Clinical studies design

Gieschke R, Reigner BG, Steimer JL. Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling. Int J Clin Pharmacol Ther 1997 35 469-74. 

Development of a Compound Outside the Basic Clinical Study Design, under What Circumstances Would the Results of a Pharmacogenetic Analysis Warrant Reporting to a Regulatory Agency ... 

In view of the multiplicity of CYPs and the many possible botanical-drug interactions, highly efficient clinical study designs using CYP probe cocktails have been explored. Following successful application to St. John s wort, other botanicals that have been evaluated in this fashion include echinacea (42), saw palmetto (43), garlic (39), peppermint oil, and ascorbyl palmitate (44). The results are summarized in Table 1. Curbicin, a botanical... 

Barrett JS Bioavailability and bioequivalence studies. In Bonate PL, Howard DR (Eds.), Pharmacokinetics in Drug Development Clinical Study Design and Analysis, Volume 1. AAPS Press, Arlington,VA (2004). 

Donahue, R.M.J. and Ruberg, S.J., 1997, Standardizing clinical study designs for accelerating drug development, Drug Information Journal, 31 655-663. 

Gieschke, R. Reigner, B.G. Steimer, J.L. Explore clinical study design by computer simulation based on pharmacoki-netic/pharmacodynamic modeling. Int. J. Pharmacol. Ther. 1997, 55, 469-474. 

P. R. Bonate and D. R. Howard, Pharmacokinetics in Drug Development, Volume 1 Clinical Study Design and Analysis. AAPS Press, New York, 2004. 

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

Describe and explain the overall clinical development plan for a drug candidate and include critical clinical study design decisions. 

Often a device company will work closely with CDRH staff to develop and submit a combination device drug product, only to find out during the application review that upon consultation by the CDRH reviewer with CDER, new issues are brought up that could have been incorporated into the clinical study design. This points out the importance of early communication with all involved parties at FDA during product development. Assuring that representatives from both Review Divisions are present at FDA sponsor meetings allows for identification and discussion of issues early in the process. 

To illustrate how these algorithms may differ in their estimates, a simple simulation was conducted. A total of 100 subjects were simulated under a Phase 2 clinical study design where 1/3 of the subjects had two samples collected, 1/3 had four samples collected, and 1/3 had six samples collected. If subjects were assigned to have two samples collected, samples were collected randomly from the time intervals (0 6 h) and (6 24 h). If subjects were assigned to have four samples collected, samples were collected randomly from the time intervals (0-2 h), (2-4 h), (4—10 h), and (10-24 h). If subjects were assigned to have six samples collected, samples were collected randomly from the time intervals (0-2 h), (2-4 h), (4-6 h), (6-10 h), (10-16 h), and (16-24 h). The sample time windows were arbitrarily chosen to cover the entire concentration time profile and to capture the absorption and elimination phases. 

Mahmood, I. Interspecies pharmacokinetic scaling Principles, applications, and limitations. In Pharmacokinetics in drug development Clinical study design and analysis. (Bonate, P.L., and Howard, D., Eds.). AAPS Press, Alexandria, VA, 2004, pp. 423-444. 

Clinical studies designed to prove this hypothesis should be focused on clinical outcome (incidence of infectious and allergic symptoms) and biomarkers representing the status of the immune system. 

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