FDA's Year-End Guidance Drop: A Detailed Breakdown
The FDA issued a slew of end-of-year guidances. We distilled the key takeaways from each of them.
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Toward the end of December, the FDA went on a mini guidance spree, publishing several guidances that fulfill legislative requirements under the 2022 Food and Drug Omnibus Reform Act (FDORA) and address the use of real-world evidence.
We’ve analyzed each of them and distilled the key takeaways below along with questions to drive alignment in case you’re impacted by them.
Talk to us if you’re in need of expert regulatory or compliance assurance support to achieve alignment in any of these areas. We regularly use our consulting and staff augmentation engagement models for gap analyses and QS/QMS remediation.
Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
The FDA finalized guidance on how medical product sponsors can use digital health technologies (DHT) for remote monitoring patients in clinical trials. The agency said it has gained more experience with DHTs during the COVID-19 pandemic and that their use can help streamline trials as well as improve trial participation.
The guidance defines a DHT as a system using computing platforms, connectivity, software, and/or sensors for healthcare and related uses and provides recommendations for using DHTs for remote data acquisition from participants in clinical investigations evaluating medical products.
Background: The FDA discusses the transformative role of advances in technology, including sensors and data processing, in clinical research. The agency also highlights the growing role of DHTs in healthcare and their potential in clinical research, such as measuring biomarkers and administering clinical outcome assessments (COAs). It emphasizes the opportunity DHTs provide for more frequent or continuous data collection, offering a broader picture of participant health in their daily lives.
Regulatory considerations and engagement with the agency: In terms of regulatory considerations, the FDA advises firms to ascertain whether their DHTs meet the definition of a device under the Federal Food, Drug, and Cosmetic Act. This is crucial for ensuring compliance with the regulatory requirements applicable to devices used in clinical investigations. For devices including DHTs, firms must understand the criteria and exemptions for investigational device exemption (IDE) applications.
Considerations when using DHTs in clinical investigations: When employing DHTs in clinical investigations, the agency tells firms to meticulously select appropriate technologies—more specifically, considering the technical and performance specifications, design, operation, and the context of their use by participants. The FDA also requires detailed descriptions of DHTs in regulatory submissions, emphasizing design, technological characteristics, data flow, privacy, and security controls. Verifying, validating, and conducting usability evaluations of these technologies are critical steps to ensure their fitness for purpose in clinical contexts. Additionally, evaluating interoperability and conducting further usability evaluations are essential to confirm the suitability of DHTs for the intended use.
Statistical analysis and trial design considerations: For evaluating endpoints involving data collected using DHTs, the FDA advises firms to justify these endpoints. This includes establishing how the endpoint reflects the participant's experience or using biomarkers as surrogate endpoints for clinical benefits. The process involves defining the endpoints, establishing novel endpoints, and ensuring the data accurately reflects the desired measurements.
Risk considerations when using DHTs: Much of the guidance is devoted to risk considerations. Firms are advised to assess and manage the risks associated with using DHTs, including both clinical and privacy-related risks. Implementing comprehensive informed consent processes that adequately describe these risks and mitigation strategies is vital.
Protection and retention: The FDA emphasizes the need for securely maintaining DHT data and associated metadata in compliance with record retention requirements. Firms are also expected to develop technical assistance and risk management plans for using DHTs in clinical investigations.
Other considerations during a clinical investigation: The guidance further details the roles of sponsors and investigators in ensuring the quality and integrity of data, the protection of participants, and compliance with regulatory requirements. This includes developing and ensuring training for trial personnel and participants on using DHTs according to the protocol and incorporating feedback from usability evaluations into this training.
Finally, appendices provide examples and justifications for the selection of DHTs and endpoints in clinical investigations. These serve as practical guides for firms to understand the application of DHTs in specific research scenarios.
A few questions to consider for alignment
Below are some questions that firms currently or planning to acquire trial data remotely should consider in light of this guidance.
Does our DHT meet the FDA's definition of a device under the Federal Food, Drug, and Cosmetic Act?
Have we ensured compliance with the regulatory requirements and exemptions applicable to devices used in clinical investigations?
Is there a clear understanding of the criteria for IDE applications in relation to our DHTs?
Have we selected DHTs based on technical performance, design, operation, and usability factors suited to our study's participants?
Does our regulatory submission accurately describe the DHTs' design, technological characteristics, data flow, privacy, and security controls?
Have we performed thorough verification and validation of the DHTs to ensure they are fit-for-purpose in the clinical context?
Are the interoperability and usability of these technologies evaluated and confirmed as suitable for their intended use?
How do we justify the endpoints measured using data from our DHTs?
Do these endpoints accurately reflect the participant's experience or biomarkers as surrogate endpoints for clinical benefits?
Are our data collection methods consistent across all study arms?
How are we addressing potential issues with missing data, and are endpoints and source data predefined in our statistical analysis plan?
Have we assessed and planned for both clinical and privacy-related risks associated with DHT use?
Is our informed consent process comprehensive in describing these risks and the strategies for mitigating them?
How are we ensuring the secure maintenance of DHT data and associated metadata in compliance with record retention requirements?
What technical assistance and risk management plans are in place related to the use of DHTs?
Have we developed and ensured effective training for trial personnel and participants on using DHTs as per the protocol?
Are we incorporating feedback from usability evaluations into this training and ensuring participant understanding and compliance?
Rare Diseases: Considerations for the Development of Drugs and Biological Products
The FDA also finalized guidance on developing drugs and biologics for rare diseases. The guidance outlines the agency's thinking on efficient trials for products that treat rare diseases.
Considerations for natural history studies: The FDA suggests that firms conduct or thoroughly review natural history studies as early in development as possible, which it says is critical for acquiring a comprehensive understanding of a disease's progression, which in turn informs drug development strategies. The FDA points firms to its March 2019 draft guidance for industry Rare Diseases: Natural History Studies for Drug Development for details about natural history studies.
Nonclinical studies: Firms are instructed to undertake in vitro and/or in vivo studies to establish drug safety. Selecting appropriate species for these studies and customizing the nonclinical program based on the drug’s characteristics and the nature of the disease are key actions. The FDA also encourages firms to leverage the flexibility offered in applying standards, especially for treatments targeting severely debilitating or life-threatening rare diseases.
Clinical development, effectiveness, and safety: The guidance outlines several specific policies here:
Firms should conduct routine clinical pharmacology assessments, including the evaluation of the drug’s disposition, interaction potential, and safety profile.
Testing multiple dosages to determine the optimal dosing is crucial, and gathering biospecimens from all study participants for pharmacokinetic and pharmacodynamic analysis is recommended.
In terms of biomarkers, the FDA advises identifying and validating relevant biomarkers, ensuring their analytical validity for the drug development process.
Clinical investigation design should incorporate controls, randomization, and blinding, and firms are encouraged to consider innovative designs such as adaptive trials or Bayesian methods.
Selecting appropriate endpoints to demonstrate drug effectiveness is vital, and early engagement with the FDA to discuss endpoint development is recommended.
Additional considerations include involving patients, caregivers, and advocates in the drug development process, considering expedited programs like fast-track or accelerated approval, and addressing specific needs of pediatric populations in the drug development process.
A few questions to consider for alignment
Below are some questions that firms pursuing rare disease drug or biologic products in clinical or pre-clinical stages should consider in light of this guidance. Contact us if you need expert support in advising around any of these areas—or would like to explore staff augmentation as a preferable alternative to complement to your CRO for staffing clinical operations roles.
Have we conducted or reviewed comprehensive natural history studies to understand the progression and impact of the rare disease we are targeting?
Does our current knowledge base include sufficient information about the disease's onset, progression, and variability among the patient population?
Have we identified the most appropriate nonclinical study models, including animal models, that are relevant to our drug’s mechanism of action and the disease's pathophysiology?