Limits...
The effect size, study design, and development experience in commercially sponsored studies for new drug applications in approved drugs.

Fukunaga S, Kusama M, Ono S - Springerplus (2014)

Bottom Line: We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis.A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials.In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.

ABSTRACT
Pharmaceutical companies incorporate different features into the trials for new drug applications (NDAs) to render them efficient, making use of their experience. The objective of this analysis was to examine the associations between outcome and features related to study design and clinical development experience in commercially sponsored clinical trials. We collected data of phase 2 and phase 3 trials of all the drugs that obtained approval for depression, schizophrenia, asthma, hypertension, and diabetes in Japan from 1970 to 2011. In total, 145 trials from 90 test drugs were eligible for our study. We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis. A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials. The analysis showed that trial features including sample size, subjective endpoints and active comparator of the same mode of action were negatively associated with effect size. In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not. The accumulation of skills and knowledge within sponsors, and accumulated experience in domestic professionals who implement clinical trials under study contracts with sponsors would be of great importance for yielding clear outcomes. This study provides additional evidence with respect to possible sizes and directions of the influence of study design features that must be considered when planning and implementing trials for new drug applications, and when retrospectively comparing outcomes from trials with different designs and environments.

No MeSH data available.


Related in: MedlinePlus

Changes in the sample size by approval year.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4320132&req=5

Fig2: Changes in the sample size by approval year.

Mentions: Among the variables related to study design, a negative correlation was found between the sample size and the effect size. No consistent correlations have been reported in other studies (Khan et al.2004; Papakostas and Fava2009; Yildiz et al.2011a), and no persuasive explanation was apparent for these associations. One plausible explanation for our result is that in our research targeting only approved drugs, most drug companies successfully achieved p values of approximately the same level (i.e., close to 0.05 or less) in clinical trials, which could lead to an inverse relationship between the effect size and the sample size. This is likely to reflect the statistical equation, T = f (N) * g (ES) (see Methods), but it is difficult in this model to distinguish this spurious association from substantial (i.e., causal) relationship of interest, if any. It is interesting to note that the negative association was observed even when recent increases in sample size were controlled by the time-trend variable “approval year” in Model 1. As Figure 2 shows, the sample size was larger in more recent trials in our dataset (r = 0.49), and similar trends have been observed in trials submitted to the US Food and Drug Administration (Khin et al.2011).Figure 2


The effect size, study design, and development experience in commercially sponsored studies for new drug applications in approved drugs.

Fukunaga S, Kusama M, Ono S - Springerplus (2014)

Changes in the sample size by approval year.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4320132&req=5

Fig2: Changes in the sample size by approval year.
Mentions: Among the variables related to study design, a negative correlation was found between the sample size and the effect size. No consistent correlations have been reported in other studies (Khan et al.2004; Papakostas and Fava2009; Yildiz et al.2011a), and no persuasive explanation was apparent for these associations. One plausible explanation for our result is that in our research targeting only approved drugs, most drug companies successfully achieved p values of approximately the same level (i.e., close to 0.05 or less) in clinical trials, which could lead to an inverse relationship between the effect size and the sample size. This is likely to reflect the statistical equation, T = f (N) * g (ES) (see Methods), but it is difficult in this model to distinguish this spurious association from substantial (i.e., causal) relationship of interest, if any. It is interesting to note that the negative association was observed even when recent increases in sample size were controlled by the time-trend variable “approval year” in Model 1. As Figure 2 shows, the sample size was larger in more recent trials in our dataset (r = 0.49), and similar trends have been observed in trials submitted to the US Food and Drug Administration (Khin et al.2011).Figure 2

Bottom Line: We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis.A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials.In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.

ABSTRACT
Pharmaceutical companies incorporate different features into the trials for new drug applications (NDAs) to render them efficient, making use of their experience. The objective of this analysis was to examine the associations between outcome and features related to study design and clinical development experience in commercially sponsored clinical trials. We collected data of phase 2 and phase 3 trials of all the drugs that obtained approval for depression, schizophrenia, asthma, hypertension, and diabetes in Japan from 1970 to 2011. In total, 145 trials from 90 test drugs were eligible for our study. We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis. A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials. The analysis showed that trial features including sample size, subjective endpoints and active comparator of the same mode of action were negatively associated with effect size. In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not. The accumulation of skills and knowledge within sponsors, and accumulated experience in domestic professionals who implement clinical trials under study contracts with sponsors would be of great importance for yielding clear outcomes. This study provides additional evidence with respect to possible sizes and directions of the influence of study design features that must be considered when planning and implementing trials for new drug applications, and when retrospectively comparing outcomes from trials with different designs and environments.

No MeSH data available.


Related in: MedlinePlus