The Bioresearch Monitoring (BIMO) Program, operated by the U.S. Food and Drug Administration (FDA), conducts on-site inspections and data audits in order to effectively monitor the compliance of all FDA-regulated research.

As a follow up to our June 2022 post, we highlight the most common violations identified in Fiscal Year (FY) 2022, in addition to those observed thus far in FY 2023.  BIMO conducted 766 inspections in FY 2022.  The majority of these inspections (approximately 79%) were of drug, biologic, or medical device study clinical investigators, institutional review boards (IRBs), sponsors, clinical research organizations (CROs), and sponsor-investigators.  Some of the most common inspection outcomes are highlighted below. Our methodology included a search of FDA’s Warning Letter database for FY 2022 and 2023, to date, for letters issued by BIMO and the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health to IRBs, CROs, clinical investigators, sponsors, and sponsor-investigators.

FY 2022:

BIMO conducted 504 inspections of clinical investigators (468 of which were assigned to FDA’s drug, biologic, and device Centers), making up over half of BIMO’s inspections conducted in FY 2022.  Inspections of IRBs, sponsors, CROs, and sponsor-investigators assigned to FDA’s drug, biologic, and device Centers comprised another 138 inspections in FY 2022. Of the 504 clinical investigator inspections, only 9 resulted in a classification of “Official Action Indicated” (OAI) and 87 resulted in a classification of “Voluntary Action Indicated” (VAI). The most common inspection observations included: (1) failure to comply with Form FDA 1572 requirements and protocol compliance; (2) failure to follow the investigational plan and protocol deviations; (3) inadequate and/or inaccurate case history records and inadequate study records; (4) inadequate accountability and/or control of the investigational product; (5) safety reporting and failure to report and/or record adverse events; and (6) inadequate subject protection and informed consent issues.

Of the Warning Letters that were issued in FY 2022 to clinical investigators, the most common observations were:

• Failure to ensure that a clinical investigation was conducted according to its investigational plan. This finding in various Warning Letters included failure to properly consent participants, failure to properly randomize participants, and/or failure to properly screen potential participants to ensure they met a protocol’s inclusion and exclusion criteria prior to enrollment in an investigational plan. For example, in one Warning Letter, an investigator did not ensure that subjects randomized to a specific intervention group received the assigned investigational drug for that intervention group and did not adhere to the blinding protocol.
• Failure to submit an IND application for the conduct of a clinical investigation with an investigational new drug. For example (and similar to trends observed in FY 2021), the FDA noted that one clinical investigator failed to submit an IND for the use of a product that was determined by the FDA to be a drug. The study design demonstrated that the investigational product was intended to cure, mitigate, and/or treat a disease or condition and therefore, an IND application should have been submitted to the FDA prior to commencing any research activities. Another Warning Letter included a finding that a protocol comprised of a combination product (a drug and device component) required an IND application.

BIMO conducted 81 inspections of sponsors and CROs in FY 2022 (all but one were assigned to FDA’s drug, biologic, and device Centers). Of these, 0 resulted in a finding of OAI, though 15 were classified as VAI. The most common inspection observations included: (1) failure to ensure proper monitoring of the study and ensure the study is conducted in accordance with the protocol and/or investigational plan; (2) failure to meet the abbreviated requirements for investigational device exemptions (IDEs); (3) failure to maintain and/or retain adequate records in accordance with 21 CFR 312.57; (4) accountability for the investigational product; (5) failure to comply with Form FDA 1572 requirements; (6) financial disclosures; (7) failure to submit an Investigational New Drug (IND) application and IND safety reports; and (8) failure to submit current list of all participating investigators to FDA at the six-month interval after FDA approval of the study.

FY 2023 Trends (to date): 

In 2023, we have already observed six Form FDA 483 Warning Letters issued to clinical investigators and IRBs, three involving the failure to submit an IND for the conduct of a clinical investigation with an investigational new drug, two involving failure to follow the clinical investigation according to its investigational plan, and one involving overall lack of IRB oversight and IRB compliance. For example, in a 2023 Warning Letter issued to an IRB, the FDA noted that the IRB: (a) failed to review proposed research at convened meetings at which a majority of IRB members were present; (b) failed to maintain adequate documentation of IRB activities, including keeping an active list of active IRB members; and (c) failed to ensure that information provided to study subjects as part of the informed consent process was done in accordance with applicable FDA regulations. Although sponsors may often make the decision to utilize a central IRB to oversee the conduct of a clinical investigation, some participating sites may be required to utilize their own local IRB, and it is important to remember that any IRB which does not adhere to FDA’s requirements can introduce a compliance risk for studies it is engaged to oversee.

Sponsors, clinical investigators, CROs, and IRBs should review the FDA’s BIMO Compliance Program Guidance Manuals regularly to ensure that they understand their responsibilities when carrying out clinical research involving human subjects. Sponsors, clinical investigators, CROs, and IRBs should ensure inspection readiness at all times while bioresearch is ongoing and following completion of bioresearch that may support marketing applications submitted to the FDA. Ensuring diligence in the research site selection process, careful monitoring during clinical trials, and corrective actions when deviations occur can help manage the risk of inspection findings of noncompliance or Warning Letters issued by the FDA. The Goodwin Life Sciences Regulatory & Compliance team provides regulatory counseling on FDA’s Good Clinical Practice requirements and the resolution of BIMO inspection findings and Warning Letters when they occur.

Contact our team to learn more.

As the life sciences industry continues to expand and grow increasingly complex, so does its legal, regulatory, and compliance landscape. To help companies and investors navigate the many evolving and emerging laws and regulations across pharmaceuticals, biologics, medical devices, diagnostics, and laboratory testing, our Life Sciences Regulatory & Compliance team regularly tracks and stays closely connect to a comprehensive list of ongoing legal and regulatory developments in the industry. We update and publish a quarterly tracker detailing these developments. You can read about the Q3 2023 updates here.

We recently published an alert in relation to the European Commission’s legislative proposals to replace the current EU regulatory framework for all medicines (including those for rare diseases and for children). One of the major elements of the proposals is a change to the legislation governing orphan medicines for rare diseases, which we examine in more detail in the client alert here.

Based on recent regulatory changes at the state and local level and the efforts by the federal government and certain foreign agencies, investors, clinical trial sponsors, life sciences companies, and investigators operating in the psychedelics industry may have reason to be optimistic about the future regulatory landscape for therapeutic psychedelic product candidate development, approval, and commercialization. The proposed Breakthrough Therapies Act is one such reason.

On March 8, 2023, US Sens. Cory Booker (D-NJ) and Rand Paul (R-KY) introduced an updated version of the Breakthrough Therapies Act. If passed, the bipartisan bill would amend the federal Controlled Substances Act (CSA) to enable the Drug Enforcement Administration (DEA) to reclassify from Schedule I to Schedule II drugs and biologics, including therapeutic psychedelics, that receive breakthrough therapy designation or are authorized for expanded access by the US Food and Drug Administration (FDA). Therapeutic psychedelics are Schedule I substances and include LSD, MDMA, and psilocybin. According to the bill’s sponsors, the “legislation [would] remove regulatory hurdles that inhibit research and compassionate use access to potentially lifesaving treatments that are heavily restricted by Schedule I of the [CSA].”

The bipartisan effort behind the Breakthrough Therapies Act signals the federal government’s evolving position on psychedelic substances, their therapeutic potential, and access. This evolution, discussed in greater detail in our Client Alert, presents an important opportunity for investors, clinical trial sponsors, life sciences companies, and investigators.

Accordingly, we have identified and answered 8 key questions that stakeholders should consider as they develop and innovate in the psychedelic space:

• What Is the Difference Between a Schedule I and a Schedule II Drug?
• What Diseases and Conditions Can Potentially Benefit From Therapeutic Psychedelics?
• What Are the Key Provisions of the Proposed Breakthrough Therapies Act?
• How Does a Drug or Biologic Obtain Breakthrough Therapy Designation From FDA?
• What Is Expanded Access?
• What Are Some Key Limitations in the Proposed Breakthrough Therapies Act?
• What Is the Status of Therapeutic Psychedelics at the State and Local Level?
• What Regulatory Changes Are on the Horizon for Therapeutic Psychedelics?

Read the full client alert here.

For a healthcare or life sciences company settling a government enforcement action, the prospect of being subject to an independent monitor, independent review organization (IRO), or other government-mandated compliance expert may become a reality. (We collectively refer to all of these individuals and entities as monitors throughout this update.) Hiring an independent monitor is a sensitive topic, as a company subject to a monitorship is required to open up its records and files, financial information, proprietary and confidential materials, IT assets, and employees to a third party — often at frequent and regular intervals, and often for a period of five years — not to mention the potential multimillion-dollar expense associated with the engagement.

Read the client alert here.

We recently published an alert in relation to the European Commission’s legislative proposals to replace the current EU regulatory framework for all medicines (including those for rare diseases and for children). One of the major elements of the proposals is a change to the period of regulatory data protection for medicines, which we examine in more detail in the client alert here.

Since the declaration of the public health emergency due to the COVID-19 epidemic, Drug Enforcement Administration (DEA) registered practitioners have been able to prescribe controlled substances, without a prior in-person visit with a patient, subject to certain conditions as outlined in our earlier blog post. Additionally, DEA waived the requirement for practitioners to obtain additional registrations with DEA in the states where the dispensing (including prescribing, and administering) occurs, for the duration of the public health emergency, if the practitioner registers with DEA in at least one state and has permission under state law to practice using controlled substances in the state where the dispensing occurs.

In anticipation of the expiration of the public health emergency on May 11, 2023, on March 1, 2023, DEA and the Department of Health and Human Services issued two notices of proposed rulemakings (NPRMs), reviewed in our earlier blog post, to authorize the prescription of controlled substances based on a telehealth consultation in certain limited circumstances. The NPRMs received over 38,000 comments from the public, all of which DEA will review to implement revisions to the NPRMs and develop a permanent rule.

Since the permanent rule is still in development, on May 10, 2023, just one day before the end of the public health emergency, DEA and the Substance Abuse and Mental Health Services Administration published a temporary rule that extends the public health emergency telemedicine flexibilities[1] for the prescription of controlled substance medications until November 11, 2023.

The temporary rule, which took effect on May 11, 2023, allows DEA-registered practitioners to prescribe controlled substance medications under the public health emergency telemedicine flexibilities to all patients through November 11, 2023. Additionally, until November 11, 2024, DEA-registered practitioners are further permitted to prescribe controlled substance medications under the public health emergency telemedicine flexibilities to patients if the practitioner established a telemedicine relationship with the patient on or before November 11, 2023. In other words, if a provider and patient established a telemedicine relationship on or before November 11, 2023, the same public health emergency telemedicine flexibilities that previously governed the relationship will apply until November 11, 2024.

In the text of the rule, DEA notes that it plans to issue one or more final rules, based on the two proposed rules, which will extend certain telemedicine flexibilities on a permanent basis and ensure a smooth transition for patients and practitioners that rely on the availability of telemedicine for controlled substance medications.

Follow our blog to receive additional updates and alerts on the DEA’s proposed rules regarding extension of the COVID-19 telemedicine flexibilities for the prescription of controlled substance medications.

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[1] In the temporary rule, the DEA references the DEA letter that authorized certain telemedicine flexibilities, including the waiver exceptions related to DEA registrations in individuals states and the in-person evaluation requirement.

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.