New FDA Draft Guidance on Use of Digital Health Technologies in Clinical Trials

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On December 23, 2021, the United States Food and Drug Administration (FDA) announced the availability of a draft guidance for industry, investigators, and other stakeholders entitled “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” (Guidance). The Guidance synthesizes the FDA’s recommendations, based on input solicited from numerous stakeholders over the course of the last six years. Once finalized, the Guidance will directly affect drug, device, and biotech companies, as well as research institutions, that sponsor FDA-regulated clinical investigations incorporating digital health technologies (when used for healthcare related purposes, “DHTs” as defined in the Guidance). It will also affect investigators, research sites, and institutional review boards (IRBs) that conduct or review those clinical investigations. FDA is accepting comments on the Guidance until March 23, 2022.

Background and Applicability

Sensors, apps, internet-connected medical devices, computing platforms, and similar technologies are widely deployed in clinical trials today. Their uses range from simple reminders or engagement for largely in-person trials to collection of data for endpoint evaluation in decentralized clinical trials. DHTs provide opportunities to record richer data than would otherwise be available, facilitate the direct and continuous collection of information from participants who are unable to report their experiences (e.g., young children and cognitively impaired individuals), improve study compliance and retention, and help to improve equity in the availability of clinical trials. They also raise issues for clinical trial sponsors, investigators, and IRBs interpreting FDA regulations written in a largely pre-DHT world.

The Guidance applies to FDA-regulated clinical investigations incorporating DHTs. The term “clinical investigation” is not separately defined in the Guidance; rather, FDA makes reference to the term as defined in its regulations governing informed consent, IRB review, investigational new drug applications (INDs), and investigational device exemptions (IDEs). These references may be a source of confusion as the definition of “clinical investigation” is not uniform across these related FDA regulations. Although a full analysis of how these different regulations apply to research studies is beyond the scope of this Client Alert, if the study sponsor has determined that a study requires an IND or an IDE, the Guidance applies. The Guidance’s recommendations on informed consent requirements and IRB review are likely to apply as well to both IDE-exempt studies (if the study data are intended to be used later in a submission to the FDA) and IND-exempt studies of legally marketed drugs.

Recommendations for Sponsors, Investigators, and IRBs

Sponsors

The Guidance provides recommendations to study sponsors for the use of DHTs in a clinical investigation, including the following topics:

  • Selection of DHTs that are suitable for use in a clinical investigation.
  • Description of DHTs in regulatory submissions to the FDA (which, per FDA, should include information about how the integrity of data collected by the DHT will be maintained).
  • Verification and validation of DHTs for use in a clinical investigation.
  • Definition and evaluation of clinical endpoints from data collected using DHTs.
  • Addressing DHTs in a statistical analysis plan.
  • Risk considerations when using DHTs.
  • Protection and retention of records.

Sponsors should consider each of these Guidance sections in the design of a clinical investigation that will incorporate a DHT. The Guidance also recommends that sponsors ensure training of study participants and personnel on the use of the DHTs, develop a plan for technical assistance for study participants and personnel, develop a risk management plan to address potential problems study participants may experience when using a DHT, develop a safety monitoring plan that addresses how abnormal DHT measurements related to participants’ safety (e.g., hypoglycemia, arrhythmia, apnea) will be reviewed and managed, and ensure that data has been downloaded from the DHT into a durable electronic data repository.

Note that in addition to being useful tools in clinical investigations of drugs, biologics, and medical devices, some DHTs are themselves considered “medical devices” under the Federal Food, Drug, and Cosmetic Act.1 Sponsors planning to use a DHT in a clinical investigation must be mindful of the regulatory status of the DHT in the context of that study. This can present traps for the unwary if, for example, a “general wellness” DHT would not be a medical device as ordinarily used but would be a medical device in the context of a study because of how the DHT will be used, or if a DHT constitutes a “significant risk device” when used in a drug or biologic trial. Sponsors should engage early with the appropriate FDA Center responsible for the medical product under investigation to discuss the proposed use of DHTs.

Institutions, Investigators, and IRBs

Research sites, as well as investigators who are not sponsoring a study, should ensure that participants understand what information will be collected by the DHT and how the security and privacy of data collected by the DHT will be maintained. They should also ensure training of participants on using the DHT according to the protocol. Sponsor-investigators and institutions sponsoring investigator-initiated research must, in addition, follow the requirements of sponsors, detailed above.

Investigators, institutions that have their own IRBs, and independent IRBs should pay particular attention to the Guidance Section IV.F., “Risk Considerations When Using Digital Health Technologies,” addressing the potential clinical and privacy risks introduced by the use of DHTs. FDA’s recommendations include, among others, ensuring that security safeguards are implemented to protect data from unauthorized access, as well as informing participants (in the informed consent documents) of any end-user licensing agreements for the use of DHTs that potentially allow for third party access to their collected data. It has been our experience that IRBs do not always assess the study approval criteria in 21 CFR Part 50 and 45 CFR Part 46 individually, and do not always assess each required informed consent element in the context of a particular study. For example, we do not think it is common for sponsors, investigators, or IRBs to consider DHT end-user license agreements and terms of service when preparing and reviewing informed consent documents (as the Department of Health and Human Services’ Secretary’s Advisory Committee on Human Research Protections said they should do last year) when the DHT is not the focus of the study, and although these stakeholders are not explicitly required to do so now, it is clear from the Guidance that the FDA believes they should in some cases. In addition to ensuring regulatory compliance, following the recommendations here for evolving technologies like DHTs can mitigate the risk of liability and adverse public relations exposure.

Next Steps

We recommend that life sciences companies, research institutions, and IRBs review the Guidance now to determine what they might need to do to comply with it if it is issued as final following the close of the comment period on March 23, 2022. Even if the Guidance is never finalized, as often happens with FDA guidance documents, the Guidance offers important insights into how the FDA thinks its existing regulations apply to DHTs used in clinical investigations. Affected stakeholders who wish to comment on the Guidance can do so here.

If you have any questions about clinical trials using DHTs and compliance with the Guidance, please contact the authors.

1 For software, Section 3060 of the 21st Century Cures Act introduced some important flexibility when it became law at the end of 2016, carving out software functions that might have previously been regulated by the FDA as a medical device. However, that flexibility comes with some additional complexity, and numerous FDA guidance documents have been drafted or amended in the years since the Cures Act’s passage that sponsors must be aware of when determining whether and how FDA will regulate a particular product that is (or uses) software.

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Firm Publication

On December 23, 2021, the United States Food and Drug Administration (FDA) announced the availability of a draft guidance for industry, investigators, and other stakeholders entitled “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” (Guidance). The Guidance synthesizes the FDA’s recommendations, based on input solicited from numerous stakeholders over the course of the last six years. Once finalized, the Guidance will directly affect drug, device, and biotech companies, as well as research institutions, that sponsor FDA-regulated clinical investigations incorporating digital health technologies (when used for healthcare related purposes, “DHTs” as defined in the Guidance). It will also affect investigators, research sites, and institutional review boards (IRBs) that conduct or review those clinical investigations. FDA is accepting comments on the Guidance until March 23, 2022.

Background and Applicability

Sensors, apps, internet-connected medical devices, computing platforms, and similar technologies are widely deployed in clinical trials today. Their uses range from simple reminders or engagement for largely in-person trials to collection of data for endpoint evaluation in decentralized clinical trials. DHTs provide opportunities to record richer data than would otherwise be available, facilitate the direct and continuous collection of information from participants who are unable to report their experiences (e.g., young children and cognitively impaired individuals), improve study compliance and retention, and help to improve equity in the availability of clinical trials. They also raise issues for clinical trial sponsors, investigators, and IRBs interpreting FDA regulations written in a largely pre-DHT world.

The Guidance applies to FDA-regulated clinical investigations incorporating DHTs. The term “clinical investigation” is not separately defined in the Guidance; rather, FDA makes reference to the term as defined in its regulations governing informed consent, IRB review, investigational new drug applications (INDs), and investigational device exemptions (IDEs). These references may be a source of confusion as the definition of “clinical investigation” is not uniform across these related FDA regulations. Although a full analysis of how these different regulations apply to research studies is beyond the scope of this Client Alert, if the study sponsor has determined that a study requires an IND or an IDE, the Guidance applies. The Guidance’s recommendations on informed consent requirements and IRB review are likely to apply as well to both IDE-exempt studies (if the study data are intended to be used later in a submission to the FDA) and IND-exempt studies of legally marketed drugs.

Recommendations for Sponsors, Investigators, and IRBs

Sponsors

The Guidance provides recommendations to study sponsors for the use of DHTs in a clinical investigation, including the following topics:

  • Selection of DHTs that are suitable for use in a clinical investigation.
  • Description of DHTs in regulatory submissions to the FDA (which, per FDA, should include information about how the integrity of data collected by the DHT will be maintained).
  • Verification and validation of DHTs for use in a clinical investigation.
  • Definition and evaluation of clinical endpoints from data collected using DHTs.
  • Addressing DHTs in a statistical analysis plan.
  • Risk considerations when using DHTs.
  • Protection and retention of records.

Sponsors should consider each of these Guidance sections in the design of a clinical investigation that will incorporate a DHT. The Guidance also recommends that sponsors ensure training of study participants and personnel on the use of the DHTs, develop a plan for technical assistance for study participants and personnel, develop a risk management plan to address potential problems study participants may experience when using a DHT, develop a safety monitoring plan that addresses how abnormal DHT measurements related to participants’ safety (e.g., hypoglycemia, arrhythmia, apnea) will be reviewed and managed, and ensure that data has been downloaded from the DHT into a durable electronic data repository.

Note that in addition to being useful tools in clinical investigations of drugs, biologics, and medical devices, some DHTs are themselves considered “medical devices” under the Federal Food, Drug, and Cosmetic Act.1 Sponsors planning to use a DHT in a clinical investigation must be mindful of the regulatory status of the DHT in the context of that study. This can present traps for the unwary if, for example, a “general wellness” DHT would not be a medical device as ordinarily used but would be a medical device in the context of a study because of how the DHT will be used, or if a DHT constitutes a “significant risk device” when used in a drug or biologic trial. Sponsors should engage early with the appropriate FDA Center responsible for the medical product under investigation to discuss the proposed use of DHTs.

Institutions, Investigators, and IRBs

Research sites, as well as investigators who are not sponsoring a study, should ensure that participants understand what information will be collected by the DHT and how the security and privacy of data collected by the DHT will be maintained. They should also ensure training of participants on using the DHT according to the protocol. Sponsor-investigators and institutions sponsoring investigator-initiated research must, in addition, follow the requirements of sponsors, detailed above.

Investigators, institutions that have their own IRBs, and independent IRBs should pay particular attention to the Guidance Section IV.F., “Risk Considerations When Using Digital Health Technologies,” addressing the potential clinical and privacy risks introduced by the use of DHTs. FDA’s recommendations include, among others, ensuring that security safeguards are implemented to protect data from unauthorized access, as well as informing participants (in the informed consent documents) of any end-user licensing agreements for the use of DHTs that potentially allow for third party access to their collected data. It has been our experience that IRBs do not always assess the study approval criteria in 21 CFR Part 50 and 45 CFR Part 46 individually, and do not always assess each required informed consent element in the context of a particular study. For example, we do not think it is common for sponsors, investigators, or IRBs to consider DHT end-user license agreements and terms of service when preparing and reviewing informed consent documents (as the Department of Health and Human Services’ Secretary’s Advisory Committee on Human Research Protections said they should do last year) when the DHT is not the focus of the study, and although these stakeholders are not explicitly required to do so now, it is clear from the Guidance that the FDA believes they should in some cases. In addition to ensuring regulatory compliance, following the recommendations here for evolving technologies like DHTs can mitigate the risk of liability and adverse public relations exposure.

Next Steps

We recommend that life sciences companies, research institutions, and IRBs review the Guidance now to determine what they might need to do to comply with it if it is issued as final following the close of the comment period on March 23, 2022. Even if the Guidance is never finalized, as often happens with FDA guidance documents, the Guidance offers important insights into how the FDA thinks its existing regulations apply to DHTs used in clinical investigations. Affected stakeholders who wish to comment on the Guidance can do so here.

If you have any questions about clinical trials using DHTs and compliance with the Guidance, please contact the authors.

1 For software, Section 3060 of the 21st Century Cures Act introduced some important flexibility when it became law at the end of 2016, carving out software functions that might have previously been regulated by the FDA as a medical device. However, that flexibility comes with some additional complexity, and numerous FDA guidance documents have been drafted or amended in the years since the Cures Act’s passage that sponsors must be aware of when determining whether and how FDA will regulate a particular product that is (or uses) software.

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