Medical Device Development Tools

(PDF – 150kb)

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Document issued on: November 14, 2013

You should submit comments and suggestions regarding this draft document within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this document, contact Katie O’Callaghan at 301-796-6349 or by electronic mail at [email protected].

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health

Preface

Additional Copies

Additional copies are available from the Internet. You may also send an e-mail request to [email protected] to receive an electronic copy of the guidance or send a fax request to 301-847-8149 to receive a hard copy. Please use the document number (1882) to identify the guidance you are requesting.

Table of Contents

1. INTRODUCTION
2. BACKGROUND
3. DEFINITION OF KEY CONCEPTS
4. OVERVIEW of CDRH QUALIFICATION POLICY
5. CONCEPTUAL FRAMEWORK
   1. Context of Use
   2. Tool Types
   3. Regulatory Considerations and Related Recommendations
6. CONSIDERATIONS FOR QUALIFICATION
   1. Considerations for CDRH Qualification
   2. Contents of a Complete Qualification Package
7. CDRH QUALIFICATION PROCESS
   • Stage 1: Pre-Qualification (Optional)
   • Stage 2: Qualification Determination
8. PROCEDURES FOR SUBMITTING MDDT CORRESPONDENCE AND DOCUMENTS
9. PROCEDURES FOR MAKING QUALIFICATION DECISIONS AVAILABLE

• APPENDIX 1 – SAMPLE OUTLINE OF PACKAGE CONTENTS

---

Medical Device Development Tools – Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

1, the results of an assessment that uses an MDDT can be relied upon to support device development and regulatory decision-making.

The intent of this voluntary CDRH qualification policy is to (1) enable faster, more efficient development of important life-saving and health promoting medical devices, (2) promote the development of tools to facilitate more timely device evaluation, (3) provide a mechanism to better leverage advances in regulatory science, and (4) more quickly and more clearly communicate to stakeholders about important advances in regulatory science that may be leveraged to speed device development and regulatory evaluation. We expect the qualification process to expedite development of publicly available tools which could potentially be used widely in multiple device development programs. Once an MDDT is qualified for a specific context of use, FDA’s expectation is that it can be used by any medical device developer for that context of use. CDRH reviewers should accept the MDDT for the qualified context of use without the need to reconfirm the suitability of the MDDT. Importantly, the existence of a qualified MDDT does not convey a requirement that the tool must be used during the device development or regulatory evaluation process. Other scientifically valid tools or approaches may also be used.

CDRH is committed to advancing regulatory science, which provides the tools, standards, and approaches needed to evaluate the safety, effectiveness, quality, and performance of the products we regulate. Through continued advances, such as this qualification process, we are modernizing the regulatory evaluation process and reducing the time and resources needed to develop and assess new products. This promotes innovation, supports the manufacture of high quality products, and speeds the rate at which safe and effective technologies reach the market.

2 Examples of BT include: an instrument or method for measuring blood pressure (e.g., sphygmomanometry); an instrument or method for measuring certain concentrations of serum proteins.

A Nonclinical Assessment Model (NAM) is a nonclinical test method or model used in device development or evaluation that reflects device function or in vivo performance. A NAM could be an in vitro (“bench”) model, animal model, or computational model and is developed to measure a parameter of interest or to substitute for another generally accepted test or measurement. Examples of NAM include: in vitro models to replace animal testing, the use of tissue and other material phantoms to evaluate imaging devices, electromagnetic phantoms, and validated computational models.

3

• For selection of clinical trial subjects
• To stratify patient population by predicted risk

Clinical Endpoints⁴

• As an intermediate endpoint⁵
• As a surrogate endpoint⁶

Non-clinical Device Assessment

• Bench or animal study methodologies which reduce test duration or minimize sample size
• As a substitute for an evaluation typically conducted through human or animal studies
• Reliance on in vitro or in silico studies to reduce or minimize the use of animals

The MDDT may also have potential value outside these boundaries. The MDDT may be used in device development programs for a different purpose other than the qualified context of use, subject to review and discussion with CDRH on a case-by-case basis. In addition, the qualified context of use for the MDDT may be expanded over time as additional data are obtained. If data become available that call into question the validity, appropriateness, or assessment of advantages and disadvantages of a previously qualified context of use, CDRH may modify or withdraw the qualification.

B. Tool Types

CDRH recognizes three types of MDDT, distinguished primarily by how the tool measures relevant parameters. Tools that measure clinical parameters via some subjective metric are Clinical Outcome Assessments (COA). Tools that measure clinical parameters via an objective approach (e.g., physical measurement or chemical analysis) are considered Biomarker Tests (BT). Tools that measure nonclinical parameters are categorized as Nonclinical Assessment Models (NAM). These MDDT types are further detailed below.

1. Clinical Outcome Assessment

A Clinical outcome assessments (COAs) is a subjective measures of how a patient feels or functions, and is sometimes used to determine whether or not a device demonstrates a treatment benefit. COAs include patient-reported, clinician-reported, and observer-reported outcome measures and are typically instruments composed of a scale or score. A widely used example is the NIH Stroke Scale.

The reporter (i.e. clinician, patient, or other observer) of the outcome distinguishes the type of COA. A clinician-reported outcome (ClinRO) assessment is based on clinical observation and interpretation by a trained clinician. An observer-reported outcome (ObsRO) is assessed by observers without the need for clinical expertise. Patient reported outcomes (PROs)⁷ are a common subtype of COA. They are a measurement of the patient’s health condition based on a direct patient (i.e., study subject) report without amendment or interpretation by someone else.

A COA includes not only the measure that produces a score but also the clearly defined methods and instructions for administration of the tool, a standard format for data collection, and well-documented methods for scoring, analysis, and interpretation of results in the targeted patient population. COAs can measure treatment benefit directly (e.g., a PRO for pain intensity) or indirectly (e.g., a diary of rescue pain medication use for pain intensity). Qualification of a COA as an MDDT includes a review of the evidence that the proposed tool is a valid assessment for how patients feel or function in day-to-day activities.

Other clinical outcomes based on subjective clinical decision-making may also be qualified as MDDTs if they may be used to assess a treatment benefit. Examples may include hospitalization rate or reoperation rate.

CDRH intends to qualify a COA based on a determination that for a specified context of use, assessment of a clinical outcome using the COA provides valid scientific evidence when used in a well-controlled investigation (see 21 CFR 860.7).

2. Biomarker Test

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or responses to a therapeutic intervention. A biomarker can be a physiologic, pathologic, or anatomic characteristic or measurement that relates to an aspect of normal or abnormal biologic function or process. Typically, a biomarker is measured using a test (e.g., by chemical analysis) or instrument (e.g., by sphygmomanometry). CDRH intends to consider MDDTs derived from medical imaging to be BTs, if the characteristic (e.g., tumor diameter) is objectively measured.

As with other MDDTs, CDRH intends for qualified BTs to be relied upon to support device-related regulatory decision-making for the defined context of use. BTs may be used to select patients for inclusion in a device clinical trial, to monitor treatment response, to predict or identify safety problems related to treatment with a medical device, or to identify patients who are or are not candidates for certain forms of therapy. Appropriate use of qualified BTs may increase the efficiency of the device development and evaluation process by providing reliable predictions about device performance.

Fundamentally, in order for a BT to be useful, it must be sufficiently accurate and precise. When considering BTs for qualification, the evaluation will assess both the strength of evidence supporting the biomarker for the specified context of use, as well as the validity of the test instrument and/or methodology to measure the biomarker. In qualifying a BT, FDA implicitly accepts the strength of evidence supporting the biomarker for the specified context of use. Subsequent BTs seeking qualification for similar contexts of use need only demonstrate the validity of the test instrument and/or methodology to measure that same biomarker.

The amount and type of new evidence needed to support qualification of a BT will depend on whether there is any test or instrument for measurement of the biomarker that is already FDA cleared or approved for clinical use through premarket review, and if so, whether the proposed context of use for the BT is consistent with the indication for use of the cleared or approved product. To qualify a BT to measure a biomarker for which there is no corresponding FDA cleared or approved device, test validity (e.g., precision and accuracy) should be demonstrated in the proposed context of use. In contrast, MDDT qualification proposals involving an FDA cleared or approved test, or involving biomarkers for which FDA has established the analytical performance criteria necessary for measurement for the specified context of use, can make use of existing data that support the analytical validity of the test, so long as the MDDT submitter is legally authorized to do so. In either case, qualification depends on meeting performance criteria for the test or instrument’s accuracy, precision, etc. as an MDDT in the proposed context of use.

Importantly, the processes and criteria for qualification of a BT as an MDDT remain distinct from requirements for pre-market product review, even when the products (biomarker test for use in device development and legally marketed medical device), the objects of the product (biomarker and analyte) and inferences drawn (biology and clinical significance) are similar or identical. However, information developed for pre-market review, such as analytical validity, may be potentially relevant to qualification of a BT, even when the proposed context of use differs from the cleared or approved indication for use of the device. The MDDT submission should clearly identify the elements of BT qualification (Section VI) that are addressed using information from a premarket submission.

MDDT qualification determinations will in no way affect the regulatory or compliance status of any product intended for commercial distribution (see Section C).

3. Nonclinical Assessment Model

A nonclinical assessment model (NAM) is a nonclinical test method or model that reflects device function or in vivo performance and is used in device evaluation to measure a parameter of interest, or to substitute for another generally accepted test or measurement. NAM examples include in vitro models that replace or minimize the need for animal testing; the use of tissue and other material phantoms to evaluate imaging devices; validated computational models; and the development and validation of a new animal model to evaluate a device in lieu of clinical data.

Qualified NAMs may be used to evaluate a new material property, modifications to an existing design, or a device feature historically evaluated through animal or human testing. The MDDT qualification process and standards recognition process⁸ may be viewed as complementary. We anticipate that NAM qualification may be most useful for models or methods which are not yet covered by standards or guidance.

In some cases, an MDDT which is addressed in an FDA-recognized consensus standard may have already been assessed in a manner similar to the MDDT qualification process and qualification for the same context would likely not be beneficial.  However, for those that have not, assessments conducted during development of the standard might contribute evidence toward MDDT qualification (e.g., round-robin testing conducted by the standards organization to assess tool validity).  In addition, models proposed for different contexts of use or which necessitate different or more specific methodology than described in existing standards could also potentially be qualified through the MDDT process.

C. Regulatory Considerations and Related Recommendations

Some MDDTs may meet the definition of a device in section 201(h) of the FDC Act and be subject to the statutory and regulatory requirements applicable to devices, such as 510(k) clearance or premarket approval. Devices intended for investigational use are exempt from most of these requirements, including clearance and approval, as long as there is compliance with applicable investigational use requirements, such as those under 21 CFR part 812. A qualified MDDT typically would be used in the research or investigation of a medical device, according to the MDDT’s context of use. Such use would generally exempt a qualified MDDT that is a device from clearance, approval, and other device requirements, as long as a clinical investigation meets applicable requirements:

• If the device that is the subject of the investigation is a significant risk⁹ device as defined by 812.3(m), the investigation, including use of the MDDT, is subject to all requirements of 21 CFR 812.
• If the device that is the subject of the investigation is not a significant risk device as defined by 812.3(m), the abbreviated requirements listed under 812.2(b) apply to the investigation, including the use of the MDDT.
• Investigations, including the use of the MDDT, that meet the criteria for one of the exemptions described in 812.2(c), including 812.2(c)(3), are not required to comply with part 812 with the exception of 812.119.

For qualified MDDTs that are devices that are not cleared, approved, or 510(k)-exempt, any statement that the device has been qualified by FDA should be accompanied by a disclaimer that qualification of an MDDT does not constitute FDA clearance or approval. Without such a disclaimer, the labeling could be considered misleading, which would render the device misbranded under sections 201(n) and 502(a) of the FDC Act. If an MDDT appears to be a “device” under the FDC Act, we will discuss these issues with you during the qualification process.

10

Capture. Does the MDDT fully capture the aggregate effect of the intervention on the true outcome of interest? Does the MDDT account for every major effect of the intervention? Are there available data which call this into question?

The amount and strength of evidence needed to support qualification of an MDDT will vary depending on the context of use and the MDDT type. For example, an MDDT proposed for use as one component of a definition of an adverse event (AE) within a clinical study may need less data compared to a BT proposed for use measuring a primary endpoint for a pivotal study to evaluate a novel high-risk device type; the latter use may need more evidence of its validity due to the potential disadvantages of accepting an inaccurate MDDT in this context.

4. Assessment of Advantages and Disadvantages

As part of the qualification determination, CDRH intends to consider an assessment of advantages and disadvantages for qualification of the MDDT. The qualification package should discuss the advantages and disadvantages of accepting the MDDT. CDRH intends to consider the following factors:

• Assessments of Advantages of Using the MDDT: This should take into account the following factors:
  • The type of advantage(s). Advantages may include: significantly accelerating the time to develop and evaluate devices; allowing for shorter or smaller clinical or nonclinical studies; allowing for safer or less invasive, easier, more convenient, or less variable measurements than the alternative; and expediting the development of a novel technology of public health importance.
  • Magnitude of advantage. This may include: whether there is a potential to impact multiple device development programs; whether the context of use includes life-threatening and/or serious chronic diseases or conditions, or diseases/conditions where there are no or poor alternatives; or whether the MDDT is to be used for novel technology where there is no established paradigm for regulatory assessment.
  • Likelihood of an advantage. This is based on the strength of evidence (tool validity, plausibility, correlation/prediction, capture) in support of the MDDT, and a comparison to the available alternatives.
• Assessments of Disadvantages of Using the MDDT: This should take into account the following factors:
  • Type(s) of risks. Considering the context of use, what types of decisions might be made based on the use of an MDDT that should not have been qualified? These are considered within the context of use, including: 1) the device or product area in which the MDDT is proposed to be qualified, 2) the stage of device development (design evaluation, animal testing, early clinical study, pivotal clinical studies to support market application, post-market design changes); and 3) the specific role of the MDDT (for clinical uses, this includes the study population or disease characteristics, as well as specific use – diagnosis, patient selection, clinical endpoints).
  • Magnitude of risk. The scope of impact of making a decision based on inaccurate conclusions from an MDDT is based on the severity of risk, a comparison of the MDDT to its alternatives, and considering the context of use.
  • Likelihood of risk. How likely is a particular risk to occur? This could be based on the evidence in support of tool validity. For a diagnostic test, this could be the likelihood of the MDDT reporting a false positive, false negative or false estimate of predictive value.
  • Risk mitigation. The use of mitigations may minimize the risks of relying on the MDDT. For example, alternative sources of information or confirmatory data from later timepoints may mitigate risks of decision-making based on information from an MDDT.
• Additional Factors for Assessing Advantages and Disadvantages of Using the MDDT: The following factors may apply:
  • Degree of certainty. If the advantages of using the MDDT are high, less certainty (less rigorous strength of evidence) may be acceptable to support its use. On the other hand, if the advantages are minimal, or if the potential disadvantages are great, more rigorous evidence may be needed to support MDDT use.
  • Novelty of technology. The assessment will consider whether MDDTs facilitate development and regulatory evaluation of devices that address areas of unmet need, or that incorporate new technologies (especially first-of-a-kind) which may offer advantages that did not previously exist. Particularly where providers and patients have limited alternatives available, MDDT use may facilitate patient access and encourage innovation.

5. Consent to Public Disclosure and Use

In order to obtain FDA qualification, MDDT submitters must provide authorized consent (1) for FDA to make public sufficient information to support use of the qualified MDDT and (2) for the general public to use the MDDT and rely on data generated using the MDDT in gaining FDA clearance or approval of other devices.

11 Submitters should include an eCopy¹² as well.

The Cover Letter should contain the following elements:

• Date:
• Subject: (in bold print) MDDT QUALIFICATION SUBMISSION
• MDDT Type: (in bold print)
  • CLINICAL OUTCOME ASSESSMENT,
  • BIOMARKER TEST, or
  • NONCLINICAL ASSESSMENT MODEL
• MDDT Tracking Record Number: (in bold print), if previously assigned
• Submission Type: (in bold print)
  • REQUEST FOR PRELIMINARY DISCUSSION or PRE-QUALIFICATION PROPOSAL or
  • INTERIM CORRESPONDENCE or
  • QUALIFICATION PACKAGE.
• MDDT Name(s): (in bold print): Identify the specific MDDT (by name) that is being submitted
• Context of Use: Describe the intended context of use of the MDDT (1 to 2 sentences)
• Complete submitter contact information including name(s), affiliation, mailing address, email address, phone and fax numbers

In Vitro Companion Diagnostic Devices” for FDA’s proposed approach on this topic.

Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Many of the issues described in that guidance are also relevant to ClinROs and ObsROs.

⁸ Information on CDRH’s standards program is available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Standards/default.htm.

Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors – Significant Risk and Nonsignificant Risk Medical Device Studies).

eCopy Program for Medical Device Submissions Guidance for Industry and Food and Drug Administration Staff.  Although submission of an eCopy for an MDDT Qualification Submission is voluntary, if you choose to submit an eCopy, it should meet the technical standards outlined in Attachment 1 of the referenced guidance.