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The objective of this study was to describe the interventions and impact made by pharmacists during clinical trials.
Methods
A specialty contract research organization that used clinical trial research pharmacists to communicate with patients to support clinical trial protocol adherence, retention, and health outcomes performed a retrospective, descriptive analysis of 12 clinical trials that involved 2 noninsulin glucose-lowering medications. Pharmacists called study participants at specific timepoints during the trials as per protocol. During each telephone call, the number and types of interventions were documented. Descriptive statistics (frequencies) were performed to determine the number and type of interventions by call and by patient across all noninsulin glucose-lowering medication drug A and drug B studies.
Findings
Overall, 25,829 calls were made across all studies. Of these calls, 11,765 calls (45.5%) had at least one intervention that involved 3573 patients (92.3%). The most frequent interventions addressed adverse events (3774 [14.6%]), protocol violations for medication use (3341 [12.9%]), concurrent medications (1630 [5.9%]), and miscellaneous concerns (1269 [4.6%]). The greatest numbers of interventions were high-impact interventions (4772 [18.5%]) (eg, serious adverse events) that would seriously affect trial outcomes and patient adherence.
Implications
Pharmacists were able to identify, support, and address multiple types of interventions related to medication management during clinical trials, including those related to concurrent medication use, adverse events, and other medication-related issues. These pharmacist interventions can result in better patient outcomes and, ultimately, more reliable study results for review and approval by regulatory agencies.
New medications and health interventions are constantly being explored to improve the health and outcomes of patients. For these trials to produce valuable results, it is important for patients to remain adherent to the treatments and protocols being studied. Adherence is defined as “persistence in practice or tenet; steady observance or maintenance” (Aronson JK. Compliance, concordance, adherence. Br J Clin Pharmacol. 2007;63(4):383–384). This term is preferred over the term compliance, and the term adherence will be used hereafter.
Studies have found that adherence to medication therapies in ambulatory clinical trials is suboptimal. In 2012, Blaschke et al
examined a cohort of 16,907 patients enrolled in 95 clinical trials. The authors found that the number of patients taking the prescribed therapy decreased by up to 40% over time. At day 100, 20% of patients had discontinued treatment, and another 12% of patients had omitted doses. By the end of the 12th month, the number of patients who had discontinued use of the drug increased to 40%.
Improper adherence stems from many causes and may be related to patient characteristics, psychological phenomena, severity of health problems, complexity of treatment regimens, drug-drug interactions, and adverse effect profile.
Nonadherence occurs for a variety of reasons (ie, adverse effects, missed doses, misunderstanding of directions) and is especially concerning in medical conditions that are chronic and prevalent, such as diabetes. Adherence in diabetes is important to minimize patient morbidity and mortality. In 2010, the TRIAD (Translating Research Into Action for Diabetes) study group found that in cases in which treatment goals were not met, 20% to 23% of patients with diabetes were found to have poor treatment adherence.
In addition to the consequences in diabetes specifically, the consequences of poor adherence can be considered on individual and community levels. At the individual level, patients with poor medication adherence have increased morbidity and mortality, as well as decreased quality of life, as noted above. In addition, poor adherence may also have a negative impact on the community, such as increased antimicrobial resistance and increased transmission of disease.
Although nonadherence may have devastating consequences in the community setting, nonadherence within the scope of clinical trials proves to be even more problematic. Nonadherence in clinical trials may lengthen studies, increase costs, confound study results, and threaten researchers’ abilities to complete statistical analyses and draw valid scientific conclusions. It is estimated that mean adherence rates for short- and long-term medication adherence within the scope of clinical trials investigating treatment regimens is 78% and 59%, respectively.
These percentages offer room for much improvement with respect to medication adherence within clinical trial research.
Factors for poor adherence may be related to treatment complexity, treatment adverse events, and drug-drug interactions, particularly in diabetes in which these issues commonly occur. Pharmacists have a unique opportunity as the medication experts to manage poor adherence during clinical trials. In 2012, Ali et al
examined the impact of a pharmacist-managed program for individuals with diabetes in the community setting on hemoglobin A1c and other cardiovascular risk factors. Patients in the intervention group received diabetes education as well as monitoring and counseling every 2 months for a 12-month period. Patients in the intervention group had significant reductions in hemoglobin A1c, blood pressure, blood glucose, and body mass index. Patients in the intervention group also experienced significant increases in quality of life, belief about the need for medication, and diabetes knowledge. In addition, these patients had fewer concerns about medication therapy.
examined the impact of a pharmaceutical care model on glycemic control and medication adherence in patients with type 2 diabetes. Participants in the control group received standard pharmaceutical services, including dispensing of the medication and brief instruction on how to take the medication. Participants in the intervention group were provided more extensive education and follow-up telephone calls to help them resolve any drug-related problems or issues. The authors found that the pharmaceutical care intervention was associated with significant reductions in hemoglobin A1c and improvement in medication adherence.
These studies found positive impacts that pharmacists have made on important markers of health, including laboratory values, quality of life, and medication adherence related to diabetes in the community setting. These findings should be explored further because these same health markers are also important in clinical trials, particularly because proper adherence is essential to ensure quality data and to minimize clinical trial costs. By using the knowledge and skills of pharmacists, researchers in clinical trials may be able to improve clinical trial retention, medication adherence, and, ultimately, patient outcomes. For example, pharmacists may be able to provide health care support by identifying and addressing medication therapy issues with patients and addressing patient questions regarding medication therapy in a timely manner.
There are currently no studies examining the types of pharmacist interventions made regarding medication use in patients with diabetes in the clinical trial setting. Understanding the types, frequency, and impact of the interventions made will help elucidate whether pharmacists provide important pharmaceutical interventions that affect the data of clinical trials. Therefore, the objective of this study was to describe the interventions and impact made by pharmacists during multiple clinical trials.
Patients and Methods
Center Point Clinical Services is a specialty contract research organization that works with pharmaceutical, biotechnological, and medical device companies in meeting their regulatory and commercialization goals. In the Clinical Trials Research Pharmacist (CTRP) program, specially trained licensed pharmacists communicate with patients to support clinical trial retention, medication and protocol adherence, and health outcomes.
A major pharmaceutical company was engaged in running a clinical trial program for 2 first-in-class diabetes medications that were administered via subcutaneous injection. The protocol for these clinical trials involved detailed administration directions for the patient; also, the therapies caused transient and troublesome adverse effects (eg, nausea, injection site reactions) that had contributed to decreased patient adherence and increased patient retention challenges in earlier trials. The CTRP pharmacist support service was in addition to the current trial model with existing clinical sites and staff monitoring the patients.
The sponsor company conducted 12 separate clinical trials that involved 2 noninsulin glucose-lowering medications (NIGLMs). For each of those trials, the CTRP called all enrolled study participants across all clinical sites at specific junctures during the trials, as outlined in the trial protocols. The purpose of the pharmacist calls was to educate patients about the study medication and reinforce protocol instructions. Pharmacists were also available 24 hours a day 7 days a week to receive patient calls for most trials. Pharmacists used sponsor-approved counseling worksheets to discuss and record specific counseling points during each patient contact.
Conversations with patients were documented, and clinical sites received written summary reports after every contact. Data points were collected by pharmacists and entered into Excel spreadsheets during telephone calls. During each telephone call, the number and types of interventions were recorded. Interventions were defined as a patient report or answer to a pharmacist question in which the pharmacist corrected or intervened to prevent protocol errors. Pharmacists then reported trends and outliers to study sponsors and clinical site monitors in real-time, allowing the sponsor and clinical site monitors to follow up with the clinical site promptly and provide additional training to other clinical sites as needed.
The interventions were classified into high-, medium-, and low-impact interventions. These classifications were made based on the level of impact that would be expected if the respective intervention had not been made through a review of the literature. High-impact interventions were those pertaining to concurrent medications, serious adverse events (such as hypoglycemia), medication use, and study medication or study information. For example, not understanding the dosing and timing of the medication affects the efficacy of the drug’s action and patient’s outcomes, which could affect a patient’s desire to properly adhere to their medication regimen.
Medium-impact interventions included those about miscellaneous concerns, supplies, and moderate adverse events. If patients are experiencing moderate adverse events, such as bruising, they may be inclined to stop taking their medications as prescribed to avoid these events in the future.
Low-impact interventions were those pertaining to the Interactive Voice Response System, proper storage of the study medication, reports of no change in blood glucose, pharmacist information (information about the pharmacist calls or contact information), and questions about the placebo, which overall were not expected to have a material influence on a patient’s adherence.
Because the data contained no patient information or identifiers, institutional review board approval was waived.
Statistical Analysis
Data were entered into Microsoft Excel and then analyzed with SPSS software, version 23.0 (IBM, Armonk, New York). Descriptive statistics (frequencies) were performed to determine the number and type of interventions by call and by patient across all NIGLM drug A and drug B studies.
Results
Interventions by Call and by Patient
In the NIGLM drug A studies, 9863 (45.7%) of the 21,582 calls made included at least one intervention (Table I). A large number of these interventions were made regarding adverse events (3085 interventions [14.3%]), medication use (2834 interventions [13.2%]), and concurrent medications (1431 interventions [6.6%]). There were 3123 patients who participated in the NIGLM drug A studies. Of these participants, 2899 patients (92.8%) had at least one intervention made during their multiple telephone calls. Most often, these patients had interventions regarding adverse events (1699 patients [54.4%]), medication use (1678 patients [53.7%]), and concurrent medications (991 patients [31.7%]).
Table INoninsulin glucose-lowering medication drug A study pharmacist interventions.
Item
Calls, No. (%) (n = 21,549)
Patients, No. (%) (n = 3123)
No intervention during the call
11,694 (54.3)
224 (7.2)
Had interventions during the call
9855 (45.7)
2899 (92.8)
Interventions made
Adverse effects
3085 (14.3)
1699 (54.4)
Medication use
2834 (13.2)
1678 (53.7)
Concurrent medications
1431 (6.6)
991 (31.7)
Miscellaneous concerns
998 (4.6)
779 (24.9)
IVRS
880 (4.2)
592 (19.0)
Glucometer question
276 (1.3)
233 (7.5)
Storage
268 (1.2)
243 (7.8)
No blood glucose change
225 (1.0)
183 (5.9)
Supplies
211 (1.0)
191 (6.1)
Pharmacist information
149 (0.7)
136 (4.4)
Study medications and study information
133 (0.6)
116 (3.7)
Placebo
125 (0.6)
115 (3.7)
Improved patient’s QOL
119 (0.6)
99 (3.2)
IVRS = Interactive Voice Response System; QOL = quality of life.
In the NIGLM drug B studies, 1909 (44.6%) of the 4280 calls made included at least one intervention (Table II). A large number of these interventions were made regarding adverse events (689 interventions [16.1%]), medication use (507 interventions [11.8%]), and miscellaneous concerns (271 interventions [6.3%]). There were 750 patients who participated in the NIGLM drug B studies. Of these participants, 674 patients (89.9%) had at least one intervention made during their multiple telephone calls. Most often, these patients had interventions regarding medication use (319 patients [57.5%]), adverse events (366 patients [48.8%]), and miscellaneous concerns (192 patients [25.6%]).
Table IINoninsulin glucose-lowering medication drug B study pharmacist interventions.
Overall, 25,829 calls were made in all the NIGLM drug A and B studies (Table III). Of these calls, 11,765 calls (45.5%) had at least one intervention (Figure 1). The most frequent interventions were regarding adverse events (3774 interventions [14.6%]), medication use (3341 interventions [12.9%]), concurrent medications (1630 interventions [5.9%]), and miscellaneous concerns (1269 interventions [4.6%]).
Table IIICombined noninsulin glucose-lowering medication drug A and B studies on pharmacist interventions.
There were 3873 patients who participated in a NIGLM drug A or Drug B study (Table III). Of these, 3573 patients (92.3%) had at least one intervention made during their multiple telephone calls (Figure 2). Most often, these patients had interventions regarding adverse events (2044 patients [52.8%]), medication use (2018 patients [52.1%]), concurrent medications (1116 patients [28.8%]), and miscellaneous concerns (971 patients [25.1%]).
Figure 2Number of patients and intervention incidence by impact.
The interventions were classified into high-, medium-, and low-impact interventions, as discussed previously (Table IV). The greatest number of interventions made involved high-impact interventions (4772 interventions [18.5%]), followed by medium impact (2066 interventions [8.0%]) and, finally, low impact (1758 interventions [6.4%]). Of the 8594 interventions made, the observed frequencies are high-impact interventions (55.5%), medium-impact interventions (24.0%), and low-impact interventions (20.5%) (Figure 3). More than 2785 patients (70%) involved in the NIGLM drug A and B studies generated at least one intervention in the high-impact intervention category.
Table IVLevel of impact of pharmacist intervention in combined noninsulin glucose-lowering medication drug A and B studies.
Intervention Type
Interventions per Call, No. (%) (n = 25,829 Calls)
Interventions per Patient, No. (%) (n = 3874 Patients)
High: concurrent medications, serious adverse effects, medication use, study medication and study information
it is important for patients in these trials to remain adherent to the treatment protocols being studied to produce valuable and accurate results. This is particularly critical because the number of patients in clinical trials who remain enrolled in the study decreases over time. As many as 40% of patients no longer take the study medication after 12 months.
This finding is critical because poor treatment regimen adherence in clinical trials can result in lengthened studies, increased costs, and confounded study results.
Tufts Center for the Study of Drug Development Impact Report. September/October 2006.
every extra trial day can cost a company $37,000 in operational costs and $1.1 million in lost revenue.
Across the 12 studies, pharmacists provided at least one intervention for 92.3% of patients. This finding constitutes a significant number of patients and indicates that participants in clinical trials have many questions and issues that needed to be resolved. This finding also points to the fact that pharmacists were effective in identifying and addressing potential problems and responding to patient questions and concerns during the clinical trial. Pharmacists were able to promote adherence to treatment regimens through patient education and reinforcement of protocol instructions. In addition, significant protocol deviations may have occurred had some of these interventions not been made. Further research directly measuring changes in medication adherence in patients participating in clinical trials after pharmacist intervention is warranted.
Researchers have identified a positive correlation between perceived adverse effects to antihyperglycemic medication and treatment adherence, with perceived adverse effects predicting decreased adherence to medications.
Given the type of interventions made, many patients may not have been adherent without the pharmacists’ involvement. With the highest incidence of pharmacist interventions falling under the category adverse events for NIGLM drug A and drug B studies, it is a strong consideration that these interventions improved medication adherence and patient retention with regard to transient nausea and injection site reactions.
In a study completed in the community setting by Murray et al,
pharmacist-led interventions and medication education in patients with heart failure resulted in an increase of 10.9% in medication adherence during the intervention period. In 2012, Hamblin et al
Prevention of adverse drug events and cost savings associated with PharmD interventions in an academic Level I trauma center: An evidence-based approach.
conducted a study in a trauma intensive care unit to identify adverse effects and cost savings provided by clinical pharmacists. They found that clinical pharmacist interventions in the intensive care unit resulted in decreased serious adverse effects and significant cost savings. Although these studies were conducted in different settings with a variety of end points, they both indicate that pharmacists can promote adherence as well as identify and address medication-related problems, such as adverse drug events. Therefore, inclusion of a pharmacist in a clinical trial may be expected to produce a similar effect.
In the NIGLM drug A and drug B studies, pharmacists could proactively identify potential problems and educate patients regarding medication use, directions, and transient adverse effects. Patients could maintain and potentially increase adherence to the study medication longer by addressing these issues and receiving education. In addition, it is possible to eliminate many problems associated with the complexity of the treatment regimen and improve medication adherence when pharmacists work with patients and study coordinators.
evaluated medication administration and storage habits of 67 patients with type 2 diabetes receiving insulin. The authors found that the manufacturer’s instructions were not followed for 75% of the insulin pens. However, correct use of the pens was significantly higher after education by a health care professional. These pharmacist interventions across these 12 studies may have contributed to more accurate study outcomes by simply and effectively ensuring accurate and adherent medication administration and use.
Most pharmacist interventions completed (55.5%) were classified as high-impact interventions. In addition, the pharmacists provided an intervention for 9 of 10 patients. The CTRP pharmacists completed nearly 3 times as many high-impact interventions as low-impact interventions (18.5% vs 6.4%). Interventions falling within the high-impact category include those that involve concurrent medications, serious adverse events medication use, study medication questions, and study information. Because adverse events and difficulty of understanding medication regimens are known to have a negative impact on adherence,
pharmacists’ interventions in this clinical trial setting may enhance adherence, improve trial retention, and reduce trial costs.
It is known that medication adherence decreases as the number of drug treatments, frequency of dosing, complexity, and length of the treatment regimen increase.
As pharmaceutical and biopharmaceutical products become more complex, their developmental process becomes lengthier, with increasing costs and risks associated with clinical trials.
Therefore, strategies aimed at improving medication adherence during clinical trials may prove beneficial to the reliability of the results. Pharmacist involvement and intervention in medication therapy regimens has consistently been found to improve medication adherence and to optimize treatment outcomes.
For any researchers achieving less than desirable results from their clinical trial, a question worth considering is, “Did the drug fail the clinical trial, or did the clinical trial fail the drug?” Similarly, one might also ask, “Would having a pharmacist actively involved with patients throughout the study have positively affected patient behavior and delivered more robust results?” The pharmacist is the drug information expert and the health care professional who possesses the most extensive training in medication therapy. Use of their expertise in a clinical trial to routinely interact with patients regarding their medications could improve the accuracy of outcomes.
The results of this study indicate that pharmacists were able to provide useful and timely interventions while promoting protocol-adherent medication use. Effective pharmacist-intervention strategies that clinical researchers should consider when designing study protocols include verbal patient counseling that focuses on adherence in addition to providing written educational materials, follow-up telephone calls to address patient questions or concerns and to reinforce adherence, and telephone reminders for specific protocol requirements. The exact cost savings of these interventions are still unknown. Additional future research should examine the potential cost savings of pharmacist-led interventions and measurements of improved patient adherence in clinical trials.
As with all research, this study has some limitations. The interventions were completed by a variety of pharmacists, which may lead to inconsistencies with respect to assessment of problems as well as data collection and intervention management. In addition, there were several areas that were not measured, such as medication adherence and cost, that limit the strength of the results. Although it may be inferred that pharmacist interventions led to increased medication adherence and decreased costs, further studies with patient outcomes data are needed. In addition, the patients enrolled in these clinical trials had a diagnosis of diabetes, and results of the study may not be generalizable to other patient populations.
Conclusion
With >9 of 10 patients requiring some type of medication intervention during clinical trials, pharmacists may be the ideal health care professionals to address medication-related issues. Previous studies in the community and inpatient settings have found that pharmacists may have a positive impact on medication adherence, adverse effects, and costs.
Prevention of adverse drug events and cost savings associated with PharmD interventions in an academic Level I trauma center: An evidence-based approach.
In addition, the pharmacist identified and addressed multiple types of interventions related to medication management during clinical trials, including those related to concurrent medication use, adverse effects, and other medication-related issues. Pharmacist-led medication management during clinical trials may also increase medication adherence and decrease costs, but more research is needed in this area.
Funding Sources
This project was funded by a grant provided by Center Point Clinical Services to Cedarville School of Pharmacy.
Conflicts Of Interest
J. Martinez is an employee of Center Point Clinical Services. Study sponsors, however, did not have a role in the study design, collection, analysis, and interpretation of the data as well as whether the study was submitted for publication. Study sponsors were allowed to provide edits to the manuscript and participate in deciding the appropriate journal, as long as the integrity of the data was maintained. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
Thank you to Tina Schlecht, PharmD, MBA, for her assistance in reviewing and preparing the data analysis and manuscript. Thank you to Aleda M. H. Chen, PharmD, PhD, for her assistance in data analysis and revising the manuscript. Thank you to Gerald Finken, RPh, MS, for creating Center Point Clinical Services to execute CTRP services to support clinical trial implementation. J. Martinez assisted in revising the manuscript as outlined in the conflicts of interest section. E. Laswell and J. Ballentine assisted in data interpretation, writing, and revising. S. Cailor assisted in data analysis, interpretation, writing and revising.
Prevention of adverse drug events and cost savings associated with PharmD interventions in an academic Level I trauma center: An evidence-based approach.
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