Chapter 23: Administration of systemic anticancer therapies
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Source: Adapted from NIHR Clinical trials toolkit (NIHR [174]).
Source: Adapted from NIHR Clinical trials toolkit (NIHR [174]).Source: Adapted from NIHR research design service (NIHR [175]).Source: Adapted from NIHR research design service (NIHR [175]).
Source: Adapted from NIHR research design service ([175]).
Related theory
Phases of clinical trials
Clinical trials are conducted in a series of stages, commonly referred to as phases. Each phase is designed to answer a specific research question (NIHR [174]). Table 23.11 provides an overview of the various clinical trial phases and their objectives.
Table 23.11 An overview of clinical trial phases
| Objective | Participants | Duration | |
|---|---|---|---|
| Phase I | To establish safety of an IMP | 20–80 | Few months – 2 years |
| To establish maximum tolerated dose of an IMP | |||
| Phase II | To establish the efficacy of an IMP | 100–250 | 2–3 years |
| Phase III | To confirm efficacy of an IMP | 1000–3000 | 2–4 years |
| To monitor side‐effects of an IMP | |||
| To compare IMP with commonly used treatments | |||
| To collect all relevant information that will allow IMP to be used safely in an clinical environment | |||
| Phase IV | To study long‐term effects of an IMP | 500–1000+ | 1–4+ years |
| To study cost‐effectiveness of an IMP |
| IMP, investigational medicinal product. |
Life cycle of a clinical trial
Clinical trials are intensely monitored by appropriate regulatory authorities. There are national regulatory bodies that govern the conduct of clinical trials. The Medicines and Healthcare products Regulatory Agency (MHRA) and Health Research Authority (HRA) in the UK, the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in European countries are a few examples. All studies involving a medical or therapeutic intervention in patients must be approved by a supervising regulatory and ethics committee before permission is granted to run the trial. The clinical trials must be conducted in accordance with ICH‐GCP and in line with national regulatory standards. Following regulatory approvals, there are multiple steps involved in conducting a clinical trial, requiring input from a variety of expert groups. The study participation sites, patients and study data are monitored throughout the study period. Clinical trials can be audited or inspected by the study sponsor or by the regulatory authorities at any time. See Figure 23.14 (ICH [109], NIHR [174]).
Figure 23.14 A clinical trial pathway that highlights the areas that are specific to research nurses. Source: Adapted from NIHR clinical trials toolkit (NIHR [174]).
Site selection
The study sponsors usually get in touch with the potential participating sites and would seek information to ensure the site has appropriate facilities to participate in the study of interest. A research nurse may be involved in liaising with the sponsor at this stage and the research nurse may be asked to review the study synopsis. See Figure 23.15 (NIHR [174]).
Figure 23.15 Information requested from study sponsor. Source: Adapted from NIHR ([174]).
Regulatory approvals and standard documents
The approvals to initiate any clinical trial vary from country to country. In general, each clinical trial site will have a study co‐ordinator who liaises with the study sponsor to facilitate the regulatory processes and ensures that all approvals are obtained prior to opening the site to run the trial. See Box 23.14 (NIHR [174]).
Box 23.14
List of approvals required prior to start of the study
- Approval from national governing bodies (e.g., MHRA, EMA, FDA, etc.)
- Approval from ethics committee (NRES, IRB, etc.)
- Approvals from any other governing bodies as per national guidelines (e.g., ARSAC, GTAC in the UK)
- Approval from the institution to conduct the study
The study nurse or study co‐ordinator will be provided with a set of documents prior to the start of the study. Depending on the responsibilities assigned by the principal investigator, it is important for the research nurse to go through these documents and understand the processes involved in the study. See Box 23.15 (NIHR [175]).
Box 23.15
General documents that are usually circulated by the study sponsor
- Clinical study protocol
- Investigator's brochure
- Patient information sheet and informed consent form
- GP letter
- Lab manual
- Imaging manual
- User guides where applicable
- Tools to capture data from patients
- Any other document that needs to be used for the study
It is good practice for the research nurse to develop a checklist and review the research protocol in advance. For a typical list of items that will need to be reviewed see Box 23.16 (NIHR [174]). If any clarity is needed the research nurse should liaise with the study sponsor at the earliest possible opportunity.
Box 23.16
Research nurse checklist
- Visit schedules
- Logistics for study participants
- Overlapping visits
- Assessments to be carried out at each visit
- Available window period
- Expected commitments from study participants to comply with schedules
- Expected duration of stay at the hospital during the visits
- Participants’ needs in terms of travel, support of overnight stay
- Liaison with support services if there are any stringent schedules to be followed
- Contact details of study team, sponsor, and medical monitor
- Details of serious adverse event reporting and emergency contact details
- Emergency unblinding procedures in a double‐blind study
- Study data collection tools
- Drug compliance work sheets
- Patient reported outcomes
- Patient diary cards
- Data collection tools
Site initiation visit (SIV)
Once all the approvals are in place, the study sponsor will arrange a visit to the site to train the site team and also meet with all the study team members. During the visit, the sponsor will provide all study‐related documents to the site including the standard investigator's file. Site staff should receive GCP training as well as training in study inclusion and exclusion criteria, study process and safety reporting criteria. The site is activated once it confirms the receipt of all study materials.
The research nurse should prepare data collection tools and nursing guides as this will primarily support day‐to‐day management of the studies.
Data collection tools
It is good practice to develop appropriate data collection methods for the study. The research nurse may prepare a form to collect study data so that all data required for the study are appropriately captured in the form. These forms could be specific to each visit. General data collection tools could be prepared for screening, cycle 1, cycle 2, etc. See Box 23.17 and Figure 23.16 (NIHR [175]).
Figure 23.16 An example of a screening study data collection tool. Source: Adapted from NIHR research design service (NIHR [175]).
Box 23.17
A toolkit to consider when reviewing a protocol during the site initiation visit
Investigational medicinal product (IMP)
Oral IMP
- If oral, is it easy to differentiate drug strengths, i.e. different shaped bottles or different shaped/coloured drugs, tablets/liquid?
- What is the dosing regimen length of cycle?
- Storage of the drug – fridge, room temperature.
- Are there food restrictions (fed or fasted)?
- Are there fasting requirements for the drug pre and post dose?
- Clarify fasting time for drug: if longer than 4 hours what is the rationale?
- Can the drug dosing time be changed, i.e. brought forward if patient was dosed late on cycle 1/day 1 (dosing time will always be out of sync on clinic days on BD dosing; do you skip a dose and single dose jump back to original time of drug)?
- Drug compliance – check if diary card is required.
- How long is a drug holiday?
- What percentage of drug intake to ensure patient is evaluable? Is it just cycle 1 or cycle 1 plus cycle 2?
Intravenous IMP
- If it is an IV drug, how long is the infusion?
- Length of infusion.
- Is it a vesicant?
- Can it be given peripherally or via central access?
- What is the regimen: dosing, days, length of cycle?
- Storage: room temperature or refrigerate, protect from light, special administration set?
- Do they want serial numbers of the IV pump used?
- Flushing instructions, clarify end of infusion.
- Post‐dose assessments.
Trial sampling
- Find out if there is a window for safety bloods, i.e. ± 2 days for cycle 1/day 1 visits.
- Visit logistics, look at all the assessment time points and check if they can fit into the department's week, i.e. do any pharmacokinetics (PKs) fall on a weekend?
- Are there windows for sampling time points? This is critical as flexibility on the time points is required.
- Will it need to start on a specific day to fit in all assessments?
- Out of hours physical examinations and samples, i.e. processing of samples such as lipase or insulin when the labs are closed and physical examinations when the ward doctors are not available.
- Has the patient had biopsies – if so when, are they feasible (clarify post‐dose biopsy, ask for windows in days not hours if possible)?
- Pharmacodynamics (PD) sampling. Who will this impact: local (ICR), central?
- Order of sampling when a few due at a specific time point, e.g. ECG, PK, PD then observations.
- Clarify fasting times for bloods, i.e. does patient fast for safety bloods, on which days, how long for?
Logistics
- How many overnight stays (or admissions) and how long for?
- Is it feasible/achievable/acceptable for the patient?
- Can frequency of visits be reduced after cycle 3?
- Extra costs, e.g. hotel stay, taxi, etc.
- Know side‐effects; provide algorithms to manage these, especially for out of hours.
Nursing guide
The nursing guide is an internal site document that is like a handbook for the research nurse. It is again good practice to prepare a nursing guide for the study. The nursing guide will contain information on the visit schedules, what to do in case of emergency, safety information about the study drug, essential contact, etc. The objective is that, should the study‐specific nurse not be available, any research nurse could get help from the nursing guide and act on immediate needs for the study participant. See Box 23.18.
Box 23.18
An example of a locally developed nursing guide
Contact numbers for the local team involved in the trial, together with contact details for the sponsor's trial‐related team
- Principal investigator
- Clinical fellows
- Clinical trial coordinator
- Lead nurse
- Data manager
- Study trial monitor
- Technical support team if applicable
Background information on the trial drug (in brief)
- Class of compound
- Mode of action
- Summary of pre‐clinical data
- Summary of clinical trial data
- Expected side‐effects
- Rationale for study
- Potential drug‐related toxicities
Drug administration requirements and restrictions
- Dietary requirements and restrictions
- Dosing schedule
- Route of administration
- Formulation
- Important contraindications with reference to the protocol
Fasting times should be clarified
- Fasting for bloods Routine e.g. glucose
- Trial bloods
- Fasting for drug Pre‐dose fast e.g. 10 hours
- Post‐dose fast, e.g. 2 hours
- Total hours of fasting prior to dose
Trial‐specific assessment and sampling procedures and management, including, but not limited to:
- Pharmacokinetic samples
- Pharmacodynamics samples
- Trial‐specific blood test sampling (safety bloods, e.g. tumour markers)
- Holter management
- ECG specifications
- Telemetry guidelines
Study recruitment and follow‐up
As soon as the site is activated, the research nurse can begin handing out study PIS‐ICFs to potential patients. The study cycle has defined steps which are listed below.
Patient selection
This is the first stage for the study participants, in which the specific clinical trial would be discussed with the patient in detail. The research nurse may be expected to go through databases to identify potential patients or liaise with other units within the hospital to raise awareness of the study. The potential participant would be referred to a clinical trial clinic where a clinician will go through the PIS‐ICF with patients. Following this discussion, a research nurse will also discuss the study with patients, primarily addressing the logistics of the study and explaining to patients the commitments required to participate in the study. A research nurse will also gather background clinical history and assess the patient's well‐being in order to understand if the patient is suitable for trial participation. Further to initial discussion, follow‐up conversations may be held over the phone or face to face with potential participants, to ensure they are fully informed about the study and the study drug/device (NIHR [174]).
Screening
Once a patient expresses interest in participating in the study, screening processes can begin. Initially the participant's written consent is taken on the study‐specific PIS‐ICF, following which screening procedures will be carried out as per the schedule of events in the protocol. The screening process may take a few days to a month, based on the nature of the assessments required. A clinician and the research nurse will monitor patients and complete the study‐specific inclusion/exclusion checklist (see Figure 23.17). The participant will need to meet all the criteria as per the checklist prior to confirming that he/she is eligible to participate in the study (NIHR [174]).
Figure 23.17 An example of a locally developed patient inclusion/exclusion checklist.
Registration
If a potential patient successfully passes screening, he/she will be registered (or randomized if required) to the study, from which point a specific batch of study medication would be assigned to the participant.
Study treatment
The procedures would be followed as per the schedule of events and a research nurse will be involved in:
- collection of observations
- ECGs
- performing a physical examination
- collection of adverse events
- collection of concomitant medication details
- providing drug infusion/review of drug compliance
- continuous monitoring of the study participant during the study.
The research nurse will also need to alert the clinician should any untoward or unexpected events occur. A follow‐up telephone call may be required if the participant is unwell. Overall, the research nurse not only collects study‐specific data but also provides holistic care to study participants.
Study discontinuation
If the clinician has evidence to confirm that the participant is no longer receiving benefit from the study drug, the participant will be taken off the study. However, he/she is followed up for a minimum of 30 days to ensure there are no adverse events resulting from study participation.
Post‐study follow‐up
The follow‐up period may vary from study to study and some studies may require monthly/3 monthly follow‐up processes until death. Some studies may require more frequent telephone calls with participants and may also involve data collection over the phone.
Study close out and study archive
Once all participants are off study and all study data has been collected, the study can be closed. The regulatory authorities and the study site will need to be informed about study closure and all study documents must be archived for 25 years or as stated by national guidelines.
During the study, the research nurse is expected to continuously monitor participants and ensure they are safe. In addition, it is also the responsibility of a research nurse to adhere to study protocol. It can sometimes be challenging to maintain compliance and support participants’ well‐being. At all times, the research nurse must keep clinicians and the study PI informed about the participants’ status. Where required, the research nurse should provide appropriate support to participants, educate them to maintain drug compliance and provide guidance on following patient‐reported outcomes. Effective communication with participants and the study team is an absolute requirement from a research nurse. In addition, a research nurse should document all events and activities so that there is a full audit train of study activities (ICH [109], NIHR [174]).
Other important activities in a clinical trial
Study monitoring and audit
Any research study will be monitored by the sponsor or sponsor's representatives (they are sometimes called clinical research associates). A study monitor will primarily verify source data and ensure the data are credible and evaluable. Based on the nature of the study, the monitoring plan may contain 100% source verification or partial source verification. A monitor will also review if study processes have been followed appropriately and there are no deviations from the study. If there are any deviations, site staff will be asked to report these deviations. A monitor will also ensure all participants have appropriately consented to the study and all site staff are following GCP guidelines.
A monitor may wish to have a short meeting with the research nurse during the visits to resolve any queries that may arise. Frequency of monitoring may vary from study to study, but at the end of each monitoring visit there will be a monitoring report which needs to be reviewed and filed in the investigator's site file.
The study may also be audited by an external auditor or inspected by a regulatory authority.
Standard operating procedures
Each clinical trial site will have its own standard operating procedures (SOPs) to standardize and harmonize the operational aspects of clinical trials. The process of consenting, reporting of serious adverse events, maintenance of study documents, out of hours contact process for study participants, etc., are some of the examples which should be covered by SOPs. It is important for the research nurse to be familiar with all SOPs as at the time of audits/inspections the site may be asked to produce their SOPs for review.
Safety reporting
Any clinical trial will have a process for reporting any adverse event (AE) to the study sponsor. GCP provides classification for adverse events, which a research nurse must be aware of. If an adverse event become serious, it is termed a serious adverse event (SAE) which needs to be reported to the study sponsor as soon as possible or within 24 hours of the clinician being made aware of it. The study protocol will have details of the SAE reporting guidelines. Although it is the clinician who makes the decision about whether an AE is upgraded to an SAE, the research nurse is also duty bound to report any untoward event to the study team so that the event is appropriately captured and the participant's well‐being is maintained. The research nurse may also be involved in collecting additional SAE information from the study participant/family/local hospital (ICH [109], NIHR [174]).
Research Explanation
- E: Clinical experience
- P: Patient
- C: Context
- R1 (a): Systematic reviews of randomized controlled trials (RCTs)
- R1 (b): Individual RCTs with narrow confidence limits
- R2 (a): Systematic reviews of cohort studies
- R2 (b): Individual cohort studies and low quality RCTs
- R3 (a): Systematic reviews of case‐controlled studies
- R3 (b): Case‐controlled studies
- R4: Case series and poor quality cohort and case‐controlled studies
- R5: Expert opinion
