Focus on your recruitment practices7 March 2013
Careful planning, a well-chosen site and a realistic protocol are key to the success of a clinical trial, writes Mercè de Frias, project manager at ADVANCELL.
When a biopharmaceutical company decides to invest huge amounts of money in the clinical development of a candidate, finalising clinical trials within the expected timeline and budget is fundamental to their success. With R&D steadily increasing over recent years, and clinical trials accounting for more than 40% of these costs, companies recognise the importance of efficiency planning and managing clinical trials.
As mentioned by Heather DiBenedetto in the previous issue of Clinical Trials Insight, 80% of trials performed in 2009 in the US were delayed by at least a month because of low levels of enrolment. Other surveys by Tufts Center for the Study of Drug Development indicate that two thirds of investigative sites fail to meet the patient enrolment requirements for a given clinical trial. Such delays have a huge impact on already high clinical development costs. So what can be done to improve recruitment rates? And, more importantly, how can we change and improve recruitment processes?
The answer is planning. It is worth investing money in the planning phases of the study, where small changes can have huge impacts in the later development of the clinical trial.
First we should focus on the early steps of the study, and assess whether the protocol and projected recruitment timelines are achievable. So before starting to worry about recruitment, we should assess two things: how we have selected the sites we are going to work with, and how the protocol we have in place has been written, especially the procedures within it.
With regard to site selection, we should start by mentioning some general considerations. Site selection should be according to medical criteria (disease prevalence, country-specific standard of care, regional presence of comparator drugs), but also on company development strategy (territorial preferences, partners' territorial presence, competent studies) and quality assurance (good clinical practices and team knowledge of quality standards). There are no correct sites; only sites that fit company and study requirements.
Assess the site's feasibility
The first step is the feasibility questionnaire. This should be carefully designed so as to assess the site's expertise in your study field and success in previous studies. Always keep in mind that sites and investigators tend to be very optimistic about the availability of study population and their recruitment capacity. This overestimation is one of the most dangerous miscalculations when planning how many sites should be used. To avoid this problem, non-data-based opinions should be discarded, and only historical metrics should be relied on. Also, the involvement of the investigator team in other, competing clinical trials and any potential lack of time or resources should be considered.
Sites and investigator teams will be the unique and direct link with the patients during the study. They are in charge of the normal care of the patients, before and after the trial. They have the responsibility to inform them about the trial and perform all (and that means all) procedures included in the protocol. It is clear that the trial performance and recruitment success is in their hands. Deservedly, all of the investigator team should feel that they are important within the trial, and their interests and motivations should be taken into account. They should be listened to, and their problems quickly resolved, otherwise recruitment will probably slow down. Each site is different and unique: if possible, the sponsor should try to adapt to every site request, and to make life easier for each team.
The protocol: keep it simple
Together with site selection, protocol writing is the other activity of clinical development that needs to be carefully planned and executed. When writing a protocol, first of all it's important to get input from all areas involved in the complete drug development cycle: non-clinical and clinical teams, team leaders, external consultants as well as those in business development.
Also, and especially for small biotech companies with no in-house medical departments, it's important to work with reliable and experienced medical consultants and to question and listen to the investigator team - something that is not always done. As mentioned above, investigators and their teams are the direct contact with the patient, and they could help to identify which procedures or visits may inconvenience the patient, or make the patient feel uncomfortable with the study. Their concerns should be taken into account because, if the investigator does not feel comfortable with a protocol, usually his patients won't either.
In general terms, a protocol should be as simple as possible, avoiding procedures far removed from daily medical practice, such as unnecessary procedures, repetitive measures with no added value, or fancy, state-of-the-art procedures in which investigators are not trained.
Also, inclusion and exclusion criteria should be crystal clear. A misleading description of these criteria would increase the work of the clinicians, as they would have to contact the CRO or the sponsor for clarification, which would complicate recruitment tasks.
Flexibility is another 'must' in the protocol. Adding a wider time window or making a procedure more flexible could be difficult for some medical procedures while feasible for others. This flexibility could have a huge impact on recruitment, with particular relevance in clinical trials where the patient is not hospitalised and has to combine his or her normal life with participation in the clinical trial.
Again, an efficient planning phase is the key to avoiding unnecessary delays. Preparing and implementing amendments to the protocol consumes much time and resources, so to succeed in getting the planned recruitment rates, it should be ensured that the protocol is realistic and achievable.
Once site selection and protocol writing are complete, it should be ensured that all stakeholders involved in the study have the necessary knowledge of it. At site level, the study could be promoted by presenting non-clinical and clinical data in internal training sessions with the attendance of clinical and non-clinical investigator teams. Posters/flyers at hospital facilities and media advertisements (always in agreement with ethics committees and national competent authorities) could help to promote the study among patients and to improve recruitment. In addition, direct contact with patient associations could be enhanced, either by attending their meetings or by presenting data in disease-specific meetings.
Impact of new technologies
These are the 'classic' tools that have been used for many years now. However, new technologies are completely changing this landscape. New internet tools, social media initiatives, mobile applications for smartphones and tablets... a lot of innovative solutions are being developed, and they can be implemented at several levels during the clinical development. Mobile apps is one of the new technology areas with the highest rates of development, and its development is so wide and fast that the Food and Drug Administration (FDA) in the US recently released a draft guideline for medical mobile applications that are considered to be medical devices. Not all apps will fall under the scope of this guideline, as it will only include apps that function as a traditional medical device or are part of or an extension of a traditional medical device, but it indicates the concerns of regulatory authorities about the use of these new tools.
In respect of clinical trials, these apps could have many uses: they remind patients of their next visits to the site or of procedures to be done at home. They also transmit test results to doctors, and allow a prompt and accurate report of adverse events. Moreover, they could be powerful tools to enhance recruitment rates. They allow immediate contact with the target population, no matter how specific or wide it is. Everyone, and especially patients, wants to be informed about the latest news on their disease and wants to be connected with other patients. Thus these new tools could help patients get the information they need, keep informed about clinical trials that are currently recruiting, and get in contact with investigator teams. There are already several companies developing these tools, and even public institutes are developing their own clinical trial apps. For example, in the US, the National Cancer Institute's (NCI's) Center for Cancer Research (CCR) has release a mobile app (NCTITrials@NIH) that directly and securely links to the NCI-CCR clinical trial database and provides details about studies being conducted at the NIH Clinical Center in Bethesda, Maryland.
This enables oncologists and patients to easily identify updated cancer clinical trial information.
However, in spite of their benefits, there are also threats that could affect the development and implementation of these apps. To guarantee their success, apps must be safe, reliable and useful, and they must ensure the security and privacy of the data transmitted. There is also an ongoing discussion about whether these apps should go through a certification procedure by regulatory authorities. Probably, in the next few years, the regulatory mark for these technologies will be more clear, and their use in clinical trials will be extended further.
Clinical trial development is highly cost and time-consuming, and although companies often push to get their candidates into clinical trials as soon as possible, spending the required time on early-phases planning is crucial to ensure the success of the study.