EU and National clinical trial legislation directs that a clinical trial must have a sponsor and each research site must have a principal investigator; where the trial involves multiple research sites a chief investigator is also required (European Community 2001a, Government of Ireland 2004).
A sponsor is responsible for the initiation, management and/or financing of a clinical trial and can be a company, organisation, institution, or an individual. In contrast, the principal investigator is the authorised healthcare professional responsible for the conduct of the clinical trial at the research site. The chief investigator, also an authorised healthcare professional, takes primary responsibility for the conduct of the trial, whether the trial takes place at a single research site or multiple sites. Legislation specifies that an authorised healthcare professional can only be a medical practitioner or a dentist. Furthermore, the sponsor and chief investigator can be the same person (European Community 2001a, Government of Ireland 2004, European Community 2005).
As medical practitioners have a primary role in this type of research, planning and implementing a clinical trial of a medicinal product for human use is very challenging for nurse researchers. Even though I developed the concept and early design of the trial, as a registered general nurse, working in a university setting, I could not act as sponsor or principal investigator for my own study. It was important to identify a medical professional who was interested and had an expertise in the research topic and methodology, and would be both approachable and supportive throughout the course of the trial. I initiated discussions with Professor George Mellotte, Consultant Nephrologist and
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Medical Director of the dialysis unit at The Adelaide and Meath Hospital Dublin, Incorporating the National Children's Hospital (AMNCH), who expressed an interest in being involved in my study, at an earlier meeting. Towards the end of November 2009, Professor Mellotte agreed to act as sponsor and chief investigator (appendix 7.2). As per clinical trial legislation, all tasks and duties relating to the trial were delegated to me (appendix 7.3) (European Community 2001a, Government of Ireland 2004). Trials such as mine, which are not sponsored by or involve the pharmaceutical industry are referred to as non-commercial clinical trials or investigator-led trials (European Community 2001a).
7.9.2
Good clinical practice & investigational product
accountability
There is an expectation that the design, conduct, recording and reporting of a clinical trial should be in accordance with the International Conference on Harmonisation (ICH) ‘Good Clinical Practice’ guidelines (ICH 1996, European Community 2001a). The principles of good clinical practice require that those involved in conducting a trial should be qualified through education, training and experience, in order to perform the necessary tasks required in a clinical trial. Appendix 7.4 provides information on the specific training I received prior to and during the trial, which ensured that the CHG Trial was designed and conducted according to the principles of good clinical practice.
Good clinical practice guidelines (ICH 1996, European Community 2001a) also stipulate that responsibility for investigational product accountability can be delegated to another appropriate individual under the supervision of the investigator. I was responsible for ordering trial interventions, maintaining records of their delivery to trial sites, applying clinical trial labels on the exterior of the products and where relevant organising the destruction of unused products.
As this was a non-commercial trial involving interventions with a marketing authorisation, the CHG Trial did not require particular manufacturing or packaging processes (European Community 2001a). In addition, as interventions were used on participants with the same indication specified in its marketing authorisation, labelling of trial interventions was subject to simplified provisions laid down in the good manufacturing practice guidelines
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on investigational products (European Community 2001a). Section 32 of Annex 13 of the EU Good Manufacturing Practice guide (2010) stipulates that the following information should be included in the label: name of sponsor, trial reference code allowing identification of the trial site, investigator and trial subject.
Trial interventions (ChloraPrep® with tint and Sani-Cloth CHG 2% medical device wipes) were provided free of charge by CareFusion and PDI. EU clinical trial legislation recognises that non-commercial trials, such as mine, may receive support from industry through the provision of medicinal products that are either free or at reduced cost. The provision of such supplies should not be taken to imply that industry is participating in the trial and therefore should not disqualify the trial from being regarded as a non-commercial trial (European Commission 2009).
7.9.3
Safety monitoring & recording
EU and National clinical trial legislation stipulate that every effort is made to monitor the safety of medicines administered in clinical trials involving medicinal products for human use (European Community 2001a, Government of Ireland 2004). This requires ongoing safety monitoring of participants, which is also referred to as pharmacovigilance.
My trial had a number of mechanisms in place that facilitated the monitoring of participant safety. Safety monitoring involves assessing participants for adverse events/adverse reactions, evaluating their seriousness and expectedness and determining if these events should be reported to the trial sponsor and/or the national competent authority (IMB) (European Community 2001a). A Standard Operating Procedure (SOP) was developed to guide safety monitoring and reporting within the trial. Another mechanism required the establishment of a Trial Monitoring Committee.
An important component of safety monitoring is to define key terms used in the monitoring process. These key terms are adverse events, adverse reactions, serious adverse event/reaction, expectedness versus unexpectedness and suspected unexpected serious adverse reactions (SUSARs).
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An adverse event is any untoward medical occurrence, in a participant who is administered an investigational medicinal product (IMP). This event does not necessarily have a causal relationship with the IMP (European Community 2001a). These events can be any sign, symptom, or disease, which is temporally associated with the use of the IMP and yet may or may not be linked to the medicinal product (ICH 1994, European Commission 2008b).
In contrast, an adverse reaction is a response to an IMP, which is noxious and unintended. This type of reaction occurs at doses normally used for the prophylaxis, diagnosis or therapy of disease. They can also occur when used for the restoration, correction or modification of physiological function (European Commission 2008b). There is a reasonable possibility that there is a causal relationship between an IMP and an adverse event (ICH 1994).
When determining the expectedness of an adverse event, consideration should be given to the underlying condition of the subject; for example, co- morbidity and/or concomitant medications, patient population and severity and frequency of the occurrence.
An unexpected adverse event or adverse reaction is an event that is not consistent with the applicable product information e.g., summary of product characteristics and meets one of the following criteria:
• Not attributed to the underlying condition of the subject being studied; • Not attributed to the patient population being studied;
• Not anticipated on the basis of prior experience with the drug under investigation or with related drugs;
• Not identified in the product information; • Not defined in the study protocol.
(ICH 1996, European Commission 2008b).
Adverse events and adverse reactions can also be classified as serious. It is important to make a distinction between the terms ‘serious’ and ‘severe’. The term ‘serious’ is associated with events that may threaten the functioning or life of participants. Severity on the other hand is used to describe the intensity of an event e.g., mild, moderate or severe. The event itself may be severe, but ultimately has little medical significance. Reporting of adverse events and reactions to the sponsor and/or national component authority is guided by the seriousness of the event (ICH 1994).
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A serious adverse event and adverse reaction is any untoward medical occurrence or effect that at any dose:
• Results in death; • Is life-threatening,
• Requires inpatient hospitalisation or prolongation of existing hospitalisation;
• Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect.
(European Commission 2006, 2008b)
An expected serious adverse event/reaction is an event that may be expected during the lifetime of the trial, when one takes into account the nature and course of the disease or condition being studied; for example, renal failure and haemodialysis and their impact on cardiac function. Expected serious adverse events in this circumstance could be death due to cardiac failure. Furthermore, serious adverse events or reaction may also be expected as a result of the medication administrated in the trial.
Finally, a SUSAR1 is a serious adverse reaction, the nature or severity of which is not consistent with the applicable product information and which requires expedited reporting to the sponsor and national competent authority (ICH 1994).
While it was not anticipated that any serious events/reactions would occur it was my responsibility, as the sponsor’s delegate, to ensure that all relevant information relating to a SUSAR was recorded and reported to the:
• Sponsor/Chief Investigator and Principal Investigator;
• IMB, no later than day 2 for any fatal/life-threatening SUSARs and by day 7 for any other SUSARs. This would facilitate the IMB’s review and assessment of the reports, allowing some time for follow- up/clarification as necessary, prior to the IMB’s subsequent submission to the EudraVigilance Clinical Trial Module (EVCTM).
• Research Ethics Committee (REC), St James’s Hospital and AMNCH.
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