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International Clinical Trials

Magnificent Seven

Keeping clinical trials on time and within budget, while delivering quality results, is no small feat; Susan Suchdev of IRW Consulting considers seven critical steps for clinical study success

When performing a clinical study, one question you should always ask yourself is ‘what is the primary goal?’ Maybe it can best be summarised as ‘to do it right’: the right quality, in the right time, for the right cost. But how? To perform a clinical study successfully usually involves solving many problems that arise along the way. When you face a problem you need to decide what impact it could have on the project before you decide how to act. It is far too common to handle every situation as if they were of equal importance to the result of the study.

Be proactive: try to foresee the risks and figure out how to minimise their impact. Typically, there are many factors to juggle at the beginning of a study which might mean one neglects to focus on the steps needed to minimise the risks later on. This article summarises important points to help you execute your clinical study in the most cost-effective and timely manner.

STUDY DESIGN

Study design is the single most important aspect in determining success in your clinical study. The critical points are:

  • Making the correct endpoint decision
  • Having the correct information about assumed effect of the investigational product (IP)
  • Establishing a set of necessary eligibility criteria

Making the Correct Endpoint Decision
Deciding on the correct endpoint is crucial: the study will not otherwise cover the needs of the IP investigation (1). As Bert Spilker writes, you need to determine the pros and cons with each efficacy parameter (2). The potential value of data obtained must be evaluated against time requirements, efforts spent, costs and additional complexity of the study. Adding more tests at some point becomes counterproductive and makes the study more inefficient. If you include an endpoint that does not measure the effect you are investigating, you could draw false conclusions and/or need additional studies that would delay your product registration – or in a worst case scenario, lead you to reject a product based on false conclusions.

The Assumed Effect
The assumed effect of the IP needs to be as accurate as possible. This is difficult to assume in early studies or studies in new indications. If you have made incorrect assumptions, your statistical calculations – for example sample size – might be wrong and your final result might not be significant.

Eligibility Criteria
When you decide what set of eligibility criteria to include in your clinical study, you should ensure it is not too extensive or too narrow. If your criteria are too extensive, you risk the resulting group being too heterogeneous, which could lead to problems when performing the analyses. It might also be difficult to recruit patients if the criteria are either too strict or lenient, and the data may not be relevant for the clinical situation (2).

You should consider excluding patient categories that could disturb any aspect of the results. Treatments or concurrent diseases that could affect the results of the analyses or measurements, or lead to adverse events that could interfere with the conclusions of IP effect, should be avoided. A balance is needed to avoid the eligibility criteria becoming too narrow; otherwise the results could be hard to apply to the intended patient population. It is important to scrutinise each criterion in turn and decide if it is necessary, as extensive eligibility criteria most often lead to slow patient recruitment. If the eligibility criteria are too extensive and need to be adjusted during the study to include more patients, the credibility of your clinical study result might be undermined.

SITE SELECTION

The choice of sites should primarily be based on the availability of patients. A secondary consideration is that the sites have the time and resources to perform the study, appropriate knowledge and facilities, GCP experience and so on. Selecting sites is a tricky aspect of the planning phase of a clinical study. To ensure that you select the most suitable sites, a feasibility study should be performed during the development of the protocol to find out if the study will be possible in a specific country or at specific sites. However, the most common feasibility study is to prepare for the site selection. The site feasibility study should include detailed questions relating to:

  • Patient availability
  • Possible obstacles with eligibility criteria
  • Available resources at the investigational site
  • Concurrent clinical studies within the same therapeutic area

PATIENT RECRUITMENT

Patient recruitment is often the most challenging aspect of planning a clinical study; few studies manage to include all patients within the primary time plan. To succeed with the patient recruitment it is important to ensure that:

  • The protocol includes sufficient eligibility criteria, but not too extensive; for example, there should be no unnecessary prohibited medication
  • Participating sites commit to a certain number of patients before they are selected, and should have a plan beforehand of how these patients should be recruited
  • Cut-off points should be planned and implemented. A cut-off point is reached, for example, when a certain number of patients have been recruited at a certain date/timepoint. Predefined actions should be implemented, such as the initiation of additional sites, discussion of study design (for example if exclusion criteria are too extensive), and additional advertisements
  • Advertisements in print publications or online reach the predefined patient group
  • External resources allocated for recruitment, such as call centre

SITE MANAGEMENT & MONITORING

Site management and monitoring are usually the most time consuming, and are therefore the most costly aspect of the clinical study. The key step is to get the site personnel to work efficiently and to perform the study correctly according to the protocol. Site initiation is important as it is the main opportunity to get all the site personnel to work together in a standardised manner according to the protocol. It is also important to gather the relevant study personnel for a thorough presentation of the protocol, study procedures and practical aspects of the study. Develop tools to help inclusion of patients, for example pocket cards with eligibility criteria and a flowchart of the study. These cards will make it easier for the site personnel to decide if a routine patient is eligible for the study.

The first site visit should be performed immediately after the first patient visit. Setting a higher frequency of monitoring visits early in the study to discover possible systematic errors and faults is also recommended.

Monitoring patient visits in close connection to the visit performance will lead to site personnel having a greater ability to perform corrections in a constructive way, and enable them avoid faults and errors. Source data verification should be performed to the extent applicable for the certain study. Take an active decision on the need of source data verification, since not all studies need to be 100 per cent source data verified. There are several ongoing discussions regarding the need of 100 per cent source data verification and how much quality one can gain from it. The ICH E6 GCP (3) states that source data verification should be performed, but does not specify the precise extent and scope of this requirement. Certain source data should always be verified, including patient identification, eligibility criteria, primary variable and AE/SAE.

Motivated site personnel are extremely important if you want your clinical study performed in the best way. This is best achieved by providing information and instruction, close communication and regular updates. Site personnel are often more motivated when they receive regular updates; along with emails or telephone calls, newsletters – including both status and information/instruction – are an easy and effective way to ensure that all involved personnel receive the same information.

COMMUNICATION

Communication channels within the study team will be the foundation of the project, and good communication will make sure that the study team is up-to-date and confident. Set up regular teleconferences, even if you only have a few details to discuss; the meeting may be very short, but everyone will be involved and aware of key issues, in turn helping team members to spot possible problems before they become an issue.

STUDY CLOSE OUT

A database lock is to be performed as quickly as possible if you are prepared. Some activities can be performed early, but the easiest way to obtain a fast database lock is to:

  • Run logical checks regularly
  • Produce and send data clarification forms/ queries regularly
  • Monitor the situation more closely towards the end of patient visits
  • List all protocol deviations as they occur in a way that makes them easy to evaluate and summarise

RISK ASSESSMENT

The risk management plan sets out the potential risks and actions needed in key situations – and most studies experience at least one scenario that leads to immediate action to avoid potential damage or delay to the study or its results. A risk assessment plan should be prepared early in the study planning phase and revised throughout the study in order to cover any situation. An evaluation of the risks should be done in accordance to the phase and indication, the timeline, possible safety issues and so on. The risk assessment should preferably be backed up by a contingency plan that describes actions to prevent the risks.

Nordic Perspective
Nordic countries have a long history operating at the frontline of clinical research. Nordic physicians have considerable experience assessing clinical trial performance and are well-versed collaborating with the life science industry. The healthcare system promotes participation in clinical trials, which has the benefit of making it easy to negotiate contracts. Patients within the Nordic countries typically show high levels of compliance to physician instructions. This results in fewer protocol deviations and low dropout levels. The ability to reach out to a large pool of patient is facilitated through social security number systems and national registries. In regulatory terms, the EU directive has been implemented extensively by Nordic RAs. RAs are easy to communicate with and are able to produce high quality work.

CONCLUSION

Following these seven key steps will help you obtain success with your clinical study with regards to time, cost and quality. The investigational product effect, however, needs to speak for itself; that is another success story.

References

  1. Pocock SJ, Clinical Trials, A Practical Approach, John Wiley & Sons, 1983
  2. Spilker B, Guide to Clinical Trials, Lippincott, Williams & Wilkins, Jan 1991
  3. Guidance for Industry, Good Clinical Practice: Consolidated Guidance (ICH-E6)

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Susan Suchdev is Country Manager for IRW Consulting in Sweden, a full-service CRO providing clinical trial services within the Nordic countries. Susan has approximately 15 years of experience with clinical trial execution working in the pharmaceutical industry (Pfizer) and within CROs (Trial Form Support and IRW Consulting). Prior to this, Susan spent a couple of years in research working at the Karolinska Institute, after obtaining an MSc in Nutrition.
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