prevalence, presentation, laboratory practices and medical standards of care.
2. Considerations for co-developing CDx with a therapeutic product
Co-developing CDx or IVDs alongside therapeutics offers several advantages, including:
· Improved patient selection: CDx and IVDs can identify patients most likely to benefit from the therapy, leading to personalized medicine approaches.
· Enhanced clinical trial efficiency: CDx and IVDs can be used to enrich clinical trials with relevant patient populations, potentially reducing trial size and cost.
· Stronger regulatory support: Regulatory agencies often encourage co-development, as CDx and IVDs can provide evidence supporting the therapeutic’s efficacy and safety in specific patient groups.
A diagnostic device can be used at any stage of drug development. In general, starting a clinical trial with a prototype assay and subsequently replacing it with a validated version is not recommended, as this may pose challenge in result interpretation due to use of two different assay version for patient selection. To align drug and device development process effectively, the following factors can be considered:
- Cross-functional collaboration
- Integrated planning
- Unified regulatory strategy
- Design control and risk management
Both drugs and medical devices go through structured clinical evaluation processes involving studies of increasing size and rigor, starting from safety and moving towards efficacy confirmation to get regulatory approvals for use in the patient population.
Figure 4 provides an overview of the standard phases of progression of how IVD and therapeutic product process can concurrently run to be most efficient.
3. Future advancements to regulatory pathways
The future of medical device regulations appears promising, with several initiatives underway to streamline approval pathways, foster collaboration and enhance safety and efficacy standards.
laboratory developed tests (LDTs): In May 2024, the U.S. FDA finalized a rule classifying LDTs as medical devices, bringing them under device regulations. The FDA will phase out its general enforcement discretion approach to LDTs over four years, with IDE regulations enforced for diagnostics by 2026. Drug programs using LDTs in trials may need separate IDE applications. This change impacts ongoing research relying on LDTs, requiring compliance with IDE regulations within two years, affecting several clinical development programs.
The VALID Act, if passed, would establish a risk-based framework for regulating LDTs and IVDs. This could expedite the development of IVDs, potentially leading to faster availability of crucial diagnostic tools. Additionally, the framework is expected to enhance transparency within the IVD market by providing a clearer structure for regulatory oversight.
Furthermore, the Combine project fosters collaboration between member state authorities for clinical trials and medical devices. This collaboration could streamline clinical trials by establishing more efficient and standardized procedures across different regions. This, in turn, could potentially reduce the overall development timeline for new medical devices.
In conclusion, multiple avenues currently exist to expedite the regulatory approval process, either based on market conditions — availability of a similar product — or based on patient needs or based on trials conducted globally. Therapeutic product approval process and associated IVD approval process can be run concurrently to reduce time to market further. While the new laws focus more on patient safety and efficacy it could pose challenges for patients going through trials and hamper innovation. Companies will need to tread the next decade carefully to balance patient needs and innovation against regulatory requirements and operations.
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