Role of co-ordinators in clinical research

Clinical trials often serve as the best opportunity for patients to receive the state-of-the art treatment. The number of clinical trials is exploding worldwide and most of the global trials are being conducted in developing countries. India is a home for many life threatening diseases and so remains an attractive country for clinical research due to its potential for rapid recruitment of patients. Skilled manpower, favourable regulatory environment that allows conduct of global trials, duty free import of drugs for use in trials and advanced medical infrastructure facilities also adds an advantage for the booming clinical trials in India. Food and Drug Administration Modernization Act (FDAMA) of 1997 mandated the creation of clinicaltrialsregistry.gov for the registration of trials in serious and life threatening diseases and interventions regulated by Food and Drug Administration. The number of trials registered in the database in the initial years was less, which had drastically increased after 2005. The below figure illustrates the number of trials registered on clinicaltrials.gov between 2001 and 2009.

The number of trials registered in the US registry, clinicaltrials.gov has increased from 10,480 in 2005 to 11,173 in 2009. In India the total number of trials in 2005 was 137, which have increased to 246 in 2009. Jayasheel in his report has delivered that about 1000 clinical trials have been registered in CTRI and a total of 987 clinical studies are currently being conducted at various centres in India.

Defining Clinical Research Coordinator
Clinical Research Coordinator (CRC) is the soul of the clinical research enterprise and is a pivotal member for proper conduct of the clinical trial. CRC are responsible for ensuring that the trial subjects are not hurt in any manner or form during their participation in the trial. The definition of Clinical Research Coordinator (CRC) as per the Association of Clinical Research Professionals is: "A Clinical Research Coordinator, Study Site Research Nurse or Study Site Coordinator, works at a clinical research site under the immediate direction of a Principal Investigator (PI), whose research activities are conducted under Good Clinical Practice regulations1".The Principal Investigator will assign the responsibility of overseeing the trial activities like recruiting trial subjects, obtaining informed consent and documentation of the study activities in compliance with the protocol, GCP and regulatory requirements to a CRC.

CRCs not only act as an imperative link between the investigator, the patient and their family, but also as a liaison between the sponsor and the CRO, the ethics committee, the laboratory and other players involved in the trial. The individuals who are responsible for overseeing the day to day performance of the conduct of the clinical trial is liable for  ensuring the safety and protection of the trial participants and also the study procedures, data collection and management. For the effective conduct of clinical trials, professional CRCS should dedicate their duties with the following aims in mind:
a. Subject protection
b. Integrity of the trial data

Qualities of a CRC
Much of the concern in the proper conduct of the trial pertains to the procedural issues which include review of the trial documents by the Institutional Review Board (IRB), informed consent forms and data monitoring. So it becomes crucial that the co-ordinators possess the skills, training and experience to exercise their duties effectively as to protect the safety of the trial subjects. The most considered skills of a CRC are: hands-on clinical trials, ability to advance research goals, communication skills, psycho-social skills and complex organizational skills that include the skills for managing the protocol, functioning as a team member and coordinating with outside units like IRB/IEC, contracted laboratory and sponsor or sponsor representatives.

The CRC should be well organized and must develop a system of document collection to ensure any deficiencies in documentation. The CRC should be able to identify and build necessary relationships with others, inside or outside the study team and sustain them. The most imperative and frequent relationships that CRCs has to build and maintain can be cited as the relationships with the investigator, the subject and their family, the IRB/IEC, the sponsor and sponsor representative. The study coordinator is the one, with whom the study subjects interact the most and is the one who identifies their needs and employs procedural safeguards. One of the most important skills a CRC should possess is to balance all the issues from the trial and the subject care and translate both to the PI and the trial subject.

Responsibilities of CRC
CRC usually have multiple responsibilities, which are categorized broadly as general and trial specific responsibilities. General responsibilities include capacity building, training new CRC, whereas, trial specific responsibilities include pre-trial documentation, coordination with Institutional Review Board/Independent Ethics Committee (IRB/IEC), financial responsibilities, training the site staff, informed consent process, patient recruitment and follow up, drug accountability, follow up with the laboratories, implementation of amendments and post-trial activities.

The following contributions of CRCs are considered to be useful for the harmonious conduct of clinical trials:
i)    providing a precise explanation of the trial to the participants, their family and key persons
ii)    understanding the needs of the investigators and appropriately assigning themselves the roles
iii) communicating between the investigator and other trial staff and laboratory personnel

The CRC, in collaboration with PI, assist in many trial related activities like protocol development, write informed consent, recruit patients, explain all aspects of the study to the subjects and their family, obtain consent from subjects, coordinate with relevant hospitals and laboratories, collect and maintain clinical data and act as a main contact person between the investigator and the trial subjects. The CRC should maintain the confidentiality of all records, identities of the subjects and communications related to subjects and the sponsor’s proprietary information. CRC is the person who is in direct contact with the subjects and their family and hence they have a vital role in the patient’s knowledge and attitude about the trial. A recent survey of the trial subject has shown that providing information, listening to and answering their questions are the most important responsibilities of the CRCs.

Association of Clinical Research Professionals (ACRP) has recommended the following responsibilities of a Clinical trial coordinator:

• hold the safety and welfare of human participants as their highest goal
• execute work according to scientific standards of objectivity, accuracy, and integrity
• advance their knowledge and understanding through education and training
• safeguard the quality and credibility of professional judgement from inappropriate influence
• ensure that principles of informed consent are honoured in spirit and in practice
• The roles and responsibilities of a CRC can also be precisely illustrated as below:
• Monitoring activities – Patient registration and randomization, recruitment, follow-up, CRF completion, collaboration with Clinical Research Associate (CRA), resolution of queries, Serious Adverse Event reporting, coordination with central labs, preparing the site for monitoring, auditing.
• Clinical Activities – inclusion/exclusion criteria assessment, completion of questionnaire, consent process, assessment efficacy and safety.
• Research activities – participation in the preparation of protocol and CRF, attending investigator’s meeting, involving in report generation and publication.

The responsibilities of the CRC do not limit to their role till the completion of trial, but it also extended after the completion of the study. As part of the quality assurance activity, the data management team reports the discrepancies to the study coordinator and the PI and they are the right and responsible person for solving the queries related to the study data. The role and responsibilities of CRC are not defined in any guidelines and it has to be modified based on the type of the  trial to make the CRC activity more effective.

Challenges
Ethical codes establish that patients for enrolment in clinical trial should be given adequate information about the trial before they give their consent to participate. It has been seen as a sufficient protection of the study participants. It is quite unusual in the private sector for physicians to discuss informed consent with potential human subjects. The Clinical Research Coordinator is critical to the clinical trials, because they carry out much of the informed consent process and spent substantial time with potential research participants, explaining them the details of the study and obtaining informed consent. Communicating about clinical trials by the coordinator and obtaining true informed consent can be challenging for many reasons. Trials frequently involve medical procedures that can evoke fear and uncertainty. They often involve complex scientific issues that are unfamiliar to the co-ordinators. For example, in complicated trials like cancer trials, written informed consents may be long, complex and these large amounts of information may sometimes enhance or hinder the understanding of the subjects. Efficient communication of the coordinators or the study staff may support the subjects in making their decision to or not to participate in the trials. Trials frequently involve medical procedures which may often involve complex scientific issues that are unfamiliar to stakeholders. And, they sometimes take place against a backdrop of distrust, born of past abuses real or imagined.

The greatest challenge, a CRC has to face in conducting a clinical trial is recruiting and retaining the trial subjects throughout the trial period. Large number of drop-outs will make a trial statistically invalid. The major advantages of involving a CRC in the clinical trial are to increase the recruitment rate and to generate a good quality data. More than 80% of the global trials fail to enrol patients on time, with 52% delayed by 1-6 months. Failure to recruit patients on time leads to loss of over 85-95% of days in a clinical trial. Many optimistic estimates suggest that patient enrolment rates in India could be 3-4 times faster than in western countries. This in addition to the presence of a wide patient population in India has been the reason for the occurrence of a large number of trials in India. A high retention of patients and control subjects is an important criterion for the credibility and accuracy of prospective, randomized, controlled clinical trials. Retention and adherence to the trial procedures, depends purely on a combination of patient, physician and coordinator related factors and careful evaluation of these will ensure success of the trial. In addition to these skills in effectively conducting a trial, the study coordinator should have the ability to identify necessary relationship with others, inside and outside the research team, and coordinating with the outside units.

Ethics to be followed
CRCs should ensure that the clinical trials are scientifically sound, clearly described in the protocol, approved and/or favourable opinion provided by the Institutional Review Board and conducted in compliance with the protocol approved by the IRB/IEC, GCP and other regulatory requirements. They should ensure that the PI is qualified by training, education and experience. They should also ensure the accuracy, completeness, legibility and timeliness of the clinical trial data and should ensure that the data are recorded, stored and handled for proper reporting, interpretation and verification.

The role of CRC and CRA are vital for the proper and ethical conduct of the clinical trial. A CRA is employed by a pharmaceutical company or a CRO and is responsible for overseeing the conduct of the trial at one or more sites, whereas a CRC is employed by an institution or site and they work under direct supervision of a PI and in direct contact with the subjects. CRA are the individuals who are responsible to ensure that the trial is conducted in accordance to the sponsor’s requirements and in compliance with the approved protocol, GCP, SOP and applicable requirements and also to ensure that the trial activities are properly documented. A CRC is responsible to safeguard the rights, safety, and well-being of the trial subjects by recruiting only appropriate patients who satisfy the inclusion/exclusion criteria, providing the investigational product only to appropriate subjects, explaining them the correct use of the IP, storage and return of the IP, resupply of IP to the subjects, scheduling the subject visits, Adverse Event and SAE reporting and ensuring that the subjects are provided medical care for the AE/SAE and documenting the AE/SAE appropriately.

 Though the role of CRA is dynamic, a CRC’s role is considered vital in conducting the trial at a site as they are the person who interacts directly with the patients and their family and acts as a liaison between the PI and the subject and their family. They are responsible for following up with the subject to ensure the correct usage of the IP, to ensure the well-being of the subject, to report the AE/SAE if any to the PI and assist in the immediate medical care provided to the subject, and also for the retention of trial subjects throughout the trial period. Thus a CRC can  be said to administer the conduct of the entire study at a site though they work under the supervision of a PI.

Conclusion
India is becoming a favourite destination for clinical trials due to many reasons. India with largest pool of patients, especially cancer, diabetes and other diseases is a main reason for the conduct of large number of trials. A study of the trials recorded in the registry, done by the Centre for Studies in Ethics and Rights, Mumbai, and published in the Indian Journal of Medical Ethics reveals that the number of trials has been growing at an astounding 36% annually from 2006-07 to 2010-11. Though Principal Investigator is the responsible person for the effective conduct of trial at a site, the ultimate responsibility for  conducting various trials simultaneously rests with the CRC. The PI, monitor, sponsor or CRO rely on the potentialities, skills and abilities of a trained, experienced and professional CRC.

The role and responsibilities of PI has drastically changed over the years. When compared to the responsibilities held by PI 15 years ago, it seems that as the number of for trials has increased, the roles and responsibility for informed consent documentation, CRF documentation, accountability of IP, follow up with the subject has been assigned by PI to a qualified CRC. The responsibilities held by a CRC includes submission of documents to the ethics committee for approval and coordination, recruitment, screening and randomization of patients into the study, CRF completion, coordination with the monitor throughout the study process, documentation of study activities, coordination with the PI, laboratory and all other activities assigned by the PI. These responsibilities are broadly grouped into three  categories: monitoring activities, clinical activities and research activities. This has led to the sponsors looking for sites with trained and experienced CRC.

The critical role of CRC in clinical trial enforces the need for the CRC to be familiarised with the study procedures, GCP, medical procedures, education related to ethical issues, knowledge of genetic science and to develop potential research integrity challenges. This has brought the necessity for involving the CRC in the investigators’ meeting and also to provide intense training in the art of communication with the patient, to improve the CRC’s understanding of ethics and science of clinical trials and to impart time management and interpersonal skills. ACRP was started in 1980 to sponsor training programs to CRC. CRC should be trained thoroughly in all disciplines for conducting the trial, which includes regulatory guidelines especially ICH guidelines, ethics in the conduct of trials, adverse event reporting timelines, effective management of trials, sponsor and/ or site SOP. Frequent training programmes should be conducted for CRC to update the knowledge and for better management of the trials.