Feasibility in Clinical Research - Foundation for Clinical Trial Success

Partha Gokhale
Head Clinical Operations
Boehringer Ingelheim India


Clinical Trial Feasibility is a process that has several steps starting from Pre-feasibility/ Project level feasibility, country feasibility culminating in site feasibility. The present article aims to look at Clinical Trial Feasibility primarily from a New Drug Development perspective . However the general principles enumerated here can also be applied with certain modifications for academic clinical trial feasibilities as well.

The word "Feasibility" as defined by the Oxford Dictionary states "The state of being easily or conveniently done". Clinical Trials Feasibility forms the foundation for translating the research idea into study execution

Purpose:

The process of clinical trial feasibility is one of the first steps in conducting a clinical study. It aims at finding if a research idea can be practically executed by assessing various factors such as the epidemiology of disease in a particular geographic area, the therapeutic paradigm as well as the existing treatment options, eligible patient population, the ethical and regulatory requirements and availability of Investigator, staff and resources for doing the research. In many cases the feasibility process is carried out with a feasibility questionnaire that is customized for the individual study. Site questionnaires should be designed to accomplish the sponsor's objectives (Goldfarb, 2009, p. 9). In particular, the questions should:
  • Be necessary to the purpose.
  • Be sufficient to the purpose.
  • Be clear and unambiguous.
  • Be straightforward to answer with readily available information.
  • Provide adequate options and space for the answer.
  • Allow a broad range of answers.
  • Accommodate the characteristics of different types of sites.
  • Generate answers that the sponsor can interpret and score.
  • Generate answers that the sponsor can validate for predictive ability .
A well-designed questionnaire gives insights into the site’s complex, subtle personality.
The idea behind using a uniform questionnaire for all clinical sites is to have responses on those questionnaires that can be compared between sites and even between countries allowing the central study teams to take an informed decision about which sites are to be ultimately selected and which are to be dropped. The present article aims to look at Clinical Trial Feasibility primarily from a New Drug Development perspective. However the general principles enumerated here can also be applied with certain modifications for academic clinical trial feasibilities which are primarily not drug development focused.

Broadly a clinical trial feasibility process aims to answer the following questions.
1) What is the prevalence and incidence of the disease in the country?
2) How is the disease being treated currently? What are the standard treatment options including the dosage of the drugs used?
3) What are the alternative treatment strategies? Are the alternative drugs approved in the country?
4) What are the ethical and regulatory requirements? Are there any specific requirements e.g. - concerns with use of placebo, compensation of patients for trial related injury etc.?
5) Where are the study patients found- specialty; in-patient vs outpatients; primary, secondary or tertiary healthcare etc.?
6) Who are the potential investigators?
7) What can be the potential recruitment rate?
8) Is the study logistically feasible- e.g., availability of translations for patient scales, special requirements for transportation of biological specimens, experience on specialized clinical study procedures etc.?
9) What are the limitation or expected bottle necks for smooth execution of the study.

Stakeholders

A credible answer to the abovementioned questions in a timely manner can only be achieved by a collaborative approach between various stakeholders in a pharma company. These stakeholders are.

1) Clinical Research department- This is the most important stakeholder as far as Study feasibility is concerned and is responsible for collating and providing the feedback on the feasibility results to the global study teams. It provides input on the operational as well as some medical and regulatory aspects of the study design.
2) Drug Regulatory Affairs (DRA) - DRA is primarily entrusted with providing feedback on the regulatory requirements for conduct of clinical studies and on registration of the product in the country. It also provides the status on the registration of comparator molecules and data on intellectual property rights associated with them.
3) Medical Affairs: This is also a very important stakeholder and provides inputs on the medical aspects of the study plan. It provides input on the positioning of the molecule in the current therapeutic paradigm for the disease. The medical affairs department also provides names of the Key Opinion leaders (KOLs) who could be consulted by the clinical research teams along with the potential study investigators for questions on the study design and characteristics of the patient population.
4) Market Access and Sales Department- Market Access and Sales teams are becoming increasingly important for future clinical development. Market Access teams in particular provide data on the size of the market as well as the competition. In countries where the healthcare is reimbursed by the government, market access will also provide feedback on probability of the new drug being considered on the government's reimbursed list.

Types of Feasibility:

Clinical trial feasibility is a process that has various steps as shown in the schematic below.






1) Pre-Feasibility/Project Feasibility: This is a top line feasibility that is done at least 1 to 1.5 years before the initiation of the study. The intent of this feasibility process is to understand the prevalence of the disease under study in a particular country and also the standard of care used in treating the disease. Data from this feasibility will be used in shortlisting countries for the next level of the feasibility process.

2) Country Feasibility: This is the second level in the feasibility process and is usually conducted at least 9-12 months before initiation of the study . The aim of this process is to find whether the study can be conducted in a particular country or not. This feasibility is usually conducted with a study synopsis or draft protocol. Hence the selection criteria for including the patients in the study are usually finalized by this time. This makes the country feasibility an extremely important part of the feasibility process as it helps in elucidating the capability of the country to recruit patients and thus in calculating the recruitment rate. Country feasibility also helps in identifying the regulatory requirements and the timelines for approval of the study within the country. Usually country feasibility is executed by discussing the synopsis or draft protocol with 5 to 6 potential investigators or KOLs and carefully validating their responses on the same. Data on the regulatory aspects is also shared with the study teams. On the basis of the feedback provided by the investigators as well as the regulatory timelines a decision is taken on allocation of a particular trial to a country.

3) Site feasibility: This is the third level of the feasibility process and is responsible for site as well as investigator selection. Site feasibility is generally done with the help of detailed study specific feasibility questionnaires that evaluate several aspects of the site's and investigator's capabilities. It assesses whether the investigator has the necessary qualifications as well as the experience and has the ability to contribute the required number of eligible patients as given in the study protocol. It also assess the support that is available with the investigator to successfully execute the clinical study like presence of qualified and experienced sub-investigators, study co-ordinators, pharmacist etc. Evaluation of site facilities like a registered institutional ethics committee that is compliant with the local as well as international regulations, time taken by the IEC to accord approval to the study, accredited laboratory, presence of diagnostic modalities like CT scan, MRI, X-ray etc. also forms an integral part of this process. In addition to the aforementioned, compliance of the investigator and site to specific local regulations e.g.; signed and valid site SOPs (Indian GCP guidelines, 2006), emergency handling facilities, etc. is also evaluated.

The Ground Reality in India:

Identifying, screening and qualifying investigative sites is an ongoing challenge for every clinical study team. The more accurate the initial feasibility assessment, the more successful the study, meaning projects enrolled on-time and completed within budget. Although Sponsor teams in India have historically met the recruitment commitments, an in depth analysis reveals that this commitment is achieved due to contribution from only 20-30% of the investigative sites (Data On File). The remaining sites either do not contribute or contribute less than half of their original patient commitment. While this does not impose any recruitment risk for diseases with widespread prevalence in India such as Type II Diabetes Mellitus, Asthma, COPD or common cancers such as Breast and Lung cancer, the lack of accuracy in feasibility numbers imposes challenges to meet the recruitment commitment in rare diseases such as Idiopathic Pulmonary Fibrosis, Cystic Fibrosis, Cerebral Venous Thrombosis and many rare cancers such as mesotheliomas. The reasons for the inaccurate prediction of eligible patients during feasibility in Indian sites are multivariate.
a) Lack of Patient database: Historically Indian sites have always relied on the patients visiting their OPDs or IPDs for participation in clinical studies. They have relied solely on their own memory for providing recruitment data during study feasibilities. This strategy worked well in the past for common diseases as those mentioned above. If the patients that were a part of the investigator’s memory recall were for some reason not found eligible for a study, one or more new patients visiting the OPD (and who were found eligible for the study) could take the place of these patients and the recruitment commitment would be achieved. However a similar strategy does not work for rare diseases as there may not be enough new patients seen by the investigator that could replace previously identified old patients who were subsequently found ineligible. To further compound the problem, hospitals have only recently started maintaining extensive electronic records of patients. Investigators in western nations as well as many South East Asian countries like South Korea, Singapore and even China have started maintaining databases of patients with several ailments. These databases are updated through the hospital’s MIS (Medical Information System ) system and hence are up to date with the patients’ current disease and treatment profile. This has allowed these countries to have a good patient contribution in clinical trials on many rare diseases. A similar patient database is sorely needed in Indian sites and is need of the hour.



b) Patient Factors- Although more than 80 percent of patients say they are willing to participate in clinical research studies, only around 10 percent actually do so. (BBK Healthcare, Inc/ Harris Interactive, 2006). Although this data is from UK, this is true for Indian sites as well moresoever after audio video recording of the informed consent process has become mandatory in India (File No GCT/20/SC/ClinJ2013 DCGI, 19 Nov 2013). It is a well-known fact that many potentially eligible patients are uncomfortable with audio video recording and hence ultimately do not consent for the study (Frazen, 2017). Hence the figures given in feasibility by an inexperienced investigator are usually downgraded by a sponsor. Usually the rule of the thumb is to have at least a 40-60% reduction in the patient numbers compared to those given by the investigator. However there are exceptions to the abovementioned rule. In many specialties India now has a growing number of experienced clinical trial investigators who do provide realistic patient recruitment figures.

c) Inadequate Discussions on Draft Protocol or Synopsis with Investigators: When feasibility surveys are conducted by the sponsor with the potential investigators, study protocols may be in a draft stage or if "country feasibility" is being conducted, only a "Study Synopsis" may be available at the time. Sponsor teams are often found negligent in that they typically do not invest as much time as is needed in training the personnel who conduct the feasibility. Moreover as most of the feasibilities are done remotely, many important data points are not effectively communicated to the investigators leading to inadequacy of the recruitment figures given by the later. Investigators on their part are also negligent as they do not give enough importance as well as adequate time when a feasibility request comes from sponsor on a new study. Often the feasibility surveys are filled by study co-ordinators who are not medically qualified and therefore the patient recruitment figures do not accurately reflect the true picture.

Conclusion

Given the importance of the feasibility process it is imperative for senior personnel within the sponsor's offices like a project manager to review each feasibility questionnaire carefully. Many times inaccuracies in filling the questionnaire can be discovered by simply reviewing the form. Patient commitment figures given in the questionnaire especially by new or inexperienced investigators must be reconfirmed by speaking with the Principal investigators themselves. This also allows the project manager to gauge the understanding of the potential investigator on the protocol. In my personal experience this is quite effective as it leads to correction of many erroneous patient commitment numbers. Incorrect clinical trial feasibility can cause significant delay in achieving the recruitment target with significant cost implications and negatively impact an organization, regardless of size or financial stability. The potential for delays can be decreased or mitigated through comprehensive planning and adequate oversight by senior personnel in the sponsor organization who are owners of the feasibility process. Clinical Trial Feasibility is the best means we have for predicting the speed at which Investigators will enroll patients and how the data flow will occur over time and provides a strong foundation for ensuring future clinical trial success.

Reference

1.BBK Healthcare, Inc/ Harris Interactive. (2006). The Will & Why Survey." Reinventing Patient Recruitment: Revolutionary Ideas for Clinical Trials Success. Surrey, UK: Gower Publishing.
2. Data On File. (n.d.).
3. File No GCT/20/SC/ClinJ2013 DCGI. (19 Nov 2013).
4. Frazen, J. M. (2017, March 2). The Changing Face Of Clinical Trials- Informed Consent. N Engl J Med, 856-867.
5. Goldfarb, N. M. (2009, November). Questions in Site Selection Questionnaires. Journal Of Clinical research Best Practices, 5(11), 10.
6. Indian GCP guidelines. (2006). Central Drugs Standard Control Organization. Retrieved Mar 16, 2017, from Central Drugs Standard Control Organization: http://www.cdsco.nic.in/html/GCP1.html