Assessing the Protocol
An important part of an investigator’s responsibility is to perform a thorough and thoughtful review of any protocol offered for consideration. Pharmaceutical companies know the required quality systems and regulatory expectations that surround the conduct of a clinical trial. What they need from their investigators is expert scientific and medical input, including a rigorous critique of their study goals and objectives, as outlined in their protocol design. The protocol should be assessed from four perspectives: scientific, regulatory, ethical, and feasibility.
Key points to determine before you conduct your review:
- Is this a draft protocol or the final version?
- What are the study objectives?
- What phase study is this study?
- Is this a single or multicenter study?
- What is the total number of subjects to be enrolled?
- What is the total number of subjects per site to be enrolled?
- How many study visits are required?
- What procedures are to be performed at each study visit?
- What is the length of the study?
- What are the inclusion and exclusion criteria?
- Does the study’s design support its objectives?
- Are the objectives and expected outcomes clearly expressed?
- Are the data to be collected appropriate for determining the product’s safety and efficacy?
- Are the inclusion and exclusion criteria realistic for the disease under investigation?
A protocol is required by regulations to contain the following information (21 CFR 312.23 (a) (6) (iii)):
- A statement of the objectives and purpose of the study
- The name and address and a statement of the qualifications (such as a curriculum vitae ) of each investigator, and the name of each subinvestigator (e.g.,research fellow, resident) working under the supervision of the investigator, the name and address of the research facilities to be used, and the name and address of each reviewing IRB
- The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied
- A description of the design of the study, including the type of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysts
- The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration of individual patient exposure to the drug
- A description of the observations and measurements to be made to fulfill the objectives of the study
- A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk
Note: The specific elements and details of the protocol are dependent on the phase of the study.
- Are the risks to the subject minimized?
- Are the risks reasonable in relationship to the knowledge or benefits to be gained?
- Is subject selection equitable?
- Are there errors or inconsistencies in the protocol that affect the site’s ability to recruit subjects ethically?
Assessing the feasibility of conducting a clinical study involves comparing the investigator’s present schedule, professional obligations, facilities, and staff with the study’s requirements for enrollment and the overall quality of the protocol’s design. If specific aspects of the protocol present problems for the site, the investigator should discuss them with the sponsor’s representative. In some cases, a sponsor may be willing to make adjustments to accommodate the concerns of a particular site; this is more likely in a study with only a small number of sites.
Consider the following questions while assessing your site’s suitability for a particular investigation.
- Does your site have the resources to meet all the requirements of the protocol—study population, staff, facilities, equipment, supplies, and time?
- Is your site able to enroll subjects and treat them according to the protocol?
- Is there a potential workload that is not specified—e.g., the time needed for reporting and following up on adverse events?
- If the site is using a local IRB, can the IRB provide approval within the time frame necessary for initiating enrollment?
- Will enrollment compete with other studies?
- Are inclusion and exclusion criteria reasonable? How will they affect enrollment?
- Does the study have any special or unusual requirements—e.g., visits to subjects’ homes?
- Will compliance to the study be difficult for the subjects?
- Do requirements for drug or device storage pose a problem?
- Is your space adequate?
- Does your site have the necessary equipment? If not, will the sponsor provide it?
- Will other departments (e.g., pharmacy, laboratory, x- ray) be able to meet the requirements of the protocol for conducting procedures and tests? Are laboratory tests required at times when the laboratory is closed?
- Will study procedures be required at inconvenient times (during shift changes, on weekends, evenings)? Will shift requirements result in overtime costs?
- Will demands placed on key personnel be excessive?
- How will staff be trained? Will there be sponsor training for the staff to administer procedures and tests? Will there be hiring and training of new staff, or training of staff members in a situation where multiple studies are in startup—all requiring additional training and commitment of time?
- Is the staff qualified to conduct all the tasks and procedures required for the study? Can more than one person do the tasks required if reassignment becomes necessary?
- How will potential staff turnover, vacations, and leaves of absence affect the conduct of the study?
- Does the investigator have enough time for the study? Although US federal regulations do not mandate how much time a principal investigator must devote to a study employing other physicians, FDA expects to see evidence of appropriate oversight
- Is the staff motivated to participate in the study?
- Have other staff (especially study coordinator) review the protocol. Ask for their feedback-listen!
- Know your patients: If you have a patient database, search by ICD-10 diagnosis code. How many patients with each diagnosis, how many patients with each diagnosis of interest, how many patients with diagnosis are seen/month, how many are research-naive?
Formula for Determining the Number of Potential Subjects
- Divide the number of potential patients in your database by 2 to estimate the number of patients who might qualify for screening.
- Divide that number by 2 to estimate the number of patients who might consent to be in the study.
- Apply the estimated screen failure rate to this number to determine the number of patients you could plausibly randomize in this trial.
Be careful! This formula depends on the protocol. For example, if patients with asthma must have a required number of Albuterol puffs/day, what percentage of patients in your practice meet that criterion? If it is 20%, apply this to the formula first.