FDA Innovation Pathway and Extension of Comment Period on Medical Device 510K Process

 

Over the past year or so, there has been a tremendous amount of attention on the Food and Drug Administration (FDA) regarding the approval of medical devices, particularly through the pathway commonly known as 510(k).  This past summer, the Institute of Medicine (IOM) published a report and recommendations on changing the 510(k) process, which is the most commonly used pathway that medical device manufacturers use to get medical devices approved. 

FDA recently extended its comment period to November 28, 2011, on its draft guidance intended to clarify what would warrant a new 510(k) premarket notification application for modified medical devices. “This will allow adequate time for interested persons to submit comments without significantly delaying action by the agency,” the FDA said in a notice. 

Since the IOM report was published, a number of congressional hearings have been held and many reports from industry, consumers, and patient groups have been published regarding medical device approval.  Most industry stakeholders assert that the FDA device approval process is cumbersome and not transparent, causing investor fear and resulting in unpredictability.  

The Center for Devices and Radiological Health (CDRH) as well as FDA as a whole have proposed and begun to implement several new ideas and programs to help speed up medical device approval, such as the Innovation Pathway.  Consequently, continuing in the direction of increased transparency for the medical device approval process, FDA recently released a Draft Guidance for Industry: Clinical Investigators, Institutional Review Boards, and Food and Drug Administration Staff FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations. 

Comments will be accepted for 90 days from publication of the Federal Register notice. Submit written or electronic comments, with Docket No. FDA–2011–D–0790 to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852 or http://www.regulations.gov.  

For questions regarding this document, contact (CDRH) Owen Faris, 301-796-6356 or Owen.Faris@fda.hhs.gov or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800. 

Background 

FDA seeks to encourage medical device research and innovation to address important clinical needs and improve patient care. In many cases, device development and evaluation includes clinical investigation. The guidance document was developed to promote the initiation of clinical investigations to evaluate medical devices under FDA’s Investigational Device Exemptions (IDE) regulations, Title 21 Code of Federal Regulations (CFR) Part 812. 

FDA approval of an IDE submission allows the initiation of a clinical investigation of a significant risk device. FDA defines a “significant risk device” under 21 CFR 812.3(m) as an investigational device that: 

(1)  Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

(2)  Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;

(3)  Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or

(4)  Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.  

The guidance is intended to provide clarification regarding the regulatory implications of the decisions that FDA may render based on review of an IDE and to provide a general explanation of the reasons for those decisions. 

In an effort to promote timely initiation of clinical investigations in a manner that protects study subjects, FDA has developed methods to allow a clinical investigation of a device to begin under certain circumstances, even when there are outstanding issues regarding the IDE submission. These mechanisms, including approval with conditions, staged approval, staged through future considerations, are described in this guidance.

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. 

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. 

IDE Decisions  

FDA’s regulations describe FDA actions on an IDE: 

(a) Approval or disapproval. FDA will notify the sponsor in writing of the date it receives an application. FDA may approve an investigation as proposed, approve it with modifications, or disapprove it. An investigation may not begin until: 

(1) Thirty days after FDA receives the application at the address in 812.19 for the investigation of a device other than a banned device, unless FDA notifies the sponsor that the investigation may not begin; or 

(2) FDA approves, by order, an IDE for the investigation 

Thus, FDA’s regulations provide for three FDA actions on IDE applications: 

• Approval
  • Approval with Conditions – FDA has traditionally referred to IDE approvals that have conditions as “Conditional Approvals.”  FDA believes that the term “Approval with Conditions” is more appropriate because the term conveys that the IDE has been approved and may begin without awaiting further FDA review. )
  • Disapproval  

FDA must inform the sponsor or sponsor-investigator (defined under 21 CFR 812.3(n) and (o), respectively) of its decision, or must notify the sponsor that the investigation may not begin, within 30 days from the date of receipt of the IDE application, or the IDE application will be deemed approved. If an IDE application is approved or approved with conditions, the sponsor may begin subject enrollment with the number of subjects and investigational sites specified in FDA’s decision letter upon receipt of Institutional Review Board (IRB) approval; the IRB approval may occur prior to FDA approval. 

If FDA does not have outstanding issues that must be addressed to support the study of the subject cohort under the proposed investigational plan, then the IDE will be approved without conditions.  Alternatively, if FDA has identified issues that must be addressed but do not preclude initiation of the clinical investigation, the IDE will be approved with conditions. 

In the case of approval with conditions, approval is granted on the condition that, within a specified timeframe from the date of FDA’s decision letter, usually 45 days, the sponsor submits information addressing the issues identified in FDA’s letter.  In certain instances, resolution of outstanding issues before subject enrollment may be necessary. In these instances, the IDE will be disapproved, meaning that the sponsor may not initiate enrollment in the clinical investigation until the sponsor responds to the issues identified in FDA’s letter and receives an approval or approval with conditions letter.

IDE Approval  

If FDA approves an IDE application and IRB approval is obtained, the sponsor may begin subject enrollment in accordance with the limits described in FDA’s decision letter, including the maximum number of subjects and investigational centers.  FDA will approve an IDE application without conditions when the IDE sponsor has submitted data and an adequate clinical investigation plan that support initiation of the study in humans.  This assessment is based primarily on FDA’s review of considerations discussed below, in addition to other issues specific to the application. 

In some cases, FDA may determine that an outstanding issue remains but that the IDE application can still be approved and the issue can be addressed with data that will be gathered in parallel with the enrollment of some portion of study subjects (i.e., staged approval).  In other cases, FDA may inform the sponsor of an issue that FDA believes should be considered in preparation for a marketing application or a future clinical investigation (i.e., future consideration). 

IDE Approval with Conditions  

If FDA approves an IDE application with conditions, the sponsor may begin subject enrollment upon receipt of IRB approval on the condition that, within 45 days from the date of FDA’s decision letter, the sponsor submits information addressing the issues identified in FDA’s letter.  An IDE may be approved with conditions if FDA has determined, despite outstanding issues, that the information provided is sufficient to justify human clinical evaluation of the device, and that the proposed study design is generally acceptable. 

Previously known as “conditional approval,” the phrase “approval with conditions” will now be used to convey that the outstanding issues do not raise concerns that preclude FDA from granting approval for initiation of the clinical investigation.  Therefore, resolution of those issues is not required prior to initiation of enrollment in the study, with exception of issues related to the informed consent document. 

If FDA identifies issues with an informed consent document, those issues must be addressed before enrollment begins in order to ensure that informed consent is obtained in accordance with 21 CFR Part 50 – Protection of Human Subjects. Outstanding issues that may lead to approval with conditions include: 

• Issues related to data analysis methods and handling if the corrections will occur prior to the gathering of important study data;
• Issues related to late stage follow-up procedures and assessments, if the corrections are made prior to beginning any late-stage procedures or assessments;
• Minor divergences from what FDA considers appropriate study endpoints, design assumptions, or key definitions;
• Issues related to the informed consent document that must be corrected before enrolling subjects but can be reviewed by FDA after study initiation;
• Requests for additional information or data involving non-clinical testing issues that do not need to be resolved prior to study initiation;
• Other minor clarifications, corrections, or modifications that do not need to be resolved prior to review completion.  

The sponsor must submit a supplement to the IDE to respond to the issues raised in FDA’s approval with conditions letter, usually within 45 days; otherwise, the IDE will be disapproved.  For each issue identified in FDA’s letter, an acceptable response provides the specific information or modification(s) requested by FDA.  In some cases, the sponsor may choose to provide a scientifically valid alternative to FDA’s request or to provide a scientifically valid rationale for why the information or modification(s) is not needed. 

FDA will inform the sponsor of its decision within 30 calendar days from the date of receipt of the supplement.  If FDA determines that the issues have been adequately resolved, FDA will grant approval without conditions.  However, if any issues remain, FDA may again grant approval with conditions and will communicate the remaining outstanding issues to the sponsor by letter. In this case, the sponsor may continue to enroll subjects in the study on the condition that, within 45 days, the sponsor responds to the remaining issues identified in FDA’s letter.  In some cases, a sponsor’s unsatisfactory response to FDA’s questions could result in FDA withdrawing approval of the IDE. 

Staged Approval or Staged Approval with Conditions  

The guidance defines a process, termed “staged approval” or “staged approval with conditions” by which FDA may grant IDE approval or approval with conditions, while certain outstanding questions are answered in parallel with enrollment in the clinical investigation.  Staged approval and staged approval with conditions permit the clinical investigation to begin in a timely manner while maintaining appropriate subject protections. 

Under staged clinical investigations, FDA will grant approval or approval with conditions for a subset of the planned subject cohort while the particular outstanding questions are addressed.  If FDA and the sponsor have agreed to the additional data that will be provided and there are no other outstanding issues to be addressed (i.e. under approval with conditions), a staged clinical investigation can receive approval without conditions, with enrollment limited to the number of subjects to be enrolled in the first stage. 

The size of the enrollment stages and the timing for the reporting of additional information should ideally be designed so that study enrollment does not need to be halted during the trial if the data submitted to address the outstanding issue(s) are acceptable.  The sponsor will be permitted to expand enrollment once an IDE supplement, which includes the necessary additional information, is submitted to FDA for review and found to be acceptable. A staged clinical investigation may be appropriate in the following situations: 

• FDA believes it is necessary to obtain clinical confirmation of the safety profile of a device or the potential for benefit by reviewing the data from subjects enrolled early in the clinical investigation before exposing the entire subject cohort to the risks of the device and the clinical investigation.
• Information has been provided that is sufficient to justify enrollment of a portion of the subjects in the clinical investigation.
  • However, long-term non-clinical testing is also required and will be conducted in parallel with early enrollment in the clinical investigation.
  • The results of the long-term non-clinical testing can be validated before FDA permits enrollment of the entire subject cohort.  

Staged approval or staged approval with conditions is most common for pivotal studies (i.e., studies that are designed to provide the primary clinical evidence to support a marketing application) in which many subjects will be enrolled over an extended period of time, but are specific to staged pivotal studies include: 

• Successful support of a marketing application under staged approval is not expected until the full planned cohort of subjects is studied.
• A staged pivotal study should only be considered if the additional information that is requested is not expected to result in changes to important elements of the clinical investigation (e.g., endpoints, sample size, stopping rules) or device design. If the information is expected to result in changes to important elements of the trial or device design, then a separate feasibility study may be more appropriate. In some cases, prospectively defined adaptive design techniques may allow for a pivotal study to accommodate pre-planned study changes based on data gathered early in the study without the need for additional feasibility data.
• If FDA determines that new feasibility data are needed prior to approval of the proposed pivotal IDE that was submitted for review, FDA may choose to grant approval of the IDE for a limited number of subjects on the condition that the sponsor considers the study to be a feasibility study rather than a pivotal study. The data from the feasibility study may be used to inform the design and support IDE approval for a future pivotal study.
• The data requested by FDA should not inappropriately unblind any of the relevant stakeholders, including the sponsor, investigators, or study management personnel, to critical study data. If the data that are needed will necessarily unblind these stakeholders to critical study elements, then a feasibility study may be more appropriate to answer these questions.  

Future Considerations in Approval, Approval with Conditions, or Disapproval Letters  

Future considerations are issues or recommendations communicated in an approval, approval with conditions, or disapproval letter that FDA believes the sponsor should consider in preparation for a marketing application or a future clinical investigation. Future considerations are intended to provide helpful advice to sponsors regarding important elements of the future application that the IDE may not specifically address. Examples of typical future considerations include discussion of:

 

• Known limitations of the IDE clinical investigation with regard to supporting certain claims or indications. For example, FDA may remind the sponsor that due to a specific exclusion criterion, any approved Indication for Use based on the investigation may be limited to that particular population and not a broader one.
• Potential limitations of the IDE that depend on currently unknown variables. For example, if FDA believes the sponsor may have slightly overestimated the effect  of the device relative to the control, FDA may wish to advise the sponsor that the clinical investigation may be underpowered to achieve its goals.
• Specific analyses that FDA will expect to see in the marketing application. For example, if the clinical investigation is being conducted in US and non-US populations, FDA may wish to inform the sponsor that FDA will expect to receive analyses demonstrating that the US and non-US data can be pooled.
• Specific non-clinical testing that, while not necessary to support approval of the IDE, will be needed to support the marketing application. For example, FDA may have accepted shorter term device durability testing to support IDE approval but may remind the sponsor that longer term testing will be needed.  

IDE Disapproval  

If an IDE application is disapproved, the sponsor may not initiate the clinical investigation until the sponsor submits an amendment to the IDE to respond to the deficiencies identified in FDA’s letter and subsequently receives a new letter from FDA granting approval or approval with conditions. There are five major reasons why FDA may disapprove an IDE, as discussed in 21 CFR 812.30(b):

There has been a failure to comply with any requirement of this part or the act, any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA.

1. The application or a report contains an untrue statement of a material fact, or omits material information required by this part.
2. The sponsor fails to respond to a request for additional information within the time prescribed by FDA.
3. There is reason to believe that the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or informed consent is inadequate, or the investigation is scientifically unsound, or there is reason to believe that the device as used is ineffective.
4. It is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of:

                      i.        The report of prior investigations or the   investigational plan;

                    ii.        The methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or

                   iii.        Monitoring and review of the investigation.

Consistent with this regulation, FDA will generally disapprove an IDE for any of the following reasons: 

• The data provided are insufficient to adequately characterize the safety profile of the device such that, based on the data provided thus far, human clinical investigation is not considered reasonable.
• The potential risks of the proposed study are not justified.
• The proposed study design or analysis plan is inadequate. This is most applicable to pivotal studies since many elements of the study design can impact the potential for the clinical investigation to support a future marketing application. Such elements include: primary safety and effectiveness endpoints, key study design assumptions, important enrollment criteria, and important study procedures and assessment methodologies.  

As noted in 21 CFR 812.30(c)(1), a disapproval letter will contain a complete statement of the reasons for disapproval. If the sponsor submits an IDE application that contains major fundamental flaws that preclude approval, FDA’s identified deficiencies may describe broad concerns rather than contain a comprehensive list of each of FDA’s specific concerns. 

In addition, FDA’s review may not focus on elements of the IDE that are likely to be substantially changed by the sponsor in order to address FDA’s broader concerns.  In such cases, FDA’s complete statement of the reasons for disapproval will clearly identify the fundamental deficiencies.   

Once the sponsor submits an amendment to the IDE submission to address the broad concerns that have been identified, FDA can complete a substantive review of the submission. FDA may advise the sponsor that a pre-submission discussion may be helpful prior to the sponsor formally responding to the IDE disapproval. Where appropriate, sponsors should consider requesting a pre-submission meeting before submitting an IDE. 

Major Considerations for IDE Applications  

FDA considers many factors when determining whether an IDE should be approved. Important factors that FDA considers, although not intended to be a comprehensive list, include:                 

• Non-clinical Testing: FDA reviews for safety and performance of the device. Depends on several factors, including: whether the device is an in vitro diagnostic, an implanted device, or a device external to the body; the duration of use; and the expected performance requirements. Examples of bench data that may be needed include testing to demonstrate acceptable biocompatibility, sterilization, electrical performance, mechanical performance and durability, drug or biologic characteristics for combination products, and software validation. In many cases, animal data may also be needed and/or performance in in vivo conditions to support initiation of a clinical investigation.
• Category of Clinical Investigation:  May impact FDA’s assessment of which elements of the IDE application are most important with regard to IDE approval.
• Risk Assessment: Whether the expected risks to study subjects are reasonable. Considers many factors, including the severity of the medical condition, the patient population being studied, the current treatment options that are available to potential study subjects, and the evidence provided to support the potential for benefit to study subjects. FDA may be more willing to accept a higher risk profile or a lesser initial demonstration of potential benefit if the medical condition is serious and/or the available treatment options are limited.
• Study Design Elements: FDA will consider the device characteristics and risk profile, the medical condition being studied, and the goals of the clinical investigation. For feasibility studies, FDA’s review will generally focus on subject safety issues, enrollment criteria, clinical methodology, and whether the information that will be gathered is appropriate to support the study goals (e.g., to support the design and initiation of a future pivotal study). For pivotal studies, FDA will focus on primary safety and effectiveness endpoints, assessment methodologies, randomization and blinding, the statistical analysis plan, case report forms, monitoring plans, and the use of external review bodies (e.g., Data Monitoring Committees, Clinical Events Committees, and core labs). If a proposed pivotal study is unlikely to generate data that would support marketing clearance or approval, FDA may consider it unreasonable to expose study subjects to the risks of the device and may therefore disapprove the study.
• Informed Consent Document: In order to support approval of the IDE, the informed consent document must meet the requirements of 21 CFR Part 50. Additional information on informed consent can be found on FDA’s website.
• Least Burdensome: FDA defines the term “least burdensome” as a successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA.

Supplements to Approved IDEs

Supplements to approved IDEs are submitted for several reasons, including the following:

To request approval for or to notify FDA of changes to the clinical investigation or the investigational device (guidance)  

• To provide the annual or final IDE reports to FDA;
• To report to FDA on unanticipated adverse events or other information related to the ongoing clinical investigation; or
• To request approval for Compassionate Use or to notify FDA of an Emergency Use.18

For IDE supplements that require FDA approval, the FDA decision process is similar to that described for original IDE submissions, with the same decision options (i.e., approval, approval with conditions, and disapproval) and review and response timelines. 

A notable difference between FDA’s review of such supplements and the review of an original IDE submission is that FDA disapproval of the supplement does not imply that the IDE study itself is disapproved. For example, if a supplement to an approved IDE requests approval for changes to the clinical investigation and that supplement is disapproved, the sponsor may not implement the requested changes. 

However, the original IDE clinical investigation remains approved and may continue. For IDE supplements that are notifications or reports, FDA will respond to the sponsor within 30 days if FDA has questions or requests for additional information; otherwise, FDA may close the submission without issuing a formal response to the sponsor.