The Trial Protocol

There are five major purposes to a clinical trial protocol, which can be summarized by a mnemonic which uses the five vowels. The purposes have to do with, anticipation, ethics, inference, organization and utmost good faith. (For the purpose of discussion I shall assume that the trial protocol and case record form are used together as one single document.) 

Anticipation is a necessary aspect of the protocol. It enables the persons involved to run a thought experiment from which, by recording in great detail which treatments will be given, which manouevres performed and which measurements taken, the likely course of the experiment can be anticipated. Thus, writing a detailed protocol is an important (if frequently tedious) discipline to be observed if problems in running the experiment are to be anticipated and hence allowed for and (if possible) avoided. 

Both major schools of statistical inference, the Bayesian and the frequentist, require prior consideration of possible analyses at the time trials are run. The Bayesian school requires specification of prior probabilities. To make these genuine priors they have to be truly prior and hence determined before the data are obtained. The frequentist school requires specification of the tests that will be performed and the decisions that will be made depending on various outcomes. For both schools, in order to design salient experiments, it is necessary to pay attention to very many aspects of design. 

Medical statistician One who will not accept that Columbus discovered America... because he said he was looking for India in the trial plan. 

The organizational purpose of a trial is also essential. The activities of a great many persons (trial physician, trial nurse, trial logistics, clinical research associates and monitors, database managers, regulatory personnel, statisticians and so on) have to be coordinated in order to bring the trial to a successful conclusion. The trial protocol is not the only document used in this, but it is the prime medium of communication. 

The sponsor with input from the investigator must prepare a trial protocol. This document should describe the objective(s), design, methodology (including subject 

---

Unlike human trials. Institutional Review Boards/Independent Ethics Committees are not involved, while informed consent is only required from the owner of the trial animals. In addition to the standard items associated with human trials, aspects such as management and housing of animals, diet and disposal of trial animals and their produce should be included in the trial protocol. Studies may be blinded from the investigators in order to avoid bias in the reporting of animal observations. 

A normal course of event in initiating a clinical trial is for the Sponsor (see below) to prepare an Investigator s Brochure and select an Investigator to conduct the trial. The Sponsor and Investigator then prepare the trial protocol. 

Based on the design of the trial protocol, statistics are used to calculate the number of people to be recruited for the trial, how the trial should be randomized (Exhibit 6.12), and finally analysis of the data. Statistics provide a nonbiased means to evaluate the trial results. 

Where a clinical trial was proposed with a marketed product then the CTMP scheme could be used. This was a streamlined process based on the fact that there were no quality issues with a product that had already been granted a marketing authorisation. The applicant submitted a copy of the trial protocol, provided information on the investigators and, depending on whether or not the applicant was the MAH, information on the procedures for reporting adverse drug reactions. It was only possible to use this procedure for UK marketed products. It did not apply to unauthorised products manufactured specifically for trial or to products, which were licensed only in countries other than the United Kingdom. 

If no procedure for dealing with outliers was foreseen in the trial protocol, one analysis with the actual values and at least one other analysis eliminating or reducing the outlier effect should be performed and differences between their results discussed. ... 

Phase 3. WHO, industry and one or more institutions located in disease endemic countries undertake to assess the efficacy of the product on a medium or large scale against a specified disease vector. Phase 3 comprises entomological, safety and, where appropriate, epidemiological evaluation. The institution supplies qualified staff for implementation, while the manufacturer supplies the insecticide and the funds needed for the trial. WHO bears the technical responsibility for the operation and is involved in the field through independent consultants. All three parties participate in drafting the trial protocol in accordance with a pre-established model that needs to be adapted to each situation. The final report is drafted by the institution, which submits it to WHO for evaluation. The report is then submitted for review to the manufacturer. 

Data from clinical studies in foreign countries are, in principle, acceptable in the USA, as long as the trial protocols comply with the US regulations and GCP standards. However, as in most countries, at least a part of the studies will have to be performed or repeated in the USA because, for example, the population may be different and the medicinal practices differ. Besides for these reasons, clinical trials are frequently conducted locally because the data tend to be more convincing. 

Differences between the trial protocol and routine practice... 

The purpose of the trial must be declared in advance. The trial protocols must be compiled in such a way as to ensure success of the aim of the trial and that valid conclusions are drawn. 

The Ethics section of the protocol deals with the fundamental requirement for prospective IRB/IEC approval of the trial protocol, protocol amendments, informed consent forms and other relevant documents (e.g. subject recruitment advertisements). 

QC activities in clinical research are manifold and comprise all activities undertaken by operational departments (such as clinical monitoring, project management, data management, etc.) to ensure that activities are performed in compliance with the trial protocol, SOPs and other procedure guides. These in-process quality controls are vital to the quality of the documents prepared (e.g. trial protocols, study reports) and the integrity of the trial conduct. 

QA s task to identify noncompliance with regulatory requirements, the trial protocol and internal procedures such as SOPs is not always an easy job. Communicating deficiencies and highlighting inadequate procedures is certainly a benefit for the company as a whole, but the individual may not appreciate being confronted with audit findings (Winchell, 2004). In order to be efficient and effective in QA, the following should be observed. 

If a generic subject information sheet and informed consent form are attached to the protocol, these documents should also be reviewed for compliance with any requirements for informed consent, such as GCP, SOPs and the Declaration of Helsinki, and for consistency with the trial protocol. The information sheet and informed consent forms must be written in a language understandable to the trial participant and should include information on data protection/privacy. Further information on protocol and informed consent audits is available in literature (Bohaychuk and Ball, 1999 DGGF, 2003). 

CRF audits should also be conducted on a draft version, just before finalization of the CRF. As the CRF is the data collection tool in a clinical trial, errors and inconsistencies in its contents and design and inconsistencies with the trial protocol may lead to serious problems if they are not identified prior to the CRF being used. This holds true for paper CRFs and electronic CRFs, as well as the use of remote data entry (RDE) or web-based data collection and transmission tools. The latter requires careful consideration of related guidelines (FDA 21 CFR Part 11 FDA Guidance for Industry, 1999). 

Complete, consistent and accurate trial documentation is the basis for any inspection by regulatory authorities or sponsor/client audit and is a proof that the study was conducted according to GCP regulations, the trial protocol and SOPs. The TMF plays a vital role in providing confidence to auditors and inspectors that the clinical data are valid and that the trial was conducted properly. 

Preparing for the site audit requires the review of key trial documents before visiting the site for the on-site part of the audit. The QA auditor should review at least the trial protocol (and amendments), the current investigator s brochure (to the extent necessary). Ideally, the following documents should be studied as well before the audit any site-related documents including the IEC submission and approval, approved informed consent form used at the site, monitoring reports for the... 

Apart from compliance with SOPs for biostatistics and report writing, the statistical analysis plan, the trial protocol, regulatory requirements and guidelines (ICH E3, 1995 ICH E9, 1998 ISO 9000 2005, 2005), QA auditors check the internal consistency of the trial report and appendices and between data in tables, figures and graphs and numbers cited in the text. All numbers and percentages must be substantiated by attached tables and listings. In summary, the trial report should be an accurate representation of the clinical data. Allocation of trial... 

The trial protocol currently being used is the following apply a single layer of Easy Phytic solution in the morning and leave it to act during the time it takes to brush the teeth. Take a shower. Repeat the application every day for 3 consecutive days. 

Results of all measured and calculated pharmacokinetic parameters should be tabulated for each subject-formulation combination together with descriptive statistics. The statistical report should be sufficiently detailed to enable the statistical analyses to be repeated if necessary. If the statistical methods applied deviate from those specified in the trial protocol, the reasons for the deviations should be stated. 

Where appropriate, beds should be available for the volimteers. The necessity for beds and facilities for overnight stays depends on the type of trial and the drug under investigation and should be specified in the trial protocol. 

In contracts relating to clinical research - in effect between a sponsor, CRO or investigator - much of the detailed provisions concerning precisely how the research will be conducted will be contained in the trial protocol. If there is no other document that constitutes the legal contract, the terms set out in the protocol will generally be implied into the oral agreement to conduct the study. However, it is now normal practice to have a specific... 

The trial protocol is the end point of research design. It is the blueprint that displays the elements of the trial plan and provides explicit instructions as to how the plan should be executed. 

---