Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.

The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.

Advances in clinical trial design: Weaving tomorrow's TB treatments.

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Induction-related cost of patients with acute myeloid leukaemia in France.

OBJECTIVE: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost. SETTING: "Induction" patient's hospital stay from admission for "induction" to discharge after induction. METHOD: The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors. MAIN OUTCOME MEASURE: Only direct medical costs were included: treatment and hospitalisation. RESULTS: Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻4). This result is robust and was confirmed by sensitivity analysis. CONCLUSION: Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML.

Capecitabine versus bolus fluorouracil plus leucovorin (folinic acid) as adjuvant chemotherapy for patients with Dukes' C colon cancer : economic evaluation in an Italian NHS setting.

BACKGROUND AND OBJECTIVE: In the recent X-ACT (Xeloda in Adjuvant Colon cancer Therapy) trial, oral capecitabine (Xeloda) demonstrated superior efficacy and an improved safety profile compared with infused fluorouracil + leucovorin (folinic acid) [FU+LV] in patients with Dukes' C colorectal cancer. We used the X-ACT results to determine the cost effectiveness of capecitabine compared with FU+LV from the perspective of the Italian National Health Service (NHS). METHODS: Medical resource use data were collected throughout the treatment period. Unit costs for drug administration, hospitalization, emergency room visits and concomitant medications were obtained using Italian published sources. A health-state transition model was used to estimate the incremental cost-effectiveness ratio per quality-adjusted life-month (QALM) gains in the intent-to-treat population (1004 and 983 patients in the capecitabine and FU+LV arms, respectively). Costs and effectiveness were discounted at 3.5%. Costs were calculated in euros (2005 values). RESULTS: Administration of capecitabine required fewer clinic visits per patient than FU+LV (7.35 vs 28.0, respectively). Mean acquisition costs per patient for capecitabine were higher than for FU+LV (euro 2533 vs euro 231, respectively), but this difference was offset by the difference in mean chemotherapy administration costs per patient for FU+LV (euro 4338, compared with euro 152 for capecitabine). Mean total hospital days and medication costs for treatment-related adverse events were higher for FU+LV than for capecitabine (euro 352 vs euro 78, respectively). The cost of emergency room visits for the treatment of adverse events did not differ between the treatment groups. With respect to the lifetime horizon, compared with FU+LV, capecitabine is projected to increase QALMs by a mean 6.5 months, with overall cost savings of euro 2234 over the treatment period. These findings show that capecitabine is an economically dominant treatment in this setting. CONCLUSIONS: Adjuvant capecitabine for patients with Dukes' C colon cancer has the same activity in terms of outcome when compared with FU+LV but is a lower cost option from the economic perspective of the Italian NHS.

Mature results from three large controlled studies with raltitrexed ('Tomudex').

Since the publication of the results of phase I dose-finding studies, an extensive phase II and III clinical study programme has been undertaken to study the clinical efficacy and tolerability of the quinazoline folate analogue raltitrexed ('Tomudex'), a novel direct and specific inhibitor of thymidylate synthase. Two international phase III trials, studies 3 and 12, have compared raltitrexed 3 mg m(-2) with 5-fluorouracil (5-FU) plus low-dose leucovorin (LV) (Mayo regimen) or high-dose LV (Machover regimen) respectively. A North American study (study 10) was originally set up to compare two raltitrexed dosage arms (3.0 and 4.0 mg m[-2]) with 5-FU and low-dose LV, but the 4.0 mg m(-2) arm was discontinued prematurely because of excessive toxicity. Minimum follow-up times for studies 3, 10 and 12 were 15.5, 12 and 9 months, respectively (for data other than survival), with corresponding survival follow-up times of 26, 12 and 17 months. Objective response rates were similar for raltitrexed and 5-FU + LV, and palliative improvements were seen to a similar extent with both treatments in all phase III studies. Survival was statistically similar for raltitrexed and 5-FU + LV in both studies 3 and 12. Raltitrexed was, however, associated with inferior survival to 5-FU + low-dose LV in study 10, but there appears to be evidence that this was linked to an unconscious effect on investigator behaviour of early toxicity problems in this trial, in that patients appeared to be withdrawn from raltitrexed treatment without progression or protocolled toxicity. Moreover, it appeared that 5-FU + LV patients were continued on treatment after disease progression. 5-FU-based therapy was associated with a higher incidence of mucositis than raltitrexed in all studies, with the attainment of statistical significance in studies 3 and 12. Elevations in hepatic transaminase levels were seen with raltitrexed, but these are thought to be of no clinical significance. Overall, much greater levels of toxicity were seen with 5-FU + LV than with raltitrexed in early treatment cycles. In addition, retrospective UK audit data have shown the monthly cost of raltitrexed therapy to be similar to that of Mayo and continuous infusion 5-FU regimens, and appreciably lower than that of the de Gramont regimen of 5-FU (bolus + 22-h infusion) + high-dose LV. Thus, raltitrexed is an effective alternative to 5-FU-based therapy in patients with advanced colorectal cancer, with an acceptable and, unlike 5-FU, predictable toxicity profile. In particular, patients receiving raltitrexed may benefit from the minimization or avoidance of mucositis, and both patients and healthcare providers may find the convenient administration schedule of the drug advantageous.