Bhavana Shivakumar , Clinical Research Associate, Musculoskeletal Clinical Regulatory Advisers LLC09.19.18
Initiating an orthopedic clinical trial (OCT) is an exciting milestone for companies as years of pre-clinical testing and conversations with the U.S. Food and Drug Administration (FDA) finally come to fruition. Focusing on specific elements of the study initiation process can pave the way to a successful trial, eventually leading to regulatory approval and improvements in the course of management for the orthopedic indication under research.
Preparing the Study Team
The foundation of an OCT is the study team, which should be comprised of all research professionals involved in the design and eventual execution of the study, including in-house personnel, contract research organization (CRO) personnel (project managers, site monitors, data managers, etc.) and vendors. Just as a house is only as strong as its foundation, an OCT can only be executed as well as the study team that is selected and trained to oversee it. The CRO and all study vendors should be chosen with careful consideration of their past experience and capabilities, and whenever possible, the vendors should already have a strong relationship with the chosen CRO. The site monitors should be efficient and effective communicators, and should have the ability to maintain a friendly yet authoritative working relationship with their sites.
Training
Study training is a commonly-overlooked aspect of OCT execution. Training of the study team allows for all members to thoroughly understand the objectives of the OCT, and clearly defines each member’s role in trial execution. This initial investment of resources benefits the sponsor by exposing potential issues specific to the study team’s specialties. This early exposure allows time for addressing and resolving them, well before on-boarding sites. The study team will maintain clarity on the processes and goals of the study, and thereby will ensure complete and accurate data collection. Additionally, a well-informed study team can troubleshoot issues in real-time, thereby reducing the burden on the sponsor. While this type of preparation will require preparation time on the part of the sponsor, it is time saved from future, and potentially larger, issues.
Communication
In addition to training, all well-executed trials maintain clear and timely communication channels from the beginning of OCT preparations. The entire study team should be kept aware of the status of all trial documents and processes on a routine basis. Though this transparency may seem to require an exceptional investment of time, the phrase “knowledge is power” comes to mind, as the more the team knows, the more efficiently it can support the execution of the OCT. For example, when a monitor is at a clinical site for the qualification visit, they will be able to identify shortcomings at the site that will save the sponsor both time and money in the long run.
Leveraging Technology
The most successful studies utilize technology not just for developing the investigational product, but also in the administration of their OCTs. Setting up and maintaining Electronic Data Capture (EDC) and Electronic Trial Master File (ETMF) systems is a worthwhile investment for ensuring the speed and security of clinical trial data and records management, particularly since many of them are optimized to meet FDA requirements. The audit-readiness of a validated EDC and eTMF system is particularly valuable to sponsors—no more sifting through boxes of paper or stacks of binders. Every data point and document has a timestamp, all changes are tracked, and the system architecture must meet HIPAA compliance requirements.
Site Selection & Qualification
Without clinical sites, no research is possible; however, unqualified sites can tie up valuable sponsor resources. Issues such as slow patient enrollment, delays in data entry, and re-training to address compliance issues are all potential roadblocks to success. A good site will be focused on active patient recruitment, rapid data entry, and timely resolution of issues. The process of selecting sites is therefore paramount to quality data collection, and is a critical stepping stone to running a successful OCT.
The site selection process is facilitated by a pre-study feasibility questionnaire. The questionnaire should be designed to elicit site-specific information that helps the sponsor decide whether the investigator has the appropriate orthopedic experience and the proper study team to conduct the OCT thoroughly. It will also help to indicate whether the investigator has access to the desired patient population after taking into account the study’s inclusion and exclusion criteria. Finally, the questionnaire should outline any facilities and equipment that may be needed for patient assessments and care, such as radiology services for study imaging, and physical therapy facilities for post-operative rehabilitation. Accurate completion of the feasibility questionnaire should be enforced, as the survey will serve as confirmation that each site can perform the required procedures, as well as an understanding of the site’s overall research capabilities. While it is known that this kind of centralized questionnaire allows for a uniform comparison of the sites under consideration, it may be overlooked that investing in the details of the questionnaire will serve as a data repository for future studies as well.
Once feasibility surveys are returned from the sites, sponsors should perform an on-site qualification visit to verify that all claims made on the form are accurate, and more importantly, to establish a good working relationship with the site staff, so the OCT journey is a smooth one. If the sponsor has a prior relationship with a site, the formal qualification visit requirement can be waived and this process can be handled remotely, with the same effect.
IRB Management
There are more than 2,000 Institutional Review Boards (IRBs) in the U.S., and while each one has its own requirements, there are a few strategies relating to IRB management that can ensure success regardless of which IRB is chosen for the study.
When possible, sponsors should elect to work with a central IRB, as they are able to review the protocol and study documents and maintain a central record of the amendments as they occur.
As sites are qualified for the trial, ideally their local IRB is willing to defer to the central IRB of choice, but regardless, the central IRB will provide approved documents that can be submitted to a site’s local IRB as well. This centralization of document review is essential to maintaining a truly audit-ready ETMF, and makes it easy for monitors when on site rectifying the site’s files. Additionally, should any changes to approved documents become necessary after the start of the trial, the central IRB will produce approved documents for each site under its jurisdiction, thereby saving the sponsor time and resources for other initiation activities.
Regardless of the type of IRB, sponsors should apply for IRB review after FDA approval and before site initiation. In the attempt to rush the IRB approval process, many sponsors submit the protocol and informed consent template in parallel with FDA review, risking additional billing by the IRB if the protocol and/or consent template require modification based on FDA’s feedback. Though it may seem to prolong site initiation, submitting to the IRB after FDA approval will prevent the sponsor from being billed for amendment reviews.
In summary, IRB submissions should be managed with attention to timing and costs. Sites will appreciate trials which do not require multiple amendments, and monitors will have more time on-site for source data verification.
Site Initiation & Activation
The Site Initiation Visit (SIV) is the culmination of the previous three phases, and if done correctly, will set the pace for the OCT through study closeout. Each site will be activated upon successful completion of an on-site SIV, for which preparation is key.
The SIV agenda is a process that deserves forethought. While the principal investigator and sub-investigator’s time may be limited, the monitor should ensure enough time is spent with the site’s research team to garner its trust and ensure a thorough understanding of the protocol training materials. When proper time is provided, the site staff will be able to process all presented material and identify issues and roadblocks the study team can address before the study is initiated. These hurdles may also apply to other sites, and lead to valuable lessons learned before other sites are activated by the study team.
The SIV duration will vary based on the agenda; however, most SIVs tend to last one business day. While there may be pressure from the sites to rush the SIV, the time investment in pre-study training is valuable and will help save costs in the long run as well as foster a positive relationship between the study coordinator and monitor.
During the SIV, the protocol training provided should be as detailed as possible to ensure the site has a full understanding of every aspect of the trial. Also, those topics which will affect the site coordinators should be emphasized, as they will be the main resource for the site investigators, should a problem arise. Along with protocol training, other topics that should be reviewed include investigator responsibilities, informed consent process, patient eligibility determination, safety management, investigational product accountability, and data entry guidelines. Of these, the two most important topics to address during the SIV include safety management/reporting and the informed consent process.
Barring any pending action items, the site can be activated, and patient recruitment can begin. Finally, the real work will begin, and even if there are setbacks along the way, the study team will address them with ease, because the trial started on the right foot.
Bhavana Shivakumar is a clinical research associate at Musculoskeletal Clinical Regulatory Advisors (MCRA), supporting their Clinical Research Organization (CRO) operations by provide consulting services to medical technology clients with respect to clinical trial administration and site management. With over eight years of experience in the clinical research industry, she is responsible for providing end-to-end support to IDE and post-approval studies. She leverages her expertise in clinical protocols, data analysis methodologies, and clinical research processes to ensure that studies are conducted in compliance with SOPs, ICH/GCP guidelines, and industry best practices.
Preparing the Study Team
The foundation of an OCT is the study team, which should be comprised of all research professionals involved in the design and eventual execution of the study, including in-house personnel, contract research organization (CRO) personnel (project managers, site monitors, data managers, etc.) and vendors. Just as a house is only as strong as its foundation, an OCT can only be executed as well as the study team that is selected and trained to oversee it. The CRO and all study vendors should be chosen with careful consideration of their past experience and capabilities, and whenever possible, the vendors should already have a strong relationship with the chosen CRO. The site monitors should be efficient and effective communicators, and should have the ability to maintain a friendly yet authoritative working relationship with their sites.
Training
Study training is a commonly-overlooked aspect of OCT execution. Training of the study team allows for all members to thoroughly understand the objectives of the OCT, and clearly defines each member’s role in trial execution. This initial investment of resources benefits the sponsor by exposing potential issues specific to the study team’s specialties. This early exposure allows time for addressing and resolving them, well before on-boarding sites. The study team will maintain clarity on the processes and goals of the study, and thereby will ensure complete and accurate data collection. Additionally, a well-informed study team can troubleshoot issues in real-time, thereby reducing the burden on the sponsor. While this type of preparation will require preparation time on the part of the sponsor, it is time saved from future, and potentially larger, issues.
Communication
In addition to training, all well-executed trials maintain clear and timely communication channels from the beginning of OCT preparations. The entire study team should be kept aware of the status of all trial documents and processes on a routine basis. Though this transparency may seem to require an exceptional investment of time, the phrase “knowledge is power” comes to mind, as the more the team knows, the more efficiently it can support the execution of the OCT. For example, when a monitor is at a clinical site for the qualification visit, they will be able to identify shortcomings at the site that will save the sponsor both time and money in the long run.
Leveraging Technology
The most successful studies utilize technology not just for developing the investigational product, but also in the administration of their OCTs. Setting up and maintaining Electronic Data Capture (EDC) and Electronic Trial Master File (ETMF) systems is a worthwhile investment for ensuring the speed and security of clinical trial data and records management, particularly since many of them are optimized to meet FDA requirements. The audit-readiness of a validated EDC and eTMF system is particularly valuable to sponsors—no more sifting through boxes of paper or stacks of binders. Every data point and document has a timestamp, all changes are tracked, and the system architecture must meet HIPAA compliance requirements.
Site Selection & Qualification
Without clinical sites, no research is possible; however, unqualified sites can tie up valuable sponsor resources. Issues such as slow patient enrollment, delays in data entry, and re-training to address compliance issues are all potential roadblocks to success. A good site will be focused on active patient recruitment, rapid data entry, and timely resolution of issues. The process of selecting sites is therefore paramount to quality data collection, and is a critical stepping stone to running a successful OCT.
The site selection process is facilitated by a pre-study feasibility questionnaire. The questionnaire should be designed to elicit site-specific information that helps the sponsor decide whether the investigator has the appropriate orthopedic experience and the proper study team to conduct the OCT thoroughly. It will also help to indicate whether the investigator has access to the desired patient population after taking into account the study’s inclusion and exclusion criteria. Finally, the questionnaire should outline any facilities and equipment that may be needed for patient assessments and care, such as radiology services for study imaging, and physical therapy facilities for post-operative rehabilitation. Accurate completion of the feasibility questionnaire should be enforced, as the survey will serve as confirmation that each site can perform the required procedures, as well as an understanding of the site’s overall research capabilities. While it is known that this kind of centralized questionnaire allows for a uniform comparison of the sites under consideration, it may be overlooked that investing in the details of the questionnaire will serve as a data repository for future studies as well.
Once feasibility surveys are returned from the sites, sponsors should perform an on-site qualification visit to verify that all claims made on the form are accurate, and more importantly, to establish a good working relationship with the site staff, so the OCT journey is a smooth one. If the sponsor has a prior relationship with a site, the formal qualification visit requirement can be waived and this process can be handled remotely, with the same effect.
IRB Management
There are more than 2,000 Institutional Review Boards (IRBs) in the U.S., and while each one has its own requirements, there are a few strategies relating to IRB management that can ensure success regardless of which IRB is chosen for the study.
When possible, sponsors should elect to work with a central IRB, as they are able to review the protocol and study documents and maintain a central record of the amendments as they occur.
As sites are qualified for the trial, ideally their local IRB is willing to defer to the central IRB of choice, but regardless, the central IRB will provide approved documents that can be submitted to a site’s local IRB as well. This centralization of document review is essential to maintaining a truly audit-ready ETMF, and makes it easy for monitors when on site rectifying the site’s files. Additionally, should any changes to approved documents become necessary after the start of the trial, the central IRB will produce approved documents for each site under its jurisdiction, thereby saving the sponsor time and resources for other initiation activities.
Regardless of the type of IRB, sponsors should apply for IRB review after FDA approval and before site initiation. In the attempt to rush the IRB approval process, many sponsors submit the protocol and informed consent template in parallel with FDA review, risking additional billing by the IRB if the protocol and/or consent template require modification based on FDA’s feedback. Though it may seem to prolong site initiation, submitting to the IRB after FDA approval will prevent the sponsor from being billed for amendment reviews.
In summary, IRB submissions should be managed with attention to timing and costs. Sites will appreciate trials which do not require multiple amendments, and monitors will have more time on-site for source data verification.
Site Initiation & Activation
The Site Initiation Visit (SIV) is the culmination of the previous three phases, and if done correctly, will set the pace for the OCT through study closeout. Each site will be activated upon successful completion of an on-site SIV, for which preparation is key.
The SIV agenda is a process that deserves forethought. While the principal investigator and sub-investigator’s time may be limited, the monitor should ensure enough time is spent with the site’s research team to garner its trust and ensure a thorough understanding of the protocol training materials. When proper time is provided, the site staff will be able to process all presented material and identify issues and roadblocks the study team can address before the study is initiated. These hurdles may also apply to other sites, and lead to valuable lessons learned before other sites are activated by the study team.
The SIV duration will vary based on the agenda; however, most SIVs tend to last one business day. While there may be pressure from the sites to rush the SIV, the time investment in pre-study training is valuable and will help save costs in the long run as well as foster a positive relationship between the study coordinator and monitor.
During the SIV, the protocol training provided should be as detailed as possible to ensure the site has a full understanding of every aspect of the trial. Also, those topics which will affect the site coordinators should be emphasized, as they will be the main resource for the site investigators, should a problem arise. Along with protocol training, other topics that should be reviewed include investigator responsibilities, informed consent process, patient eligibility determination, safety management, investigational product accountability, and data entry guidelines. Of these, the two most important topics to address during the SIV include safety management/reporting and the informed consent process.
Barring any pending action items, the site can be activated, and patient recruitment can begin. Finally, the real work will begin, and even if there are setbacks along the way, the study team will address them with ease, because the trial started on the right foot.
Bhavana Shivakumar is a clinical research associate at Musculoskeletal Clinical Regulatory Advisors (MCRA), supporting their Clinical Research Organization (CRO) operations by provide consulting services to medical technology clients with respect to clinical trial administration and site management. With over eight years of experience in the clinical research industry, she is responsible for providing end-to-end support to IDE and post-approval studies. She leverages her expertise in clinical protocols, data analysis methodologies, and clinical research processes to ensure that studies are conducted in compliance with SOPs, ICH/GCP guidelines, and industry best practices.