Mitigating Administrative Risks in Industry-sponsored Clinical Trials

Abstract

Just as industry sponsors work to protect themselves by mitigating their risks as just described, research directors also must carefully consider the proposed clinical trial before committing to it. Research directors use the fundamental principles of project management, which are directly applicable to clinical research trial management. Administrating clinical trials is, on the surface, no different from administrating any other project, such as constructing a building or developing a new food additive. However, clinical research can directly and immediately impact a person's health. Therefore, a high degree of scrutiny is needed to minimize the potential for physical or emotional harm to the subjects, and this takes precedence over the “business” side of clinical research (4Angell M. Industry-sponsored clinical research: a broken system.JAMA. 2008; 300: 1069-1071Crossref PubMed Scopus (186) Google Scholar). After appropriately protecting the human subjects, the research director can implement the project management aspect of clinical trials. Specifically, he or she can apply the concept of triple constraint to clinical research management: scope, time, and cost (5Steurer J. Bachmann L.M. [Managerial considerations in research].Ther Umsch. 2007; 64: 683-686Crossref PubMed Scopus (2) Google Scholar, 6O'Brien J.A. Clinical trials finance and operations.J Med Pract Manage. 2007; 22: 369-371PubMed Google Scholar). As with all projects, however, the research director cannot predict whether a clinical trial can be executed successfully. Therefore, a level of negative risk is involved. Unlike positive risks (e.g., increased prestige for the institution, publications), negative risks are issues (e.g., financial, logistical) that potentially can deleteriously impact the clinical trial. The negative risk is directly related to triple constraint. Appropriate management of a project's negative risk, especially before accepting a clinical trial, is absolutely critical.ScopeThe first component of negative risk management—before agreeing to be an investigative site for a clinical trial—involves evaluating the scope of the project. The research director must review the protocol and assess some key components that indicate the reasonable feasibility of completing the trial.First, the research director must evaluate whether or not the investigative site has the patient population that the industry sponsor wants. For example, it is not a good match if the industry sponsor is looking for a site that treats a lot of patients with type I diabetes, but the investigative site treats mostly patients with type II diabetes.Second, the research director must assess whether or not the site has the resources needed. If the clinical trial necessitates a specific quantitative laboratory test but the investigative site is not able to perform that test, then the investigative site may not be an ideal location due to the added logistics of outsourcing this test. If the clinical trial requires a certain number of subjects with a specific disorder that the investigative site does not see, then the investigative site is not ideal; the project will never be completed if the clinical trial requires 100 patients with type II diabetes to be recruited within 1 month but the investigative site only sees 75 in that timeframe. If the potential investigative site has other clinical trials currently running with similar inclusion criteria, then there may not be enough patients available because (1) most clinical trials do not permit a subject to participate in more than 1 clinical trial at a time and (2) there is a finite pool of subjects available.Finally, the research director must evaluate the specific aims of the project. He or she must evaluate whether or not there is a clinical interest within the institution in participating in the clinical trial. In project management terms, there needs to be stakeholder buy-in or a principal investigator who will serve as the project champion (7Pant R. Joshi Y. A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials.J Young Pharm. 2011; 3: 60-64Abstract Full Text PDF PubMed Scopus (2) Google Scholar). The clinical trial is doomed to fail if there is no buy-in from the clinicians. The clinical research trial must contain an area of particular interest to a physician. A thorough examination of the scope before accepting a clinical trial allows for negative risk mitigation.TimeTime is the second consideration in negative risk management. The research director must consider 2 components: (1) length of the study, and (2) hours spent by the research staff on the study. A clinical trial that lasts 8 weeks is more likely to be completed successfully than a study that lasts 8 months. In addition, the number of follow-up visits required is also related to the successful completion of a study. For the length of the study/hours spent by research staff and the number of follow-up visits, increasing numbers correlate to an increasing subject drop-out rate (8Blanton S. Morris D.M. Prettyman M.G. McCulloch K. Redmond S. Light K.E. Wolf S.L. Lessons learned in participant recruitment and retention: the EXCITE trial.Phys Ther. 2006; 86: 1520-1533Crossref PubMed Scopus (123) Google Scholar).If there is a high drop-out rate, enrollment milestones may not be met. Industry sponsors use enrollment milestones to provide incentives to the investigative sites to enroll subjects. Payments are withheld until the milestones are achieved. Unless these enrollment milestones are met, the time spent by the research staff will not be compensated.Additionally, the research director must review the protocol to assess the complexity of the clinical trial. More time will be spent by the investigative site's research staff if a clinical research trial is logistically complicated. The research director must weigh the potential time spent on this new trial with the time spent on other ongoing clinical trials. He or she must ensure that there is enough time available for the successful completion of the project.CostCost is the third and final constraint that must be evaluated carefully before accepting an industry-sponsored clinical trial, and it may be the most important constraint of all (9Jacobs V.R. Making or losing money with participation in clinical trials: a decision analysis.Onkologie. 2009; 32: 411-416Crossref PubMed Scopus (11) Google Scholar). A clinical research budget is an educated guess and does not precisely account for all clinical trial–related costs (10McKoy J.M. Samaras A.T. Luu T.H. Bennett C.L. Upping recruitment in clinical trials: are costs worth it?.Onkologie. 2009; 32: 378-379Crossref PubMed Scopus (1) Google Scholar). Typically, the industry sponsor and the investigative site negotiate a budget before signing the agreement. Before accepting an industry-sponsored clinical trial, the research director must ascertain whether the budget is sufficient to cover the costs of running the trial (11Beal K. Dean J. Chen J. Dragaon E. Saulino A. Collard C.D. Budget negotiation for industry-sponsored clinical trials.Anesth Analg. 2004; 99: 173-176Crossref PubMed Scopus (7) Google Scholar). In most cases, it is difficult to predict the exact costs. The majority of the budget reflects costs related to research personnel (12Moinpour C.M. Costs of quality-of-life research in Southwest Oncology Group trials.J Natl Cancer Inst Monogr. 1996; 20: 11-16PubMed Google Scholar). As discussed previously, time is related to costs. If time estimates are uncertain, then costs will be uncertain.Cost-associated negative risks can be minimized by negotiating higher budgets, decreasing the number of subjects needed to reach each milestone, and increasing the budget for start-up costs. It is uncommon to have money left over after a clinical trial's completion; however, in many instances, the budget falls short of costs actually involved in the completion of the clinical trial. Therefore, negotiating the highest budget amount possible is important. Further, because enrollment milestones must be met before the industry sponsor provides payment for the work performed, it is critical to reduce the number of subjects needed to reach each milestone.Budgeting for start-up funds is important. Significant costs are associated with beginning a new clinical trial; multiple meetings, emails, and phone calls are needed before the first subject is enrolled. Further, filling out and submitting documents to the appropriate departments (e.g., institutional review boards) takes effort and time. These endeavors must be accounted for in the budget as part of the start-up costs. Often, start-up activities are the most important aspect of running a clinical trial. For example, if enrollment milestones are not reached after the study begins, no payment will be made to the investigative site, despite the effort that was spent on the trial. The start-up budget needs to reflect the effort required in case all or none of the enrollment milestones are met. This is an insurance policy for work conducted if the clinical research trial cannot be completed. An institution should not accept being a clinical trial site if the cost issues cannot be resolved.ConclusionA clinical trial is a complex process involving many components. Careful consideration must be made before agreeing to be an investigative site for an industry-sponsored clinical trial. Clinical research uses the project management principle of triple constraint. A research director is a project manager, and a clinical trial is synonymous with a project. If the negative risks are unacceptable, the research director must be ready to decline participation in an industry-sponsored clinical research trial. Ultimately, the research director must consider both the positive and negative risks involved and attempt to decrease the negative risks. Both the industry sponsor and the investigative site will benefit from this careful analysis. Just as industry sponsors work to protect themselves by mitigating their risks as just described, research directors also must carefully consider the proposed clinical trial before committing to it. Research directors use the fundamental principles of project management, which are directly applicable to clinical research trial management. Administrating clinical trials is, on the surface, no different from administrating any other project, such as constructing a building or developing a new food additive. However, clinical research can directly and immediately impact a person's health. Therefore, a high degree of scrutiny is needed to minimize the potential for physical or emotional harm to the subjects, and this takes precedence over the “business” side of clinical research (4Angell M. Industry-sponsored clinical research: a broken system.JAMA. 2008; 300: 1069-1071Crossref PubMed Scopus (186) Google Scholar). After appropriately protecting the human subjects, the research director can implement the project management aspect of clinical trials. Specifically, he or she can apply the concept of triple constraint to clinical research management: scope, time, and cost (5Steurer J. Bachmann L.M. [Managerial considerations in research].Ther Umsch. 2007; 64: 683-686Crossref PubMed Scopus (2) Google Scholar, 6O'Brien J.A. Clinical trials finance and operations.J Med Pract Manage. 2007; 22: 369-371PubMed Google Scholar). As with all projects, however, the research director cannot predict whether a clinical trial can be executed successfully. Therefore, a level of negative risk is involved. Unlike positive risks (e.g., increased prestige for the institution, publications), negative risks are issues (e.g., financial, logistical) that potentially can deleteriously impact the clinical trial. The negative risk is directly related to triple constraint. Appropriate management of a project's negative risk, especially before accepting a clinical trial, is absolutely critical. ScopeThe first component of negative risk management—before agreeing to be an investigative site for a clinical trial—involves evaluating the scope of the project. The research director must review the protocol and assess some key components that indicate the reasonable feasibility of completing the trial.First, the research director must evaluate whether or not the investigative site has the patient population that the industry sponsor wants. For example, it is not a good match if the industry sponsor is looking for a site that treats a lot of patients with type I diabetes, but the investigative site treats mostly patients with type II diabetes.Second, the research director must assess whether or not the site has the resources needed. If the clinical trial necessitates a specific quantitative laboratory test but the investigative site is not able to perform that test, then the investigative site may not be an ideal location due to the added logistics of outsourcing this test. If the clinical trial requires a certain number of subjects with a specific disorder that the investigative site does not see, then the investigative site is not ideal; the project will never be completed if the clinical trial requires 100 patients with type II diabetes to be recruited within 1 month but the investigative site only sees 75 in that timeframe. If the potential investigative site has other clinical trials currently running with similar inclusion criteria, then there may not be enough patients available because (1) most clinical trials do not permit a subject to participate in more than 1 clinical trial at a time and (2) there is a finite pool of subjects available.Finally, the research director must evaluate the specific aims of the project. He or she must evaluate whether or not there is a clinical interest within the institution in participating in the clinical trial. In project management terms, there needs to be stakeholder buy-in or a principal investigator who will serve as the project champion (7Pant R. Joshi Y. A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials.J Young Pharm. 2011; 3: 60-64Abstract Full Text PDF PubMed Scopus (2) Google Scholar). The clinical trial is doomed to fail if there is no buy-in from the clinicians. The clinical research trial must contain an area of particular interest to a physician. A thorough examination of the scope before accepting a clinical trial allows for negative risk mitigation. The first component of negative risk management—before agreeing to be an investigative site for a clinical trial—involves evaluating the scope of the project. The research director must review the protocol and assess some key components that indicate the reasonable feasibility of completing the trial. First, the research director must evaluate whether or not the investigative site has the patient population that the industry sponsor wants. For example, it is not a good match if the industry sponsor is looking for a site that treats a lot of patients with type I diabetes, but the investigative site treats mostly patients with type II diabetes. Second, the research director must assess whether or not the site has the resources needed. If the clinical trial necessitates a specific quantitative laboratory test but the investigative site is not able to perform that test, then the investigative site may not be an ideal location due to the added logistics of outsourcing this test. If the clinical trial requires a certain number of subjects with a specific disorder that the investigative site does not see, then the investigative site is not ideal; the project will never be completed if the clinical trial requires 100 patients with type II diabetes to be recruited within 1 month but the investigative site only sees 75 in that timeframe. If the potential investigative site has other clinical trials currently running with similar inclusion criteria, then there may not be enough patients available because (1) most clinical trials do not permit a subject to participate in more than 1 clinical trial at a time and (2) there is a finite pool of subjects available. Finally, the research director must evaluate the specific aims of the project. He or she must evaluate whether or not there is a clinical interest within the institution in participating in the clinical trial. In project management terms, there needs to be stakeholder buy-in or a principal investigator who will serve as the project champion (7Pant R. Joshi Y. A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials.J Young Pharm. 2011; 3: 60-64Abstract Full Text PDF PubMed Scopus (2) Google Scholar). The clinical trial is doomed to fail if there is no buy-in from the clinicians. The clinical research trial must contain an area of particular interest to a physician. A thorough examination of the scope before accepting a clinical trial allows for negative risk mitigation. TimeTime is the second consideration in negative risk management. The research director must consider 2 components: (1) length of the study, and (2) hours spent by the research staff on the study. A clinical trial that lasts 8 weeks is more likely to be completed successfully than a study that lasts 8 months. In addition, the number of follow-up visits required is also related to the successful completion of a study. For the length of the study/hours spent by research staff and the number of follow-up visits, increasing numbers correlate to an increasing subject drop-out rate (8Blanton S. Morris D.M. Prettyman M.G. McCulloch K. Redmond S. Light K.E. Wolf S.L. Lessons learned in participant recruitment and retention: the EXCITE trial.Phys Ther. 2006; 86: 1520-1533Crossref PubMed Scopus (123) Google Scholar).If there is a high drop-out rate, enrollment milestones may not be met. Industry sponsors use enrollment milestones to provide incentives to the investigative sites to enroll subjects. Payments are withheld until the milestones are achieved. Unless these enrollment milestones are met, the time spent by the research staff will not be compensated.Additionally, the research director must review the protocol to assess the complexity of the clinical trial. More time will be spent by the investigative site's research staff if a clinical research trial is logistically complicated. The research director must weigh the potential time spent on this new trial with the time spent on other ongoing clinical trials. He or she must ensure that there is enough time available for the successful completion of the project. Time is the second consideration in negative risk management. The research director must consider 2 components: (1) length of the study, and (2) hours spent by the research staff on the study. A clinical trial that lasts 8 weeks is more likely to be completed successfully than a study that lasts 8 months. In addition, the number of follow-up visits required is also related to the successful completion of a study. For the length of the study/hours spent by research staff and the number of follow-up visits, increasing numbers correlate to an increasing subject drop-out rate (8Blanton S. Morris D.M. Prettyman M.G. McCulloch K. Redmond S. Light K.E. Wolf S.L. Lessons learned in participant recruitment and retention: the EXCITE trial.Phys Ther. 2006; 86: 1520-1533Crossref PubMed Scopus (123) Google Scholar). If there is a high drop-out rate, enrollment milestones may not be met. Industry sponsors use enrollment milestones to provide incentives to the investigative sites to enroll subjects. Payments are withheld until the milestones are achieved. Unless these enrollment milestones are met, the time spent by the research staff will not be compensated. Additionally, the research director must review the protocol to assess the complexity of the clinical trial. More time will be spent by the investigative site's research staff if a clinical research trial is logistically complicated. The research director must weigh the potential time spent on this new trial with the time spent on other ongoing clinical trials. He or she must ensure that there is enough time available for the successful completion of the project. CostCost is the third and final constraint that must be evaluated carefully before accepting an industry-sponsored clinical trial, and it may be the most important constraint of all (9Jacobs V.R. Making or losing money with participation in clinical trials: a decision analysis.Onkologie. 2009; 32: 411-416Crossref PubMed Scopus (11) Google Scholar). A clinical research budget is an educated guess and does not precisely account for all clinical trial–related costs (10McKoy J.M. Samaras A.T. Luu T.H. Bennett C.L. Upping recruitment in clinical trials: are costs worth it?.Onkologie. 2009; 32: 378-379Crossref PubMed Scopus (1) Google Scholar). Typically, the industry sponsor and the investigative site negotiate a budget before signing the agreement. Before accepting an industry-sponsored clinical trial, the research director must ascertain whether the budget is sufficient to cover the costs of running the trial (11Beal K. Dean J. Chen J. Dragaon E. Saulino A. Collard C.D. Budget negotiation for industry-sponsored clinical trials.Anesth Analg. 2004; 99: 173-176Crossref PubMed Scopus (7) Google Scholar). In most cases, it is difficult to predict the exact costs. The majority of the budget reflects costs related to research personnel (12Moinpour C.M. Costs of quality-of-life research in Southwest Oncology Group trials.J Natl Cancer Inst Monogr. 1996; 20: 11-16PubMed Google Scholar). As discussed previously, time is related to costs. If time estimates are uncertain, then costs will be uncertain.Cost-associated negative risks can be minimized by negotiating higher budgets, decreasing the number of subjects needed to reach each milestone, and increasing the budget for start-up costs. It is uncommon to have money left over after a clinical trial's completion; however, in many instances, the budget falls short of costs actually involved in the completion of the clinical trial. Therefore, negotiating the highest budget amount possible is important. Further, because enrollment milestones must be met before the industry sponsor provides payment for the work performed, it is critical to reduce the number of subjects needed to reach each milestone.Budgeting for start-up funds is important. Significant costs are associated with beginning a new clinical trial; multiple meetings, emails, and phone calls are needed before the first subject is enrolled. Further, filling out and submitting documents to the appropriate departments (e.g., institutional review boards) takes effort and time. These endeavors must be accounted for in the budget as part of the start-up costs. Often, start-up activities are the most important aspect of running a clinical trial. For example, if enrollment milestones are not reached after the study begins, no payment will be made to the investigative site, despite the effort that was spent on the trial. The start-up budget needs to reflect the effort required in case all or none of the enrollment milestones are met. This is an insurance policy for work conducted if the clinical research trial cannot be completed. An institution should not accept being a clinical trial site if the cost issues cannot be resolved. Cost is the third and final constraint that must be evaluated carefully before accepting an industry-sponsored clinical trial, and it may be the most important constraint of all (9Jacobs V.R. Making or losing money with participation in clinical trials: a decision analysis.Onkologie. 2009; 32: 411-416Crossref PubMed Scopus (11) Google Scholar). A clinical research budget is an educated guess and does not precisely account for all clinical trial–related costs (10McKoy J.M. Samaras A.T. Luu T.H. Bennett C.L. Upping recruitment in clinical trials: are costs worth it?.Onkologie. 2009; 32: 378-379Crossref PubMed Scopus (1) Google Scholar). Typically, the industry sponsor and the investigative site negotiate a budget before signing the agreement. Before accepting an industry-sponsored clinical trial, the research director must ascertain whether the budget is sufficient to cover the costs of running the trial (11Beal K. Dean J. Chen J. Dragaon E. Saulino A. Collard C.D. Budget negotiation for industry-sponsored clinical trials.Anesth Analg. 2004; 99: 173-176Crossref PubMed Scopus (7) Google Scholar). In most cases, it is difficult to predict the exact costs. The majority of the budget reflects costs related to research personnel (12Moinpour C.M. Costs of quality-of-life research in Southwest Oncology Group trials.J Natl Cancer Inst Monogr. 1996; 20: 11-16PubMed Google Scholar). As discussed previously, time is related to costs. If time estimates are uncertain, then costs will be uncertain. Cost-associated negative risks can be minimized by negotiating higher budgets, decreasing the number of subjects needed to reach each milestone, and increasing the budget for start-up costs. It is uncommon to have money left over after a clinical trial's completion; however, in many instances, the budget falls short of costs actually involved in the completion of the clinical trial. Therefore, negotiating the highest budget amount possible is important. Further, because enrollment milestones must be met before the industry sponsor provides payment for the work performed, it is critical to reduce the number of subjects needed to reach each milestone. Budgeting for start-up funds is important. Significant costs are associated with beginning a new clinical trial; multiple meetings, emails, and phone calls are needed before the first subject is enrolled. Further, filling out and submitting documents to the appropriate departments (e.g., institutional review boards) takes effort and time. These endeavors must be accounted for in the budget as part of the start-up costs. Often, start-up activities are the most important aspect of running a clinical trial. For example, if enrollment milestones are not reached after the study begins, no payment will be made to the investigative site, despite the effort that was spent on the trial. The start-up budget needs to reflect the effort required in case all or none of the enrollment milestones are met. This is an insurance policy for work conducted if the clinical research trial cannot be completed. An institution should not accept being a clinical trial site if the cost issues cannot be resolved. ConclusionA clinical trial is a complex process involving many components. Careful consideration must be made before agreeing to be an investigative site for an industry-sponsored clinical trial. Clinical research uses the project management principle of triple constraint. A research director is a project manager, and a clinical trial is synonymous with a project. If the negative risks are unacceptable, the research director must be ready to decline participation in an industry-sponsored clinical research trial. Ultimately, the research director must consider both the positive and negative risks involved and attempt to decrease the negative risks. Both the industry sponsor and the investigative site will benefit from this careful analysis. A clinical trial is a complex process involving many components. Careful consideration must be made before agreeing to be an investigative site for an industry-sponsored clinical trial. Clinical research uses the project management principle of triple constraint. A research director is a project manager, and a clinical trial is synonymous with a project. If the negative risks are unacceptable, the research director must be ready to decline participation in an industry-sponsored clinical research trial. Ultimately, the research director must consider both the positive and negative risks involved and attempt to decrease the negative risks. Both the industry sponsor and the investigative site will benefit from this careful analysis.