There are a number of critical steps related to the conduct of clinical trials that the sponsor must complete in bringing a new implantable medical device to market. Once the design is locked and the preclinical testing is completed, the sponsor prepares the investigational plan and, for significant risk devices, obtains Investigational Device Exemption (IDE) approval from the FDA. The clinical trial is conducted, data analyzed, and a regulatory submission prepared. After regulatory approval is obtained and the product launched, there may also be requirements for postmarket surveillance if the device is an implant or life supporting. The focus of this discussion will cover the important aspects of conducting clinical trials for significant risk devices from the sponsor’s perspective.
IDE Application and Approval
Before the clinical trial can begin, the sponsor must gain IDE approval. Whether the device is novel or offers potential benefits over existing technology, it is highly recommended that the sponsor take advantage of early collaboration meetings with FDA. These meetings are also a good time to talk about a Modular premarket approval (PMA) approach and concur with the agency on the major elements. This can save a great deal of time and can allow the sponsor to complete all requirements while the study is underway, making the last step the submission of the final data analysis and labeling. Pre-IDEs can be opened to submit preclinical test plans to get early FDA input into design verification and validation test protocols. Another key purpose of the pre–IDE process is to get FDA input on the Investigational Plan. This can be formal (binding) or informal and can be accomplished through teleconference, videoconference, or face–to–face meetings. A sponsor also has the option of preparing a formal pre–IDE submission. Several Divisions at ODE have guidance documents on the content of these submissions and sponsors are encouraged to check with the appropriate ODE Division before submitting a pre–IDE. The sponsor should also plan to allow 60 days for a pre–IDE review and feedback. Once the final, original IDE is submitted, FDA almost always takes less than 30 days to either approve, approve with conditions, or disapprove.
Investigational Plan
Preparing a well–written and scientifically sound Investigational Plan is a key first step in preparing to conduct a clinical trial. The sponsor must ensure that the regulatory requirements, as defined in 21 CFR 812.25, are fulfilled in preparing this important document. Some of the key elements include the purpose, written protocol, risk analysis, device description, monitoring procedures, labeling, copies of informed consent documents, information about Institutional Review Boards (IRBs), list of institutions involved, and description of the records and reports that will be maintained.
Checklist of Essential Elements of a Clinical Protocol
There are a number of essential elements that are critical to a well–prepared clinical protocol. Each of these should be fully described within the content of the sponsor’s protocol. Some are more important than others, but none can be overlooked. A checklist of those key elements can be found in Table 1 .
Table 1: Key Elements of a Clinical Protocol
Good Clinical Practices
Both the sponsor and investigator have an obligation to ensure that the trial is conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The International Conference on Harmonization of Good Clinical Practices (GCP) has developed 13 principles. These range from ensuring that the risk versus benefit is clearly understood, to always obtaining informed consent. It’s a good idea to always incorporate these 13 principles into your investigator/site training program.
Points to Consider when Conducting the Trial
Once the investigational plan is prepared, and IDE and IRB approval obtained, there are a number of considerations to keep in mind. First is the financial planning. The cost of conducting a clinical trial is a significant part of the total cost of getting a new device to market. When estimating the resources needed, a sponsor should consider the HCFA classification, cost of using contract IRBs, number of centers and patients required, training and monitoring costs, the cost of the devices (investigational and control), and the length of follow–up required. A thorough analysis of the costs involved to conclude a clinical trial should be done up front to avoid delays caused by unplanned expenses. Care should be taken in selecting investigators. Sponsors should make sure they are qualified (training/experience) and have the understanding of the logistics as well as the resources to conduct clinical research. Informed consent documents should comply with 21 CFR Part 50, and the sponsor is also responsible for ensuring that the IRB conforms with the requirements of 21 CFR Part 56.
Not to be overlooked in importance is investigator training. This is critical in getting your trial started on the right foot. It’s a good idea to send the agenda and training materials a week or so in advance. The first part of effective training should cover the regulatory considerations, background and purpose of the study, protocol, IRB conditions, informed consent, case report forms, monitoring procedures reporting requirements, and include a list of contact personnel. The second part of effective training should thoroughly cover the device application. There is no substitute for hands-on training; this should be included if at all possible. Monitoring is critical to the successful outcome of any clinical trial. Incomplete data or poor compliance can leave the sponsor with unusable data to support regulatory clearance and cause lengthy delays in the completion of the trial. There are four major types of monitoring: prestudy visit to select investigators and sites; initiation visit used to train the investigator and on-site staff in the protocol and regulatory requirements; monitoring visits geared to ensure compliance and protect the rights of patients as well as ensure data integrity; and lastly, the close-out visit, which is important in resolving any remaining issues at the end of the study and bringing the trial to a close. Standard forms and procedures should be developed that support these four types of monitoring activities. Device accountability is also important in conducting a clinical trial. The sponsor should have written procedures to ensure proper control of any investigational product. Records should be kept to document shipment, receipt, disposition, return, or destruction. Investigational product should always be properly labeled and stored in a locked cabinet or room under the control of study personnel.
There are a number of reporting requirements for which the sponsor is responsible to ensure compliance with 21 CFR Part 812.150. These include, but are not limited to, adverse events, withdrawal of approval, progress reports, recalls, device use without informed consent, and a final study report. Failure to comply with these reporting requirements can cause regulatory concerns and impact device approval. The sponsor should therefore make sure all reporting requirements are completed within the specified time limits.
Data Management and Analysis
Incomplete follow–up is a major concern in the data entry and analysis process. It is extremely important that this proportion is as close to 100% as possible. Data entry personnel should have suitable expertise to assure the collection and input of valid data. They should be properly trained on the study design and the terminology used. Quality control techniques should be used for verification of measurement, transfer, and entry of clinical trial data. Before statistical analysis begins it is important to validate assumptions, such as how missing data will be handled. The final dataset should be described and tabulated by group, subgroup, and strata. The next step in the statistical analysis process is to test the hypothesis. The tools used, confidence intervals, and risk factors should be carefully stated. All subjects and adverse events should be accounted for in tabular form. Once these steps are complete you’re ready to crunch the data. Something to consider before starting a clinical trial, but that really comes into play during the data management and analysis phase, is the use of advanced statistical methods known as the Baysian model that allows the incorporation of historic information into the clinical trial data. Recent regulatory changes (FDA Modernization Act) encourage FDA to consider “least burdensome” means of demonstrating effectiveness, allowing the possibility under certain conditions of using historic data. Using historic data can save the sponsor time and resources. The FDA is currently preparing a guidance document on the use of advanced statistical methods.
Conclusion
In summary, a few key points to remember. First, the sponsor should meet early and frequently with FDA in the IDE approval process. Thoroughly planning human and capital resources needed to complete a clinical trial is a critical early planning step. The sponsor should avoid making changes to the investigational device during the clinical trial; this can result in problems pooling data and prolong the study. Investigator selection is critical to successful completion of any clinical trial. The clinical trial should be monitored diligently throughout the study to avoid costly mistakes. Data analysis should be direct, simple, and complete. Finally, the successful completion of a clinical trial is a time worthy of celebration.
