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In the early 1990s Lilly Sananthan and Carl Peck had published a paper titled
"The Randomized Concentration-Controlled Trial: An Evaluation of Its Sample
Size Efficiency". I recollect the concept of RCCT being formally proposed by
Dr Peck at a number of scientific meetings. I also recollect signficant
discussions between Drs Gerhardt Levy and Carl Peck about the utility of RCCT
in drug development. Have you have had the experience of conducting a RCCT
trial in a Phase 2 or 3 setting treating extremely ill patients? Was the RCCT
study done as a Phase 2 proof of concept study or was it done as a Phase 3
safety and efficacy study? It would be interesting to know whether such a
trial was compared to a randomized, dose-controlled trial (RDCT). I am
interested in the logistical aspects of conducting such a trial in a Phase 2 or
3 setting. Can this really be conducted in several hundred patients in a
multi-center (50 to 100 centers) setting? More importanly, I would like to
hear about labeling for dosing with a Phase 3 RCCT. Since the doses are
adjusted based on concentrations, technically, lots of different doses are
administered during the Phase 3 trial. Therefore, the sponsor does not getting
experience of safety and efficacy after a fixed dose of a formulation that
would be marketted. At the end of a RCCT trial, it is theoretically possible
to show efficacy with fewer patients than with a RDCT. However, since a fixed
dose is not administered, would the sponsoring company be stuck with a label
that indicates dosing to achieve a specific blood/plasma concentration-time
profile instead of a fixed dose even if it is appropriate?
All comments and thoughts are welcome.
Chetan D. Lathia
Bayer Corporation
400 Morgan Lane
West Haven, CT 06516
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Dear Chetan,
I have not personally been involved in RCCT but have been involved in=20
the design
of what is called randomised effect controlled trials (RECT). The RCCT has a
number of logistic problems as well as scientific problems. One of the basic
assumptions in the RCCT is the notion that PK variability is significantly
larger than PD variability (that's partly the reason why you do=20
RCCT)). However,
there is increasing hard evidence that PD variability is as great (if even
greater) than PK variability. As you mention, Gerhard Levy has pointed this =
out
in a number of papers. Before engaging yourself in a RCCT, I strongly recomm=
end
you to read a scientific commentary G. Levy wrote in CPT (Concentration-or
effect-controlled clinical trials with sparse data - Clin Pharm Ther 56 (1);
1-8, 1994). Another important paper dealing with implications of=20
pharmacodynamic
variability is:
Levy G. Predicting effective drug concentrations for individual patients;
Determinants of pharmacodynamic variability.
Clin Pharmacokinet 34(4), 323-333, 1998.
I hope these comments will guide you to a rational approach to your problems
Best regards
Anders Grahn=E9n
Anders Grahnen, Ph.D.
Assoc. Professor
Vice-President R&D
Quintiles Scandinavia
Islandsgatan 2
753 18 UPPSALA
SWEDEN
Phone +46 18 680100
Fax +46 18 680150
Email: agrahnen.at.qupp.quintiles.com
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)