Discrepancies between multicriteria decision analysis-based ranking and intuitive ranking for pharmaceutical benefit-risk profiles in a hypothetical setting.

WHAT IS KNOWN AND OBJECTIVE: Multicriteria decision analysis (MCDA) has been generally considered a promising decision-making methodology for the assessment of drug benefit-risk profiles. There have been many discussions in both public and private sectors on its feasibility and applicability, but it has not been employed in official decision-makings. For the purpose of examining to what extent MCDA would reflect the first-hand, intuitive preference of evaluators in practical pharmaceutical assessments, we conducted a questionnaire survey involving the participation of employees of pharmaceutical companies. METHODS: Showing profiles of the efficacy and safety of four hypothetical drugs, each respondent was asked to rank them following the standard MCDA process and then to rank them intuitively (i.e. without applying any analytical framework). RESULTS AND DISCUSSION: These two approaches resulted in substantially different ranking patterns from the same individuals, and the concordance rate was surprisingly low (17%). Although many respondents intuitively showed a preference for mild, balanced risk-benefit profiles over profiles with a conspicuous advantage in either risk or benefit, the ranking orders based on MCDA scores did not reflect the intuitive preference. WHAT IS NEW AND CONCLUSION: Observed discrepancies between the rankings seemed to be primarily attributed to the structural characteristics of MCDA, which assumes that evaluation on each benefit and risk component should have monotonic impact on final scores. It would be difficult for MCDA to reflect commonly observed non-monotonic preferences for risk and benefit profiles. Possible drawbacks of MCDA should be further investigated prior to the real-world application of its benefit-risk assessment.

Assessment of factors associated with dose differences between Japan and the United States.

Although it is well known that there are differences in approved doses between Japan and the United States, there has been no comprehensive research into the causes thereof. This study furthers the discussion of our previous investigation in 2010, with particular focus on pharmaceutical industry strategy and regulatory policy, among drugs approved in Japan between 2001 and 2009. Dose differences were observed in 73 of 190 drugs. Non-Japanese firms were more likely to have a similar dose approved between Japan and the United States, the association being more pronounced when limiting the analysis to drugs for which a Japanese dose-finding study was not conducted. Furthermore, dose differences were less frequent when non-Japanese efficacy data were included in the application data package. No relation between potential intrinsic ethnic difference and dose difference could be identified. The results suggest that the pathway of drug development is more strongly associated with dose difference than are drug characteristics.

Analysis of regulatory review times of new drugs in Japan: association with characteristics of new drug applications, regulatory agency, and pharmaceutical companies.

WHAT IS KNOWN AND OBJECTIVE: Various factors have been reported to be associated with the duration of regulatory review of new drug applications (NDAs). We investigated potential links between the review times in Japan and the attributes of NDAs, the regulatory agency and pharmaceutical companies. METHODS: We analysed new drugs approved in 2000-2009 in Japan using a proprietary database collected through annual surveys to pharmaceutical companies. Regression models in which individual firms were treated as either a fixed effect or a random effect were applied to examine factors associated with the overall review time and the duration of each step of the review. RESULTS AND DISCUSSION: The fixed effect model analysis using variations within each firm indicated that new molecular entities that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA), priority reviews and pre-NDA consultations were associated with a shorter overall review time, whereas additional studies during the review resulted in a longer review. In the random effect model analysis using both within- and between-firm variations, use of end-of-phase 2 consultations and foreign clinical data also had negative coefficients, suggesting the effect of these two vary among firms. Analysis of each step of the review process revealed NDAs reviewed by the Committee on Drugs under the Ministry of Health, Labour and Welfare, and the number of NDAs assigned to a review team were significantly linked with their duration, whereas consultation services and the number of reviewers had no relation. WHAT IS NEW AND CONCLUSION: Factors associated with each step of the review process as well as the differences in attributes and strategies among pharmaceutical companies should be considered to further improve the speed, quality and efficiency of the regulatory review.

Analysis of labeling decisions regarding therapeutic indications during new drug application reviews in Japan.

We analyzed regulatory reviews in Japan to study the modifications made in drug labeling with respect to proposed therapeutic indications, and investigated factors associated with these changes so as to gain insight into the reasons behind the decisions. Of 220 new molecular entities (NMEs) approved in Japan from 2000 to 2009, 70 received more restricted indications and 14 received more expanded indications than those proposed by the applicants. Multinomial regression analysis suggested that the presence of competitive drugs in the market, higher estimated peak sales, and higher complexity of the proposed indication were factors that significantly increased the likelihood of the indications being restricted on review, in addition to factors related to adequacy of efficacy data. Our results give us a clue to how the approved therapeutic indications reflect the characteristics of the applicants, drugs, review areas (RAs), and clinical evidence in the submitted data package, as well as to the principle behind the decisions.

Clinical development and review times for new drugs in Japan: associated factors.

The length of clinical development and review procedures related to new drugs approved in Japan in 2000-2009 were analyzed. The length of time taken for clinical development varied depending on diversification of strategies, and the review times showed a decline during this period. Regression analyses suggested that clinical development times were significantly shorter for non-new molecular entities (non-NMEs), priority reviews, conditional approvals, and drugs utilizing foreign clinical data. The review times were shorter for new drug applications (NDAs) submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) and for priority reviews. The effects of pre-NDA consultations were mixed; the review time was shorter, but the clinical development period was prolonged.

Delays in new drug applications in Japan and industrial R&D strategies.

The gap between Japan and both the United States (US) and the European Union (EU) with regard to access to new drugs is becoming a major issue in Japan. We analyzed the time lags involved in new drug application (NDA) and biological license application submissions in Japan, the US, and the EU in order to identify the causes of delayed access. The time lag related to submission of applications ("submission lag") was longer for in-licensed products and for non-Japanese companies. Factors related to costs of clinical studies and potential volumes of sales were not associated with the submission lag. A bridging strategy (extrapolative use of foreign clinical data in the clinical data package based on International Conference on Harmonisation guideline E5) seemed to reduce submission lag, but the association between the two diminished when the cause-and-effect relationship was specifically investigated. These results suggest that multinational companies are likely to place more emphasis on the choice of development strategies that successfully lead to their goal rather than on direct costs and expected sales when deciding to introduce their pharmaceutical products in Japan. Our findings indicate that the clinical development guidances that helps pharmaceutical companies decide on investment and strategies are also the key to narrowing the gap in access to new drugs.

Clinical trials and the new good clinical practice guideline in Japan. An economic perspective.

Japanese clinical trials have been drastically changing in response to the implementation of the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guideline in 1997. The most important aim of the new guideline is to standardise the quality of clinical trials in the US, European Union and Japan, but it inevitably imposes substantial costs on investigators, sponsors and even patients in Japan. The study environment in Japan differs from that in the US in several ways: (i) historical lack of a formal requirement for informed consent; (ii) patients' attitudes to clinical trials in terms of expectation of positive outcomes; (iii) the implications of universal health insurance for trial participation; (iv) the historical absence of on-site monitoring by the sponsor, with the attendant effects on study quality; and (v) the lack of adequate financial and personnel support for the conduct of trials. Implementation of the new GCP guideline will improve the ethical and scientific quality of trials conducted in Japan. It may also lead to an improved relationship between medical professionals and patients if the requirement for explicit informed consent in clinical trials leads to the provision of a similar level of patient information in routine care and changes the traditional paternalistic attitude of physicians to patients. The initial response of the Japanese 'market' for clinical trials to the implementation of the ICH-GCP guideline has been clinical trial price increases and a decrease in the number of study contracts. These changes can be explained by applying a simple demand-supply scheme. Whether clinical trials undertaken in Japan become more or less attractive to the industry in the long term will depend on other factors such as international regulations on the acceptability of foreign clinical trials and the reform of domestic healthcare policies.

[Assessment of systematic nodal dissection by VATS lobectomy for lung cancer].

The feasibility of the complete systematic nodal dissection by the video-assisted thoracic surgery was prospectively assessed in 22 cases of clinical stage I lung cancer (16 right, 6 left cases). Resection of the designated lobe with the mediastinal lymph node dissection was carried out by the small thoracotomy with the aid of the thoracoscope, followed by the standard surgery to verify the completeness of systematic nodal dissection. Although residual lymph nodes were found in 14 of 22 cases, the residual rate was 2.9% and 2.7% by the number and 2.3% and 2.1% by the weight in right and left cases, respectively. Average time and hemorrhage for performing the procedure were 196 minutes, 216.7 minutes and 157.5 g, 145 g in right and left cases, respectively. As a consequence, sufficient systematic nodal dissection in lung cancer was suggested to be feasible by VATS lobectomy.

Assessment by transesophageal echography of atherosclerosis of the descending thoracic aorta in patients with hypercholesterolemia.

This study assesses atheromatous lesions and aortic stiffness of the descending thoracic aorta (DTA) in patients with hyperlipidemia by transesophageal echography (TEE) and investigates the relations between atherosclerotic lesions and aging or serum cholesterol levels in these patients. Subjects included 16 patients with familial hypercholesterolemia (FH), 15 non-FH hyperlipidemic patients (non-FH), and 17 age-matched normal subjects. With use of TEE, the DTA was divided into 4 longitudinal portions of equal length, and the atheromatous lesions of each portion of DTA were scored according to their character and extension by biplane 2-dimensional TEE. The scores of atheromatous lesions from all 4 portions were added together to give the total atheromatous score. Then, after measuring the instantaneous dimensional changes of DTA in a cardiac cycle by M-mode TEE and blood pressure (BP) by a cuff method, we calculated the aortic stiffness parameter beta = ln(systolic BP/diastolic BP)/([Dmaximum - Dminimum]/Dminimum). The beta was significantly higher in FH and non-FH subjects than in normal subjects. In both FH and non-FH subjects, the total atheromatous score correlated with total serum cholesterol levels (r = 0.64 [p <0.01]; r = 0.58 [p <0.05], respectively). There were significant correlations between age and beta in all 3 groups (FH, r = 0.67 [p <0.005]; non-FH, r = 0.53 [p <0.05]; normal subjects, r = 0.49 [p <0.05]), and the slopes of the regression lines of FH and non-FH subjects were much steeper than those of normal subjects. The incidence of atherosis in the DTA was significantly higher in hyperlipidemic patients than in normal subjects, even among the younger members of the hyperlipidemic population with progressive aortic stiffness.

The influence of coronary collateral flow on the assessment of myocardial perfusion by videodensitometry.

OBJECTIVES: Coronary collateral flow often mitigates the effects of coronary artery obstruction and has a significant impact on the prognosis of patients with coronary artery disease. In the presence of variable degrees of coronary collateral flow, digital radiographic assessment of myocardial blood flow has not been quantitatively validated. METHODS: A distal coronary arterial collateral path was created into the left anterior descending coronary artery (LAD) bed in 8 anesthetized pigs. Both LAD and collateral paths were pump-perfused and corresponding flows measured. A number of commonly used digital indices and parametric images of myocardial perfusion were then extracted from the sequence of images filmed before and during the injection of contrast. Data were acquired at 5 levels of total flow (LAD flow + collateral flow): 100, 85, 70, 55 and 40% of maximally vasodilated, baseline flow. At each level of total flow, data were acquired at 4 levels of collateral flow ratios (collateral flow/total flow): 0, 10, 25 and 50%. RESULTS: Regional percent segment shortening, reflecting myocardial blood flow, decreased as total flow fell, and remained unaltered when coronary collateral ratio alone was altered without change in total flow. On the other hand, linear regression between total flow and digital indices at 10, 25 and 50% coronary collateral flow ratios, compared with 0%, showed a successive and significant downward displacement, documenting an underestimation of flow by all digital indices in the presence of collateral flow. CONCLUSIONS: In the absence of a collateral pathway and during maximal coronary vasodilation with adenosine, digital radiographic indices of myocardial perfusion, based upon indicator dilution theory, show a relatively good correlation with regional transmural myocardial blood flow. However, due to underestimation of total transmural blood flow, these indices have limited utility when myocardial perfusion is provided in part by a collateral pathway. The effect is probably related to an alteration in the regional vascular volume into which iodinated contrast is injected.

In vivo assessment of left ventricular remodelling after myocardial infarction by digital video contrast angiography in the rat.

OBJECTIVE: The aim was to develop a digital video contrast angiographic method for assessing global left ventricular function and volume in vivo in the rat and then to apply it to a study of ventricular remodelling after coronary occlusion, with and without reperfusion. METHODS: Digital contrast angiography was performed on 29 rats, including the following groups: sham operated (n = 11), non-transmural myocardial infarction produced by reperfusion (n = 8), and transmural infarction produced by permanent occlusion (n = 10). Under anaesthesia three weeks later, biplane fluoroscopic images were acquired following venous contrast injection. Levophase images were digitised, and left ventricular end diastolic and end systolic volumes and ejection fractions were obtained using an area-length method. Left ventricular ejection fraction data also were calculated by videodensitometry from video density curves. RESULTS: Compared to the sham operated group, the reperfused group showed a significant decrease in left ventricular ejection fraction, at 53(SD 7) v 70(5)% (p < 0.01), and an increase in end diastolic volume. The permanent occlusion group showed a further decrease in the ejection fraction [40(8)%] and a further significant increase in end diastolic volume compared to the reperfused group (p < 0.01). Left ventricular ejection fraction correlated inversely with percent infarct size (r = 0.882) and showed a positive correlation with the spared epicardial area (r = 0.721). Most haemodynamic variables, including maximum left ventricular dP/dt, failed to discriminate between the groups. The methods showed reasonable accuracy when tested in vitro using contrast filled balloons. In vivo, the left ventricular ejection fraction calculated by densitometry showed adequate interobserver variability (2 SD +/- 8.5 percentage points), but the area-length method showed somewhat more scatter. CONCLUSIONS: Digital video contrast angiography is a feasible method for the assessing global left ventricular function in the rat and should be useful in other small animal models. Significant differences in left ventricular volumes and ejection fractions were detected between reperfused and permanent occlusion groups, whereas haemodynamic variables showed non-significant trends. Reperfusion after 45 min of occlusion caused sparing of the epicardium, prevented unfavourable remodelling, and improved the ejection fraction compared to permanent occlusion.

[Assessment of myocardial metabolic reserve with positron emission tomography and C-11 acetate].

Positron emission tomography (PET) with C-11 acetate allows noninvasive quantification of myocardial oxidative metabolism. To assess the myocardial metabolic reserve, clearance of C-11 acetate from the myocardium was measured with PET in 8 normal subjects at rest and during the infusion of dobutamine (inotropic agent) or dipyridamole (vasodilator). During dobutamine infusion, the clearance rate constant of C-11 acetate increased significantly (0.063 +/- 0.014 vs 0.109 +/- 0.016, p < 0.002) in good correlation with the rate-pressure product (r = 0.83). During dipyridamole infusion, myocardial acetate clearance also significantly increased (0.088 +/- 0.024, p < 0.05) in correlation with the rate-pressure product (r = 0.54). In normal myocardium, myocardial oxidative metabolism increased in response to increased work load with pharmacological stress. These findings suggest that PET with C-11 acetate and pharmacological stress may be a promising approach for the evaluation of metabolic reserve in patients with ischemic heart disease.

[Assessment of atherosclerotic lesions and distensibility of the thoracic aorta in familial hypercholesterolemia by biplane transesophageal echocardiography].

Atherosclerosis involving the thoracic aorta frequently occurs in patients with familial hypercholesterolemia (FH). In this study, we employed two-dimensional (2-D) transesophageal echocardiography (TEE: 5 MHz) to assess atherosclerotic lesions of the thoracic aorta in 9 patients with FH (47.8 +/- 10.3 yrs) and 11 age-matched normal control subjects. Biplane TEE probe (i.e., transverse or sagittal scan transducer) was used to permit direct imaging of the distal half of the ascending aorta. The atherosclerotic lesions were classified based on the severity of the aortic wall sclerosis as intimal thickening (I.), atheromatous plaque, (II.) and calcification (III.). In all of the patients with FH, atherosclerotic lesions of grade I. or greater were observed particularly in the aortic arch and descending aorta, while, lesions more severe than grade I. in the thoracic aorta were not observed in any of the control subjects. In 6 FH patients (67%), atherosclerotic lesions more severe than grade II. were frequently observed, which were more frequent in the aortic arch and descending aorta than in the ascending aorta.

[Assessment of resting thallium-201 reinjection after stress-delayed Tl imaging (I): Comparison with 24-hour scan and regional wall motion].

Clinical value of resting reinjection of 1 mCi (37 MBq) of Tl after stress-delayed scan was assessed in comparison with 24 hr delayed scan and regional wall motion (RWM) in 37 patients with coronary artery disease. Of 101 segments with initial perfusion abnormality, concordant findings were observed after Tl reinjection in 67 segments (66%). But redistribution (RD) after Tl reinjection was observed in 19 of the 52 persistent defect (PD) segments (37%), and complete RD was observed 15 of the 43 segments (35%) where 3 hr scan showed incomplete RD. On the other hand, concordant findings were observed on 24 hr delayed scan in 11 of the 20 segments with perfusion abnormality (55%). RD on 24 hr delayed scan was observed in 5 of the 13 PD (38%), but it was not apparent in 3 of the 7 segments where 3 hr scan showed RD. Furthermore the segments which showed RD after Tl reinjection in PD segments tend to have less severe RWM abnormality than the sustained PD segments (RWM score: 1.65 +/- 1.17 vs. 2.29 +/- 1.05, p less than 0.05). These data indicate that Tl reinjection which permits assessment of RD with good quality images on the same day is considered as a valuable means for assessing myocardial viability.

[Assessment of bone scintigraphy showing markedly increased accumulation in mandibular lesion of cementifying fibroma].

This report concerns two cases of cementifying fibroma showing markedly accumulation of 99mTc -MDP in mandibular lesions. The bone scintigraphic and histopathological findings are presented and discussed.