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Careful advance design of clinical trial may avoid problems later
The FDA’s senior medical advisor outlines the basics of successful clinical trials for bringing ophthalmic devices to the U.S. market.
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Ophthalmologists who invent new medical devices face the daunting task of shepherding their creations through the U.S. regulatory approval process before they can come to market. To guide these entrepreneurs on the journey toward approval, a physician and government regulatory advisor recently spoke about the steps involved in properly designing a clinical trial for an ophthalmic device.
At the ASCRS Summer Refractive Congress in Seattle, Malvina B. Eydelman, MD, described for attendees the framework for designing a clinical trial for an ophthalmic device. Dr. Eydelman is an ophthalmologist and the Food and Drug Administration’s Senior Medical Advisor for the Division of Ophthalmic and ENT Devices.
“There is no way I can teach you all you must know in a brief presentation,” Dr. Eydelman said. “I am hoping that today’s talk will help you navigate through the regulatory maze in the least burdensome way.”
She recommended that inventors or sponsors of clinical trials should work with the FDA ahead of time to ensure that the design of their study is appropriate. This can save time and trouble trying to fix a flawed design at a later point, she said.
“I strongly encourage all of you who are in the process of designing a clinical study to come in and talk with the division and try to figure out what safety and efficacy endpoints the FDA will find acceptable for your devices,” Dr. Eydelman said.
Is it a device?
The first thing the inventor must do after creating a product is to determine what category it belongs in: whether it is a biologic, a drug or a device, Dr. Eydelman explained. She said a product is considered a medical device if it “diagnoses, cures, mitigates, treats or prevents a disease or condition, affects the function or structure of the body, is not metabolized and does not achieve its intended use through chemical action.”
After determining that one’s product is indeed a device, Dr. Eydelman recommended going to the FDA Web site to determine the classification of the device, check the availability of guidance and review any relevant FDA-recognized standards.
Classification
All medical devices are assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device, Dr. Eydelman said.
“The class to which your device is assigned determines, among other things, the type of premarketing submission and application required for FDA clearance to market,” she said.
There are three classes of devices. Class 1 devices are low risk, of simple design and usually exempt from premarket submissions. Class 2 devices are more complex, involving higher risk and requiring a premarket notification, known as a 510(k). Class 3 devices carry the highest level of risk to the patient or the user and usually require a premarket application (PMA), she explained.
“Class 3 is the most complex. The PMA needs to show the device is reasonably safe and effective for its intended use,” she said.
Guidance and standards
After determining the classification of the device, Dr. Eydelman recommended, the inventor or sponsor should check the availability of FDA guidances and recognized standards.
A guidance is different from a regulation in that it is nonbinding, she said.
“A guideance describes the FDA’s interpretation of or policy on a regulatory issue,” Dr. Eydelman said.
“If guidance for clinical studies of the device type in question is available, it is extremely helpful to the sponsor because it can explain the regulatory pathway, study design, protocol, analysis and data presentation,” she said.
Similarly, recognized standards can help a sponsor to determine the preclinical testing and study parameters needed and to outline the recommended clinical trial. Some standards provide specifics about trial design, duration, inclusion and exclusion criteria, clinical tests, examination schedule and safety and efficacy analysis, Dr. Eydelman said.
“A recognized standard is a consensus standard the FDA has evaluated and recognized for use in satisfying the premarket submission requirements,” she said.
After sponsors identify their device’s classification and become familiar with appropriate guidances and standards, they can start thinking about study design.
Correct study design
According to Dr. Eydelman, appropriate clinical study design opens the door to the FDA.
“To any sponsor who is at this stage of the game, I always recommend ‘take your time,’” she said, “The extra time you take at the clinical trial design is going to pay off greatly down the line.”
Dr. Eydelman said there are several key protocol elements that the sponsor must focus on when designing a clinical trial. A clear objective is the first element that must be established.
“The objective has to clearly state whether you are trying to obtain a superiority or equivalency claim, needs to clearly identify its intended population and always needs to correlate with the draft indication,” she said.
Dr. Eydelman recommended that the following be taken into consideration to determine appropriate study design: the ability of the trial design to answer the primary research question, the availability fo any established treatment for the condition the device is intended to treat, and the potential risks and benefits to trial participants and the population to be studied.
“Every clinical trial submitted to the FDA needs to state parameters to maximize patient safety, and that should incorporate a detailed description of all potential risks to the subjects,” Dr. Eydelman said, “Your safety and efficacy endpoints always need to be clinically relevant, clearly defined, objectively measured — assessed by validated tests — and primary and secondary endpoints must be delineated .”
Success and failure criteria must be characterized as accurately and precisely as possible given the nature of the device, she added.
Study type, duration
Before approaching the design of the clinical trial, the sponsors must consider whether they are writing a protocol for a feasibility study, a pilot study or a pivotal study, she said.
If it is a feasibility study, the trial must demonstrate that the device can be used without undue injury to the patient. A pilot study is the “next step,” Dr. Eydelman explained, and a pivotal study is “the final step,” which should provide the “basis of valid scientific evidence.”
In addition, the sponsor must decide whether the study will be observational or experimental. If the study will be observational, the designer has to determine whether it will be prospective or retrospective, she said.
“Study duration needs to be adequate to assess both the immediate effects of the device as well as predict the long-term effects of the device,” she said. “If the physiological stability of an organ in question is reached at 24 months after treatment, a 1-year trial would not be found sufficient.”
Statistics and sample size
Statistics must be used in several aspects of clinical study design, Dr. Eydelman said.
“A statistically powerful study is essential to determine a clearly clinical, meaningful difference on the primary endpoint,” she said.
She explained that statistical designs can include parallel, paired, pre and post comparison, and historical control. Pre and post comparison is the most common in ophthalmology, Dr. Eydelman said, especially in refractive surgery. She noted that a historical control design may seem to be the easiest, “but it tends to be the most complicated.”
“You need a statistician to help you if you are not sure how statistics drive the clinical trial design,” Dr. Eydelman said.
Dr. Eydelman recommended determining adequate sample size early in planning the clinical trial. She recommended incorporating the dropout rate in the sample size.
“A sample size should be big enough to detect a change of clinical significance,” she said.
Controls and assignment
When choosing the study population, the sponsor should consider the intended use for the device, Dr. Eydelman said.
“Make sure the inclusion/exclusion criteria truly represent the eventual population for whom the device is intended,” she said.
The type of control to be used in the study – active, placebo, no treatment or historical — must also be determined. When choosing the type of control to be used, Dr. Eydelman said, it is important to remember that “study and control groups need to be comparable with respect to all characteristics of your study.”
“If you are using historical controls, you need to select literature articles that specify the treatments and details on subjects’ demographic distribution and details for outcome assessment,” she noted as an example.
The potential for bias in assigning subjects must also be minimized, Dr. Eydelman said. In a randomized clinical trial, treatment should be masked as much as possible.
“Treatment allocation on the basis of patient preference does introduce bias,” she said.
Assessment and analysis
According to Dr. Eydelman, the trial design also needs to include details for assessing each variable and a plan for analyzing the data. “All the variables to be assessed in the trial need to be specified in the protocol,” she said.
Data analysis should be well planned in advance to address any event that can affect the data or prove or disprove the hypothesis.
“Make sure there is a plan for handling missing data,” Dr. Eydelman said. “Plan assessment for the effect of possible compounding variables.”
The sponsor should identify any important covariate and stratify data accordingly, Dr. Eydelman said. She recommended that the sponsors “avoid linear extrapolation beyond the domain of the data.”
Dr. Eydelman finished her presentation by stressing the importance of correct interpretation of the data.
“The power of the study should be great enough to be clinically useful or important,” she said.
For Your Information:
- Malvina B. Eydelman, MD, is a senior medical advisor in the U.S. Food and Drug Administration’s Center for Devices and Radiological Health, Division of Ophthalmic and ENT Devices. She can be reached at 301-594-2205; e-mail: mbe@cdrh.fda.gov.
- Michele L. Stratton is Associate Editor of the OSN Europe/Asia-Pacific Edition.