Appendices
As often as not, a protocol will almost certainly have to contain Appendices. For example, in many cancer clinical trials toxicity is a major concern so that the criteria for reporting adverse events as recommended by the National Cancer Institute (2003) will often be reproduced.
As informed consent is such a critical process, reviewing committees will almost certainly wish to see the proposed patient information sheets and the consent forms to be used. Figure 3.2 gives part of the patient information provided and Figure 3.3 the corresponding consent form for the COMPLIANCE (2015) trial protocol described by He, Tan, Wong, et al. (2018) concerning compliance with medication in women with breast cancer.
Figure 3.2 Part of the Information Sheet utilised in the multicentre COMPLIANCE (2015) trial in patients with breast cancer.
Source: COMPLIANCE (2015).
Figure 3.3 facilitates the consent approval process in cases when a prospective patient may not speak, in this case, English, is illiterate, or is otherwise compromised.
3.16 Regulatory requirements
3.16.1 Protocol amendments
Although great care should be taken in preparing the trial protocol, once the approved trial has opened for patient recruitment and is in progress, unforeseen circumstances may arise that impact on what is contained within the protocol. Such circumstances could range from the relatively trivial to the very serious. At one extreme, perhaps the packaging of a study drug is changed by the supplying pharmaceutical company without change to the potency or any significant aspects. At the opposite extreme, perhaps unanticipated and serious reactions in some patients occur, raising concerns about whether the trial medication is safe and consequently impacting on whether or not the trial should continue as originally planned. The consequences of the latter might for example either result in restricting the trial entry criteria by identifying those who are likely to be vulnerable and making them no longer eligible, or reducing the dose should the anticipated reaction occur. Both of these represent an important change to the protocol. The protocol would then have to go through a reapproval process. In contrast, the minor change in packaging may only require informing the authorities of this fact. Of course, in this instance, if the protocol has to be changed for any other minor reason(s), then it would be prudent to make this change(s) at the same time.
Figure 3.3 Consent form designed to obtain assent from a patient to be randomised in the multicentre COMPLIANCE (2015) trial in patients with breast cancer.
Source: COMPLIANCE (2015).
Since protocol modifications are not infrequent, it is wise to keep the protocol as concise as possible; exclude all irrelevant detail; ensure main sections start on new pages; ensure page breaks do not break paragraphs (perhaps not important in the Background but may be critical if describing details of an intervention); number sections, tables and figures in such a way as to minimise the need for future renumbering or repagination of the protocol. Without such precautions, there can be severe consequences if any additions or modifications happen to occur in sections from the early pages of the protocol.
3.17 Guidelines
As we have indicated GCP, set out in ICH E6 (R2) (2016), will dictate in full the items that are mandatory for such a protocol. Similarly, the SPIRIT 2013 statement provides recommendations for a minimum set of scientific, ethical and administrative elements that should be addressed in a clinical trial protocol. It is particularly important, and especially for clinical trials seeking formal registration of a new product, that investigators check local, national and even international requirements for what has to be included in the protocol itself. The definition of what is a ‘protocol’ given by Day (2007) and slightly amended in our Glossary includes the phrase ‘important details’ so it is imperative to check the current status of exactly what current versions of the guidelines are suggesting as they are continually changing. For example, the ICH E6 (R2) (2016, Section 6) specifies for protocols sections on: Direct access to source data/documents; Quality control and quality assurance; Data handling and record keeping: Financing and insurance which we do not include in Figure 3.1. In this document Section 8 also includes: Before the clinical phase of the trial commences; During the conduct of the trial; After completion or termination of the trial. Although these sections may be more appropriate to trials for products seeking regulatory approval, they contain many items pertinent in a wider context. Day (2007) in Appendix 1 of his dictionary lists 18 ICH ‘Efficacy’ Guidelines. The latest updates of these can be obtained from the ICH official website: http://www.ich.org.
1 ICH E6 (R2) (2016). Guideline for Good Clinical Practice. EMA/CHMP/ICH/135/1995.
2 ICH E9 (R1) (2018). Statistical Principles for Clinical Trials. CPMP/ICH/363/96.
3 SPIRIT 2013 Statement (2013). Defining Standard Protocol Items for Clinical Trials. http://www.spirit‐statement.org (see Chan, Tetzlaff, Gøtzsche, et al., 2013).
3.18 Protocols
1 AHCC01 (1997). Randomised trial of tamoxifen versus placebo for the treatment of inoperable hepatocellular carcinoma. Clinical Trials and Epidemiology Research Unit, Singapore.
2 ENSG5 (1990). Comparison of high dose rapid schedule with conventional schedule chemotherapy for stage 4 neuroblastoma over the age of one year. UKCCSG, Leicester, UK.
3 COMPLIANCE (2015). Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: study protocol of a randomised controlled trial to evaluate the effect of short message service (SMS) reminder.
4 EXPEL (2016). Extensive peritoneal lavage after curative gastrectomy for gastric cancer (EXPEL): an international multicentre randomised controlled trial.
5 PRESSURE (2000). Pressure relieving support surfaces: a randomised evaluation. University of York, York and Northern and Yorkshire Clinical Trials Research Unit, Leeds, UK.
6 SQCP01 (2006). A randomised controlled trial comparing speech and growth outcomes between 2 different techniques and 2 different timings of surgery in the management of clefts of the secondary palate. KK Women’s & Children Hospital, Singapore and Chang Gung Memorial Hospital, Taiwan.
7 SQGL02 (1999). Brimonidine as a neuroprotective agent in acute angle closure glaucoma. Clinical Trials and Epidemiology Research Unit, Singapore.
8 SQNP01
