Considerations in Designing and Executing a Clinical Trial: A CRO’s Perspective

Q: What are the main concepts to consider when designing a study protocol?

A: You need to ask yourself the following questions:

Does the protocol measure efficacy? If you are conducting a trial where efficacy is the primary outcome, your protocol must have appropriate measurements included that will address this. For example, a study researching the efficacy of a drug for osteoarthritis, will likely want to include a WOMACTM scale as a valid primary measure of efficacy. You can then look at secondary measurements as well such as a Visual Analogue Scale (VAS), Patient and/or Physician overall rating, amount of rescue medication taken over the duration of the study, etc. It is important to select one primary outcome as your main study parameter. You may have other outcomes of interest which can be followed as secondary outcomes in your study.

Is it designed to reduce bias? Measures should be taken to minimize bias in your study design including randomization and blinding. It is very important to identify any potential risks of bias so that you can make reasonable attempts to limit these as much as possible. The more you can provide up front in the protocol itself to alleviate this from happening, the more firm your results may be.

What is the best design of study for this application? There are many trial designs that can be considered such as open-label versus placebo-controlled; parallel versus cross-over.

Are the statistical analysis procedures clearly defined? Your statistical analysis plan should be clearly defined in the protocol, as well as what considerations will be taken for any anticipated problems with that analysis. For example, will any considerations be taken into account for more than the anticipated number of participants being withdrawn from the study? Will this be taken into account for only those who meet a certain criteria? Remember, your subject number may have been determined by a statistical power calculation in order to determine the greatest amount of statistical significance using the minimum number of subjects to accomplish this. Should a greater number of subjects be withdrawn from the study than was accounted for in this calculation, your significance may decline. The calculation of your subject number should be based on your primary outcome measurement.

Q: What are the most important elements to consider when placing your trial and whom can you depend on?

A: There are many options in placing a clinical study. If you are working with a large number of subjects it can be very beneficial to work with a Contract Research Organization (CRO) who is contracted to work with the sponsor in many capacities such as protocol design, selection and/or monitoring of investigator sites, regulatory submissions (FDA, Health Canada and Ethics), evaluations of data, statistical analysis and writing a final report. It is important to communicate your needs with your CRO so that they may select the most appropriate sites to place your study. Many sites are stronger in some areas than others, such as recruitment for a particular population of subjects. If you are working with a small number of subjects, you may opt to work directly with the investigator at a single site. If this is the choice, be sure that you have identified who will complete the statistical analysis, reporting, etc.

Investigators should be selected based on expertise in the appropriate field, experience in conducting trials according to GCP guidelines and integrity. It is also important that you understand the regulatory environment at the location(s) that you select to conduct your study. The appropriate submissions must be completed and submitted prior to commencing a study to governing bodies and an IRB and this changes from country to country (ie. FDA & Health Canada).

Q: Recruitment is usually the most difficult obstacle to overcome in conducting a trial, how can you be assured that enrolment will be completed in an anticipated timeframe?

A: Recruitment is often the portion of the study that takes longer than anticipated. At the outset, when you are designing the protocol, it is important to understand how the criteria for the trial are going to impact recruitment. Obviously, the more narrow the subject criteria for inclusion, the more difficult recruitment will be to complete. On the other hand, you do not want to compromise the trial design by making this criteria too wide. Once your trial is underway, you can revise the criteria if recruitment is truly going to impede your timeline. An amendment to the applicable regulatory bodies is required, but it may be an option to consider if you realize recruitment can be improved without compromising your study design. Another more viable option is to arrange with your CRO to implement a competitive enrolment strategy for multi-centre trials. This would allow for those sites that are excelling at enrollment to continue recruiting until the trial is full, with no limitation. This is a good alternative to placing a defined number at each site and being delayed if recruitment is slow at even one site. Tying enumeration to enrollment also adds an additional incentive for investigators to recruit and enroll more subjects than they may otherwise attempt to recruit (remunerate per subject enrolled).

Q: What can be done to minimize any issues arising throughout the duration of the clinical trial?

A: In planning the clinical study, it is a good idea to brainstorm negative ‘what if’ scenarios. Use these potential problems to plan a course of action should any of these scenarios occur. For example, what if your test product requires a precise refrigeration temperature or other specific storage conditions and a power outage occurs at one of the clinical sites? Does the site have a back up generator? Do you have replacement product?

About KGK Synergize Inc.:

KGK Synergize Inc. is a full service Contract Research Organization (CRO) that spun out of The University of Western Ontario in 1997. Many partnerships with both Canadian and U.S. sites have allowed KGK to manage multi-centre trials recruiting thousands of subjects across North America. KGK has been awarded trials in a wide range of therapeutic areas including weight loss, cardiovascular disease, endocrinology and arthritis to name a few. KGK works with the sponsor to provide protocol feedback, obtain necessary regulatory approvals, identify appropriate sites, contract negotiations, site initiation and close-out, monitoring, data capture and management, statistical analysis and provide a comprehensive final report.

What makes us unique?

Having five physicians on staff (four GP’s and one surgeon specialized in obesity), multiple study coordinators and dieticians allow KGK to also act as a site for the sponsor. Trials in which we can offer the expertise in-house can be conducted at our own out-patient clinic, located in London, Ontario, Canada. KGK’s Laboratory is well equipped with analytical equipment (HPLC, LC/MS/MS) and scientific expertise to analyze many of the clinical trial samples on-site.