The validity of biomarkers as surrogate endpoints in Alzheimer's disease by means of the Quantitative Surrogate Validation Level of Evidence Scheme (QSVLES).

OBJECTIVE: To evaluate the validity of biomarkers that are currently being proposed as potential surrogate endpoints in AD clinical trials with the aid of the "Quantitative Surrogate Validation Level of Evidence Schema" (QSVLES) proposed by Lassere et.al. (1). PROCEDURE: A Pubmed literature search was conducted to identify AD biomarkers with SEP potential, and the QSVLES was applied to determine the extent of the SEP validity. RESULTS: MRI, PET and MRS measures attained a total validity score of 4, NAA/Cre a total score of 5, and cerebral blood flow (SPECT), Abeta , Tau and APP a total score of 2. None of these biomarkers could fall into the rank of Levels 1 or 2, reserved for SEPs, according to the QSVLES criteria. This was mainly attributed to the lack of sufficient evidence that was derived from high ranking studies (RCT, prospective observational studies). CONCLUSION: Though residing on SEPs as sole determinants of the benefit/risk ratio of AD medications seems to be pretty far, there could be certain cases where the use of SEPs may be beneficial, making efficient therapies available faster when there is a major public health interest involved. However, the potential risks of relying on invalid SEPs should not be underestimated and therefore the research on SEP validation and the development of specific validation guidance should be encouraged. The QSVLES, though not devoid of criticism, may be proposed as a starting point.

The prognostic influence of neuroendocrine differentiation in breast cancer: results of a long-term follow-up study.

Reports about neuroendocrine (NE) differentiation in breast carcinomas and its possible relation with prognosis are scarce. Furthermore the results of some studies have not been subjected to multivariate survival analysis and the follow-up periods were relatively short. Therefore, in the present long-term follow-up study, the prognostic influence of immunohistochemically defined NE cells, present in the tumours of 40 out of 317 (12.6%) curatively operated breast cancer patients, was studied. The mean follow-up period was 104 months. NE differentiation (NED) was determined by the immunohistochemical detection of chromogranin A and/or synaptophysin. This is concordant with other studies focussing on NED in breast cancer. In contrast to the literature in our series only in 9 out of 40 cases (23%) we were able to detect coexpression of chromogranin A and synaptophysin. This might be due to the characteristics of the antibodies we used. Although most tumours in our series were of the usual type, some tumours with NED were of a special type. Neither univariately, nor taking account of various known prognostic factors, does focal NED appear to carry a special prognostic significance. This finding is in line with results of previous studies.

Natural course and placebo response in short-term, placebo-controlled studies in major depression: a meta-analysis of published and non-published studies.

BACKGROUND: This study was conducted to investigate the role of natural course of a major depressive episode in short-term, placebo-controlled studies. METHODS: We analyzed for sustained response all placebo arms and tricyclic arms from all randomized three-arm studies that were conducted in patients with a major depressive episode and were submitted to the Medicine Evaluation Board (1979-1991). The Medicine Evaluation Board is the regulatory authority of the Netherlands. A responder was defined as a patient with at least 50% improvement on the Hamilton Depression Rating Scale as compared to baseline score. A study responder was defined as a patient meeting response criteria at endpoint (Last Observation Carried Forward). A sustained responder was defined as a patient who, after becoming responder, remained a responder until the end of the study. RESULTS: The ITT population incorporated 1989 patients in the tricyclic arm and 2042 patients in the placebo arm. There was a statistically significant difference for study responders: 39.3% in the tricyclic treatment group and 27.9% in the placebo group (difference 11.4; CI (95%): 8.5% 14.3%). However, no significant differences in sustained response patterns were found, with the exception of a significantly higher sustained response rate for initial responders at week 4. CONCLUSIONS: While efficacy of tricyclic antidepressants was confirmed in this meta-analysis, the sustained response patterns of active treatment and placebo did not differ substantially, suggesting that many of the patients included in the studies were close to, or at the end of, their episode.

Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study.

The original data from the placebo-arms and the tricyclic-arms of all parallel randomized controlled three-arm studies, which had been conducted in the period 1979-1991 for a drug under development in order to obtain marketing authorization for the indication major depression, were included in a meta-analysis. Thirty-two placebo-controlled studies including 4314 patients were analyzed. The intention to treat analysis resulted in 46% responders (at least 50% improvement on the Hamilton Depression Rating Scale) in the tricyclic antidepressant group and 31% in the placebo-group (CI(95%-difference) 11.5-17.1%). The number needed to treat for responders was 7 (CI(95%) 5-8). In 10 out of 32 studies, a statistically significant difference in favor of tricyclic antidepressant compared to placebo was found for responders. The responder rate in the placebo-group varied from 6 to 52%. We conclude that tricyclic antidepressants are efficacious in the short-term treatment of major depression. However, the magnitude of the effect is rather modest. Because 69% of the placebo-controlled studies with a tricyclic antidepressant did not show a statistically significant difference in favor of tricyclic antidepressant and the placebo rate varied considerably from study to study, equivalence studies with tricyclic antidepressant as comparator without a placebo-control are not sufficient for demonstrating efficacy. Therefore in major depression, placebo-controlled studies are still necessary to demonstrate efficacy.

Schizophrenia: do we really need placebo-controlled studies?

OBJECTIVE: To investigate whether placebo control is necessary to prove efficacy in short-term studies in schizophrenia. DESIGN: This study compares the efficacy results of placebo-controlled studies versus positive controlled studies, that is controlled studies without a placebo control, in the short-term treatment of chronic schizophrenia. RESULTS: Concerning mean improvement on the BPRS, the placebo arms showed in two cases a worsening, in one case almost no change, and in the remaining studies (6) the improvement was between 1 and 5%. The percentage mean improvement in the haloperidol arms of the placebo-controlled studies was comparable to the percentage mean improvement in the corresponding arms of the non-placebo-controlled studies. The highest percentage responders in the placebo-groups was 43% and the lowest was 6%. Moreover the responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, in the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. The overall dropout rates in the placebo arms was between 48% and 80% and were higher than the drop out rates in the atypical neuroleptic arms and haloperidol arms of the placebo-controlled studies. The dropout rates due to an insufficient response in the atypical neuroleptic arms and haloperidol arms of the non-placebo-controlled studies were lower when compared to corresponding treatment arms of the placebo-controlled studies. CONCLUSION: In contrast to the mean improvement on the BPRS, responder rates in the placebo arms varied considerably from study to study. Responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, of the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. These results indicate that placebo control is necessary. Moreover as responders are a more clinically relevant outcome measure when compared to mean improvement on a rating scale, placebo-controlled studies are still needed. However, consensus on responder definition should be agreed upon. For the moment, alternatives to placebo-controlled studies are inadequate in demonstrating efficacy in studies with schizophrenic patients.

Regional cues and visual discrimination in the rabbit.

Rabbits were trained to discriminate patterns consisting of straight bars and rows of dots of different orientation. It was found that using proximal pattern presentation, at a distance of 5 cm in front of the animal, dot rows of different orientation are not discriminated on the basis of tilt extrapolation, but by the use of regional cues.

Binocular and monocular tiltdiscrimination in the rabbit: evidence for hemispheric dominance?

Twenty eight rabbits were trained to discriminate striated patterns of different orientation, first binocularly, than with each eye separately. There was no evidence of systematic dominance of either the left or the right hemisphere.