National and transnational drug shortages: a quantitative descriptive study of public registers in Europe and the USA.

BACKGROUND: Drug shortages are a growing global problem, posing clinical and economic challenges. To understand them better, we conducted an inventory of national public drug shortage registers and their comparability in Europe and the USA. METHODS: The study was based on openly accessible drug shortage notifications published by national drug authorities. These data were obtained from all national data sources mentioned on the European Medicines Agency's (EMA's) web page and FDA in the USA. After selection of the countries with comparable data, descriptive statistics were used to present characteristics of the shortages both across countries and within countries for 9 months (January-September) in 2020. We studied whether the shortages that occurred in these countries were the same, and how shortages were distributed by therapeutic uses and formulations. We also investigated price variation between the United States and Finland among drugs in shortage in one formulation category (creams and gels). RESULTS: Finland, Sweden, Norway, Spain, and the United States had suitable registers and were included. Altogether 5132 shortage reports from Finland (n = 1522), Sweden (n = 890), Norway (n = 800), Spain (n = 814), and the United States (n = 1106) were published during the study period. Of active ingredient level shortages 54% occurred in only one country, and 1% occurred in all five. However, at the country level, where there was one or more shortage notifications in an ATC active ingredient category, 19-41% were in a single country. The distributions by ATC therapeutic class and drug formulation differed substantially between countries, particularly between the USA and European countries. Injectables had a high shortage risk in the USA (57% of all shortages versus 17-31% of all shortages in the European countries). By contrast, shortages in gels and creams occurred only in European data (4-6% of all shortages). In the price comparison, creams and gels in shortage in Finland were 160% more expensive in the USA where these shortages were not detected. CONCLUSIONS: Public drug shortage registers are vital data sources for proactively maintaining and managing a reliable drug supply. However, our study demonstrates that much work remains to standardize the contents and quality of public register data. Shortages may not be solely a consequence of manufacturing disruptions but may reflect other contributing factors in the international drug distribution and supply mechanisms, including price differences and profit margins between national pharmaceutical markets. Data to perform practical and useful international comparisons to understand these shortages are required.

Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial.

AIM: We compared the efficacy of melatonin and placebo as adjuvants in the withdrawal of patients from long term temazepam, zopiclone or zolpidem (here 'BZD') use. METHODS: A double-blind, placebo-controlled, randomized trial was conducted in a primary health care outpatient clinic. Ninety-two men or women (≥55 years) with primary insomnia and chronic BZD use received controlled release melatonin 2 mg (CRM) (n = 46) or placebo (n = 46) during the 1 month withdrawal from BZDs. Psychosocial support was provided. Follow-up continued for up to 6 months. Successful BZD withdrawal by the end of 1 month was confirmed by BZD plasma determinations, while reduction in BZD use and abstinence continuing for 6 months were noted. RESULTS: There were two drop-outs on CRM and one on placebo. After a 1 month withdrawal, 31 participants (67%; 95% CI 54, 81) on CRM and 39 (85%; 74, 95) on placebo had withdrawn completely (intention-to-treat analysis between groups, P = 0.051; per protocol P = 0.043). Reduction in BZD use was similar or even more rare in the CRM than in the placebo group (P = 0.052 per protocol). After 6 months, 14 participants in the CRM group and 20 in the placebo group remained non-users of BZD (NS between groups). BZD doses were higher in the CRM than in the placebo group at the end of the 6 month follow-up (P = 0.025). Withdrawal symptoms did not differ between the groups. CONCLUSIONS: Gradual dose reduction of BZDs combined with CRM or placebo, and psychosocial support produced high short term and moderate long term BZD abstinence. CRM showed no withdrawal benefit compared with placebo.

Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults.

PURPOSE: The aim of this study was to assess the effect of withdrawal from the long-term use of temazepam, zopiclone or zolpidem as hypnotics drugs (here referred to as BZD) on cognitive performance. METHODS: Ninety-two adults (age ≥55 years) with primary insomnia and who were long-term daily users of BZD volunteered to participate in a 1-month medically supported withdrawal attempt from BZD use, with a subsequent 5-month follow-up. Withdrawal was based on plasma BZD measurements at baseline, at 1 month and during subsequent regular clinical appointments. Attention and psychomotor performance were measured using the CogniSpeed® at baseline and at 1, 2 and 6 months. Reaction times were determined in the Simple Reaction Time (SRT), Two-Choice Reaction Time (2-CRT) and Vigilance tests, and errors were measured by the 2-CRT and Vigilance tests. The cognition data of the withdrawal group were also compared with a cohort of BZD non-users. RESULTS: Eighty-nine (97 %) participants (59 women, 30 men) were followed-up for a maximum of 6 months. During the follow-up period, changes in reaction times and errors did not differ between short-term withdrawers (no residual BZD at 1 month; N = 69), non-withdrawers (residual BZD at 1 month; N = 20) or long-term withdrawers (N = 34). Compared to the reaction times of the BZD-free cohort, those of BZD users were slower at baseline. The reaction times of BZD withdrawers based on the results of the SRT or 2-CRT tests during follow-up did not reach those of the BZD-free cohort, but there was no difference between these groups in the Vigilance test. CONCLUSIONS: Long-term use of BDZ as hypnotic drugs by older adults is related to prolonged impairment of attentional and psychomotor cognitive functioning that persists for at least 6 months after withdrawal.

Content validation of a tool for assessing risks for drug-related problems to be used by practical nurses caring for home-dwelling clients aged ≥65 years: a Delphi survey.

PURPOSE: Home care services are becoming a critically important part of health care delivery as populations are aging. Those using home care services are increasingly older, more frail than previously, and use multiple medications, making them vulnerable to drug-related problems (DRPs). Practical nurses (PN) visit home-dwelling aged clients frequently and, thus, are ideally situated to identify potential DRPs and, if needed, to communicate them to physicians for resolution. This study developed and validated the content of a tool to be used by PNs for assessing DRP risks for their home-dwelling clients aged ≥65 years. METHODS: The first draft of the tool was based on two systematic literature reviews and clinical experience of our research group. Content validity of the tool was determined by a three-round Delphi survey with a panel of 18 experts in geriatric care and pharmacotherapy. An agreement by ≥80% of the panel on an item was required. RESULTS: The final tool consists of 18 items that assess risks for DRPs in home-dwelling aged clients. It is divided into four sections: (1) Basic Client Data, (2) Potential Risks for DRPs in Medication Use, (3) Characteristics of the Client's Care and Adherence, and (4) Recommendations for Actions to Resolve DRPs. CONCLUSIONS: The Delphi process resulted in a structured DRP Risk Assessment Tool that is focused on the highest priority DRPs that should be identified and resolved. The tool also assists the PNs to identify solutions to these problems, which is a unique feature compared to similarly purposed prior tools.

Handgrip strength and balance in older adults following withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotics.

BACKGROUND: Benzodiazepines and related drugs affect physical functioning negatively and increase fall and fracture risk. As impaired muscle strength and balance are risk factors for falls, we examined the effects of hypnotic withdrawal on handgrip strength and balance in older adult outpatients during and after long-term use of temazepam, zopiclone and zolpidem (here collectively referred to as "benzodiazepines"). METHODS: Eighty-nine chronic users (59 women, 30 men) of temazepam, zopiclone or zolpidem aged ≥55 years participated in a benzodiazepine withdrawal study. Individual physician-directed withdrawal was performed gradually over a one-month period and participants were followed up to six months. Handgrip strength was assessed using a handheld dynamometer, and balance using the Short Berg's Balance Scale during the period of benzodiazepine use (baseline), and at 1, 2, 3 weeks, and 1, 2 and 6 months after initiating withdrawal. Withdrawal outcome and persistence were determined by plasma benzodiazepine-determinations at baseline and at four weeks ("short-term withdrawers", n = 69; "short-term non-withdrawers", n = 20), and by interviews at six months ("long-term withdrawers", n = 34; "long-term non-withdrawers", n = 55). Also most of the non-withdrawers markedly reduced their benzodiazepine use. RESULTS: Within three weeks after initiating withdrawal, handgrip strength improved significantly (P ≤ 0.005) compared to baseline values. Among women, long-term withdrawers improved their handgrip strength both when compared to their baseline values (P = 0.001) or to non-withdrawers (P =0.004). In men, improvement of handgrip strength from baseline was not significantly better in withdrawers than in non-withdrawers. However, men did improve their handgrip strength values compared to baseline (P = 0.002). Compared to balance test results at baseline, withdrawers improved starting from the first week after withdrawal initiation. There was, however, only a borderline difference (P = 0.054) in balance improvement between the long-term withdrawers and long-term non-withdrawers. Of note, the non-withdrawers tended to improve their handgrip strength and balance compared to baseline values, in parallel with their reduced benzodiazepine use. CONCLUSIONS: Withdrawal from long-term use of benzodiazepines can rapidly improve muscle strength and balance. Our results encourage discontinuing benzodiazepine hypnotics, particularly in older women who are at a high risk of falling and sustaining fractures. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT2008000679530. Registered 31 October 2008.

Opioids, antiepileptic and anticholinergic drugs and the risk of fractures in patients 65 years of age and older: a prospective population-based study.

BACKGROUND: in men, the concomitant use of two or more benzodiazepines or two or more antipsychotics is associated with an increased risk of fracture(s). Potential associations between the concomitant use of drugs with central nervous system effects and fracture risk have not been studied. OBJECTIVE: the purpose was to describe the gender-specific risk of fractures in a population aged 65 years or over associated with the use of an opioid, antiepileptic or anticholinergic drug individually; or, their concomitant use with each other; or the concomitant use of one of these with a psychotropic drug. METHODS: this study was part of a prospective, population-based study performed in Lieto, Finland. Information about fractures in 1,177 subjects (482 men and 695 women) was confirmed with radiology reports. RESULTS: at 3 years of follow-up, the concomitant use of an opioid with an antipsychotic was associated with an increased risk of fractures in men. During the 6-year follow-up, the concomitant use of an opioid with a benzodiazepine was also related to the risk of fractures for males. No significant associations were found for females. CONCLUSION: the concomitant use of an opioid with an antipsychotic, or with a benzodiazepine may increase the risk of fractures in men aged 65 years and older.

State of the European Union's early notification obligation for drug shortages: enforcement and compliance in eight European countries (2020-2022).

BACKGROUND: Early notification of impending drug shortages is essential for mitigating or preventing shortages. Since 2019 pharmaceutical companies in the European Union (EU) and European Economic Area (EEA) must notify authorities of drug shortages at least two months in advance. This study's aim was to investigate how advance notification of pharmaceutical shortages is functioning in EU/EEA countries and factors possibly associated with differences in notification times. METHODS: This was a retrospective register study using data from publicly available drug shortage registers of all national authorities in the EU/EEA area having such a register. Actual notification times for all drug shortages during January 2020-November 2022 were calculated and included in the descriptive quantitative analysis. RESULTS: Data from eight countries (Belgium, Croatia, Finland, Germany, Norway, Slovakia, Slovenia, and Sweden) were available (18,987 notifications in total). Only 5.2% of all shortage notifications were made at least 60 days in advance and 56.2% of all notifications were made on the shortage's starting day or even later. Data on production-related shortages were available in Belgium, Croatia, Germany, and Norway (n = 2097 showing that 3.9% of those shortages were notified at least 60 days in advance, but 74.3% were made on the starting day or even later. The longest advance notification times for drug shortages were found in Finland during a 12-month period in June 2021-May 2022 when progressive notification fees were in effect. During this national policy experiment, 20.0% of the shortages (n = 1754) were notified at least 60 days in advance, while 24.9% of the notifications occurred on the starting day or even later. Data on notification times for permanent market withdrawals of drugs were available in three countries (Belgium, Slovenia, and Slovakia, n = 1737): 21.2% of these notifications were made at least 60 days in advance, while 45.5% of the notifications occurred on the starting day or even later. CONCLUSIONS: The EU regulatory requirement adopted in 2019 for early notification of drug shortages was unsuccessful in the eight countries having openly available statistics for follow-up. The national policy experiment in Finland with a progressive notification fee seemed to increase compliance with early notification.

The symptom mitigation path of mobile community residents: community pharmacy's role.

OBJECTIVES: Most medical conditions that community residents experience are managed in that setting. Often this involves prescription and/or non-prescription medicines and a visit to a community pharmacy. This study explores actions taken by mobile community residents to seek relief from their symptoms and pharmacy's role in symptom mitigation. METHODS: Five focus group discussions (n=30) of Finnish citizens living at least part of the year in Southern Spain were conducted. Both inductive and deductive methods were employed. RESULTS: Participants identified community pharmacies as a critical element of their symptom mitigation path--both because of easy access and free, fast service. According to participants' reports, both pharmacists and sales clerks (1) assumed responsibility for their symptoms and medications, (2) participated in diagnosing conditions and in prescription renewals, (3) both prescription and non-prescription medicines were dispensed and (4) some pharmacies dispensed prescription medications without a valid prescription. Many pharmacies offered medication counselling, but language barriers sometimes forced medicine users to rely on other Finns and written patient information leaflets. CONCLUSIONS: Among mobile community residents, the pharmacy has a trusted role in managing symptoms and medications. However, several medication safety risks are present in the current pharmacy practice: unlicensed sales clerks participate in medication dispensing, prescription medicines may be sold without a prescription, and medication counselling is variable.

Finnish immigrants' experience of community pharmacy services in Spain: an example of a developing E.U. issue.

Emigration within the European Union has increased, especially toward southern countries. This places complex demands on health care providers and community pharmacists, yet there is no E.U. policy that harmonizes health care services and pharmacy practice across member countries. This exploratory study examined immigrants' experiences with community pharmacy services. A survey of 1000 Finnish immigrants living in Spain's Costa del Sol region was performed in 2002, using a questionnaire that included structured and open-ended questions. Respondents were mostly satisfied with pharmacy services; however, some services had higher medication safety risks-related to medication counseling (for prescription and nonprescription medicines) and obtaining some prescription drugs without a prescription-due mainly to lack of a common language. Pharmacy services in the European Union may not provide adequate assurances of medication safety for immigrants. Consistent E.U.-wide minimum pharmacy practice standards for immigrant populations are needed.

A novel index of elevated risk of inpatient hospital admission immediately following outpatient surgery.

HYPOTHESIS: Patients with increasing comorbidities are at increased risk of admission to an inpatient facility after outpatient surgery. DESIGN AND SETTING: Data from operations performed in hospital-based and freestanding ambulatory surgery centers in New York during 1997 were obtained under the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project. PATIENTS: Of the 783 558 patients eligible for inclusion in this study, 4351 were discharged directly for short-term hospitalization (1:180), and 19 died (1:41 240). We performed a split-half analysis by randomly assigning the study sample to an analysis half for estimation or a holdout half for testing. MAIN OUTCOME MEASURES: We developed an outpatient surgery admission index from independent predictors of immediate hospital admission using the following point values: 65 years or older (1), operating time longer than 120 minutes (1), cardiac diagnoses (1), peripheral vascular disease (1), cerebrovascular disease (1), malignancy (1), seropositive findings for human immunodeficiency virus (1), and regional (1) or general anesthesia (2). RESULTS: Increasing scores were associated with higher odds of admission relative to scores of 0 or 1. For scores of 4 or higher, the odds ratio was 31.96 (95% confidence interval, 26.29-38.86), and 2.8% of these patients were discharged to the hospital. For the holdout half of the data set, scores of 4 or higher had an odds ratio of 34.62 (95% confidence interval, 28.55-41.97). CONCLUSION: The proposed outpatient surgery admission index provides an evidence-based guide to assist clinicians and the health care systems in which they work in identifying patients at higher risk of immediate hospital admission.

Pharmacy Benefit Management Companies: Do They Create Value in the US Healthcare System?

Pharmacy benefit management companies (PBMs) perform functions in the US market-based healthcare system that may be performed by public agencies or quasi-public institutions in other nations. By aggregating lives covered under their many individual contracts with payers, PBMs have formidable negotiating power. They influence pharmaceutical insurance coverage, design the terms of coverage in a plan's drug benefit, and create competition among providers for inclusion in a plan's network. PBMs have, through intermediation, the potential to secure lower drug prices and to improve rational prescribing. Whether these potential outcomes are realized within the relevant budget is a function of the healthcare system and the interaction of benefit design and clinical processes-not just individually vetted components. Efficiencies and values achieved in price discounts and cost sharing can be nullified if there is irrational prescribing (over-utilization, under-utilization and mis-utilization), variable patient adherence to medication regimens, ineffective formulary processes, or fraud, waste and abuse. Rising prescription drug costs and the increasing prevalence of 'high deductible health plans', which require much greater patient out-of-pocket costs, is creating a crisis for PBM efforts towards an affordable pharmacy benefit. Since PBM rebate and incentive contracts are opaque to the public, whether they add value by restraining higher drug prices or benefit from them is debatable.

An In-home Advanced Robotic System to Manage Elderly Home-care Patients' Medications: A Pilot Safety and Usability Study.

PURPOSE: We examined the safety profile and usability of an integrated advanced robotic device and telecare system to promote medication adherence for elderly home-care patients. METHODS: There were two phases. Phase I aimed to verify under controlled conditions in a single nursing home (n = 17 patients) that no robotic malfunctions would hinder the device's safe use. Phase II involved home-care patients from 3 sites (n = 27) who were on long-term medication. On-time dispensing and missed doses were recorded by the robotic system. Patients' and nurses' experiences were assessed with structured interviews. FINDINGS: The 17 nursing home patients had 457 total days using the device (Phase I; mean, 26.9 per patient). On-time sachet retrieval occurred with 97.7% of the alerts, and no medication doses were missed. At baseline, Phase II home-dwelling patients reported difficulty remembering to take their medicines (23%), and 18% missed at least 2 doses per week. Most Phase II patients (78%) lived alone. The device delivered and patients retrieved medicine sachets for 99% of the alerts. All patients and 96% of nurses reported the device was easy to use. IMPLICATIONS: This trial demonstrated the safety profile and usability of an in-home advanced robotic device and telecare system and its acceptability to patients and nurses. It supports individualized patient dosing schedules, patient-provider communications, and on-time, in-home medication delivery to promote adherence. Real time dose-by-dose monitoring and communication with providers if a dose is missed provide oversight generally not seen in home care.

Hospitalization and death associated with potentially inappropriate medication prescriptions among elderly nursing home residents.

BACKGROUND: This study examines the association of potentially inappropriate medication prescribing (PIRx) with hospitalization and death among elderly long-stay nursing home residents. METHODS: We defined PIRx using the combined version of the Beers criteria. Data were from the 1996 Medical Expenditure Panel Survey Nursing Home Component. The study sample included 3372 residents, 65 years and older, who had nursing home stays of 3 consecutive months or longer in 1996. We performed multivariate logistic regression analyses of longitudinal data using generalized estimating equations. RESULTS: Residents who received any PIRx had greater odds (odds ratio [OR], 1.27; P = .002) of being hospitalized in the following month than those receiving no PIRx. Residents with PIRx exposure for 2 consecutive months were at increased risk (OR, 1.27; P = .004) of hospitalization, as were those receiving PIRx in the second month only (OR, 1.80; P = .001), compared with those receiving no PIRx. Residents who received PIRx were at greater risk of death (OR, 1.28; P = .01) that month or the next. Residents with intermittent PIRx exposures were at greater odds of death (OR, 1.89; P<.001), compared with those with no PIRx exposure. CONCLUSIONS: The association of PIRx with subsequent adverse outcomes (hospitalization and death) provides new evidence of the importance of improving prescribing practices in the nursing home setting.

Cost and quality trends in direct contracting arrangements.

This paper presents the first empirical analysis of a 1997 initiative of the Buyers Health Care Action Group (BHCAG) known as Choice Plus. This initiative entailed direct contracts with provider-controlled delivery systems; annual care system bidding; public reports of consumer satisfaction and quality; uniform benefits; and risk-adjusted payment. After case-mix adjustment, hospital costs decreased, ambulatory care costs rose modestly, and pharmacy costs increased substantially. Process-oriented quality indicators were stable or improved. The BHCAG employer-to-provider direct contracting and consumer choice model appeared to perform reasonably well in containing costs, without measurable adverse effects on quality.

Potentially inappropriate medication prescriptions among elderly nursing home residents: their scope and associated resident and facility characteristics.

OBJECTIVE: To estimate the scope of potentially inappropriate medication prescriptions (PIRx) among elderly residents in U.S. nursing homes (NHs), and to examine associated resident and facility characteristics. DATA SOURCES: The 1996 Medical Expenditure Panel Survey Nursing Home Component (MEPS NHC), a survey of a nationally representative sample of NHs and residents. STUDY DESIGN: The PIRx, defined by Beers's consensus criteria (1991, 1997), was identified using up to a year's worth of NH prescribed medicine data for each resident. The study sample represented 1.6 million NH residents (n=3,372). RESULTS: At a minimum, 50 percent of all residents aged 65 or older, with an NH stay of three months or longer received at least one PIRx in 1996. The most common PIRx involved propoxyphene, diphenhydramine, hydroxyzine, oxybutynin, amitriptyline, cyproheptadine, iron supplements, and ranitidine. Resident factors associated with greater odds of PIRx were Medicaid coverage, no high school diploma, and nondementia mental disorders. Facility factors were more beds and lower RN-to-resident ratio. Factors associated with lower odds of PIRx were fewer medications, residents with communication problems, and being in an accredited NH. Onsite availability of pharmacists or mental health providers was not related. IMPLICATIONS: With quality of care and patient safety as major public health concerns, effective policies are needed to avoid PIRx occurrences and improve the quality of prescribing among elderly residents in NHs. Additional studies are needed to determine the impact of PIRx on this NH population.

Improved medication use in long-term care: building on the consultant pharmacist's drug regimen review.

Elderly and long-term care (LTC) patients often require complex medication regimens that increase their risk of adverse drug events or suboptimal pharmacotherapy. Currently, oversight of medication use in LTC facilities consists of a federally mandated monthly audit, the drug regimen review (DRR), performed by a consultant pharmacist, and yearly onsite government surveys. Although the DRR's purpose is to improve drug use and to avoid adverse drug events, the Centers for Medicare and Medicaid Services's (CMS) current DRR guidelines focus on a limited selection of medications and indications rather than on patient outcomes. An expanded model building on CMS's survey guidelines and the American Society of Consultant Pharmacists' Fleetwood Model is proposed to improve oversight of medication use. The proposed model includes using consultant pharmacists with demonstrated geriatric pharmacotherapy expertise, direct patient assessments by the pharmacist, increased interaction among healthcare professionals, evidence-based practices, and explicit patient outcome assessments. It is both feasible and timely: (1) the LTC prospective payment system aligns financial incentives between payers and providers; and (2) the Institute of Medicine has made quality improvement and error reduction a priority.

Current status of prospective drug utilization review.

BACKGROUND: The Omnibus Budget Reconciliation Act of 1990 offered the promise that prospective drug utilization review (pDUR) systems would improve the quality of drug prescribing and patient drug use. There is little evidence that this promise has been fulfilled. To the contrary, there is growing evidence that suboptimal use of drugs (in terms of preventable drug-related morbidity) is at least as costly as the prescription drugs themselves. Online computerized pDUR has been the subject of numerous critical examinations in the pharmacy and medical literature. Recent publications have sought to illustrate perceived shortcomings in the DUR systems currently in use. OBJECTIVE: We focus on the state of the art with regard to pDUR, what is known about its effectiveness, and how emerging technologies may change pDUR and consider the work that may be needed to establish its effectiveness. SUMMARY: A growing body of literature documents numerous problems and concerns with respect to the quality of DUR criteria, DUR alerts, and the response of health care professionals to these alerts. Problems with the current pDUR "system" can be grouped into those involving technical aspects (e.g., duplicate messaging from in-store and online systems, or message text limitations) and into those involving human aspects, specifically how pharmacists and other health care providers interpret and respond to potential drug therapy problem alerts generated by the electronic systems. CONCLUSION: DUR is a quality assurance system that holds promise as a tool that, if implemented effectively, could enhance appropriate drug use. We believe a more systematic approach to DUR is needed. Evaluation and management of public and private pDUR systems must link documentation of processes of care, such as pharmacists. cognitive services, patient interventions, etc. To address technical aspects, we strongly recommend (a) a national effort to validate DUR screen criteria relying upon evidence-based studies and (b) adoption of a minimal set of.critical. pDUR screen criteria by pharmacy service providers and third-party intermediaries, including pharmacy benefit managers. To address the human component of pDUR systems, we advocate (a) adoption of performance standards for pharmacists and (b) explicit remuneration for time spent identifying and responding to drug therapy problems.