Fourth edition Essentials of Clinical Research
Fourth edition Essentials of Clinical Research
What is study monitoring and why is it important to drug discovery projects?
Pharmaceutical companies need to ensure that their drugs are safe but also that they work. In drug development this requires numerous studies to be presented to international regulators, and these pre- clinical studies are often conducted by Contract Research Organizations (CROs). This activity needs to meet stringent standards for regulators to allow clinical trials to go ahead without any interruption.
Without this oversight, companies run the risk of having studies that are not fit for purpose of trial. This could mean repeating studies, incurring delays and perhaps attracting greater scrutiny from regulators; all of which can be expensive – ranging from a few thousand to a few million GBP. And as well as lost sales because of limited patent times, long-term delays prevent an effective therapy reaching patients in good time.
ORTHOPEDICS COMPLETE : UPDATED FROM " MAHESWARI AND WHEELESS TEXTBOOK OF ORTHOPEDICS"
Unfortunately, it’s a fact of life that during a study sometimes things don’t go to plan: people can make unforeseen errors and omissions, the unexpected happens and this can lead to bad outcomes. Ultimately, the biggest risk for the project is not obtaining complete data to satisfy the study’s objectives.
According to ICH GCP, What is monitoring?
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Essential Orthopaedics(Including Clinical Methods)
Why do we do monitoring?
TO VERIFY THAT:
ATED FROM " MAHESWARI AND WHEELESS TEXTBOOK OF ORTHOPEDICS"
1. The rights and well-being of human subjects are protected: (needs to check the following things)
- Investigator obtains written informed consent for all trial subjects prior to any protocol specific procedures.
- Investigator enrolls only eligible subjects.
- Investigator reports all adverse events including serious adverse events appropriately.
- Investigator provides all applicable documentation for ethics committee review in a timely manner.
2. The reported trial data are accurate, complete, and verifiable from source documents:
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- Investigator accurately completes all source documents, logs and CRFs.
- All data entered in the CRF is verifiable from source data and has adequate supporting documents.
- Investigator appropriately corrects all errors, omissions, and illegible data in source and CRF.
- Follow ALCOA+
- Investigator maintains and dispenses investigational product(s) adequately.
3. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
- Investigator conducts the study in compliance with the protocol.
- Investigator has adequate qualifications and resources to conduct the trial.
- Investigator maintains all essential trial related documents.
Study monitors help a project to run smoothly and ensure that work outsourced by a sponsoring company is running in the right direction and within the required timelines. They also bring an understanding of the “big picture” and how what happens today can affect future clinical trials.
If problems arise during a study – as things do when testing for safety – a study monitor provides expert insight to make the right decisions, such as lowering dose levels, temporarily pausing a study or terminating it early.
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Equally, monitoring visits and audits mean a study monitor gets face-to-face in the laboratory, observing the study techniques, checking the paperwork and providing a quality assurance that’s often not possible from a distance.
However, it’s important to stress that the team work developed between the study monitor, the sponsor and the CRO is a powerful triumvirate. Having input from each side raises the likelihood of getting a better study and ensuring quality that satisfies Good Laboratory Practice (GLP) and regulatory requirements.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Who is a monitor?
Monitor is a person appointed by the sponsor who is appropriately trained, having and Scientific/Clinical knowledge required for monitoring of the clinical trial. (Documentation for the same should be maintained).
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A monitor oversees the progress of a clinical trial. Monitor ensures that clinical trial is conducted, recorded, and reported in accordance with the protocol, SOP, GCP, and the applicable regulatory requirements. monitor also serves as a communication link between the Investigator and Sponsor.Monitor is a primary contact person for all trial-related issues at the site. Monitor supports the site on trial set-up & logistic issues during the whole trial. The major responsibility of monitor is motivating & training the site team during the whole trial process.
What are the types of monitoring?
- Targeted on site motoring
- Risk based monitoring
Fourth edition Essentials of Clinical Research
1.
Targeted monitoring generally refers to onsite monitoring that focuses on critical processes and critical data as well as aspects of the study that cannot easily be evaluated remotely. It includes on-site pharmacy review and usually a brief regulatory review. Most of the pharmacy review, such as ensuring that the drug is being maintained correctly and counting the drug, must be done on-site. Many clinical research sites are handling regulatory documents electronically so that most of the regulatory review can now be done remotely.
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In performing targeted monitoring, the monitoring plan is the most important piece of “equipment”. The monitor brings a copy of the monitoring plan with on-site to remind himself of what should and should not be doing. The monitoring plan states the frequency and length of on-site visits. If the monitor finds that more time is necessary, the monitor must discuss this with the project manager. There are many methods for targeted monitoring, such as 100% SDV (source data verification) on 50% of participants, or review of 100% of patients with 100% SDV of Screening and Cycle 1, then review of just dosing, AEs, (adverse events) and outcome for further cycles. On some studies, the author has monitored 100% for the first three participants, and if there were no major deviations, every other participant after that.
Fourth edition Essentials of Clinical Research
Essential Orthopaedics(Including Clinical Methods)
Requirements for regulatory, pharmacy, and/or laboratory review should be outlined in the monitoring plan. The author has monitored some studies where pharmacy was reviewed once a year, and the author has monitored others where if the first pharmacy review was fine, pharmacy was not reviewed again. The monitoring plan states the scope of source data review and the percentage of participants for source data review, the critical variables, and thresholds and triggers for changes to the plan. Monitoring will cover 100% SDV for the critical variables.
Fourth edition Essentials of Clinical Research
Since on-site monitoring is less frequent when using targeted monitoring, the monitor needs to know what is happening between monitoring visits. In one study that the author worked on, on-site monitoring was performed for each participant after Cycle 2, after Cycle 6, at one year, and every year after that. The time that is saved by fewer on-site monitoring visits should be spent performing centralized and remote monitoring.
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Source data review is the review of source documentation for protocol compliance, adequacy of site processes, and quality of the records. The author believes that 100% of the source documentation should be reviewed. Monitors should start with the source documentation and read it like a book, one chapter at a time. They should then check the critical variables in the CRFs and then go on to the next chapter. Monitors must also review what happens between study visits, such as participant visits to the emergency room.
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Performing source data review requires critical thinking skills and goes beyond looking for transcription errors. Many problems are missed if the monitor only compares the CRFs to the source documentation for transcription errors. That monitor is not checking whether the clinical research site is following the protocol because this is not all captured in the CRFs. For example, one study that the author is working on requires the dose of the drug to be lowered in patients that have a platelet count of under 100,000. One clinical research site that the author monitored did not do this for the two patients she reviewed. Merely checking the CRFs for the dose administered and the platelet counts for transcription errors is much different than looking for protocol compliance.
Fourth edition Essentials of Clinical Research
One hundred percent review of 100% of the data could result in perfect data; however, this does not guarantee that the clinical research site followed the protocol. When the FDA does an audit, it cares most about whether the site followed the protocol and the participants’ response to the study treatment. The CRFs must contain the patients’ response as per the protocol criteria, not the doctor’s definition of response. Thus, monitoring must be done at a higher level. Targeted monitoring provides more time for this.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
On site monitoring is preplanned. So before approaching for monitoring certain preparations and check list should be prepared.
Pre monitoring: planning and preparation:
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Pre monitoring: Check list:
- Protocol (study summary)
- IB
- Monitoring report template- previous report
- CRF completion guidelines
- Vendor manuals/contacts
- Monitoring plan
- Data monitoring guidelines
- Monitoring manuals
- Monitoring Tracker
- Enrollment log
- SDV checklist
- Essential documents review
- log
- ICF log
- Outstanding queries
- Stationary
- Copies of relevant essential documents for filing
- Study training slides
- Plan Visit site as early as possible after the first subject has been enrolled.
- Review of CRFs prior to the visit.
- Review of previous monitoring visit reports/follow up letters
- Review of trial master file
- In the first few visits after start of recruitment, budget extra time for site training.
- Plan your visit so that you can complete the activities in time
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Pre monitoring: Preparation:
- Monitoring
Monitoring: Site selection:
ICF documentation and process: (what to check on ICF documents)
- Is a signed ICF available for the subject?
Was the correct version of the ICF used? Has the EC approved it? - Was the ICF signed and personally dated by the:
- Subject (or subject’s legally acceptable representative)
- Person who conducted the informed consent discussion
- Impartial witness, if applicable
- Is all the ICF-related source data for the subject available?
- Can you reconstruct what happened to the subject during the ICF process?
- Was the ICF process completed prior to any study-related procedure?
- Who was responsible for all these activities?
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Monitoring: Protocol adherence:
A Deviation is any non-conformance to the protocol, related to study conduct, for a specific subject. This could be related to subject data or the conduct of the trial affecting the integrity of the trial.
Monitoring: source document verification, subject elegiblity
- Post monitoring: Follow up and report writing
2. Risk based monitoring or remote monitoring or centralized monitoring:
Targeted monitoring is the component of risk-based monitoring that is conducted on-site and focuses on the aspects of clinical research that have the most potential to impact participant safety and the credibility of the study's results.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Centralized monitoring is a more statistical approach to handling this information and looking across sites or across patients within a clinical research site. The FDA definition of centralized monitoring states that it:“Consists of a remote evaluation carried out by sponsor personnel or representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location other than the sites at which the clinical investigation is being conducted.”
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Review of the submitted data for quality is part of centralized monitoring, which is performed in order to identify and address missing and inconsistent data, data outliers, and potential protocol deviations that might not be identified without this approach. Centralized monitoring also enables sponsors to conduct statistical analyses to uncover data trends such as range, consistency, completeness of data, or unusual distribution of data within and between clinical research sites.
Centralized monitoring can be used to analyze performance metrics, verify certain critical source data remotely, and complete some administrative and regulatory tasks. Clinical research site performance metrics such as high screen failures or withdrawals, a high number of subject eligibility violations, or study delays can be analyzed to uncover poor performance or noncompliance.
Centralized monitoring has many benefits. It enables sponsors to look at the protocol and look at critical data to see what might affect efficacy or safety variables. This information can then be used to fix issues or lessen their affect. This methodology has been used in the past to identify data fabrication. Often, people who fabricate data are not creative, and the data similarities are fairly large and obvious.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
On-site monitoring can be targeted to higher-risk clinical research sites. Centralized monitoring enables the sponsor to identify sites that are having more difficulty than other sites. Perhaps one site does not understand the protocol or has new staff members who require training.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
Many regulators hope that centralized monitoring will increase communication with clinical research site staff. With the sponsor, CRO, and site staff looking at the data, issues can be addressed before they become large problems. Centralized monitoring will also help monitors prioritize on-site monitoring to the processes that are critical to the success of the study.
Focusing on what matters is a key benefit of centralized monitoring. Monitoring should focus on the primary efficacy and safety variables, not on spending limited resources dealing with data that will not impact the study results.
Targeted On-Site Monitoring:
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•Sites with data anomalies or a higher frequency of errors,
•Protocol violations
•Dropouts relative to other sites
If you have any queries or suggestions please feel free to tell us.
CLINICAL RESEARCH: Essentials of Drug Development and Clinical Trial
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