1. Deputy Director, Division of Biostatistics No Conflict of Interest
Statistical Design and Analysis for Medical Device Trials with a Regulatory Perspective
Lilly Yue, Ph.D.
Deputy Director, Division of Biostatistics
CDRH/FDA
CRT 2013, Washington, DC
Feb. 25, 2013
No Conflict of Interest

2. I/we have no real or apparent conflicts of interest to report.
Lilly Yue, PhD
I/we have no real or apparent conflicts of interest to report.

3. Today’s Topics Clinical Device Development Study Design Study Conduct
Study Analysis

4. Clinical Device Development
Three Stages for new medical devices or significant changes to marketed devices:
Exploratory (first-in-human, feasibility)
Allow for any iterative improvement of device design
Advance the understanding of how the device works and its safety
Set stage for the pivotal study
Pivotal
Generate valid scientific evidence to support the primary safety and effectiveness evaluation of device for its intended use.
Post-market
Design improvement,
Better understanding of device safety and effectiveness
Development of new intended uses

5. Today’s Topics Clinical Device Development Study Design Study Conduct
Study Analysis

6. Study Design Study objectives Subject selection
Study objectives should provide support for the intended use of device, including any desired labeling claims.
Subject selection
Subjects selected should adequately reflect the target population for the device, based on specific inclusion/exclusion criteria.
In considering the target population, FDA encourages sponsors to enroll subjects that would reflect the demographics of the affected population with regard to age, sex, race and ethnicity.
Study should be properly powered with sufficient number of subjects.

7. Study Design Study site (center) selection
A multicenter study may assure a more representative sample of the target population and make it easier to generalize the findings of the study.
Where applicable, special care should be taken to ensure that the study sites will include subjects who reflect the epidemiological distribution of the disease being treated with respect to variables such as sex, age, race, ethnicity and socio-economic status.
It may be important to consider diversity of sites in terms of investigator or operator experience.
To support a PMA in U.S., sufficient information of device performance on U.S. patients is essential.

8. Study Design Key study variables (clinical endpoints) selection
The endpoints should be clinically meaningful and statistically appropriate, and relevant to the stated study objectives and desired intended use.
Whenever possible, the endpoint should be objective, be internally and externally valid, and determined with minimal bias.
The endpoints should be carefully selected to avoid a situation where they are undefined or may be unobtainable for a substantial proportion of subjects.
Use of surrogate endpoints may be appropriate when they are validated and directly correlated to clinical benefit.

9. Study Design Example: Coronary study endpoints
Clinical composite TLF (target lesion failure) endpoint: CV death, target vessel MI, and target lesion revascularization
Surrogate endpoint: angiographic late lumen loss (LLL), which correlates strongly with target lesion revascularization
The clinical TLF composite is typically used as the combined primary safety and effectiveness endpoint in pivotal trials for new coronary drug-eluting stents.
The surrogate late lumen loss may be considered as a primary effectiveness endpoint for an iterative change(s) to an approved stent. 

10. Study Design Type of study
Comparative study with a comparator (control)
Randomized Controlled Trials (RCT)
Observational studies with concurrent or historical control.
Non-comparative study (single-arm study with OPC or PC)
RCT is gold standard.
Non-randomized (observational) studies could play a substantial role in the pre-market and post-market evaluation of medical device.
However, there are limitations with observational studies which could compromise the objectivity of resulting study results.

11. Study Design Statistical hypothesis testing
Depends on study objectives, primary endpoints and control
Should be clinically meaningful and statistically appropriate
Example: Coronary drug eluting stent: Primary endpoint: TVF
Control: BMS  superiority hypothesis
Approved DES -> could be non-inferiority or superiority
Assume DES (exp) v.s. DES (ctr), non-inferiority
Study hypothesis: P(DES, exp) – P (DES, ctr) < δ , non-inferiority margin
δ should be clinically relevant and acceptable, and practical
Need to make sure that the choice of delta does not lead to a situation where the new DES is not much better or even worse than BMS. E.g.
if P(BMS) = 14%, P (DES, ctr) = 7%, then δ = 5% may not be good!

12. Today’s Topics Clinical Device Development Study Design Study Conduct
Study Analysis

13. Study Conduct
The study protocol should be strictly followed and all types of protocol deviations, including those deemed minor, should be minimized.
Study subjects should be consistently and completely followed according to the study protocol.
Great effort should be made in the study design and conduct phases to reduce the occurrence and impact of missing data due to subject loss-to-follow-up.
The study data should be carefully protected to prevent biases due to early looks unless explicitly pre-planned in the Statistical Analysis Plan.

14. Today’s Topics Clinical Device Development Study Design Study Conduct
Study Analysis

15. Study Analysis
Statistical Analysis Plan (SAP) should be well developed in design stage and pre-specified in study protocol.
Study success criteria
Study hypotheses
Sample size estimation
Statistical methods used
……..
In data analysis, some important issues should be addressed, e.g., center effect, data poolability, subgroup of interest, missing data, and reliability of study results.

16. Concluding Remarks
Good study design, conduct and analysis are essential in establishing the safety and effectiveness of a medical device.
Pivotal clinical study design draft guidance: Design Considerations for Pivotal Clinical Investigations for Medical Devices