On September 6, 2023, the US Food and Drug Administration (FDA) released a trio of draft guidances in its efforts to “strengthen and modernize” the 510(k) Program and provide for more “predictability, consistency, and transparency” for the 510(k) premarket review process. In this post, we discuss the two new draft guidances with broad applicability to the 510(k) Program:

• “Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission”
• “Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions”

The two draft guidances address a number of fundamental issues of concern with the 510(k) process.

Read the full client alert here.

Background

Earlier this year, the UK’s medicines regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), announced that a new International Recognition Procedure (IRP) will be put in place for the approval of new medicines from 1 January 2024. On 4 September 2023, the MHRA announced the publication of detailed guidance on this new procedure, which will replace the European Commission Decision Reliance Procedure (ECDRP). The Decentralised and Mutual Recognition Reliance Procedure (MRDCRP), which allows the MHRA to have regard to approvals in the EU through the decentralised and mutual recognition procedures, will be incorporated under the umbrella of the IRP.

European Commission Decision Reliance Procedure

The ECDRP was introduced post-Brexit as a temporary measure to try and ensure continued access to new medicines from the EU for patients in Great Britain until 31 December 2023.

Under the ECDRP, the MHRA may rely on a decision taken by the European Commission on the grant of a new marketing approval in the EU through the centralized procedure, in order to grant a new marketing approval in Great Britain more quickly.

International Recognition Procedure

From 1 January 2024, the MHRA will have regard to decisions already made by medicines regulators in Australia, Canada, the European Union, Japan, Singapore, Switzerland and the United States (Reference Regulators).

The IRP will be open to applicants that have already received a marketing approval for the same product from one of the MHRA’s specified Reference Regulators. The MHRA defines “same product” as “as having the same qualitative and quantitative composition (active substance(s) and excipients), and the same pharmaceutical form, from applicants belonging to the same company or group of companies or which are licensees.”

There are two procedures that can be used for initial applications for a new marketing approval using the IRP:

• Recognition A – applications under this procedure will be approved within 60 days (excluding clock stops), unless there are any major objections which cannot be resolved within 60 days. If this occurs, the timetable may revert to Recognition B. To qualify for this procedure, the Reference Regulator must have given approval for the product within the last two years, the manufacturing process must be unchanged and the product must not meet any of the 24 listed conditions of Recognition B.

• Recognition B – applications under this procedure will be approved within 110 days (excluding clock stops), unless there are any major objections at day 110. If this occurs, the timetable will then revert to 210 days and formal advice from the Committee for Medicinal Products for Human Use will be sought on approvability. To qualify for this procedure, the Reference Regulator must have given approval for the product within the last ten years, and at least one of 24 listed conditions must apply. The conditions include if the product is: (i) designated as an orphan medicinal product in Great Britain, (ii) an advanced therapy medicinal product, (iii) a cutting-edge technology, or (iv) a first-in-class active substance.

Practical Implications

The IRP will allow the MHRA to take into account the expertise and decision-making of trusted medicines regulators when approving a new medicine from 1 January 2024.

It is unclear if there are any specific requirements for choosing the Reference Regulator if the product is approved by more than one eligible medicines regulator.

As a final note, the IRP will sit alongside the MHRA’s current national procedures. Any ECDRP and MRDCRP applications for marketing approval received by the MHRA after 1 January 2024 will be assessed under the new IRP. Any ECDRP and MRDCRP applications for marketing approval received by the MHRA before 31 December 2023 will be assessed under the current ECDRP and MRDCRP respectively.

Throughout August 2023, the Office of Information and Regulatory Affairs, Office of Management and Budget, Executive Office of the President (“OIRA”) has held stakeholder meetings regarding a proposed rule which, if enacted, would amend the U.S. Food and Drug Administration’s  (“FDA’s”) regulations to make explicit that laboratory developed tests (“LDTs”) are devices under the Federal Food, Drug, and Cosmetic Act. The next stakeholder meeting on the proposed rule is scheduled for September 6, 2023.

Per its website, OIRA received the proposed rule from FDA on July 26, 2023. The proposed rule was initially published this past spring on the Biden Administration’s Unified Agenda of Regulatory and Deregulatory Actions with a target publication date of August 2023. The forthcoming stakeholder meeting on September 6th suggests that OIRA may continue its review process well into September, if not later.

The publication of the proposed rule would mark the first significant FDA action on LDTs since its two 2014 draft guidances (available here and here) and 2017 discussion paper. The proposed rule is also expected to be controversial after prior U.S. Department of Health & Human Services statements concerning regulation of LDTs and legislative attempts to further define the LDT regulatory framework. Once cleared by OIRA, the proposed rule will be published in the Federal Register and subject to public comment.

We will continue to monitor for updates on the LDT proposed rule. Contact Goodwin Life Sciences Regulatory & Compliance team members for any questions.

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.