PHARMACEUTICAL STATISTICS

Pharmaceut. Statist. 2006; 5: 83–84

Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pst.224

Guest Editorial

Adaptive Design: A Concept Whose Time has Come

A major problem facing the pharmaceuticalindustry at the moment is the high failure rate ofPhase III trials. With failure rates of 45% onaverage, and well over 50% in some areas [1],radical change is needed if the situation is toimprove. A Phase III trial should be confirmatory:it is not the place to discover that the chosen doseor dosing regimen is not as efficacious as expected.

Selection of the most appropriate dose is theobjective of Phase II, which is the learning phase.If the dose is wrong in Phase III, it is because notenough was learned or done in Phase II. Of course,the root cause of the problem may lie much earlierin the development pipeline. However, increasingthe knowledge gained during Phase II will make asignificant contribution to lowering Phase IIIfailure rates.

It is not only the pharmaceutical industry that isconcerned with the reduction in the number ofeffective drugs reaching patients: the regulatoryagencies are concerned too. The FDA’s [2]‘Critical Path’ document draws attention to the‘. . . slowdown in new medical products reachingpatients in recent years despite growing public andprivate investment in R&D’ and that better’biomedical ideas alone are not enough’. The EU’s[3] ‘Innovative Medicines Initiative’ also highlightsthe high attrition rates in drug development andthe need for changes that will ‘encompass thewhole path from discovery . . . to approval’.

How can statisticians make a contribution tolowering attrition rates? Probably in many ways,but certainly by improving the way Phase II trials

are designed and analyzed. Here, perhaps, iswhere the effective use of adaptive designs willhave greatest impact. Stopping a trial early forfutility releases research funds for other projectsthat may have more chance of success. Samplesize re-estimation at an interim analysis mayreveal a trial is underpowered and remedial stepscan be taken. In Phase II adding and/or droppingdoses as the trial progresses may increase thechance that effective doses are taken into furtherdevelopment. Increased application of Bayesianmethods may make more use of the (usually)large amount of prior information that is availablewhen trials are planned as well as allowingthe formal combination of emerging data withprior knowledge. Where appropriate, combi-ning Phase II and Phase III trials into a single‘seamless’ trial may lead to a more efficient use ofresources.

So, it seems, the time is right for the (greater) useof adaptive designs. The industry and the regula-tors have thrown down the challenge and patientsare waiting for effective and safe medicines. It iswith this in mind that we have devoted this issue ofPharmaceutical Statistics to the topic of AdaptiveDesign. The authors come from the pharmaceu-tical industry, the FDA and academia and havewritten papers on a wide range of related topics.The statistical literature on Adaptive Design isalready large and is still growing. If you are new tothe topic, we hope the papers here will whet yourappetite and you will want to learn more. If youare already familiar with the current literature, wehope you find this issue of PharmaceuticalStatistics a welcome addition.

Copyright # 2006 John Wiley & Sons, Ltd.

REFERENCES

1. Kola I, Landis J. Can the pharmaceutical industryreduce attrition rates? Nature Reviews DrugDiscovery 2004; 3:711–715.

2. FDA. Innovation and stagnation: challenge andopportunity on the critical path to new medicalproducts. FDA White Paper. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html, 2004.

3. EFPIA. Innovative medicines for Europe. EuropeanFederation of Pharmaceutical Industries andAssociations. http://europa.eu.int/comm/research/fp6/p1/innovative-medicines/pdf/vision en.pdf, 2004.

Byron Jones

Senior Statistical Consultant

Statistical Research and Consulting Centre

Pfizer Global Research and Development

Sandwich Kent, UK

Copyright # 2006 John Wiley & Sons, Ltd. Pharmaceut. Statist. 2006; 5: 83–84DOI: 10.1002/pst

84 Guest Editorial