Kathleen Sanzo

	The US Food and Drug Administration (FDA or Agency) published a final rule on FDA’s standards for accepting data from clinical investigations for medical devices on February 21.

 Under the new rule, FDA is requiring sponsors and applicants to affirm that clinical investigations outside the United States were conducted in accordance with Good Clinical Practices (GCPs) when the data are submitted for medical device applications. The final rule also amends criteria for investigations conducted within the United States to require applicants and sponsors to state that the investigation complies with FDA regulations for human subject protection, institutional review boards, and investigational device exemptions (IDEs).

 If an investigation is not conducted in accordance with those regulations, a brief statement of the reason for the noncompliance is required.

	FDA also published a guidance document, 

Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions

 (Guidance), to clarify requirements outlined in the final rule.

	The effective date for the rule is February 21, 2019, one year after its publication. The regulations will not be applied to clinical investigations outside the United States that begin prior to the effective date, meaning studies that enroll their first subjects before February 21, 2019. A subject is considered enrolled when the subject or subject’s authorized representative agrees to participate in the study by signing the informed consent form. Foreign investigations that enroll their first subjects prior to the rule’s effective date will be subject to the old requirements in 21 CFR § 814.15 regulating premarket approval (PMA) applications. For these investigations, FDA will accept the data if the data is valid and the investigators have conducted the studies in conformance with the 

 or the laws and regulations of the country in which the research is conducted.

	The rule applies to data obtained from clinical investigations conducted outside the United States, inside the United States, or both outside and inside the United States that are intended to support an investigational device exemption (IDE) application, a premarket notification (510(k)) submission, a request for De Novo classification, a PMA application, a product development protocol (PDP) application, or a humanitarian device exemption (HDE).

Clinical Investigations Outside the United States

	The final rule establishes 21 CFR § 812.28, which identifies criteria for FDA acceptance of data from clinical investigations conducted outside the United States. The criteria require the investigations to be conducted in accordance with GCPs, replacing prior PMA regulations and creating new regulations for IDE applications and other device marketing applications that previously did not address acceptance of data from clinical studies conducted outside the United States.

	FDA states that it does not intend to regulate clinical investigations conducted outside the United States and the rule does not identify a specific GCP standard for sponsors and applicants to follow.

 Instead, the rule defines a GCP as “a standard for design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical investigations in a way that provides assurance that the data and results are credible and accurate and that the rights, safety, and well-being of subjects are protected. GCP includes review and approval . . . by an independent ethics committee (IEC) before initiating an investigation, continuing review of an ongoing investigation by an IEC, and obtaining and documenting the freely given informed consent of the subject . . . before initiating an investigation.”

	This definition allows sponsors flexibility to choose an appropriate standard to use that will produce data to support an application or submission to FDA that is consistent with the local laws and regulations of the foreign country where the research is being conducted. If needed, the rule allows sponsors and applicants to explain why a GCP was not followed and to describe the steps taken to ensure integrity of the data and protection of the human subjects.

 In addition, the rule outlines a waiver provision that allows sponsors and applicants to request a waiver from the criteria if a country’s clinical investigation requirements prevent a sponsor from complying with GCPs.

 Diagnostic Devices Using De-identified Specimens

 diagnostic (IVD) devices using leftover de-identified specimens.

 FDA states that it intends to continue exercising enforcement discretion for not obtaining informed consent under circumstances described in this guidance, and the Agency will not object if sponsors and applicants follow this guidance for similar IVD investigations conducted outside the United States, provided there is no other conflict with local laws and regulations.

	A sponsor or an applicant submitting data from outside the United States is now required to include a description of the actions taken to ensure the research conducted conformed to GCPs. The supporting information must include the information outlined in Section 812.28(b). The level of information will vary based on the level of risk of the investigation, with significant risk device investigations requiring more supporting information, as described in FDA’s accompanying Guidance.

	Notably, FDA states that it may need to review documents such as medical records to verify data, whether through an onsite investigation or a request for documents. Therefore, FDA recommends including a statement in the informed consent documents that international regulatory authorities may need to have access to a subject’s medical records, which FDA requires to be retained for at least two years after the Agency has issued a decision.

	Finally, as FDA states in the Guidance, while the supporting information required by the new rule addresses acceptance of clinical data in terms of quality and integrity, other factors including the applicability of the investigations to the US population and medical practice should also be considered.

Multicenter Clinical Investigations Conducted Inside and Outside the United States

	The preamble notes that for multicenter investigations with sites both inside and outside the United States, each site is required to comply with the local requirements. Thus, clinical investigations conducted in the United States would be subject to 21 CFR §§ 50, 56, and 812 and investigations conducted outside the United States would be required to comply with 21 CFR § 812.28. The sponsor or applicant may provide a statement addressing compliance with FDA regulations and a statement regarding conformance of GCPs along with the supporting information when necessary.

	· Medical device companies will now need to implement new standard operating procedures and systems including audit processes to ensure GCP compliance for ex-US clinical trials.

	· Additional education of contract research organizations (CROs) and ex-US clinical trial sites around GCP compliance will be necessary.

	· Clinical trial agreements will need to be modified to require representations concerning GCP compliance.

	· Additional costs of GCP compliance may affect strategic decisions about where to conduct future clinical trials (within versus outside the United States).

 US Food & Drug Admin., Human Subject Protection; Acceptance of Data from Clinical Investigations for Medical Devices, 

 (Feb. 21, 2018) (hereinafter Medical Device Rule).

 US Food & Drug Admin., Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions, Guidance for Industry and Food and Drug Administration Staff, (Feb. 21, 2018).

 Diagnostic Device Studies Using Leftover Human Specimens That Are Not Individually Identifiable

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The FDA published a final rule on FDA’s standards for accepting data from clinical investigations for medical devices on February 21.

FDA Issues Final Rule on Data Acceptance from Clinical Investigations for Medical Devices

	As precision medicine gains momentum and in vitro diagnostics (IVDs) become increasingly used in clinical trials, pharma and biotech companies will need to develop expertise in evaluating IVD risk and, if working with IVD partners, to develop processes to ensure the partner is also properly considering risk and filing appropriate regulatory documents consistent with clinical trial timelines.

	· Be aware that the IVD you plan to use in your clinical trial may be considered a Significant Risk (“SR”) device and require an Investigational Device Exemption (“IDE”).

	· Make sure the clinical trial team is working closely with the IVD manufacturer to assess the risk status of the IVD as it is used in the clinical trial; understand the level of validation of the test, including any software used; and understand how it will affect the design and implementation of the trial.

	· Incorporate the IVD review and possible IDE submission into the clinical trial timeline.

	· Ensure the IVD manufacturer has the regulatory experience and data to support a successful IDE, if necessary, or assume responsibilities for the IDE submission.

	· Prepare for early dialogue with the IRB reviewing the trial about the risk status of the test, how it potentially affects study subject safety, and appropriate informed consent discussion.

	· Have systems and controls in place to reassess throughout the trial the risk status of the IVD.

	On January 5, 2018 FDA issued a new draft Guidance on Investigational IVDs Used in Clinical Investigations of Therapeutic Products

. Based on concerns that drug clinical trial sponsors do not appreciate the need to follow device regulations when using “investigational” IVDs in clinical trials, the new guidance provides more structure around the incorporation of IVDs into clinical trials, and sets out FDA’s expectations about sponsor’s scope of review of the risk of use of such IVDs.

	The draft Guidelines will need to be factored into how pharma clinical trial sponsors use IVDs in a clinical trial, study design, timeline for protocol development, IND submission, and study initiation.

	The burden to properly assess the risk presented by the use of an IVD in a clinical trial is on the clinical trial sponsor and its IRB. Under the draft Guidelines, FDA intends Sponsors to:

	1) notify its IRB of the use of investigational IVDs in clinical trials, even if the IRB does not request information;

	2) provide the IRB with a risk assessment of the IVD in the clinical trial;

	3) if the IVD presents a significant risk as it is used in the clinical trial, obtain either through or with the IVD manufacturer an IDE (see below section on Q submission meetings to obtain FDA advice on this determination);

	4) continually assess the risk status of the IVD throughout the clinical trial, and if it changes from non-significant (NS) to significant, obtain an IDE;

	5) ensure the lab processing the IVD is CLIA compliant.

	FDA/CDRH will provide risk assessments for IVDs if requested or meet with clinical trial sponsors to discuss the need for an IDE in “Q” submission meetings before starting the clinical trial to discuss questions about IVD risk, study design, and regulatory requirements.

Exchanging Data with the IND Manufacturer Will Be Necessary

	Whether the IVD risk status is determined with or without specific FDA guidance, there will be a need for the drug and device manufacturer to exchange trade secret/confidential information. This can be accomplished between the parties through and non-disclosure agreement or, if there is a need to provide the information about the IVD to FDA, either as part of a meeting package or in a filing (IND or IDE), FDA recommends the use of Master Files and Letters of Authorization (LOAs) between the parties to give FDA access to reference and/or discuss relevant IVD materials.

	An IVD is considered an investigational device if it has not yet been cleared or approved by FDA for its intended use. FDA states that if a clinical trial will provide data about the safety or efficacy of an IVD, it is subject to the IDE requirements under 21 C.F.R. Part 812. These requirements will apply whether or not the IVD manufacturer intends to seek FDA clearance/approval for the IVD or commercialize the IVD.

	AN IVP will be considered “significant risk” if the IVD is for a use of  . . . “(3) substantial importance in diagnosing. . . or otherwise preventing impairment of human health and presents a 

 for serious risk to health or safety or welfare of a subject” or “(4) otherwise presents a potential for serious risk to health, safety or welfare to a subject.” 21 C.F.R. 812.3 (m) (3)-(4). Thus, the risk status can be dependent on the clinical consequences of erroneous or inaccurate results under this criteria, or potentially on the sampling procedures used to obtain tissue for the IVD. An IVD could present a significant risk if it:

	· produces incorrect test results that lead to misdiagnosis and/or mismanagement of a subject’s care;

	· produces a false positive for certain markers that could cause subjects to be exposed to toxic therapies without any benefit;

	· requires invasive or additional specimen sampling (biopsy or surgery) that may pose serious risk (note: additional blood draws do not increase risk);

	· produces test results that may lead to some subjects foregoing treatment known to be effective or delaying treatment in a way that they could irreversibly degrade their health condition;

	· produces test results that may expose subjects to safety risks/ adverse events that exceed the risks of the control arm therapy or standard of care.

	Note that, as clinical evidence around a biomarker’s positive or negative relationship increases during a trial, a non-significant risk IVD may become a significant risk IVD, so increasing data must be monitored in an ongoing basis. Other clinical consequences that can affect the IVD risk assessment include:

	· using it to include/exclude certain subjects

	· using it to determine likelihood of experiencing Serious Adverse Events (“SAEs”)

	· monitoring effect to adjust dose or other aspect of care

	· stratification or randomization of study subjects

	o equipment, reagents and supplies, calibration and control materials

	o installation requirements and calibration parameters

	o description of any analytes detectable by the IVD (e.g., SNPs, gene rearrangements, PCR primers and probe design)

	o all software and the level of software validation available for the software

	o type of specimens and collection technologies

	o intended use of the IVD, e.g., analyte to be detected and how it relates to the investigational therapy; does the IVD produce a quantitative or qualitative result

	o disease/condition, population, frequency of test, intent to treat vs. (not to treat) population

	o description of cut-off values (i.e., clinical decision points)

	o test performance and analytical validity

	o preclinical or clinical information on the IVD performance

	o benefit-risk assessment: why the benefits to the study subjects outweigh their exposure to the IVD from invasive sampling to potential erroneous results

	· If the IDE is adequate for review, FDA will review it within 30 days from receipt of IDE and notify the Sponsor by letter.

	· FDA can approve an IDE with conditions, which would allow the Sponsor to proceed to enroll subjects while it responds to FDA’s conditions within 45 days.

	· If resolution of any issue needs to occur before subject enrollment, the IDE will be disapproved and the study cannot be initiated.

	As precision medicine gains momentum and IVDs become increasingly used in clinical trials, pharma and biotech companies will need to develop expertise in evaluating IVD risk, and, if intended to be delegated to IVD partners, processes to ensure the partner is also properly considering risk and filing appropriate regulatory documents consistent with clinical trial timelines.

Morgan Lewis & Bockius LLP partners Kathleen Sanzo and Michele Buenafe advise clients on regulatory, compliance, and enforcement issues related to the development, manufacturing, marketing, labeling, and advertising of medical devices, human tissue products, pharmaceuticals, controlled substances, listed chemicals, and combination products.

This article is provided as a general informational service and it should not be construed as imparting legal advice on any specific matter.

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm589083.pdf

 FDA does not address in these draft Guidelines the use in clinical trials of Laboratory Developed Tests, i.e., IVDs developed and used solely within one laboratory.  If an LDT is being used in a clinical trial, the trial sponsor should have evidence to support the LDT status.  See 

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm416685.pdf

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm416684.pdf

The FDA's new draft IVD Guidelines will need to be factored into how pharma clinical trial sponsors use IVDs in a clinical trial, study design, timeline for protocol development, IND submission, and study initiation.

Kathleen Sanzo

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FDA Issues Final Rule on Data Acceptance from Clinical Investigations for Medical Devices

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