Feasibility In the Age of International Clinical Trials

The success of a clinical trial depends on the sponsor’s ability to effectively execute clinical trials programs. Both quality of research and aptitude to complete the study on time determine the likelihood of advancement of a product candidate to the next stage of development or to commercialization. The design of clinical trial protocol not only heavily influences the outcome of the study, but also determines the ability to recruit appropriate patient populations both domestically and internationally. 

It is our firm belief that trial feasibility should start at the protocol design stage. We recommend creating a short list of potential countries based on internal business drivers, local recruitment potential and local technical capabilities assessments. It is also important to engage with the countries of interest as soon as the study synopsis is developed. The feedback from the international study team or from external partners with strong local expertise can become an invaluable asset in subsequent protocol design. Asking prospective international investigators to weigh in on the proposed protocol not only provides critical information about the overall capabilities of a given country but also helps build relationships with future sites. 

If a certain country is strategically important to the company and there is a strong interest in its inclusion in the study, then a very close attention should be paid to the local input as it may considerably impact the design of the study.

Example: Upon the review of the synopsis, local KOLs in several countries raise concerns about the comparator that is being chosen for the control group. They suggest a different agent that is more commonly used at their institutions. As the proposed selection is in line with applicable international standards of medical care, the company makes a decision to adjust the protocol and to add the recommended second comparator as an option based on investigators’ discretion. Subsequently, this protocol adjustment plays an important role in the ability to recruit large patient populations from given geographies and to complete the trial ahead of schedule.

There are instances where objective reasons for why a particular country cannot participate in the proposed study become obvious after the initial consultations with the local experts. This can save the sponsor company both time and resources by avoiding a formal feasibility at a later stage.

Country Selection

It is imperative that all pivotal trials be run with the participation of the country where registration is being sought. As an example, if the goal of the trial is to receive an FDA NDA approval, then it would be imperious to tailor the trial design to FDA guidelines and to identify and engage suitable PIs and trial sites in the United States. The FDA does not have an official “cut-off” guideline on how many sites and how many patients should be U.S.-based for the trial to be deemed satisfactory by the agency. Clearly, disease prevalence plays an important role in the decision making, and clinical trials in orphan indications with very low incidence would justify very wide geographic spread and make high ex-US patient recruitment both logical and necessary. For pivotal FDA trials in high prevalence indications, it is generally recommended that the number of US patients be equal or exceeded 30% of the total study population.

As the trend towards “globalization” of clinical trials continues, and with the current number of studies with ex-U.S. contribution standing at around 25% and growing, venturing into other parts of the world to attain adequate recruitment has become a valuable and often indispensable option.

When discussing which countries should be considered for an international clinical trial, the following characteristics should be taken into account:

1. Disease prevalence in proposed geographies

This information may not be readily available in some countries where epidemiologic studies are not commonly performed. In such circumstances, a surrogate assessment of prevalence can be performed in the form of questionnaires sent out to the KOLs and to prospective investigators. An answer to a simple question of, “how many patients with XYZ disease/condition do you see monthly?” can be very telling. However, when investigators are interested in being selected for a particular trial there may be some optimistic thinking on their part. Thus it is preferable to obtain the information from several sources, including the breakdown of past and ongoing trials in the same or similar indication. Another caveat may be in the way a certain condition or disease entity is perceived in the local culture. 

Example: While prevalence of schizophrenia and depression in India is common to that of the Western world, societal acknowledgement of psychiatric illnesses is restrained and can result in a significantly lower level of patients’ compliance and willingness to participate in clinical trials.

2. Local standards of care

Standards of care and even diagnostic standards vary considerably between different countries. Nonetheless, for a country to be selected, its local standards of care must be in line with the requirements of the study and submission criteria of the target regulatory agency. Evaluation of the local standards of care can be a rather complex undertaking and is frequently influenced by the type of therapeutic field that is being studied. For instance, a simple oral or injectable therapy or a medical device that requires treatment in the intensive care unit may not be plausible if the general standards of ICU care are not harmonized with international standards. 

It is also important to find out if the standard of care treatment would be paid by the government or by state insurance or if it needs to be covered by the sponsor of the trial.

Example: Biologics are the officially recommended standard of care in treatment of rheumatoid arthritis in most of the former Soviet Republics, however, due to the high costs of biologics it remains unattainable to most patients and only a fraction of them is provided with recommended medications under state programs because older and less expensive treatment protocols are frequently employed.

3. Level of country’s technical capabilities

One needs to evaluate country’s technical sophistication, especially if the expected trial requires sophisticated imaging equipment, such as PET/CT, functional MRI, etc. While leading medical centers in most countries are likely to have all of the needed diagnostic modalities, determining if the country has the “critical mass” of sites with needed equipment is essential. Thus asking the vendor or the local office to ascertain as to how many of the prospective sites meet the study’s technological requirements may quickly rule out the country in question as a study candidate. 

Assessing the level of IT connectivity at the sites is also critical; especially if electronic data entry is anticipated or if remote monitoring is being planned. Simply inquiring if the site has internet connection is not enough and specific questions about bandwidth and IT security should be raised.

4. Local regulatory landscape and time to first site initiation

Regulatory approval timelines are of great importance as in many cases delays in study approval can outweigh the potential benefits of accelerated patient recruitment. Thus it came at no surprise that recent delays in approval timelines in China and India have significantly diminished clinical trial attractiveness of both countries.

One common cause of delay is the requirement by some countries to submit signed site agreements with other study-related documents as part of the study approval application dossier, where in other countries site agreements are negotiated and signed in parallel with the review of study documents by the RA and EC(s).

5. Close attention should be paid to specific categories of medicinal products. For example, an approval of a study that involves a controlled substance in Russia can meet significant obstacles or be outright rejected.

6. Clear understanding of the mechanisms of IMP and clinical trial material importation and biological sample exportation are paramount to making sure that the study can be initiated on time. Extra attention should be paid and targeted questions should be asked when dealing with complex medicinal entities such as cellular therapies, live vaccines, etc. Temperature control is one topic that should not be overlooked and the ability of a local vendor to store, transport and adequately monitor the product en route in sometimes extreme climates should be thoroughly investigated. 

7. Comparator sourcing 

In international comparator trials, local or regional sourcing is uniformly more economical and feasible than central sourcing. If the study requires a comparator it is vital to make sure that it is:

• Locally registered and available 

• Considered to be the local standard of care 

• Available at all sites or can be supplied without any difficulties

Site Selection

Once the above factors have been evaluated, weighed and a preliminary decision regarding which countries to include in the anticipated international trial has been made, the next step that is as important is the selection of appropriate clinical trial sites. In fact, in countries where a sponsor company has limited or no experience, this step may even dwarf country selection.

Here are some sobering statistics. According to 2011 Tufts Center for the Study of Drug Development (CSDD) report, 60% of clinical trial sites did not meet enrollment requirements. The same CSDD later reported that 11% of sites failed to enroll a single patient and 37% under-enrolled,¹ less than one-third recruited to their original target within the time originally specified, and around one-third were required to file for extensions.² Other studies found that 50% of the sites enroll one or no patients at all, nearly one-fifth of investigators do not enroll any patients and about one-third enroll only 5% of evaluable patients;³ that recruitment challenges amount to 45% of all study delays;⁴ that nearly 80% of clinical trials fail to meet enrollment timelines and approximately a third of Phase III study terminations are due to enrollment difficulties, making recruitment the single biggest reason for trial failure.⁵

It wouldn’t be hard to envisage that once an international site has been initiated and is underperforming, the sponsor company’s ability to influence foreign investigators would be limited. 

Here are some of the factors that should be evaluated during site selection:

1. Site’s accreditation for clinical trials

Many countries require having special accreditation for clinical trial sites and only the approved sites can participate in clinical trials. Such accreditation may be specific to a particular therapeutic area and the sponsor should make sure that the indication of the planned trial is in line with the one that the site is accredited for. Fore example, there is a requirement for accreditation in Russia and the accreditation is specific for a particular phase of the study (e.g. site can be accredited to run a Phase I study only, or Phases II-III, or Phases I-IV) and valid for five years only. The same requirements are applicable to Belarus.

2. Clinical trial experience

Ask about the number of international clinical trials conducted by the site/investigator in the last five years and the number of ongoing clinical trials in the pre-specified field of medicine. To gain a better understanding of site’s and investigator’s capabilities it is prudent to widen the net and to ask about experience that is not limited to a specific pathology. For instance, when assessing a site for a trial in a solid cancer indication, one should ask about all cancer trials that a particular investigator had conducted. It is likely that if the investigator has a strong track record in hematologic malignancies, then the same investigator will do well with all malignancies. If a certain procedure is required to be performed by the investigators in the planned trial, then a very careful review of prior their experience, including the number of procedures performed in the last 12 months, questions about the technique being used, should be performed.

3. Site’s previous record 

Whenever possible, the decision to include an individual site into a study should be based on previous experience with this site/investigator. It is not uncommon for the company to be guided by marketing considerations and to include the local key opinion leaders (KOLs). While these decisions should be made internally, an objective evaluation of the site shouldn’t be omitted and evaluation of competing trials, staff availability and of recruitment potential should be performed. This is where trusted CRO partners can be of invaluable help. They usually have their “black lists” of sites to be avoided as many of them feel that having a KOL site that has not recruited a single patient is a questionable accomplishment.

4. The number of competing clinical trials, both ongoing and planned

While the information about ongoing trials is usually easy to attain, finding out about the studies that are being planned could be challenging. One way of identifying such trials is by getting the information from the regulatory authorities. Most countries have well established and accessible databases that list all clinical trials that have received approvals and even the clinical sites that have been included therein. If the competing international study is of significant size and the information about the involvement of a particular site is unavailable, then a direct question about investigator’s participation should be asked.

5. Anticipated enrollment

It is very common for ex-US investigators to be highly motivated to be included in the studies. While such enthusiasm is always commendable, it can sometimes exaggerate enrollment projections. There is no universal remedy to corroborating that the projected numbers reflect the factual picture. However, some surrogate indicators can reduce this risk and the most effective approach is to employ a local vendor who has past experience working with a particular site and investigator and who can gage the enrollment capabilities through the scope of prior trials. In addition there is a higher likelihood that more realistic numbers will be shared with a trusted vendor who has the ability to bring future projects to the site and to the investigator. Notwithstanding , it is advisable to exercise healthy skepticism and cautiously base future enrollment projections on more conservative estimates, taking the lowest figure out of the promised enrollment range (e.g. 5 out of “5-8 pts/month” estimate).

6. Site equipment

Where country-wide capabilities give the sponsor company a general idea about its overall fit with the trial, site-level access to necessary medical equipment is crucial for selection of each participating site and needs to be carefully vetted during feasibility assessment. There may be selected sites that fit every criterion but lack a single imaging modality (e.g. SPECT, PET/CT, MUGA). In such situations in may be prudent to inquire about the site’s routine practices of performing tests (e.g. trusted external imaging center, partner facility, etc.). If the provided logistics is relatively straightforward and the site otherwise is a great fit, then this may become a compelling reason to engage it.

7. Site management organization 

In some instances a quick study start-up and its future smooth conduct can be augmented by having the sites operate under the unified umbrella of a site management organization (SMO). This often simplifies and accelerates the contracting process, allows investigators to concentrate on the patients while all the legal, financial and logistical tasks are managed by the SMO. Obviously, engagement of SMOs should be trial-and country-specific and should be evaluated individually.

As stated earlier, an experienced CRO usually has a better understanding of site’s enrollment potential than any feasibility questionnaire can ever provide. When selecting a CRO to perform a feasibility study consider using it for study conduct. Making a CRO aware of such plans and negotiating a risk-sharing model upfront can be very beneficial. Such a model penalizes CROs for its underestimation of study approval timelines, overestimation of sites’ recruitment capabilities and rewards it for exceeding of the same. This way the information presented in a feasibility report is much more likely to be accurate.

Vlad Bogin, MD, FACP is the CEO of Cromos Pharma.

References

1. Impact Report, Tufts Center for the Study of Drug Development, Vol. 15, No. 1, Jan/Feb 2013.

2. Campbell MK et. al. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study. Health Tech Assess Vol: 11; 48 Nov 2007.

3.  V.Rajadhyaksha. Conducting Feasibilities in Clinical Trials: An Investment to Ensure a Good Study Perspect Clin Res. 2010 Jul-Sep; 1(3): 106–109.

4. Anderson D.L. A Guide To Patient Recruitment. CenterWatch/Thomson Healthcare; Boston, Massachusetts, USA: 2001

5. “Performance-Based Site Selection Reduces Costs and Shortens Enrollment Time,” Monitor, December 2011. Based on analysis of 5,000 terminated clinical trials.