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How to Put Together a Protocol for a Clinical Study

A protocol is a document that lays out exactly what you plan to do in a clinical study. Ideally, every study involving human subjects should have a protocol.

Standard elements of a protocol

A formal drug trial protocol usually contains most of the following components:

  • Title: A title conveys as much information about the trial as you can fit into one sentence, including the protocol ID, study name (if it has one), clinical phase, type and structure of trial, type of randomization and blinding, name of the product, treatment regimen, intended effect, and the population being studied (what medical condition, in what group of people).

    A title can be quite long — this one has all the preceding elements:

    Protocol BCAM521-13-01 (ASPIRE-2) — a Phase-IIa, double-blind, placebo-controlled, randomized, parallel-group study of the safety and efficacy of three different doses of AM521, given intravenously, once per month for six months, for the relief of chronic pain, in adults with knee osteoporosis.

  • Background information: This section includes info about the disease (such as its prevalence and impact), known physiology (at the molecular level, if known), treatments currently available (if any), and information about this drug (its mechanism of action, the results of prior testing, and known and potential risks and benefits to subjects).

  • Rationale: The rationale for the study states why it makes sense to do this study at this time, including a justification for the choice of doses, how the drug is to be administered (such as orally or intravenously), and the duration of therapy and follow-up.

  • Aims, goals, objectives, and hypotheses: These terms are often used interchangeably in casual conversation, but in biological and clinical research they're not the same. The aim of a study is a general statement (the "big picture") of what the study is intended to do; the objectives (or specific goals) are more detailed descriptions of all the specific things you're hoping to accomplish with this study. The hypotheses are usually formal statements of the objectives in terms of relationships between the observed variables (e.g.: the average weight loss in the treatment group will be larger than the average weight loss in the placebo group).

  • Detailed descriptions of all inclusion, exclusion, and withdrawal criteria

  • Design of study: The study's design defines its structure, the number of treatment groups, and the consecutive stages (screening, washout, treatment, follow-up, and so on). This section often includes a schematic diagram of the structure of the study.

  • Product description: This description details each product that will be administered to the subjects, including the chemical composition (with the results of chemical analysis of the product, if available) and how to store, prepare, and administer the product.

  • Blinding and randomization schemes: These schemes include descriptions of how and when the study will be unblinded (including the emergency unblinding of individual subjects, if necessary).

  • Procedural descriptions: This section describes every procedure that will be performed at every visit, including administrative procedures (such as enrollment and informed consent) and diagnostic procedures (for example, physical exams and vital signs).

  • Safety considerations: These factors include the known and potential side effects of the products and test procedures (such as X-rays, MRI scans, and blood draws), including steps taken to minimize the risk to the subjects.

  • Handling of adverse events: This section describes how adverse events will be recorded — description, severity, dates and times of onset and resolution, any medical treatment given for the event, and whether or not the investigator thinks the event was related to the study product. Reporting adverse events has become quite standardized over the years, so this section tends to be very similar for all studies.

  • Definition of safety, efficacy, and other variables and endpoints: Endpoints are variables or changes in variables that serve as indicators of safety or efficacy).

  • Definition of safety, efficacy, and other analytical populations: This section defines the various subsets of subjects who have sufficient data to be analyzed to assess safety, efficacy, pharmacology, or other components of the study.

  • Planned enrollment and analyzable sample size: This section provides the justification for number of subjects to be enrolled. For early-stage or exploratory studies an informal justification may be provided ("twenty subjects were considered sufficient to meet the goals of the study"); for more crucial studies (like pivotal phase-3 drug trials) a formal power / sample-size analysis must be carried out to justify the planned enrollment numbers.

  • Proposed statistical analyses: Some protocols describe, in detail, every analysis for every objective; others have only a general outline of the proposed analytical strategy, and refer to a separate Statistical Analysis Plan (SAP) document for details of the proposed analysis. This section should also include descriptions of the treatment of missing data, adjustments for multiple testing to control Type I errors, and whether any interim analyses are planned.

    If a separate SAP is used, it will usually contain a detailed description of all the calculations and analyses that will be carried out on the data, including the descriptive summaries of all data and the testing of all the hypotheses specified in the protocol. The SAP also usually contains mock-ups, or "shells" of all the tables, listings, and figures (referred to as TLFs) that will be generated from the data.

Administrative details of a protocol

A protocol also has sections with more administrative information:

  • Names of and contact info for the sponsor, medical expert, and primary investigator, plus the physicians, labs, and other major medical or technical groups involved

  • A table of contents, similar to the kind you find in many books (including this one)

  • A synopsis, which is a short (usually around two pages) summary of the main components of the protocol

  • A list of abbreviations and terms appearing in the protocol

  • A description of your policies for data handling, record-keeping, quality control, ethical considerations, access to source documents, and publication of results

  • Financing and insurance agreements

  • Descriptions of all amendments made to the original protocol

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