On May 2, 2023, the U.S. Food and Drug Administration (“FDA”) published draft guidance titled “Decentralized Clinical Trials for Drugs, Biological Products, and Devices” (the “Draft Guidance”). The Draft Guidance expands on the FDA’s 2020 recommendations issued in response to the COVID-19 pandemic and its 2021 draft guidance on the use of digital health technologies (“DHTs”) in clinical trials, and fulfills the directive under Section 3606 of the Food and Drug Omnibus Reform Act to “issue or revise draft guidance [ ] to clarify and advance the use of decentralized clinical studies to support the development of drugs and devices” no later than December 29, 2023.

The Draft Guidance defines a decentralized clinical trial (“DCT”) as a clinical trial where some or all of the trial-related activities occur at locations other than traditional trial sites.  The FDA clarifies that its regulatory requirements for clinical investigations are the same for DCTs as for traditional clinical trials; however, the Draft Guidance outlines how clinical trial sponsors, investigators, and other stakeholders may meet these requirements in the context of DCTs given the FDA’s recognition of the significant potential benefits of DCTs, such as expanding access to clinical trials, increasing trial efficiency, and improving trial participant engagement, recruitment, enrollment, retention, and diversity.

Some of FDA’s key recommendations include:

• An important initial determination is whether it is appropriate for a particular trial to be conducted as a fully decentralized or hybrid DCT. Whereas a fully decentralized trial may be appropriate for an investigational product (“IP”) that is simple to administer, has a well-characterized safety profile, and does not require complex medical assessments, a hybrid approach may be more appropriate where the trial involves more complex medical assessments or supervision and monitoring of IP administration. The FDA recommends that questions related to the feasibility, design, implementation, or analysis of a DCT should be discussed early with the relevant FDA review division.
• Given that trial-related activities for a DCT may involve a network of locations where clinical trial personnel, local health care providers (“HCPs”), and trial-related services (e.g., labs) may be provided, for inspectional purposes the investigator should select a physical location, to be listed on Form FDA 1572 – Statement of Investigator or in the investigational device exemption (“IDE”) application, where trial participant records will be stored and where trial personnel may be interviewed.
• Both sponsor and investigator should evaluate whether certain trial-related activities may be delegated to DCT personnel located near participants’ homes. Such activities should not require detailed knowledge of the protocol or IP. Trial-related activities that are unique to the trial or require detailed knowledge of the trial protocol or the IP should be performed by qualified trial personnel who have been appropriately trained.
• Obtaining informed consent remotely may be appropriate for a DCT as long as the process is adequate and appropriate. Oversight by institutional review boards (“IRBs”) should ensure that electronic informed consent at remote locations meets applicable requirements, and the FDA recommends the use of a central IRB in DCTs to provide for more streamlined review of the informed consent documents as well the protocol and other trial-related documents.
• As with any trial, sponsors must ensure proper monitoring of DCTs based on the sponsor’s risk assessment. Sponsors should also implement a safety monitoring plan that accounts for the decentralized nature of the clinical trial, including by prespecifying whether safety data will be collected via telehealth or in-person visits and whether DHTs will be used to collect certain safety information.  The Draft Guidance underscores the importance of providing sufficient instruction and contact information to the trial participant should an adverse event occur and allowing the participant to arrange an unscheduled visit (either remotely or in-person), as appropriate. The FDA also recently finalized its Q&A guidance on risk-based monitoring of clinical investigations, which we blogged about here.
• FDA notes that the “variability and precision” of data obtained from a DCT may differ from data obtained in a traditional site-based clinical trial. For example, remote assessments may vary from on-site assessments, particularly if trial participants are performing their own assessments at home.  Similarly, assessments performed by local HCPs may be less precise and consistent than assessments conducted by on-site trial personnel.  FDA states that while such variability may not affect the validity of a finding of superiority, it could compromise a finding of non-inferiority relative to an active control drug that has been evaluated in a traditional site-based trial.  FDA therefore recommends that sponsors consult with the relevant review division if planning a DCT with a non-inferiority design.
• For telehealth visits during a DCT, investigators should confirm a participant’s identity during each visit and complete the relevant case report forms and other documentation for each visit. Additionally, the sponsor and investigator are responsible for ensuring that remote clinical trial visits comply with relevant state telehealth laws and as applicable, the telehealth laws of countries outside the U.S.
• Given multiple sources of data collection in a DCT, the sponsor should develop a data management plan that includes the data origin and data flow from all sources to the sponsor; methods for acquiring remote data from trial participants and personnel; and a list of vendors for data collection, handling, and management.

The Draft Guidance demonstrates the FDA’s support of more widespread use of DCTs. At the same time, the Agency acknowledges that DCTs can be challenging to implement successfully, including because DCTs require coordination of trial activities with numerous parties in multiple locations that are not traditional trial sites.  The Draft Guidance also notes that if significant safety risks emerge due to remote administration or use of an IP, or if other circumstances arise that warrant in-person visits, the sponsor should discontinue remote administration or use of the IP, inform the FDA, IRB, and investigators, and determine whether the trial should be amended or continue.

Interested stakeholders may submit comments on the Draft Guidance by August 1, 2023 to Docket FDA-2022-D-2870.

Contact the authors or another Goodwin FDA team member with any questions or if you would like to submit comments to the FDA on the Draft Guidance.

The Controlled Substances Act, as amended by the Ryan Haight Act, generally prohibits prescribing controlled substances via telehealth without a prior in-person examination, subject to certain very limited exceptions. Those exceptions include prescriptions issued during a public health emergency. Thus, since the January 31, 2020 declaration of a public health emergency due to the COVID-19 epidemic, eligible providers have been able to prescribe controlled substances, without a prior in-person visit with a patient, provided:

• The prescription is issued for a legitimate medical purpose by a practitioner acting in the usual course of his/her professional practice;
• The telemedicine communication is conducted using an audio-visual, real-time, two-way interactive communication system; and
• The practitioner is acting in accordance with applicable Federal and State laws.

The public health emergency is scheduled to end on May 11, 2023.

Read the client alert here.

BACKGROUND

On 28 April 2023, the UK’s medical devices regulator, the Medicines & Healthcare products Regulatory Agency (MHRA), announced its intention to extend the acceptance of CE marked medical devices in Great Britain (England, Scotland and Wales) beyond 30 June 2023.

Following the UK’s departure from the EU, CE marked medical devices can currently be placed on the Great Britain market under the existing transitional arrangements until 30 June 2023. The proposed extension will support the ongoing safe supply of medical devices to Great Britain and ease the transition to the future regulatory framework for medical devices.

The government intends to introduce regulations in the future that will implement a substantial reform of the current regulatory framework for medical devices in the UK and is now aiming for core aspects of the UK’s future regime for medical devices to apply from 1 July 2025.

PROPOSED EXTENSION TO TRANSITIONAL ARRANGEMENTS

The UK Medical Device Regulations 2002 (UK MDR) currently provide that the acceptance of CE marked medical devices on the Great Britain market will end on 30 June 2023. However, the MHRA intends to introduce legislation before 30 June 2023 which will provide that CE marked medical devices may be placed on the Great Britain market to the following timelines:

• General medical devices compliant with the EU medical devices directive (EU MDD) or EU active implantable medical devices directive (EU AIMDD) with a valid declaration and CE mark can be placed on the Great Britain market up until the sooner of (i) the expiry of the CE mark certificate or (ii) 30 June 2028;
• In vitro diagnostic medical devices (IVDs) compliant with the EU in vitro diagnostic medical devices directive (EU IVDD) can be placed on the Great Britain market up until the sooner of (i) the expiry of the CE mark certificate or (ii) 30 June 2030; and
• General medical devices, including custom-made devices, compliant with the EU medical devices regulation (EU MDR) and IVDs compliant with the EU in vitro diagnostic medical devices regulation (EU IVDR) can be placed on the Great Britain market up until 30 June 2030.

The above extensions will not include class I medical devices and general IVDs (for which the conformity assessment under EU MDD or EU IVDD did not involve a notified body), which can only be placed on the Great Britain market if the involvement of a notified body would be required under the EU MDR or IVDR (i.e., if it is an up-classified device or a reusable surgical instrument Class I device). Similarly, the extensions will not include custom-made devices that are compliant with the EU MDD or EU AIMDD, which can no longer be placed on the Great Britain market.

WHAT HAPPENS NEXT?

The legislation to implement the proposed extension will now be considered by the UK Parliament, and final approval is expected before 30 June 2023.

The U.S. Food and Drug Administration recently issued its draft guidance entitled “Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions.” The draft guidance follows the passage of the Food and Drug Omnibus Reform Act of 2022 (FDORA), which explicitly authorized the Agency to approve or clear Predetermined Change Control Plans (PCCPs).

We summarize some of the key takeaways from FDA’s draft guidance.  Read the client alert here.

On 26 April 2023, the European Commission published two legislative proposals – a new Regulation 2023/0131 and a new Directive 2023/0132 – to replace the current EU regulatory framework for all medicines (including those for rare diseases and for children).

The Directive contains all the requirements for authorisation, monitoring, labelling and regulatory protection, placing on the market and other regulatory procedures for all medicines authorised at the EU and national level. The Regulation sets specific rules (on top of the ones in the Directive) for medicines authorised at the EU level, in particular the most innovative ones.

The proposals aim to reduce costs, expedite the introduction of new medicines and prevent medicine shortages.

Read the key points in the client alert here.

The U.S. Food and Drug Administration (FDA) recently finalized its guidance, “A Risk-Based Approach to Monitoring of Clinical Investigations” (the “2023 RBM Guidance”) which follows up on the Agency’s March 2019 draft guidance (the “Draft Guidance”) of the same name and expands on (but does not supersede) the FDA’s August 2013 guidance, “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring” (the “2013 RBM Guidance”), with new recommendations summarized below to aid sponsors in implementing an effective and efficient risk-based approach to monitoring both risks to participants and to data integrity throughout all stages of clinical investigations of human drug and biological products, medical devices, and combination products.

(1) Approach: Identify, assess and re-assess risks. Create a plan to manage, mitigate, and/or eliminate those risks, including those risks that are newly identified or may not have been anticipated.

• Risk assessments should inform clinical trial protocol design, investigational plans, and monitoring plans and should be reevaluated and revised throughout the investigation. The monitoring plan should be comprehensive in highlighting identified risks, even those less likely to occur but that could have a significant impact on trial quality or subject safety, and should note how risks will be managed, mitigated, or eliminated.
• Consider how easily detectable the identified risks are, and the severity and consequences of those risks to human subject welfare and data quality if not detected and addressed.
• Assess systemic risks, as well as site-specific risks, and consider whether site-specific risks have the potential to become systemic risks.
• Determine an approach to on-site monitoring visits by taking into account the risks identified and the complexity and intensity of a clinical investigation. Monitoring activities should evolve based on risks identified during trials and should be proportionate to the risks to participants’ rights or safety or to data integrity.
• Implement a centralized monitoring approach to help minimize missing data and protocol deviations in real-time, such as through the use of electronic data capture systems.
• The risk assessment should guide how and to what extent source data verification (SDV) will be utilized during on-site monitoring visits.
• Establish processes to ensure appropriate blinding is maintained. Identify and monitor deviations which could result in unintentional unblinding.
• Be prepared during an FDA inspection to furnish documentation of the sponsor’s initial risk assessment, if requested.

(2) Content: Components of the monitoring plan should help explain how the sponsor intends to address the risks that could affect the investigation.

• Include the following components (in addition to those recommended in the 2013 RBM Guidance) in the monitoring plan:
  • Overall investigation design, including blinding and randomization procedures and processes for confirming randomization is performed according to the protocol and investigational plan
  • Sample plan(s), including rationale for, and approach to, identifying the records and data that will be monitored
  • Description of particular issues that would trigger immediate escalation
  • Approach for assessing and addressing a site issue that could escalate into a systemic issue that may warrant protocol or investigation plan changes
• Reference other clinical investigation management plans in the monitoring plan rather than repeating the information in the current monitoring plan to avoid inconsistencies.

(3) Communicate: Promptly address and communicate monitoring results to the appropriate parties to mitigate and eliminate risk.

• Perform monitoring in accordance with the pre-established monitoring plan and address issues as the monitor identifies them, including escalation, if needed.
• Perform a root-cause analysis of issues and promptly implement corrective and preventive actions (CAPAs).
• Consider amendments or revisions to the protocol or the investigational plan.
• Communicate and document significant issues to the relevant parties involved at the sponsor and site level, which may also include institutional review boards, data monitoring committees, and/or regulatory agencies, such as the FDA.
• Provide reports of monitoring activities in a timely manner to the site and discuss the findings with the clinical investigator and site staff. Reports should follow the 2013 RBM Guidance.

While the FDA’s regulations require sponsors to monitor the conduct and progress of their clinical investigations, there are no specifics on how sponsors are to conduct such monitoring. FDA’s guidance provides helpful direction on clinical trial monitoring while recognizing that a monitoring approach should evolve over the course of a trial as risk assessments evolve. Sponsors with upcoming or ongoing clinical trials should consider FDA’s recommendations in monitoring plan development and execution of monitoring activities throughout a trial.

On March 24, 2023, the FDA’s Center for Devices and Radiological Health announced the issuance of two much anticipated final guidances that describe the Agency’s transition plans for medical devices that fall within certain COVID-19 enforcement policies or that were issued emergency use authorizations (“EUA”s):

• Transition Plan for Medical Devices That Fall Within Enforcement Policies Issued During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency (the “Enforcement Policies Final Guidance”)

• Transition Plan for Medical Devices Issued Emergency Use Authorizations (EUAs) Related to Coronavirus Disease 2019 (COVID-19) (the “EUA Transition Final Guidance”)

The guidances follow the announcement in early 2023 that the Biden Administration plans to wind-down a number of pandemic-related programs and to allow the COVID-19 public health emergency (“PHE”) declaration, which has been in effect since January 2020, to expire on May 11, 2023.

We summarize some of the key takeaways from FDA’s finalized transition plans.  Read the client alert here.

Companies are developing, deploying, and interacting with artificial intelligence (AI) technologies more than ever. At Goodwin, we are keeping a close eye on any regulations that may affect companies operating in this cutting-edge space.

For companies operating in Europe, the landscape is governed by a number of in force and pending EU legislative acts, most notably the EU AI Act, which is expected to be passed later this year; it was covered in our prior client alert here: EU Technology Regulation: Watch List for 2023 and Beyond. The United Kingdom has recently indicated that it may take a different approach, as discussed in our client alert on the proposed framework for AI regulation in the United Kingdom here: Overview of the UK Government’s AI White Paper.

For companies operating in the United States, the landscape of AI regulation remains less clear. To date, there has been no serious consideration of a US analog to the EU AI Act or any sweeping federal legislation to govern the use of AI, nor is there any substantial state legislation in force (although there are state privacy laws that may extend to AI systems that process certain types of personal data).

Read the client alert here.

The U.S. Food and Drug Administration (FDA) recently issued General Considerations for Animal Studies Intended to Evaluate Medical Devices – Guidance for Industry and Food and Drug Administration Staff (fda.gov). Following a 2015 draft guidance and replacing a 2010 guidance focused on animal studies for cardiovascular devices, this guidance document identifies general considerations for animal studies intended to provide evidence of safety, including performance and handling, in device premarket submissions “when a suitable alternative to an animal study is not available.” Among other topics, the guidance provides recommendations related to personnel credentials, selecting an appropriate animal model, testing facility selection, and how to prepare an animal study report for premarket submissions to FDA. The Agency encourages sponsors with specific questions on an animal study, including the animal model selected, or compliance with FDA’s Good Laboratory Practice (GLP) regulations, or who seek to use a non-animal testing method, to request feedback from FDA through the Q-Submission process.

Since the beginning of the COVID-19 pandemic, the United States Food and Drug Administration (“FDA”) has issued more than eighty (80) guidance documents describing flexibilities that would be available to manufacturers of medical devices, drugs and biological products, and foods during the public health emergency.  Several of these guidance documents have been modified, updated, or withdrawn as circumstances have changed, and on March 13, 2023, the FDA issued a notice in the Federal Register that outlines how it intends to unwind a large swath of COVID-19-related guidance documents that are still in effect.  FDA sorted seventy-two (72) COVID-19-related guidances into several categories, based on how long and in what form they will continue to be in effect after the expiration of the public health emergency declaration, which is expected on May 11, 2023.

Read the client alert here.