action plan for clinical research

Resolving and Preventing Repetitive Problems in Clinical Trials

April Bishay, BA, MBA Senior Manager, Clinical Compliance, MedImmune

Anatoly Gorkun, MD, PhD Chartered MCIPD, Senior Manager, Scientific & Compliance Training, MedImmune

Abstract : Clinical trial findings from audits reveal the same type of problems year after year despite the implementation of quality systems, compliance training, and corrective and preventive action plans. This article provides an overview of the root cause of these problems and how to ensure that corrective and preventive actions are addressing the actual problem rather than its symptoms. Actual case study illustrates some of the common problems in clinical trials.

Introduction

Today, clinical trial professionals are provided with guidelines, regulations, company policies, procedures, and endless amounts of training to help them with the conduct of clinical trials.

Despite all the training one receives or all the guidelines, regulations, company policies, and procedures in place to assist with the conduct of a clinical-trial, problems including unanticipated situations or safety issues may arise (Table 1). Clinical research professionals are often unable to give their full attention to every detail of the study due to the speed in which the trial progresses, the strain on company resources, or many of the other day-to-day factors that impact ones’ time and attention.

An auditor is at an investigator’s site performing a clinical trial audit. The auditor reviews the site documentation including personnel signature/delegation forms and source documents and notes the following issues:

• Delegated responsibilities were assigned to everyone regardless of their role on the study. The site personnel signature/delegation form was not completed correctly or in a timely manner. For example, the dates for the clinical investigator’s signature were changed and updated. Some of the dates were after the person began conducting protocol-required procedures.
• Dr. MJ signed the electronic version of a physical exam for Subject 1285’s visit for Cycle 1, Day 1. Dr. MJ, however, was not listed on the delegation log to perform protocol-required procedures.
• The number of site personnel listed on the signature/delegation form far exceeded the number of people who actually worked on the clinical trial.

Additional background related to the audit finding:

• No protocol deviations or violations were recorded in the monitoring reports for these issues. The monitor identified the issues only as follow-up actions and has not seen the clinical investigator in months.
• Communication between the monitor and the clinical investigator occurred primarily through follow-up letters sent after each monitoring visit.
• Issues noted in the audit finding had been ongoing for approximately one year.
• The clinical research site routinely lists everyone working in their department on the Form FDA 1572 rather than determining which staff members actually work on a specific clinical trial.

Corrective and Preventive Action P lans

A corrective and preventive action (CAPA) plan is a series of actions taken to resolve a compliance issue, and most importantly, to prevent further recurrence (Table 2). A CAPA plan will focus on the immediate noncompliance and the broader scope of the problem. It involves investigating and understanding the issue, correcting the issue, and preventing the root cause. CAPAs can be used for audit or inspection observations, compliance improvement, or risk mitigation.

The first step in developing a CAPA plan is to identify the issue. Issues can include deviations or violations, findings identified through quality control, as well as audit and inspection findings. Quality issues may be isolated or they may have a broad impact across trials and programs and can represent:

• A single occurrence or a cluster of occurrences
• Gaps indicating noncompliance with regulations, policies, and/or procedures
• Risk to subject safety and/or data integrity, and, as a result, risk to the company’s license to operate.

After identifying the issue, one must evaluate its severity and impact by considering:

• The potential for a broader impact across clinical trials
• The impact on company processes and procedures
• How the issue will impact other departments
• Whether the issue requires immediate action

For example, an email from an investigative site with the subject’s name has just arrived. Should immediate action be taken or should clinical research professionals wait for a CAPA? In this specific case, the clinical research professional should act immediately. They must redact the subject’s name because it violates data privacy regulations and the Health Insurance Portability and Accountability Act (HIPAA). The recipient must also discuss the problem with the sender of the email and report it internally, as required by company policy.

Root Cause Analysis: Getting to the Real Issue

A root cause analysis (RCA) is a method used to examine and identify the underlying reason for why an issue has occurred. Performing an RCA allows one to identify effective actions to correct or eliminate the cause and prevent the issue from recurring.

Case Study (Continued)

Now we return to the case study.

The monitor performed the root cause analysis on the audit findings which states:

“The site staff was not updating the site delegation log upon completion of training.”

This, however, is not the real root cause of the issue. It is a symptom. How do we know this is just the symptom of the issue?  Simple. We can still ask the question “Why?”

• Why hasn’t the site delegation log been updated?
• Why are the other issues in the audit finding not addressed with this root cause?

The root cause identified by the monitor does not address the real issue. It is only a brief observation without knowing why the problems are occurring.

There are several different methods available to help us identify the real root cause of an issue. One of the most common and simplest methods used is the 5-Whys method. The method allows one to explore the cause and effect of an underlying problem by asking the question “Why?” five times. Asking a “Why?” question may lead to another “Why?” question until “Why?” can no longer be asked. One may not necessarily need to ask five “Why?” questions to identify the root cause. One may be able to get the root cause with three “Why?” questions, for example, while other times it may take more than five.

One of the findings from the case study audit involved changed dates. The clinical investigator’s signature dates had been changed and some dates were recorded after the staff began clinical trial-related activities. Now let’s try to determine the root cause by using the 5-Why method.

Question #1: Why were the clinical investigator’s signature dates changed?

Site’s Response: The study coordinator asked the clinical investigator to update the delegation log at the start of the study. The clinical investigator made updates to the log and updated the signature dates.

Question #2 : Why were some dates recorded after the person started protocol-related procedures?

Site’s Response: The clinical investigator was busy and focused on other priorities, wrongly assuming that the study coordinator was keeping up with this activity.

Question #3: Why did the clinical investigator assume that the study coordinator was keeping up with this activity?

Site’s Response:  The clinical investigator feels that this is an administrative task; therefore, he assumed that the study coordinator was keeping up with all of the paperwork.

Question #4: Why didn’t the study coordinator follow up with the clinical investigator to remind him to update the form?

Site’s Response: The study coordinator was too busy to follow up on general study paperwork due to the rapid enrollment of subjects into the study, prioritized work related to subject enrollment, and ongoing subject visits.

Question #5: Did the study coordinator ask for assistance?

Site’s Response: No.

Question #6 : Why hasn’t the study coordinator asked for additional assistance?

Site’s Response : There is no room in the department budget to hire additional staff.

Question #7: Why hasn’t the investigator slowed recruitment to allow the study coordinator to catch up?

Site’s Response: Study recruitment is going quicker than expected. The clinical investigator is required, by contract, to enroll a defined number of subjects; therefore, subject enrollment cannot slow down.

Other findings from the case study audit were the incorrect assignment of delegated responsibilities and the number of site personnel listed on the delegation log exceeded the number that worked on the trial. The audit report states that the same activities were assigned to everyone regardless of their role on the study. The following questions can be asked to identify the root cause:

Question #1: Why were physician-related activities, to be conducted only by the clinical investigator or sub-investigators, delegated to non-physician roles on the delegation log?

Site’s Response: Physician-related activities are not being conducted by non-physicians. These activities were assigned in error.

Question #2: Why were there so many people listed on the delegation log?

Site’s Answer: We routinely list everyone on the delegation log rather than those who actually work on a trial.

Question #3: Why was Dr. HS left off of the delegation log when it is routine to list everyone?

Site’s Response: The delegation log was not routinely updated to keep up with new and departing staff.

Question #4: Why are you unable to perform ongoing maintenance of the delegation log?

Site’s Response: We were unable to keep up with both recruitment activities and administrative tasks.

We can continue asking “Why?” questions after Question #4, but this would only lead back to workload issues, which have already been questioned previously.

Another finding from the case study audit showed that the monitor had followed up on issues previously, yet some of the issues have remained open for over a year.

Question #1: Why do the issues remain open when recoded over a year ago?

Monitor’s Response: Due to high recruitment, the study coordinator struggles to keep up with the work on the study.

Question #2:   There is no evidence that you have escalated this to your (CRO) study manager. Why haven’t you escalated this issue to your manager?

Monitor’s Response:   The issues were documented for follow-up in monitoring reports and follow-up letters after each site visit. I was not aware of the need to escalate site workload issues to my (CRO) study manager. I assumed that my study manager was aware of the issue, and I would have said something, especially because it is my study manager who reviews my monitoring visit reports for this site.

Question #3: Why haven’t you escalated or reported the lack of investigator oversight/study management as a potential quality issue?

Monitor’s Response:   I was unaware that this would qualify as a potential quality issue. I only thought that it was an issue for follow up.

Information gathered while performing the 5-Whys method clearly shows that there are communication problems between the monitor, clinical investigator, and site staff. Communication problems are also present between the monitor and the CRO study manager. Poor communication within the CRO study team kept the issue from being escalated to the sponsor. The sponsor could have tried to help resolve issues at the site if the sponsor had been informed. Unfortunately, the sponsor was only made aware of the issue when the audit report was released.

The root cause analysis provides information that can be used to develop corrective and preventive actions. Common themes identified in the case study audit include (Table 3): (a) site staff have a high workload due to rapid subject enrollment, (b) there are no site processes indicating who is responsible for performing tasks, (c) poor delegation of study tasks as assumptions are made about who does what, (d) lack of adequate oversight by the clinical investigator, (e) the monitor did not provide sufficient follow up, and (f) poor communication between all parties.

Corrective Actions

Developing effective corrective actions should eliminate the cause of a detected non-conformity or other undesirable situation or event.

The below are some corrective actions that can be put into place to help address issues identified during the audit. There are more corrective actions that can be implemented, but here are a few to start with:

• At the next monitoring visit, the monitor will review the site delegation log with the clinical investigator and the study coordinator to ensure that all staff members who have contributed to the study are listed and responsibilities are appropriately delegated. This activity will be documented in the monitoring visit report and in the follow-up letter to the site.
• The monitor, clinical investigator, and site staff will discuss responsibilities for performing various study tasks and address workload issues. Information from the discussion will be provided to the CRO study manager and sponsor to see if additional support can be provided. This activity will be documented in the monitoring visit report and in the follow-up letter to the site.

Preventive Actions

Implementing corrective actions alone will not prevent non-compliance. Preventive action must be taken to eliminate the cause of non-compliance or other undesirable potential situations or events.

Developing effective preventive actions:

• Should prevent issue(s) from occurring or recurring
• May require changes to a process in order to correct a weakness
• Must target the underlying root cause identified in the root cause analysis
• Should aim to ensure that the issue will not be repeated.

Preventative actions for the case study should focus on the common themes that came out of the root cause analysis: (a) site staff have a high workload due to rapid subject enrollment, (b) there are no site processes indicating who is responsible for performing tasks, (c) poor delegation of study tasks because assumptions are made about who does what, (d) lack of adequate oversight by the clinical investigator, (e) the monitor did not provide sufficient follow up, and (f) poor communication between all parties.

A few examples of preventive actions include:

• The monitor will schedule the next monitoring visit while meeting with the clinical investigator and site staff in an attempt to improve meeting attendance with the clinical investigator.
• At each monitoring visit, the monitor will speak with the study coordinator or clinical investigator to see if there have been changes in study staff, to see about completion of training, and to review the delegation of study procedures with the clinical investigator.
• The clinical investigator and the study coordinator will dedicate time for the review of site activities with an agreed-upon frequency.
• The monitor will receive training/mentoring on effective communication, escalation, follow-up, and issue resolution. The monitor’s manager should periodically check on the monitor to see if additional training and mentoring are required to improve communication skills and issue resolution.
• The monitor and the clinical investigator will agree on the study oversight process at the investigative site, utilizing regular review meetings to evaluate current and potential issues, findings, and workload. They will continuously implement the required changes to improve the quality of the study conduct.

Follow-up and Closing the CAPA Checking the effectiveness of implemented corrective and preventive actions is an important part of the CAPA process, especially for issues that are deemed as critical or serious. Continued oversight and monitoring is required to verify that the actions taken have been effective and that the issue does not recur.

In some cases, actions taken may not be effective. In such cases, it is necessary to re-examine the root cause and agree upon additional actions to address the issue.

CAPAs are closed when actions and documentation are completed and corrective and preventive actions have effectively resolved the incident and mitigated the risk of recurrence. This requires evaluating the effectiveness of the actions taken and whether goals were achieved.

Documentation to Support the CAPA When a CAPA plan is implemented due to an audit or inspection, one must be able to show the range of activities taken to address the issue. CAPA documentation must be maintained to demonstrate planning and implementation in addition to providing evidence of decisions made and actions taken.

Documentation can include:

• A factual description of what happened
• Root cause analysis description
• Immediate and planned actions
• People responsible for ensuring that the actions are taken
• Timelines for completion
• Documentation to support corrective and preventive actions implemented.

Documentation must be updated with ongoing actions until the CAPA plan is closed. Supporting documentation must be always available.

In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) may consider repetitive problems as a serious breach of Good Clinical Practice (GCP). For example, the inclusion and exclusion criteria in a protocol states that a procedure must be completed and results must be within a given range. The site enrolls a subject into a trial and administers investigational product prior to receiving the results. Fortunately, the subject’s results were received and were within the range specified in the protocol. The subject was not harmed in this instance, but there was the potential to harm the subject should the results have shown that the subject was not suitable for participation in the trial. Enrollment of a subject prior to confirming that all inclusion and exclusion criteria were met would be documented as a protocol violation, and discussion would occur between the CRO and sponsor on how to proceed with this subject and the site. Would this situation need to be reported to the regulatory agency as a serious breach?  Most likely not, but if the site should do this again, the CRO and sponsor would need to consider if the site’s actions fit the criteria of a serious breach.

Successful issue resolution depends on identifying the real cause of the issue by performing a root cause analysis and finding effective corrective and preventive actions. Successful resolution involves the development of a corrective and preventive action plan that addresses the actual root cause of the issue. The CAPA is closed when the corrective and preventive actions have effectively resolved the issue and prevent it from recurring in the future. Continuing process improvement is vitally important because minor issues can grow and may have a negative impact on the safety of patients, the study results, and the reputation of the CRO and sponsor.

TABLE 1:  Reasons for Repetitive Problems in Clinical Trials

• Unexpected situations like safety issues may arise
• Lack of attention due to other priorities
• Logistical problems like shipping, etc.
• Technical issues with equipment, etc.
• Limited amount of control over the people they work with
• Investigative site
• Contract research organization
• Laboratories and other vendors

TABLE 2:  Corrective and Preventive Action

• Resolve a compliance issue or incident
• Prevent further recurrence of the issue
• Investigating
• Understanding
• Preventing the root cause
• Audit or inspection observations
• Compliance improvement
• Risk mitigation
• Identify the issue
• Evaluate the impact
• Conduct root cause analysis
• Develop the corrective action
• Develop preventive actions
• Follow up and close

TABLE 3:  Common Themes in the Case Study Root Cause Analysis

• The study coordinator and the clinical investigator have a high workload
• No site processes or proper delegation: who does what?
• More oversight of site activities required by the clinical investigator
• Lack of follow-up by the site and the monitor
•  Communication problems:
• At the site
• Between the monitor and the clinical investigator and site staff
• Between the monitor and the CRO study manager
• Communication
• Escalation of issues
• Follow-up on issues
• Resolution of issues

TABLE 4:  Successful Resolution of an Issue

• Identify the actual root cause
• Develop a corrective and preventive action plan addressing the actual root cause
• Close the case upon agreement that the corrective and preventive actions have effectively resolved the issue
• Continually improve processes

12 thoughts on “Resolving and Preventing Repetitive Problems in Clinical Trials”

One of the most important causes of problems in clinical trials is a limited amount of influence over people you work with. Additionally, escalation of issues is often corrective & not preventive. Better oversight of clinical trials by the monitor & a pro-active PI/QI can be helpful in prevention & mitigation of these issues.

Very informative post related to clinical research. It is great help for my new project .By reading this article, I learn some important things that I need to improve. I continuously check this site for regular updates in field. Thanks for putting top notch content in article. I would like to be here again to find another masterpiece article.

Thank you for your useful addition, Aditya. I agree with what you say. Lack of influence over the people we work with might be challenging, at the same time it depends on a particular situation. If it concerns compliance, we may want to try to influence those people in an assertive way, regardless of their role’s hierarchy. With regards to escalation of issues it depends on what and when is escalated, if that’s already existing problem or a potential issue. In the first case it will be corrective action and preventive in the second one. That’s the idea of risk-based-monitoring, to start acting before a problem occurs.

When significant deviations or noncompliance occur in research, it is important to identify the causes of the problem so that they can be resolved to prevent further noncompliance. There can be multiple reasons or causes that contribute to one single problem. Conversely, there may be multiple methods to resolve each cause. The root cause is the initiating, most basic cause of a problem that may or may not lead to a chain of causes or other problems. Eliminating the root cause should prevent recurrence of the problem.

Very informative post.

Clinical Trials do get neglected at some parts because of which some glitches take place. This article gives an overall view where improvement is needed. Very Nice article. Keep sharing your information and keep us updated.

In this scenario I am confused about the definitions of corrective and preventive action. I thought that corrective action involves both correction which is rectifying the problem plus corrective action which includes how to prevent recurrence versus preventive action which involves resolution or elimination of root causes of potential problems to prevent occurrence. Essentially for corrective action there is a problem that has occurred and for preventive action it’s to protect against a potential problem that has not occurred.

Hey thanx for sharing this blog over here. It seems useful to start career in clinical research. We will look forward for more updates.

great article.

Informative

Very Informative post for every clinical trial professional.

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• Compliance & Education

Corrective and Preventive Action (CAPA) Plans

While conducting research, even the most experienced and diligent research teams may deviate from the approved protocol or experience unexpected events.  Research teams must identify, evaluate, and respond to these deviations and unexpected events to protect the rights, safety, and welfare of participants and others and the integrity of the research data.

Step 1: Take Immediate Corrective Actions

If you become aware of a deviation or unexpected event that endangers the rights, welfare, or safety of participants and others, you must first take immediate corrective actions without first obtaining IRB approval.

The actions may be in the form of a phone call or an office visit with a qualified research team member. The investigator may need to order tests and other procedures to ensure the participant is safe.  You must document the deviation within the research records, including why it occurred and the immediate corrections taken to address the deviation or event.

Step 2: Conduct a Root Cause Analysis

It is important to identify the cause or source of a deviation or problem to prevent a recurrence.  There may be multiple reasons or causes that contribute to a problem.  Conversely, there may be multiple methods to resolve each cause.  The root cause is the initiating, most basic cause of a problem that may or may not lead to a chain of causes or other problems.  Eliminating the root cause should prevent a recurrence.

A root cause analysis (RCA) is the process of identifying and documenting the root cause and the downstream effect on the causal chain. An RCA should focus on identifying underlying problems that contribute to error rather than focusing on mistakes made by individuals.

• Identify the problem
• Interview those impacted by the problem
• Interview those people responsible for the problem, if applicable

Questions to identify root causes:

• What happened? What is the problem?
• Why and how did the problem occur? What were the steps?
• Who was affected by the problem? Was it one subject or all subjects in the study?
• What is the magnitude of the problem? Is it in one study, or does the problem exist in all studies under this PI or even in an entire clinical department?
• Keep asking "why" and "how" until you reach the root cause.

Once you have identified the root cause, your next step is to develop a corrective and preventive action plan to eliminate the root cause.

Step 3: Prepare the CAPA Plan

Corrective actions are those taken to resolve a problem, and preventive actions are those actions that keep the problem from recurring.

Corrective Actions

Now that you have assessed the participants' rights, welfare, and safety and have identified the root cause, you should consider additional reporting to the sponsor and IRB.  The PI should review Reportable New Information (RNI) criteria to determine whether to report the event to the IRB.  Ensure that the reports to the sponsor and IRB are accurate and thorough and that you include the CAPA plan in the report.  Additionally, there may be actions that you should take to correct the problem but have not taken before IRB review since implementation of the changes was not needed to protect participants' rights, welfare, and safety.

Preventive Actions

Preventive actions are necessary to ensure that the problem does not reoccur. An example, create and document a process or standard operating procedure (SOP).  Then, train on the process, implement the process, evaluate the process, and amend the process as necessary.  Consider whether you need to revise the protocol or informed consent forms as a part of your plan.

Step 4: Document the CAPA Plan

CAPA plans must be thorough and well documented. In your plan, include information that is: 

• Specific: Identify the actions you or others will take to address the root cause, the individual (role) responsible for taking the actions, and where you will document the actions.
• Timely: Include the date(s) when you or others will complete the actions.
• Measurable: Include a process of assessing the action plan effectiveness and a process by which the plan will be amended if it is ineffective.

 A thorough CAPA plan must also include the following elements:

• Action type (corrective or preventive)
• Action description
• Responsible person
• Plan for effectiveness check
• Effectiveness check outcomes

You must create and maintain documentation that demonstrates that you implemented the CAPA plan. The IRB or sponsor may request to review this documentation.

CAPA Plan Example

• Root Cause: There was no process to ensure that new hires to the research team had all required actions taken before participating in Human Subject Research.
• Corrective Actions: The Research Manager reviewed the study history and IRB-approved personnel log with the study team history and determined that there was only one occurrence where an unapproved member of the study team participated in the research.  The Research Manager documented these actions in a note-to-file, see attached, stored in the regulatory record.
• Preventive Actions: The research manager created an SOP for new hire onboarding and a supporting checklist; see attached.  The research manager and principal investigator will ensure they appropriately onboard new hires before they participate in research by utilizing the new hire checklist.  The final step of the onboarding process is the sign-off on the checklist by both the research manager and the principal investigator.  The research manager created a note-to-file indicating the start date of the new SOP and checklist; see attached.  The completed checklists will be kept in the regulatory record with the delegation of authority log.  The research manager and the principal investigator will review the implementation of the new SOP and checklist after each of the next three new hires.  They will document their review in a note to file to be kept in the regulatory record.  If the result of the reviews is that the SOP and checklist are working as expected, a note to file will be placed in the regulatory record indicating the plan as effective with effectiveness check moving to an annual review.  If the SOP and checklist require revision, those revisions will be documented in a note to file kept in the regulatory record, and the process for evaluating the next three new hires will start again.

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Corrective and Preventive Action Plans

Corrective and preventive action (capa) plans.

IU Human Research Protection Program (HRPP) irb@iu.edu

Introduction

Despite a study team’s best efforts, errors in the conduct of research may occur. Errors may include deviations from the IRB approved study plan or noncompliance with applicable research regulations or policies. Whether the result of human oversight, process deficiencies, or technology failures, such errors should be identified and when appropriate, the steps taken to resolve them, and to ensure they do not happen again, should be well documented in the research records. This important documentation is known as a Corrective and Preventive Action (CAPA) Plan.

What is a CAPA Plan

A CAPA Plan is a collective process, or series of measures, to correct the immediate problem, to determine the cause or causes of the problem, and to develop and implement a plan to prevent the problem from recurring. Developing an effective CAPA Plan requires analysis and problem-solving skills and should represent a collaborative effort by the members of the study team. CAPA Plans should be followed through completion and should be monitored by the study team for their success in preventing recurrence of the problem. The entire process should be documented, and this documentation should be maintained as part of the research record.

How to develop and document a CAPA Plan

The IU HRPP Quality Improvement Office (QIO) has developed a CAPA Plan Template to assist study teams with this activity. This template is designed to incorporate the steps described below but should be modified as needed to capture additional steps taken by the study team and/or specific departmental processes. Examples of how to use the CAPA Plan Template, as well as additional information on the Root Cause Analysis (RCA) methods described below, may be requested by emailing Ashley Meyers at [email protected] .

The following activities should be included in the CAPA Plan:

• Describe the identified problem and how it was discovered.
• Determine whether the problem should be promptly reported to the IRB .
• RCA is a process of inquiry that is necessary to identify the source of a problem so that it can be effectively resolved and prevented. There may be multiple causes that contribute to a problem and multiple methods to resolve each cause. The “root cause” is the most basic cause of a problem that may trigger a chain of additional causes.
• The RCA process is most effective when conducted with a team of people to help with brainstorming. It is important to talk to all people involved in the initial problem and to ask objective, open-ended questions in order to eliminate assumptions and pull together only facts about why a problem occurred.
• Gilbert’s Behavior Engineering Model (BEM) – a performance measurement tool to evaluate six key areas of potential deficiencies or contributors to a root cause. Potential contributors are categorized as organizational/environmental factors (subclassified as expectations and feedback, tools and resources, and consequences or incentives) and personal/individual factors (subclassified as knowledge and skills, staff capacity and qualification, and motives or preferences).
• The 5 W’s – an approach to clearly identify what happened in relation to additional details including where, when, and why the event happened, along with who was involved in the event’s occurrence in an effort to pinpoint the root cause.
• The 5 Why’s – an iterative or progressive method of “digging deeper” into an event by repeating the question “Why?” after each possible cause to ensure the ultimate root cause is identified. The answer to each “Why?” forms the basis of the next question. Of note, the question may need to be repeated more or less than 5 times, or may need to be replaced with “Why did the process fail?” in order to successfully identify the root cause. When the last answer ultimately identifies a broken process or a process that does not exist, you may have reached the root-cause level.  
• Fishbone Diagram (Cause and Effect Method) – a graphic technique to help visually identify and display potential causes of a problem and their relationship to each other. Potential causes may be grouped under the classic model categories of Materials, Methods, Equipment, Environment, and People, or the RCA participant group may come up with their own major categories as a starting point.   
• Document the RCA process (including maintaining the group’s notes taken during the process) and record the ultimate root cause.
• Data corrections should be made in accordance with IU HRPP Policy, and Notes to File in the Participant’s Study File should be used to explain why such actions were taken.
• Record the planned corrective actions including who will complete them, and when they will be completed.
• As the corrective actions are completed, evidence of their completion should be maintained with the CAPA Plan. Examples might include items such as copies of email correspondence with the study sponsor, copies of corrected study documentation, copies of IRB submissions, and/or explanatory Notes to File.
• Depending on the identified problem, preventive actions might include training on research policies or related topics, development of checklists or other tools, development of new processes, revision of study materials, or sequestering of outdated materials (e.g., from active folders into archive folders).
• If study materials need to be revised, refer to HRPP Policy to determine what changes require IRB review .
• How will you prevent the problem from affecting all subjects in the study?
• How will you prevent the problem from affecting other studies conducted by the PI or within a department?
• What processes and procedures will prevent this problem from recurring?
• Record the planned preventive actions including who will complete them, and when they will be completed.
• Examples might include copies of new checklists or SOPs, training materials and/or training logs, copies of IRB submissions, or copies of email communication sent amongst the study team to notify them of the changes.
• Determine and record who is responsible for implementing, assessing, and closing the CAPA Plan.
• Record any changes to the plan that occur prior to implementation.
• Record when actions were completed and who completed them.
• Complete a self-assessment, self-audit, or evaluation , to identify potential recurrences of the problem.
• If the CAPA Plan did not prevent recurrence, revisit the RCA documentation to determine if the true root cause was ever identified. Often, when a CAPA Plan is ineffective, it is because the true root cause of the problem was not identified.
• Document the assessment process and the outcomes of the assessment.
• Confirm the completion of the CAPA Plan and document the CAPA Plan as complete or closed.
• Document the process and any discussions that took place to come to this determination.

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The IRB-approved research plan includes all information submitted and approved by the IRB, including 1) the scientific protocol, 2) information in the IRB applications, modifications and reported events, and 3) any other study-specific IRB determination or requirement. The federal regulations and Good Clinical Practice guidelines do not allow deviations from the IRB-approved plan except where necessary to eliminate apparent immediate hazards to human participants. Even with the most cautious and careful research and participant teams, however, protocol compliance can be difficult to maintain in the increasingly complex clinical trial environment. Studies are technical with multiple requirements and the human participants are volunteers with individual medical and life situations that may influence compliance. 

The investigator and research team members must make a concerted effort to comply with the protocol and educate participants on the requirements through the continuing informed consent process. When deviations from the IRB-approved research plan occur, the investigator must act quickly to ensure participant safety and reporting to sponsor and/or IRB when necessary.

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If study team members become aware of a deviation that has already occurred, taking immediate corrections will protect the rights, welfare, and safety of the participant(s). Immediate corrections may include a phone call or an office visit with a qualified research team member. The investigator may choose to order tests and other procedures to ensure the participant is safe. Document the deviation, reason it occurred, and immediate corrections taken. Consider the reporting requirements of the sponsor and IRB; report appropriately. Do not wait to report—if there isn’t time to complete an electronic application then report by phone and finish the application when time allows. The Emory IRB requires noncompliance and deviations meeting reporting criteria to be reported within 10 business days of becoming aware. The study team may also need to notify participant(s) of the problem; the IRB will advise on how to do this (e.g., letter to participants, phone, or reconsent). Immediate corrections should  focus on rights, welfare, and safety of participants and reporting .

Evaluate risk

After immediate corrections have been taken, evaluate the risk of the severity and frequency of the deviation.  To evaluate severity of a problem, start by using the Emory IRB reporting requirements, which considers events that adversely affect the rights, welfare, or safety of participants (among other things) to be major. 

To evaluate frequency, consider recurrence of the problem in the future and history of the problem in the past.  For future assessment, consider the risk of the event recurring in the same participant or other participants in the study.  For past assessment, review the protocol deviation log for other occurrences of the event.  If there is a risk of the problem recurring in the future or if you notice it becoming a pattern on the protocol deviation log, the risk of frequency is apparent.

If there is a risk of severity and/or frequency, continue to investigate the problem through root cause analysis.  If there is no risk of severity or frequency, the immediate corrections taken initially should resolve the problem. Lastly, document the deviation, corrections, and risk assessment and continue to monitor the protocol deviation log for patterns. 

Immediate Corrections

There are distinct differences between immediate corrections and corrective actions.  Corrections are the immediate steps taken to resolve a problem and ensure the rights, welfare, and safety of participants and reporting . Corrections may resolve minor deviations, but they will not effectively resolve more significant noncompliance (reminder: risk = severity + frequency).  Corrective actions are developed and implemented for more significant or systematic noncompliance once the root cause is known.

Root Cause Analysis

When significant deviations or noncompliance occur in research, it is important to identify the causes of the problem so that they can be resolved to prevent further noncompliance. There can be multiple reasons or causes that contribute to one single problem. Conversely, there may be multiple methods to resolve each cause. The root cause is the initiating, most basic cause of a problem that may or may not lead to a chain of causes or other problems. Eliminating the root cause should prevent recurrence of the problem.

A root cause analysis (RCA) is the process of identifying and documenting the root cause and the downstream effect on the causal chain. RCA should focus on identifying underlying problems that contribute to error rather than focusing on mistakes made by individuals.

1. Identify and document the problem with a problem statement

• Description of the problem
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• What happened? What is the problem?
• Why and how did the problem occur? What were the steps?
• Who was affected by the problem? Was it one participant or all participants in the study?
• What is the magnitude of the problem? Is it in one study or does the problem exist in all studies under this PI or even in an entire clinical department?
• Keep asking “why” and “how” until you reach the root cause

Once the root cause has been identified, the next step is to develop a corrective and preventive action plan to eliminate the root cause.

Corrective and Preventive Action (CAPA) Plans

The FDA indicates that corrective and preventive actions (CAPAs) are necessary to resolve problems and noncompliance in clinical investigations.  Corrective actions are those taken to resolve a problem and preventive actions are those actions that keep the problem from recurring.  Although investigators have implemented CAPAs for decades, federal agencies, sponsors and IRBs now expect CAPAs to resolve problems in research. CAPAs must be thoroughly documented, implemented, and evaluated over time for effectiveness.

Corrective actions

The first and most critical corrective action is to ensure that the immediate corrections previously taken removed any risk of harm or further harm to the participant and future participants and that the deviation was appropriately reported to the sponsor and IRB.  When study teams have assessed the rights, welfare, and safety of the participant and the root cause is known, they may consider additional reporting to the sponsor and IRB.  Ensure that the report to the sponsor and IRB is accurate and thorough and that the CAPA is included.

Preventive actions

Preventive actions are necessary to ensure that the problem does not repeat in one or more participants.  Preventive actions should be based on process.  Create and document a process or standard operating procedure (SOP).  Train on the process, implement the process, evaluate the process, and amend the process as necessary.  Consider revising the protocol or informed consent as necessary.

CAPAs must be thorough (SMART CAPA)

Specific: Compliant with regulations, addresses the full observation or root cause, accountable to named individual or role

Measurable: Action can be measured to demonstrate whether it is adequate to address root cause

Achievable: Addresses all implicated processes and levels

Realistic: Plan can be carried out given resources, knowledge and expertise

Time-bound: Assigned to a person or role who can accomplish action in a given time period

CAPAs must be implemented

Ensure that the CAPA is well documented and that all study team members have been trained and understand their roles and responsibilities for successful CAPA implementation. The CAPA and associated SOP may be relevant only for the study or it may need to be implemented systematically across the clinical department. The CAPA and SOP can be rolled out in stages. The important thing is to take action and document it.

CAPAs must be evaluated over time

Effectiveness check is the final step of the CAPA process.  Ensure that the CAPA has addressed the root cause and that the problem has not recurred.  If the CAPA has not addressed the root cause, amend the CAPA as necessary, train on the process, implement the process, and re-evaluate.

CAPA must be well documented

Documenting the CAPA

• Action type (corrective or preventive)
• Action description
• Plan for effectiveness check
• Effectiveness check outcome

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Principles of Good Clinical Trial Design

1 Department of Mathematics and Statistics, Vassar College, Poughkeepsie NY

2 Department of Health Sciences Research, Mayo Clinic, Rochester MN

J Le-Rademacher

S.j. mandrekar.

Clinical trials are a fundamental component of medical research and serve as the main route to obtain evidence of the safety and efficacy of a treatment before its approval. A trial’s ability to provide the intended evidence hinges on appropriate design, from background knowledge and trial rationale to sample size and interim monitoring rules. In this article, we present some general design principles for investigators and their research teams to consider when planning to conduct a trial.

Introduction.

Clinical trials are a fundamental component of medical research. Before any treatment is approved and offered to patients in the general population, rigorous evidence of its safety and efficacy must be shown. Clinical trials are the main route to obtain this required evidence. In this article, we present some general principles of good clinical trial design, which are often used as the basis to evaluate the quality of the evidence presented in manuscripts reporting trial results. By trial “design,” we include aspects from background knowledge and trial rationale to sample size and interim monitoring rules. Given that mistakes in design can seldom be later rectified, we strongly encourage investigators to consider these guidelines before beginning a study.

The critical component for a successful design is the relationship among the different members of the scientific team. This is important because each person on the team contributes their area of expertise to come up with a feasible study that meets the scientific hypothesis. It is crucial to involve statisticians in the very early stage of the study design instead of waiting to involve them at the time of data analysis. Not only can statisticians help with assessing the design parameters and calculating the sample size needed to address the study aims, they also ensure that the statistical hypotheses appropriately align with the study objectives and that the corresponding statistical analyses are correctly applied. Note that it is very difficult to fix a poorly-designed study once it is implemented.

The design process of a clinical trial is iterative in nature with some of the steps being inherently connected to others, but it can be helpful to divide the process into two phases – conceptual planning and implementation ( Figure 1 ). The conceptual planning phase includes establishing prior knowledge/background, thinking through the rationale for the proposed trial as it relates to the patient population and the intervention under consideration, considering the outcomes of interest and statistical design parameters including stratification factors, and determining trial phase. The implementation phase is where the design parameters necessary to actually run the trial are specified, and consists of performing sample size calculations, defining interim monitoring and stopping rules, and conducting simulation studies to evaluate the operating characteristics of the proposed design. In the remainder of this paper, we frame our guidelines around these phases in the design process of a clinical trial. Throughout the paper, we provide references for the interested reader to find further details and explanations of concepts and terms.

Principles for conceptual planning and implementation stages

Conceptual Phase

In this section, we outline the different areas that need careful attention when considering a clinical trial.

Prior knowledge/background:

A first step in designing a clinical trial is to establish what is known about the disease being studied. Specifically, this includes identifying the current standard of care and reviewing what is already known about the intervention(s) being studied including its safety profile and whether it has been tested in humans.

Trial rationale:

It is important to justify the need for the proposed trial, to identify the population of interest and to determine the disease or biomarker prevalence in this population. When the disease is rare and/or a targeted subgroup is of interest, then specific study designs for these settings may need to be considered; see Le-Rademacher et al. (2018) , Gupta et al. (2011) , and Mandrekar and Sargent (2009) . Similarly, there is extensive work in the literature on study designs for personalized medicine in oncology, see for example Renfro and Mandrekar (2018) .

Outcomes of interest:

Once the rationale for a trial has been established, selection of the outcome(s) of interest is essential. Trial outcomes can be either health- or treatment-related. Examples of health outcomes include quality of life, symptoms, adverse events, and patient-reported outcomes. Treatment outcomes include assessing safety or efficacy of the intervention; examples include tumor shrinkage, hematologic outcomes, intermediate or surrogate outcomes, time to event outcomes (e.g. overall survival or progression-free survival), and surgical outcomes. It is common to have one or two primary outcomes, and one or two secondary outcomes. The primary outcome should be directly related to the mechanism of action of the intervention, clinically meaningful, relevant to the patient, clearly defined, and measurable. These principles highlight the importance of the design process being collaborative, not only among clinicians and statisticians, but also including patient advocates, patients and their caregivers. Friedman et al. (2010) and Wu and Sargent (2010) offer more considerations on choosing endpoints.

Statistical design:

Estimating treatment effect is a common goal of many studies. Single-arm designs – wherein all patients receive the same intervention and are generally compared to a historical control group – can provide some information on treatment effect. However, often the single arm of patients and the historical control group do not represent the same populations of interest nor receive treatment under similar trial conditions. As such, single-arm designs are limited in the conclusions they can draw and less desirable than randomized trials. In randomized trials, there are at least 2 treatment groups (or “arms”) to which patients are randomly assigned. The random assignment, or randomization, aims to create groups that are similar with respect to all factors, besides the intervention, that might affect the outcome. This is a key principle of randomized trials that ensures a fair comparison. Randomized trials can additionally incorporate other design components. Common examples include the use of a control arm (i.e. an arm that receives the standard of care) and blinding (i.e. patient and/or clinician do not know the treatment assignment) to reduce bias. Randomization can be balanced where both groups are of equal size or unbalanced where groups are of unequal size. Finally, when confounding factors may be of concern, stratification may be considered as an additional design component. Although randomization aims to reduce confounding by making treatment groups as similar as possible except for the treatment assigned, it is nevertheless possible for the groups to differ with respect to some important factors. Examples of such factors include gender and age, and other factors specific to the study context. To avoid this possibility, identify these potential confounding factors and include stratification as part of the randomization process. Specifically, patients are grouped into strata according to the important factors and then randomized within each stratum. For considerations on other study designs, including adaptive, group sequential and Bayesian designs, see Pallmann et al. (2018) , Bhatt and Mehta (2016) , Vandemeulebroecke (2008) , Lee and Chu (2012) , and Berry (2006) . For considerations when drafting a statistical analysis plan for clinical trials, see Gamble et al. (2017) .

Trial phase:

The traditional development of new therapeutic interventions occurs in phases of trials, from pre-clinical to post-market, and so one must consider the available information about the intervention, the targeted population, etc. to better understand the trial phase for the study under consideration. Early phases of clinical studies include pilot studies, phase I, phase II single arm, and proof of concept. Later phases of clinical studies include randomized phase II, phase II/III, and phase III trials. Phase II trials aim to further understand the safety and efficacy of an intervention to help decide whether or not to proceed to a phase III trial. Phase II and Phase III trials typically have different endpoints; Phase II trials utilize short-term, early endpoints such as response rate or event-free survival rate at a predetermined time point whereas Phase III trials utilize longer-term clinical outcomes such as overall survival ( Foster, Le-Rademacher, & Mandrekar, 2019 ). Given the role of Phase II trials in determining the go/no-go decision to proceed for further testing in large confirmatory Phase III trials, it is crucial to select an appropriate endpoint, particularly in Phase II trials. Phase II endpoints should ideally be a strong surrogate for the Phase III endpoints ( Yin et al., 2018 ).

Implementation Stage

Once the design elements in the conceptual phase have been identified, and there is consensus to move forward with designing a clinical trial, the design elements necessary for actually running the trial need to be specified. This constitutes the implementation phase, the steps for which are outlined below.

Sample size calculation:

The purpose of sample size calculation is to determine the number of patients needed to enroll in the study to provide sufficient information to address the primary objectives. For traditional randomized designs, this depends on three primary factors that the research team must decide together – effect size, (statistical) power, and statistical significance level. Effect size refers to the minimum treatment effect that one hopes to detect in the study. Power refers to the likelihood of detecting an effect when in fact there is an effect of a priori specified size. Significance level refers to the p-value threshold for concluding statistically significant results; it also corresponds to the type I error rate (the chance of concluding an effect when in fact none exists). In general, larger sample sizes are needed to detect a smaller effect size, achieve greater power, and/or reduce the type I error rate. In addition to these factors, sample size calculations for trials should anticipate loss to follow-up and withdrawals, patient non-compliance to treatment, and protocol violations and ineligibility. Sample size calculations should be adjusted (specifically, increased) based on expected rates of these various sources of patient “drop-out.” Finally, examining the population of interest will help determine the expected accrual rate, and in turn, the expected time to accrue the total required number of patients to the trial. Sample size considerations for Bayesian designs depend on additional factors, most notably the prior distribution of the effect size; see Pezeshk (2003) .

Interim monitoring and stopping rule:

Clinical trial monitoring is critical to the conduct – especially the ethical conduct – of the trial, and as part of this, it is important to decide the number and timing of interim analyses to be conducted prior to the completion of data collection, and build this as part of the design. Further, it is important to specify parameters for all stopping rules for stopping the trial early. In a Frequentist design, stopping rules are defined in terms of boundaries for safety, efficacy and futility; see Chapter 8 in Ellenberg, Fleming, and DeMets (2002) . In a Bayesian design, stopping rules are typically defined in terms of posterior probabilities or predictive probabilities; see Saville et al. (2014) .

Simulation studies:

Finally, even with the best trial design, actual trials seldom go as planned as unanticipated scenarios may arise. Therefore in designing the trial, it is helpful to brainstorm as much as possible these unanticipated scenarios and understand their implications using simulation studies. Simulation studies, when designed well with realistic scenarios, are a valuable tool for evaluating different trial designs and scenarios without exposing patients to an ineffective or harmful therapy or incurring the high financial costs associated with running an actual trial. The insights gained from simulation studies can help further guide the design process.

The goal of this paper is to provide an initial guidance to investigators through the design process of a clinical trial. It is not meant to be a strict set of rules to be followed in some prescribed order, rather it is meant to be a set of guidelines to consider in active collaboration with the study team including a statistician. These principles should apply for designing any clinical trial, regardless of who initiates and conducts the study (e.g. research group vs. industry). The involvement of the statistician throughout the entire research cannot be overemphasized. The statistician can aid in each step, from formulating appropriate scientific hypotheses to designing and conducting simulation studies. In addition to being collaborative, the design process is also iterative; it may be that some design elements need to be modified after other design elements are considered. For example, trial phase is typically driven by the level of available evidence on the drug being tested. However, occasionally the choice of trial phase (e.g. Phase II vs. Phase III) may be driven by feasibility to launch a large trial. Ultimately the design must be feasible and appropriate to answer the research question(s) of interest.

This paper is also not meant to provide an extensive review of design principles; for that, we refer the interested reader to the references included in this paper that offer detailed guidelines for designing trials. Further, the International Conference on Harmonisation has drafted two reports on statistical design: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human Use (1998 , 2016 ). The frequently-cited reference by Altman et al. (1983) outlines statistical guidelines for preparing a manuscript for medical journals.

Expanding these principles for novel study designs, including immunotherapy and cellular therapy trials, and cancer care delivery research that spans multiple disciplines and where randomization must be made at the patient, provider, and site levels, could be considered in future work.

ACKNOWLEDGMENTS:

This work is funded in part by 5K12CA090628 and P30CA15083 (Mayo Clinic Comprehensive Cancer Center Grant).

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

CONFLICTS OF INTEREST: The authors declare no potential conflicts of interest.

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Understanding Clinical Trials

Clinical research: what is it.

Your doctor may have said that you are eligible for a clinical trial, or you may have seen an ad for a clinical research study. What is clinical research, and is it right for you?

Clinical research is the comprehensive study of the safety and effectiveness of the most promising advances in patient care. Clinical research is different than laboratory research. It involves people who volunteer to help us better understand medicine and health. Lab research generally does not involve people — although it helps us learn which new ideas may help people.

Every drug, device, tool, diagnostic test, technique and technology used in medicine today was once tested in volunteers who took part in clinical research studies.

At Johns Hopkins Medicine, we believe that clinical research is key to improve care for people in our community and around the world. Once you understand more about clinical research, you may appreciate why it’s important to participate — for yourself and the community.

What Are the Types of Clinical Research?

There are two main kinds of clinical research:

Observational Studies

Observational studies are studies that aim to identify and analyze patterns in medical data or in biological samples, such as tissue or blood provided by study participants.

Clinical Trials

Clinical trials, which are also called interventional studies, test the safety and effectiveness of medical interventions — such as medications, procedures and tools — in living people.

Clinical research studies need people of every age, health status, race, gender, ethnicity and cultural background to participate. This will increase the chances that scientists and clinicians will develop treatments and procedures that are likely to be safe and work well in all people. Potential volunteers are carefully screened to ensure that they meet all of the requirements for any study before they begin. Most of the reasons people are not included in studies is because of concerns about safety.

Both healthy people and those with diagnosed medical conditions can take part in clinical research. Participation is always completely voluntary, and participants can leave a study at any time for any reason.

“The only way medical advancements can be made is if people volunteer to participate in clinical research. The research participant is just as necessary as the researcher in this partnership to advance health care.” Liz Martinez, Johns Hopkins Medicine Research Participant Advocate

Types of Research Studies

Within the two main kinds of clinical research, there are many types of studies. They vary based on the study goals, participants and other factors.

Biospecimen studies

Healthy volunteer studies.

Clinical trials study the safety and effectiveness of interventions and procedures on people’s health. Interventions may include medications, radiation, foods or behaviors, such as exercise. Usually, the treatments in clinical trials are studied in a laboratory and sometimes in animals before they are studied in humans. The goal of clinical trials is to find new and better ways of preventing, diagnosing and treating disease. They are used to test:

Drugs or medicines

New types of surgery

Medical devices

New ways of using current treatments

New ways of changing health behaviors

New ways to improve quality of life for sick patients

 Goals of Clinical Trials

Because every clinical trial is designed to answer one or more medical questions, different trials have different goals. Those goals include:

Treatment trials

Prevention trials, screening trials, phases of a clinical trial.

In general, a new drug needs to go through a series of four types of clinical trials. This helps researchers show that the medication is safe and effective. As a study moves through each phase, researchers learn more about a medication, including its risks and benefits.

Is the medication safe and what is the right dose?   Phase one trials involve small numbers of participants, often normal volunteers.

Does the new medication work and what are the side effects?   Phase two trials test the treatment or procedure on a larger number of participants. These participants usually have the condition or disease that the treatment is intended to remedy.

Is the new medication more effective than existing treatments?  Phase three trials have even more people enrolled. Some may get a placebo (a substance that has no medical effect) or an already approved treatment, so that the new medication can be compared to that treatment.

Is the new medication effective and safe over the long term?   Phase four happens after the treatment or procedure has been approved. Information about patients who are receiving the treatment is gathered and studied to see if any new information is seen when given to a large number of patients.

“Johns Hopkins has a comprehensive system overseeing research that is audited by the FDA and the Association for Accreditation of Human Research Protection Programs to make certain all research participants voluntarily agreed to join a study and their safety was maximized.” Gail Daumit, M.D., M.H.S., Vice Dean for Clinical Investigation, Johns Hopkins University School of Medicine

Is It Safe to Participate in Clinical Research?

There are several steps in place to protect volunteers who take part in clinical research studies. Clinical Research is regulated by the federal government. In addition, the institutional review board (IRB) and Human Subjects Research Protection Program at each study location have many safeguards built in to each study to protect the safety and privacy of participants.

Clinical researchers are required by law to follow the safety rules outlined by each study's protocol. A protocol is a detailed plan of what researchers will do in during the study.

In the U.S., every study site's IRB — which is made up of both medical experts and members of the general public — must approve all clinical research. IRB members also review plans for all clinical studies. And, they make sure that research participants are protected from as much risk as possible.

Earning Your Trust

This was not always the case. Many people of color are wary of joining clinical research because of previous poor treatment of underrepresented minorities throughout the U.S. This includes medical research performed on enslaved people without their consent, or not giving treatment to Black men who participated in the Tuskegee Study of Untreated Syphilis in the Negro Male. Since the 1970s, numerous regulations have been in place to protect the rights of study participants.

Many clinical research studies are also supervised by a data and safety monitoring committee. This is a group made up of experts in the area being studied. These biomedical professionals regularly monitor clinical studies as they progress. If they discover or suspect any problems with a study, they immediately stop the trial. In addition, Johns Hopkins Medicine’s Research Participant Advocacy Group focuses on improving the experience of people who participate in clinical research.

Clinical research participants with concerns about anything related to the study they are taking part in should contact Johns Hopkins Medicine’s IRB or our Research Participant Advocacy Group .

Learn More About Clinical Research at Johns Hopkins Medicine

For information about clinical trial opportunities at Johns Hopkins Medicine, visit our trials site.

Video Clinical Research for a Healthier Tomorrow: A Family Shares Their Story

Clinical Research for a Healthier Tomorrow: A Family Shares Their Story

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• 16 February 2023

FDA to require diversity plan for clinical trials

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The US Food and Drug Administration (FDA) will soon require researchers and companies seeking approval for late-stage clinical trials to submit a plan for ensuring diversity among trial participants.

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doi: https://doi.org/10.1038/d41586-023-00469-4

Hwang, T. J. & Brawley, O. W. N. Engl. J. Med. 387 , 1347–1349 (2022).

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Action Plan Developed To Enhance Enrollment In Acute Stroke Trials

By Deborah Borfitz 

November 14, 2023 | Time is of the essence when it comes to acute stroke trials, where investigators may have mere minutes to obtain consent—in many cases, from a loved one of the patient. Because consenting delays can impact the potential efficacy of an experimental treatment, they represent the biggest obstacle to both participant enrollment and scientific advancement in the field, according to Joseph Broderick, M.D., professor in the University of Cincinnati’s department of neurology and rehabilitation medicine and a principal investigator (PI) of the National Coordinating Center for the NIH StrokeNet . 

Many countries outside the U.S. recruit patients into acute stroke trials at a higher rate per institution, he notes, largely because their process for emergency consent is a lot easier to navigate. The “exception from informed consent” (EFIC) process of the Food and Drug Administration (FDA) requires community consultation and public disclosure prior to institutional review board (IRB) approval for a study to start. 

When the COVID pandemic struck and public gatherings were effectively banned, the EFIC process shut down some stroke studies simply because trial investigators couldn’t meet with community members, says Broderick. The requirement was intended to protect individual autonomy and preserve public trust in instances where emergency trials are allowed to enroll patients without informed consent. 

Enhancing and streamlining startup emergency consent in the U.S. is one of 12 action items for improving enrollment and completion in acute stroke trials that came out of a Stroke Treatment Academic Industry Roundtable (STAIR) meeting held earlier this year. The meeting’s review and recommendations published recently in Stroke ( DOI: 10.1161/STROKEAHA.123.044149 ). 

EFIC does not mean investigators don’t obtain consent, only that they don’t have to get it immediately, Broderick stresses. The time window for enrollment in an acute stroke trial is often within one to two hours of stroke onset, necessitating the special allowance to enable the testing of therapies that could potentially salvage brain tissue and help prevent disability.  

Without patient enrollment and completion of trials, progress in treating strokes comes to a standstill, Broderick says. “While we may have a lot of good ideas, none of them are going to get tested without recruitment.”  

Emergency Consent

The STAIR brought together stroke physicians and researchers, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the FDA to discuss strategies for improving enrollment, Broderick says. Industry generally has more resources to devote to clinical trials than the investigator-initiated, government-funded studies done by NIH StrokeNet, and are better at doing global trials because of their presence in multiple countries. But the issues faced by academic and industry-sponsored trials have “huge overlap.” 

As a PI for the National Coordinating Center for all NINDS-sponsored stroke trials conducted around the country and in some cases globally, as well as a PI on other large trials, Broderick has a lot of firsthand experience with the enrollment challenges. The U.S. has been behind other countries for more than a decade now when it comes to getting patients admitted into stroke trials, and the situation is now urgently in need of redress.  

The prerequisite of community engagement and consultation is the key difference in how emergency consent in the U.S. differs from that of other countries, says Broderick. In practical terms, that means planned events where investigators talk about a trial with groups of at-risk individuals living in the geographic area from which study participants will be drawn and, if an IRB deems it appropriate and feasible, some sort of opt-out mechanism for those who know they would not consent (e.g., a medical identification bracelet or wallet card). 

Elsewhere, IRBs might simply approve emergency consent based on the recognized need for the study provided it is judged to be ethically sound. There is consensus across most countries that consent be obtained from patients if their condition improves or at the earliest feasible opportunity from a family member or legal representative.  A few countries, including Japan and India, don’t even have an emergency consent process, he notes.  

In the U.S., a conference regarding emergency consent will be held in December for relevant parties, including the FDA, Broderick says. The published recommendation is for centralizing some of the EFIC workload and using national data in conjunction with local community events. 

Procedural differences are inevitable country to country because of the various ways trials get reimbursed, jobs are created, and healthcare systems operate, he adds. Enrollment takes a bit of a hit in places like the U.S. where studies are conducted at many different sites that aren’t necessarily interested or focused on research rather than centralized within academic centers. 

Investigators on an acute stroke trial typically have no preexisting therapeutic relationship with eligible patients and their families, highlighting the need to build community ties to understand their perspectives. Patients and their family members might even be tapped as advisors, says Broderick, pointing to a tactic deployed in the I-ACQUIRE stroke recovery trial enrolling infants and toddlers where the parents were “highly involved” in decision-making about how best to support and communicate with families. 

“This past year we added stroke survivors to our working groups that help design future trials,” he continues. They’re engaged with an assortment of questions, among them: Does this make sense to you? Do you think this would be worthwhile? How would you present this trial opportunity to a potential patient?  

Site Issues

Stroke not only happens suddenly, says Broderick, it also “doesn’t respect business hours.” Given that reality, another identified action item emerging from the STAIR meeting was for sponsors to offer financial support to investigators doing after-hours enrollment of eligible participants.  

As learned in the ongoing Multi-arm Optimization of Stroke Thrombolysis ( MOST ) trial, sites open for enrollment seven days a week recruited participants twice as fast as sites open only during regular weekday hours, Broderick shares. Enrollment in other acute stroke trials might similarly improve if industry sponsors, like NIH StrokeNet, routinely offered compensation to investigators and study coordinators for their after-hours efforts.  

It also makes sense to have people available at the hospital, day and night, who understand the trial—including a pharmacist who knows how to prepare the study drug.  Some sites have done this by having the research pharmacist train the pharmacist in the emergency department to prepare study medications, Broderick says. By moving investigational products to the emergency room, enrollment in acute stroke trials becomes an around-the-clock affair. 

A site champion as well as monetary incentives for meeting study startup milestones, such as getting contracts signed and IRB approvals within a certain timeframe, can make a difference with site-level obstacles, says Broderick. The reality is that sites can sometimes take many months to launch a study either because investigators aren’t doing their job, or the center lacks the infrastructure to efficiently get things done. 

Among other action items listed in the published paper are discussions with certifying agencies and leadership from national stroke research networks about how sites might demonstrate that they have adequate clinical and research infrastructure, and prior successful trial enrollment. 

Protocol Design

Acute stroke studies can be set up to answer multiple clinical questions, separately or together, says Broderick. The STAIR group recommends trial designs that allow for co-enrollment in other studies—especially those not testing another intervention. For example, a study of a medication to open blood clots acutely in stroke could logically be combined with a study predicting how well those patients will recover.  

Alternatively, a study could be designed to test more than a single intervention. A so-called factorial trial might funnel patients into one of four different groups where they receive medication A, medication B, both drugs, or neither of the two treatments. Another option is to enroll patients in one of two different studies based on the day of the week or some other agreed-upon system.   

From the standpoint of both patients and study teams, protocols that deviate too far from standard care just feel burdensome, says Broderick. Given a choice of two studies, they will invariably opt for the one that’s easier to do. The rule of thumb is to “use what you are already collecting [e.g., blood pressure checks] in a standard fashion and apply them to what you are trying to address and test [blood pressure management],” he says.  

Recommendations coming out of the STAIR meeting are not mandates, but tasks that will require the combined efforts of everyone—including investigators, sites, and patients, says Broderick. Stroke research in the future will ideally garner the same level of attention, and large-scale quest for trial participation, which today is rarely witnessed outside of oncology.  

Investing in Clinical Research to Improve Patient Outcomes | Varian

Investing in Clinical Research to Improve Patient Outcomes

As an integral part of Siemens Healthineers, Varian works to pioneer breakthroughs in healthcare. We know that clinical research is an essential part of developing the evidence that will drive advances in the standard of care by enabling the most personalized, effective treatment approaches possible.

Varian is committed to investing in research that supports the development of newer treatment technologies and advancements, with the hope of bringing needed therapies to more patients across the globe. Our goal is to give clinicians the power to make more informed decisions so they can deliver the right care at the right time to improve outcomes.

“For Varian, this means supporting research that establishes the value of our innovations in improving patient outcomes and quality of life, and whenever possible, improving survivorship,” said Dr. Ricky Sharma, Vice President Clinical Affairs at Varian. “Just as important, we seek to ensure that our technologies and services make it easier for clinical teams to deliver the most advanced standards of care, everywhere in the world.”

Working collaboratively with cancer care teams, research institutions, patient advocacy groups, and professional medical societies across the globe, Varian is investing in projects that are designed to contribute to the body of knowledge about cancer treatment as well as other treatment areas where targeted radiation can make a difference.

Through sponsored trials and investigator-initiated studies, Varian is supporting over 100 clinical studies, generating evidence across many topics and treatment areas, as outlined below.

Varian’s Current Clinical Research Project Portfolio

Recently, Varian has focused the lion’s share of its research support for projects in five main areas: Adaptive Radiotherapy, Advanced Imaging in the Radiotherapy Treatment Process, Interventional Radiology, Proton FLASH Therapy, and Cardiac Radioablation. Other, smaller focus areas include such topics as: stereotactic body radiotherapy (SBRT), proton therapy, MR-guided boost, treatment planning, dual-energy CT, hypofractionated dose escalation, pelvic bone sparing RT, the use of embolics to treat osteoarthritis of the knee, and AI-based detection of treatment errors.

Adaptive Radiotherapy

Varian’s Ethos adaptive radiotherapy system is an AI-driven solution that enables treatment teams to plan and deliver adaptive treatments.

Varian is supporting a portfolio of adaptive trials, including the Varian-sponsored ARTIA clinical research program (Adaptive Radiation Therapy using an Individualized Approach). To date, some 20+ institutions are participating in more than 30 studies, covering some 16 disease sites.

Early reports from clinical researchers appear to support the idea that the use of Ethos adaptive therapy, by enabling more accurate tumor targeting daily, can result in a reduction in acute toxicities. For example, in the DARTBOARD study at the University of Texas Southwestern Medical Center, daily adaptive radiotherapy with Ethos allowed the use of very narrow margins around targets for patients with head & neck cancer (1-2 mm). Compared to patients treated with standard margins (5 mm) there was significantly less high-grade acute dermatitis and significantly less patient-reported sticky saliva at 6 months. 1

At the recent European Society for Radiotherapy and Oncology Congress (ESTRO 2024), activities centering on Varian’s Ethos adaptive radiotherapy technology included two oral presentations 2,3 and some 50 abstracts encompassing digital, mini-oral, and poster discussion sessions. Of those, four—two poster discussions and two digital posters—reported encouraging early clinical outcomes in breast, cervical, and head & neck cancer. 4,5,6,7 (The rest covered topics like dosimetry, RTT workflow, feasibility of adaptive workflows, and other important themes not directly related to patient outcomes).

Advanced Imaging in the Radiotherapy Treatment Process

In 2022, Varian introduced the optional HyperSight imaging solution for its Halcyon and Ethos radiotherapy systems. Earlier this year, HyperSight became available for use on TrueBeam and Edge systems as well. HyperSight allows clinicians to acquire high-quality cone-beam CT (CBCT) images with Hounsfield Unit (HU) accuracy, so that the images can be used for online and offline adaptive treatment planning. The enhanced image quality is designed to improve the ability to target tumor volumes more precisely and spare healthy tissue for patients receiving radiation therapy treatments, with the goal of improving patient outcomes.

Recent research on HyperSight presented at the recent ESTRO Congress shows that image quality 8,9 and utility for treatment planning 10 are superior to what was possible using earlier generations of in-room CBCT imaging technology, except where breathing motion introduces artifacts that hamper accurate dose calculation. In addition, online adaptive radiotherapy is feasible as seen in stage II-III rectal cancer patients, without the need for generating a separate planning CT, enabling a reduction in time to treatment. 11

Interventional Radiology

Varian is supporting studies relating to interventional radiology in two areas: the use of microwave ablation as a treatment for metastatic colorectal cancer, and the use of genicular artery embolization to treat symptomatic knee osteoarthritis.

Image-Guided Microwave Ablation for the Treatment of Metastatic Colorectal Cancer Over the past decade or so, evidence has accrued to suggest that image-guided microwave ablation is a viable approach to treating metastatic colorectal cancer. 12,13 Nevertheless, surgical resection remains the standard of care in treatment guidelines and tumor board reviews don’t always include an interventional radiologist.

To support the additional in-depth research needed to truly evaluate image-guided microwave ablation as a treatment for metastatic colorectal cancer, Varian joined with other industry partners to support a clinical trial under the auspices of the Society of Interventional Oncology (SIO), " Ablation with Confirmation of Colorectal Liver Metastases (ACCLAIM) Prospective Trial for Microwave Ablation as a Local Cure ."

The ACCLAIM trial, SIO’s first, is “the first global, prospective trial to use an objective and reproducible technical outcome in its study design, which SIO believes will drive important changes to future treatment guidelines,” according to the SIO press release announcing the launch of the study.

Genicular Artery Embolization for Symptomatic Knee Osteoarthritis: Genesis II and GRAVITY Genicular artery embolization (GAE) is an investigational treatment for knee osteoarthritis, an extremely common, painful, and debilitating condition that’s also one of the leading causes of disability. In a GAE procedure, a small catheter is advanced into one or more of the arteries supplying the knee joint known as the genicular arteries. Embolic microspheres are delivered through the catheter to reduce the blood supply to the vessels, which may decrease inflammation. 14

Varian is among those supporting two studies of GAE for the treatment of knee osteoarthritis (OA). GENESIS II , based in the UK, is a double-blind, sham-controlled, randomized trial investigating the use of a permanent embolic agent for embolization of abnormal genicular arterial vasculature to reduce pain in patients with mild to moderate knee osteoarthritis.

Varian is also providing support for GRAVITY , a prospective, randomized open-label U.S. Food and Drug Administration-approved investigational device exemption study being conducted at UCLA. This trial seeks to compare clinical outcomes of GAE and observation, as well as to identify biomarkers and imaging endpoints for this emerging therapy.

“At Varian, we believe that new, innovative, and minimally invasive treatment options that support patients in their activities of daily living can have tremendous overall impact on patient lives,” says David Hahn, chief medical officer for Varian’s Interventional Solutions business. “We are excited about addressing the important scientific questions on the role of GAE in treating knee OA as part of our commitment to developing meaningful clinical data within the field of interventional radiology and look forward to seeing the results.”

Proton FLASH Therapy – FAST-01 and FAST-02

Varian received Investigational Device Exemption (IDE) approval from the Food and Drug Administration (FDA) for two clinical trials of FLASH therapy, an experimental treatment modality that involves delivering therapeutic doses of radiation very quickly—in just a fraction of a second. In the first study, FAST-01 ( F e A sibility S tudy of FLASH Radiotherapy for the T reatment of Symptomatic Bone Metastases), concluded in 2023, the technology for proton FLASH radiation treatment was shown to be as safe and appeared to be as effective as conventional radiation without causing unexpected side effects. 15 These findings led to a new IDE for FAST-02 , launched in February 2023, which builds on the clinical evidence from FAST-01 and will include the treatment of bone metastases in the chest, providing critical insights into potential of FLASH treatment for cancer metastases.

Cardiac Radioablation

Last year, the U.S. Food and Drug Administration (FDA) approved an IDE for a pivotal RADIATE-VT clinical trial , sponsored by Varian. This is the first international, multi-center, randomized controlled trial to evaluate the safety and efficacy of Varian’s cardiac radioablation (CRA) system compared to repeat catheter ablation for patients with high-risk refractory ventricular tachycardia (VT).

RADIATE-VT is open and enrolling, and will enroll 380 participants across 20+ institutions. Please note that Varian’s CRA system is an Investigational Device, limited by United States law to investigational use.

"Varian has long been a leader in radiotherapy innovation, and through this trial we're looking at the viability of expanding the application of our technology for a new patient population,” said Deepak "Dee" Khuntia, M.D., Senior Vice President and Chief Medical Officer at Varian. “We are eager to see this solution evaluated in the clinical trial setting at leading institutions around the world, which also would support future submissions for regulatory marketing authorization.”

Study outcomes described in this article encompass “post-market” studies of labeled uses (e.g., the ARTIA studies) and investigational research into new uses (e.g., GAE, the FAST studies, and CRA). As results may be preliminary, we recommend you review the actual study reports for more detail as your results may vary.

• Sher DJ, Avkshtol V, Lin MH et al. Acute Toxicity and Efficiency Outcomes in the DARTBOARD Randomized Trial of Daily Adaptive Radiotherapy for Head and Neck Squamous Cell Carcinoma . Int J Radiat Oncol Biol Phys. 2023;117(4):e6.
• Koen J Nelissen, Eva Versteijne, Suresh Senan, et al. Clinical experience with same-day delivery of adaptive palliative radiotherapy without a planning CT .
• Karin Goudschaal, Sana Azzarouali, Jorrit Visser, et al. Support system in an RTT-only Conebeam CT-guided online adaptive radiotherapy workflow .
• Angelique R.W. van Vlaenderen, Koen J. Nelissen, Judith G. Middelburg-van Rijn et al. CBCT-guided online adaptive radiotherapy in breast cancer patients – a prospective trial . NL2021.0624
• Ajcharee Nuengsigkapian, Petch Alisanant, Kanokphorn Thonglert, et al. AI-enhanced Adaptive Intensity Modulated radiotherapy for Cervical cancer (AIM-C): Early experience .
• Philip Blumenfeld, Eduard Arbit, Robert Den, et al. Daily artificial intelligence-assisted online adaptive radiotherapy for head and neck cancer .
• Sridhar Papaiah Susheela, Anuradha Pinninti, Priyasha Damodara, et al. Early response assessment of Ca cervix treated with PETCT based SIB-Online Adaptive Radiotherapy .
• Britt Kunnen, Agustinus J.A.J. van de Schoot, Kimm P. Fremeijer, et al. Ethos HyperSight: what is the added value compared to conventional ring gantry cone-beam CT .
• Nienke D. Sijtsema, Joan J. Penninkhof, Agustinus J.A.J. van de Schoot, et al. HyperSight CBCT directly suitable for offline adaptive radiotherapy for prostate, but not for lung .
• Vicki T Taasti, Colien Hazelaar, Marta Bogowicz, et al. Clinical evaluation of CT number stability of advanced cone-beam CT for thorax and pelvic patients .
• Claudia S.E.W. Schuurhuizen, Judith H. Sluijter, Pim J.J. Damen, et al. Online adaptive radiotherapy without planning CT scan: a prospective clinical trial in rectal cancer .
• Takahashi, H., & Berber, E. (2019). Role of thermal ablation in the management of colorectal liver metastasis. Hepatobiliary Surgery and Nutrition , 9(1), 49-58.
• Meijerink MR, Puijk RS, van Tilborg A, et al. Radiofrequency and Microwave Ablation Compared to Systemic Chemotherapy and to Partial Hepatectomy in the Treatment of Colorectal Liver Metastases: A Systematic Review and Meta-Analysis . Cardiovasc Intervent Radiol 2018;41:1189-204.
• Padia SA, Genshaft S, Blumstein G et al. Genicular Artery Embolization for the Treatment of Symptomatic Knee Osteoarthritis . JB JS Open Access. 2021 Oct 21;6(4):e21.00085. doi: 10.2106/JBJS.OA.21.00085. PMID: 34703964; PMCID: PMC8542160.
• FLASH radiation therapy shows promise in first-in-human trial - American Society for Radiation Oncology (ASTRO). Accessed May 7, 2024.

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• Handwashing
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About Hand Hygiene for Patients in Healthcare Settings

• Patients in healthcare settings are at risk of getting infections while receiving treatment for other conditions.
• Cleaning your hands can prevent the spread of germs, including those that are resistant to antibiotics, and protects healthcare personnel and patients.
• Patients and their loved ones can play a role in asking and reminding healthcare personnel to clean their hands.

Your hands can spread germs.

• Hands have good germs that your body needs to stay healthy. Hands can also have bad germs on them that make you sick.

Alcohol-based hand sanitizer kills most of the bad germs that make you sick.

• Alcohol-based hand sanitizers kill the good and bad germs, but the good germs quickly come back on your hands.

Alcohol-based hand sanitizer does not create antimicrobial-resistant germs.

• Alcohol-based hand sanitizers kill germs quickly and in a different way than antibiotics.
• Using alcohol-based hand sanitizers to clean your hands does not cause antimicrobial resistance.

Steps to take

When patients and visitors should clean their hands.

• Before preparing or eating food.
• Before touching your eyes, nose, or mouth.
• Before and after changing wound dressings or bandages.
• After using the restroom.
• After blowing your nose, coughing, or sneezing.
• After touching hospital surfaces such as bed rails, bedside tables, doorknobs, remote controls, or the phone.

How to clean hands

With an alcohol-based hand sanitizer:.

• Put product on hands and rub hands together.
• Cover all surfaces until hands feel dry.
• This should take around 20 seconds.

With soap and water:

• Wet your hands with warm water. Use liquid soap if possible. Apply a nickel- or quarter-sized amount of soap to your hands.
• Rub your hands together until the soap forms a lather and then rub all over the top of your hands, in between your fingers and the area around and under the fingernails.
• Continue rubbing your hands for at least 15 seconds. Need a timer? Imagine singing the "Happy Birthday" song twice.
• Rinse your hands well under running water.
• Dry your hands using a paper towel if possible. Then use your paper towel to turn off the faucet and to open the door if needed.

Clean Hands Count Campaign Materials‎

Ask your healthcare provider to clean their hands.

• Wearing gloves alone is not enough for your healthcare provider to prevent the spread of infection.
• "Before you start the exam, would you mind cleaning your hands again?"
• "Would it be alright if you cleaned your hands before changing my bandages?"
• "I didn't see you clean your hands when you came in, would you mind cleaning them again before you examine me?"
• "I'm worried about germs spreading in the hospital. Will you please clean your hands once more before you start my treatment?"

Speak up for clean hands in healthcare settings

• Clean your own hands and ask those around you to do the same.
• Don't be afraid to use your voice: it's okay to ask your healthcare provider to clean their hands.
• "I saw you clean your hands when you arrived some time ago, but would you mind cleaning them again?"

Frequently asked questions

Is there such a thing as too clean.

• Germs are everywhere. They are within and on our bodies and on every surface you touch. But not all germs are bad. We need some of these germs to keep us healthy and our immune system strong.
• Your hands have good germs on them that your body needs to stay healthy. These germs live under the deeper layers of the skin.
• Your hands can also have bad germs on them that make you sick. These germs live on the surface and are easily killed/wiped away by the alcohol-based hand sanitizer.
• Using an alcohol-based hand sanitizer is the preferred way for to keep your hands clean.

Washing with soap and water: 15 versus 20 seconds

• Wash your hands for more than 15 seconds, not exactly 15 seconds.
• The time it takes is less important than making sure you clean all areas of your hands.
• Alcohol-based hand sanitizers are the preferred way to clean your hands in healthcare facilities.

Which one? Soap and water versus alcohol-based hand sanitizer

An alcohol-based hand sanitizer is the preferred method for cleaning your hands when they are not visibly dirty because it:

• Is more effective at killing potentially deadly germs on hands than soap.
• when moving from soiled to clean activities with the same patient or resident.
• when moving between patients or residents in shared rooms or common areas.
• Improves skin condition with less irritation and dryness than soap and water.

Guidelines for Hand Hygiene in Healthcare Settings Published 2002

Core Infection Prevention and Control Practices for Safe Healthcare Delivery in All Settings

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