What is a Medical Device?
Section 201(h) of the Food, Drugs, and Cosmetics Act defines a medical device as any healthcare product that does not achieve its principal intended purposes by chemical action or metabolized.
Medical Device Classes
- Class I — General Controls — Most exempt from premarket submission.
- Class II — Special Controls — Premarket Notification [510(k)].
- Class III — Premarket Approval — Require Premarket Application [PMA].
510(k) Premarket Notification
- Substantial equivalence.
- 10–15% require clinical data.
- Performance testing.
- Usually confirmatory.
- Type of study dictated by
- The ability of bench and animal testing to answer questions.
- Amount of difference between subject device and predicate.
PMA Premarket Approval Application
- Establish reasonable assurance of safety and effectiveness.
- Clinical Studies.
- Feasibility and pivotal.
Stages of Review for PMA Device
- Pre-Sub: Discuss the device design, bench/animal testing, and the clinical trial
- IDE: Request approval for a clinical trial.
- PMA: Request market approval.
- PMA-S: Request approval for device change or upgrade.
What is an Investigational Device Exemption (IDE)?
The FDA approval of an IDE is required for US human study of a significant risk device that is not approved for the study's indication.
Device trials are unique.
- Trials tend to be smaller than drug trials.
- Some novel, many “me-too.”
- Many difficult to blind, randomize, and control.
- Many depend on physician technique.
- Device modifications occur during the trial.
- Endpoints are highly diverse.
- Typically, a single pivotal trial follows the feasibility stage(s).
- Designed to support a “reasonable assurance of safety and effectiveness” for the marketing application.
Types of IDEs
- May provide support for a future pivotal study or may be used to answer basic research questions.
- Not intended to be the primary support for a marketing application.
- Endpoints and sample size are generally not statistically driven.
- Often required by the FDA before the pivotal study to assess basic safety and potential for effectiveness.
- Generally ~10–40 patients but may be larger.
- The FDA review is primarily focused on safety and whether the data's potential benefit or value justifies the risk.
- Designed to demonstrate a “reasonable assurance of safety and effectiveness. ness.”
- Generally intended as the primary clinical support for a marketing application.
- Endpoints and sample size are statistically driven.
- Designed to assess both safety and effectiveness.
- FDA review is much more complex.
Basic Submission Elements
Background of medical issue, the study goals, and why this study will further the science.
A Detailed Description of the Device Understudy
- Previous studies (preclinical and clinical).
- Summary of available data.
- Why is a clinical study needed at this stage?
- What evidence supports this study/device's safety and the study data's potential to be meaningful?
- Are there outstanding safety questions that should be addressed with preclinical data?
- What are the potential risks to the patient?
- Does the study mitigate the risks where possible?
- Are the risks outweighed by the potential for benefit and/or value of the study?
- Patient monitoring and follow-up plan.
- Inclusion and exclusion criteria.
- Informed consent document.
- Sample size and the number of investigational centers, with justification.
Submission Elements, Pivotal IDEs
Primary and Secondary Endpoints
Discussion of the appropriateness of endpoint parameters, hypotheses, and success criteria
Basic Trial Design
- Controlled? If not, why not?
- Randomized? If not, why not?
- Blinded? If not, why not?
Trial Conduct and Study Monitoring
- Sponsor blinding
- Data handling and adjudication process
- Independent committees
- Case report forms
- Is the right information being gathered to support the study endpoints, and are investigators adequately prompted to report adverse events?
Primary Endpoint Design
Should evaluate the safety and effectiveness of the device in the population expected to be indicated.
- Generally divided into 1 or more “safety” endpoints and 1 or more “effectiveness” endpoints.
- A study will be considered successful if both the safety and effectiveness endpoints are met.
- The clinical protocol should clearly and prospectively detail: — Methods for obtaining endpoint data — Definitions for what will be counted as a primary event in the analysis — Situations in which patient data will be excluded — How missing data will be handled — How the impact of covariates will be assessed.
Sample Size & Follow-Up
Driven by either:
- Primary safety endpoint
- Primary effectiveness endpoint
The minimum number of patients and/or minimum duration of follow-up may be required depending on:
- Understanding of the device's safety and effectiveness
- concerns regarding the durability of device safety or effectiveness.
Generally used to evaluate additional meaningful claims.
- Generally only considered if primary endpoints are successful.
- It should be used to provide further insight into the device's effects and mechanisms of action.
- Definitions and analysis methods should be clearly detailed prospectively.
- Not considered “statistically significant” unless a pre-specified alpha allocation plan is in the protocol, even if the p-value is < 0.05.
FDA’s IDE Review Decisions
- Approval — Approves the trial for a specified number of patients and investigational centers.
- Approval with Conditions — Allows sponsor to begin the trial if the sponsor agrees to address the conditions (deficiencies) from the conditional approval letter within 45 days.
- Disapproval — The trial may not start until the sponsor addresses the letter's deficiencies, submits this information to the FDA, and receives approval.
One size does not fit all for device trials. Pivotal studies should be designed to evaluate whether there is a “reasonable assurance of safety and effectiveness.” PMA approbation is based upon a Benefit-Risk assessment that strongly considers the outcome of primary safety and effectiveness endpoints. Secondary endpoints are generally used to support claims if the primary endpoints are successful. All endpoint analyses and definitions should be clearly pre-specified in the approved clinical protocol.