The termination of a trial due to the adverse effects of a drug or agent is one of the most important aspects of clinical studies on drugs and drug agents. Known as a trial “close out,” the procedure of terminating a clinical trial is the act of ensuring that all the activities related to the clinical trial are reconciled in the appropriate manner, recorded and reported at the abrupt end of the process (Chow & Liu, 2012).
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This should be done in accordance with the standard operating procedures, the GCP, as well as any other applicable regulatory requirement (Chow & Liu, 2012). Clinical trial closes out due to adverse effects or any other reason, including participant walkout, is an important step in ensuring the quality of the study according to the requirements by the SOPs, GCP, sponsors and the law (Fortwengel, 2010).
In addition, it is designed to ensure that all the necessary documents are put in place when a need for information retrieval arises in the future. In case of a clinical trial closeout due to adverse effects of the drug or agent, it is the role of the principal investigators (PIs) to ensure that terms and conditions of the trial project and its related budget are in place (Pocock, 2011).
The purpose of this research paper is to carry out an investigate analysis of the closeout procedures due to the adverse effects of an agent designed to lower cholesterol in humans. The drug agent is in its Phase II trial under a double-blind placebo study. However, it has faced problems due to adverse effects on the participants. There is an urgent need to terminate the study.
Clinical trial closeout
For the purpose of quality assurance and protection of information and participant’s rights, a number of activities are conducted at the end of a clinical trial either due to completion of the project or termination (Friedman, Furberg & DeMets, 2011). All the activities carried out at the end of a study for any reason constitute ‘study closeout’ (Fortwengel, 2010). One of the main reasons for study closeout is to ensure that the study records are collected in the right manner and archived.
In addition, it ensures that leftover study articles, materials, and equipment are returned to the appropriate party or disposed of (Foresterhill, 2009). It also ensures that any loose end is tied up. In most cases, project sponsors tend to hold up the final payment until a complete closeout has been completed. In Canada, food and drug administration requires proper inspections at the end of a clinical trial.
Indications for a trial closeout: Termination due to adverse effects versus normal closeout
Although the processes of the closeout for a clinical trial follow a common protocol, it is worth noting that a number of differences exist between the processes indicated for a trial closeout due to advise effects and those indicated for a normal closeout.
In case a trial is terminated prematurely due to the adverse effect of the drug or agent on the participants, a number of indications are provided for both the investigators and the sponsors (Foresterhill, 2009). First, the investigators are required to promptly inform the trial subjects and assure appropriate therapy and follow-up on all the subjects. In addition, the investigator should inform the regulatory authorities of the incident and the protocols in use.
This is in contrast to the normal close up of a clinical trial, where investigators are required to provide information on the results of the study. Clinical close up due to completion of the study does not focus on following up or providing any form of therapy to the study subjects (Pocock, 2011).
On the other hand, it is a mandatory requirement that investigators carry out an immediate and comprehensive follow-up on all the subjects exposed to the trial and provide a compulsory therapy to counter the adverse effects of the drug or drug agent in case of an adverse effect on any subject (Friedman, Furberg & DeMets, 2011).
It is indicated that an investigator must inform the institution or authorities, where applicable if they decide to terminate the clinical trial due to adverse effects without a prior agreement of the sponsor (Foresterhill, 2009). It is mandatory for the investigators to inform the relevant authorities, especially Health Canada and Food and Drug authorities, of the incident even prior to the knowledge of the sponsor. A sponsor is then provided with a detailed explanation of the causes and processes of termination of the clinical trial.
On the other hand, closeout procedures due to completion of the study does not have a focus on involving the authorities. Rather, the investigator is required to develop a comprehensive analysis of the procedure and communicate with the sponsor prior to involving the authorities (Chow & Liu, 2012).
Although authorities are provided with frequent updating on the progress of the project, successful completion of a clinical trial mostly leads to some useful information from research, which is likely to be held confidential prior to the final release. As such, the sponsor has a right to obtain the information prior to any other party.
On the other hand, the authorities are required to have full information about any incident of adverse effect on the subjects, which means that the termination of the trial will not progress towards yielding confidential information about the study (Fortwengel, 2010). Thus, the focus is mainly on the health of the subjects who have been exposed to the drug or drug agent.
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An additional difference in indication between normal closeout and closeout due to adverse effect is the involvement of the authorities in the process of close up procedures. In this case, the authorities have the right to terminate or suspend a clinical trial in case of availability of adequate information to prove that the trial has some adverse effects on the subjects (Fortwengel, 2010).
In this case, the role of the investigator or the institution carrying out the clinical trial in terminating or suspending the project is outdone by the powers given to the authorities. In such cases, the opinion of Health Canada is the absolute power to terminate the study for protecting the health of the subjects. In this case, the investigator is required to provide a detailed report of the termination or suspension to the sponsor (Fortwengel, 2010).
On the other hand, closeout of the trial due to completion of the project has little, if any, the involvement of the power of authorities in controlling the process. In this case, the investigator or the institution carrying out the trial is responsible for carrying out the entire close procedures, including authorization of recording and reporting of information obtained from the study (Friedman, Furberg & DeMets, 2011).
The authorities are provided with a detailed report of the procedure, especially the health status of the subjects at the end of the project and the steps taken to ensure that their health status is safe after exposure to the drug or drug agent.
Duties and roles of the Principal Investigator, PI
According to the directions given by Health Canada (2013), each site of a clinical trial must have no more than one qualified investigator. However, the restriction does not apply to any sub-investigator at the site. The PI has a huge volume of responsibilities throughout the entire life of a clinical trial. The PI is responsible for the terms and conditions of a research project and its budget. They are required to understand and comply with all the rules of Health Canada and food and drugs administration.
PIs are required to ensure the appropriate qualifications for the trial being carried out prior to the start of the project (Foresterhill, 2009). It is the role of the PI to provide a declaration of any conflicts of interest, information, payment, and other aspects from any other party.
In addition, the PI must maintain a comprehensive list of any duties and responsibilities delegated to other persons with respect to the trial and the qualifications of these individuals in relation to the process and completion of the project. The PIs are also required to demonstrate the possibility of adequate recruitment of subjects for the clinical trial. They are required to show that necessary time to conduct the study under the HC requirements, adequate facility, and staffs are available.
The type of medical care given to the trial subjects is one of the main requirements of HC. It is the role of the PI to ensure that the necessary medical care is provided to the subjects in any event of adverse events experienced during the process or after the trial. The PIs have the responsibility of processing a favorable HC endorsement of the protocol prior to the commencement of the project.
Patient information and consent, procedures of subject recruitment, and consent updates are mandatory documents that should be provided and maintained by the PIs (Fortwengel, 2010). It is the role of the PI to ensure that the approved protocol is followed throughout the procedure, with additional responsibility of reporting any form of deviation from the protocol. In addition, any deviation from the approved protocol must take place with the endorsement of the relevant authorities.
Roles of the Sponsor
The sponsor is an organization or an individual who oversees the clinical study. The sponsors have a number of roles in any clinical trial. They are responsible for the implementation of quality assurance and quality control protocols. In turn, this ensures that clinical trials are conducted in the right manner, data is gathered, and reporting is done according to the approved protocol (Foresterhill, 2009).
In addition, it is the role of the sponsor to ensure that medical expertise is available for patient care and trial-related medical issues. The sponsor is the main party required to develop the trial design and analysis of the procedure. Data is an important aspect of any clinical trial. The sponsor must ensure that data collection, handling, recording, and overall management of the trial information is done according to the approved protocols.
The process of selecting the appropriate investigators and institutions for conducting the clinical trial is the duty of the sponsor. The process of providing the appropriate assurance and indemnity for the subjects and staff is under the responsibilities of the sponsor (Frank, 2008). The sponsor must also evaluate the safety of the ongoing process throughout the project lifespan.
Responsibilities of the coordinator
The study coordinators (SCs) are hired to direct and organize a clinical trial. However, there are some differences between the roles of the SC and the PIs. While the PIs are responsible for the study, the SCs are assigned the duties of coordination of the process (Foresterhill, 2009). The major role of the SC is to protect human subjects in any trial.
They are responsible for ensuring that the relevant authorities approved the study and all the consent documents provided to the subjects. In addition, the SC has the role of ensuring that the consent process is complete, with the patients answering all the questions. The SC must ensure that the consent is done in the right manner to protect individuals from coercion (Frank, 2008).
Key components of a closeout a monitoring report
A written report should be provided and submitted to the sponsor and the relevant authorities during the closeout phase of a clinical trial (Foresterhill, 2009). The report has a number of key components. The report must specify the name of the site visited, the date of visit, and the monitor’s particulars.
The name of the PI and other contacted parties must also be provided. The report should have a detailed analysis of the reviewed contents of the procedure. This section should present the statements the monitor makes at the study site, including the data and any findings made. In addition, the summary must provide a detailed analysis of any deviations from the approved protocols as well as deficiencies noted (Chow & Liu, 2012).
Possible issues that are likely to arise at the study site due to the delay of the closeout
Quite evidently, the termination of a study due to adverse effects of the drug agent on the subjects is the initial step that an investigator should consider when the problem is recorded. It aims at protecting the human subjects from any potential harm caused by the drug or the process involved in the trial. According to Chow and Liu (2012), any failure or delay in carrying out an immediate closeout when the adverse effects are seen is usually likely to result into a number of clinical, legal and ethical issues.
First, clinical issues are the most complicated impacts of delay in closeout during adverse effects. For instance, the continuation of the trial process is likely to increase the rate and consequence of adverse effects on the subjects, especially if there is a delay in providing comprehensive medical care and intervention to the affected individuals (Foresterhill, 2009).
Secondly, the PI is likely to face legal consequences in case there is a delay in reporting or termination of the procedure with adverse effects. It is likely that the PI will be responsible for negligence and irresponsible behavior relating to the public health. In ethics and legal perspectives, the delay in closeout is likely to amount to a violation of the rights of the study subjects (Frank, 2008).
Chow, S-C., & Liu, J. P. (2012). Design and Analysis of Clinical Trials: Concepts and Methodologies. Mason, OH: Cengage
Foresterhill, A. (2009). A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet, 365, 711-22.
Fortwengel, G. (2010). Guide for Investigator Initiated Trials. New York: Karger
Frank, G. (2008). Current challenges in clinical trial patient recruitment and enrollment. SoCRA Source, 2(February), 30-38.
Friedman, L. M., Furberg, C. D., &. DeMets, D. L. (2011). Fundamentals of Clinical Trials. New York: Springer
Health Canada, HC. (2013). Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Web.
Pocock, S. J. (2011). Clinical Trials: A Practical Approach. Toronto: Ontario: John Wiley & Sons Canada.