PEST: Planning and Evaluation of Sequential Trials


Sequential clinical trials consist of a series of interim analyses, at each of which the trial might be stopped and a conclusion drawn, otherwise the trial continues. Such methods are used by the pharmaceutical industry and other medical research institutes. PEST 4.4 is designed to perform the computations associated with sequential clinical trials. This general term includes methods sometimes referred to as group sequential trials or interim analyses. Its procedures fall into five modules.

  • Design: From entry of a power specification and an indication of the type of sequential design that is wanted, PEST 4.4 will calculate the stopping rule. The distribution of the sample size at stopping will be described.
  • Simulate: PEST 4.4 enables the user to simulate sequential clinical trials, to illustrate how a trial might proceed under various user-specified conditions.
  • Monitor: During the trial, PEST 4.4 can be used to determine whether the trial should stop. A graphical summary of the evidence to date will be generated.
  • Analyse: At the end of the study, PEST 4.4 will calculate the achieved significance level, and point and interval estimates of the true treatment difference. Conventional analyses are invalidated by the presence of the stopping rule: instead PEST 4 uses appropriate and valid methodology.
  • View: This option allows the user to view calculations from any of the above modules that have already been performed.



Response types

  • binary (success/fail)
  • ordinal
  • survival times
  • interval censored survival times
  • normally distributed responses
  • matched case-control studies


  • triangular and double triangular
    • stopping for evidence of treatment difference or for lack of difference
  • restricted procedure and open top
    • stopping only for evidence of treatment difference
  • safety monitoring procedures
    • stopping in the case of evident harm
  • futility design
    • stopping as soon as it is evident that the trial outcome will be negative


  • for learning how to use the wide variety of options in PEST 4.4
  • for demonstrating the methodology to investigators
  • for investigating the accuracy and robustness of the asymptotic theory


  • takes interim data entered in summary form or read from a SAS dataset
  • calculates test statistics and plots them together with the stopping boundaries
  • allows adjustment for prognostic factors through stratification or linear modelling
  • the “Christmas tree” adjustment allows for flexible and unpredictable timing of interim analyses

Final analysis

  • computes the p-value based on the stagewise ordering (Fairbanks and Madsen, Biometrika 69, 69-74, 1982).
  • computes estimates and confidence intervals that allow for the sequential nature of the design
  • plots the p-value function


PEST 4.4 comes with installation instructions and an extensive printed manual. Test datasets are supplied, and the manual includes click-by-click instructions for using the facilities of the package.



PEST 4.4 is written in the languages C and SAS/AF. PEST 4 is run within a SAS session, making interfacing with other SAS procedures straightforward. Minimum system requirements are: Microsoft Windows and SAS version 8 or 9 with BASE, STAT, GRAPH and IML.



PEST is not longer developed or maintained. If you do have a question, please send an email to


Publications related to PEST

  • Whitehead, J. The Design and Analysis of Sequential Clinical Trials. Revised Second Edition (1997), Chichester: Wiley.
  • Johnson, C.D., Puntis, M., Davidson, N., Todd, S. and Bryce, R. (2001). Randomized, dose-finding phase III study of lithium gamolenate in patients with advanced pancreatic adenocarcinoma. British Journal of Surgery 88, 662-668.
  • Todd, S., Whitehead, A., Stallard, N. and Whitehead, J. (2001). Interim analyses and sequential designs in phase III studies. British Journal of Clinical Pharmacology, 51, 394-399.
  • Whitehead, J. (2001). Predicting the duration of sequential survival studies. Drug Information Journal, 35, 1387-1400.
  • Whitehead, J. (2001). Sequential methods. In Biostatistics in Clinical Trials, Eds. Redmond, C. and Colton, T. Chichester: Wiley, 414-422.
  • Whitehead, J. (2001). Monotherapy trials: sequential design. Epilepsy Research, 45, 81-87.
  • Whitehead, J. (2001). Use of the triangular test in sequential clinical trials. In Handbook of Statistics in Clinical Oncology, Ed. Crowley, J., New York, Marcel Dekker, 211-228.
  • Whitehead, J., Whitehead, A., Todd, S., Bolland, K. and Sooriyarachchi, M.R. (2001). Mid-trial design reviews for sequential clinical trials. Statistics in Medicine, 20, 165-176.
  • Whitehead, J. (2002). Sequential methods in clinical trials. Sequential Analysis 21, 285-308. Sooriyarachchi, M.R., Whitehead, J., Matsushita, T., Bolland, K. and
  • Whitehead, A. (2003). Incorporating data received after a sequential trial has stopped into the final analysis: implementation and comparison of methods. Biometrics, 59, 701-709.
  • Whitehead, J. and Matsushita, T. (2003). Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment. Statistics in Medicine, 22, 677-687.
  • Bolland, K., Weeks, A., Whitehead, J. and Lees, K. R. (2004). How a sequential design would have affected the GAIN International study of gavestinel in stroke. Cerebrovascular Diseases 17, 111-117.
  • Whitehead, J. (2004). Stopping clinical trials by design. Nature Reviews: Drug Discovery 3, 973-977.
  • Whitehead, J. and Todd, S. (2004). The double triangular test in practice. Pharmaceutical Statistics 3, 39-49.
  • Baksh, F., Todd, S., Whitehead, J. and Lucini, M. M. (2005). Design considerations in the sequential analysis of matched case-control studies. Statistics in Medicine 24, 853-867.
  • Brodie, M. J. and Whitehead, J. (2006). Active control comparisons: the ideal trial design. Epilepsy Research 68, 70-73.


Published trials that have used PEST

The Triangular Test

  • Anaesthesia for outpatient termination of pregnancy. Hackett et al. (1982). British Journal of Anaesthesia, 54, 865-870.
  • Immunotherapy regimens in bone marrow transplantation for leukaemia. Storb et al. (1986). New England Journal of Medicine, 314, 729-735.
  • Corticosteroids in AIDS-induced pneumonia. Montaner et al. (1990) Annals of Internal Medicine, 113, 4-20.
  • Insulin and glucagon in severe alcoholic hepatitis. Trinchet et al. (1992). Hepatology, 15, 76-81.
  • Enoxaparin in deep vein thrombosis resulting from hip replacement surgery. Whitehead (1992). Pharmaceutical Medicine, 6, 179-191.
  • Cisplatin in limited small-cell lung cancer. Arriagada et al. (1993). New England Journal of Medicine, 329, 1848-1852.
  • Spinal anaesthesia during Caesarian section (in a design also using the play-the-winner rule). Rout et al. (1993). Anaesthesiology, 79, 262-269.
  • Isradipine in stroke. Whitehead (1993). Drug Information Journal, 27, 733-740.
  • Comparison of salmeterol and terbutaline in nocturnal asthma. Brambilla. et al. (1994). Allergy, 49, 421-426.
  • Surfactant in infantile respiratory distress. Gortner et al. (1994). Acta Paediatrica, 83, 135-141.
  • Lipiodol chemoembolisation in hepatocellular carcinoma. Group d'Etude et Traitement du Carcinoma Hepatocellulaire. (1995). New England Journal of Medicine, 332, 1256-1261.
  • Vinorelbine and fluorouracil in advanced breast cancer. Dieras et al. (1996). Journal of Clinical Oncology, 14, 3097-3104.
  • Defibrillators in coronary heart disease. Moss et al. (1996). New England Journal of Medicine, 335, 1933-1940.
  • Somastatin in acute oesophageal variceal bleeds. Avegerinos et al. (1997). The Lancet, 350, 1495-1499.
  • Metoclopramide in gastroesophageal reflux. Bellissant et al. (1997). Clinical Pharmacology and Therapeutics, 61, 377-384.
  • Viagra in erectile dysfunction. Derry et al. (1997). Neurology, 51, 1629-1633.
  • Interferon and cytarabine in chronic myelogenous leukaemia. Guilhot et al. (1997). New England Journal of Medicine, 337, 223-239.
  • Interferon α-2a as adjuvant therapy in resected primary melanoma. Grob et al. (1998). Lancet, 351, 1905-1910.
  • Nicotinamide in the prevention of type 1 diabetes in children. Lampeter et al. (1998). Diabetes, 47, 980-984.
  • Alpha-interferon in renal cancer. MRC Renal Cancer Collaborators (1999). The Lancet, 353, 14-17.
  • Dexamethasone in severe adult bacterial meningitis. Thomas et al. (1999). Intensive Care Medicine, 25, 475-480.
  • Electrical defibrillation in an animal model of ventricular fibrillation. Niemann et al. (2000). Journal of the American College of Cardiology, 36, 932-938.
  • Lenograstim in leukaemia. Bradstock et al. (2001). Leukemia, 15, 1331-1338.
  • Embolisation in hepatocellular carcinoma. Llovet et al. (2002). The Lancet, 359, 1734-1739.
  • The influence of reactive oxygen species on cervical cancer. Rogers et al. (2002). Gynecologic Oncology, 84, 383-387.
  • Olanzapine in the prevention of psychotic relapse. Beasley et al. (2003). Journal of Clinical Psychopharmacology, 23, 582-594.
  • Creatine in amyotrophic lateral sclerosis. Groeneveld et al. (2003). Annal of Neurology, 53, 437-445.
  • Comparison of methotrexate-mifepristone and methotrexate-placebo in ectopic pregnancy. Rozenberg et al. (2003). Human Reproduction, 18, 1802-1808.
  • Comparison of shock forms for direct ventricular defibrillation during open heart surgery. Schwarz et al. (2003). Anesthesiology, 98, 1063-1069.
  • Antibiotic therapy after acute myocardial infarction. Zahn et al. (2003). Circulation, 107, 1253-1259.
  • A nitric oxide synthase inhibitor in septic shock. López  et al. (2004). Critical Care Medicine, 32, 21-30.

The Double Triangular Test

  • Intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative normal-tension glaucoma study group. (1998). American Journal of Ophthalmology, 126, 498-505.
  • Comparison of theatre mattresses in respect of pressure sore incidence during surgery. Nixon et al. (1998). International Journal of Nursing Studies, 35, 193-203. Brown et al. (2000). Statistics in Medicine, 19, 3389-3400.
  • Diltiazem in acute myocardial infarction. Boden et al. (2000). The Lancet, 355, 1751-1756.
  • Glycopyrolate in elective Caesarian section. Yentis et al. (2000). International Journal of Obstetric Anaesthesia, 9, 156-159.
  • Chemotherapy in high-risk breast cancer. Bergh et al. (2000). The Lancet, 356, 1384-1391.
  • Thromboembolism during hormone replacement therapy. Hoibraaten et al. (2000). Thrombosis and Haemostasis, 84, 961-967.
  • Remacamide and carbamazepine in newly diagnosed epilepsy. Whitehead (2001). Epilepsy Research, 45, 81-87.
  • Lithium gamolenate in pancreatic cancer. Johnson et al. (2001). British Journal of Surgery, 88, 662-668.
  • Reliability of contrast agents in assessing the potency of Fallopian tubes. Boudghene (2001). Ultrasound Obstet. Gynecol., 18, 525-530.

The Truncated Sequential Probability Ratio Test

  • Comparison of chemotherapy regimens in advanced Hodgkin's disease. Diehl et al. (2003). New England Journal of Medicine, 348, 2386-2395.

The Double Truncated Sequential Probability Ratio Test

  • Comparison of triflusal with aspirin following acute myocardial infarction. Cruz-Fernandez et al. (2000). European Heart Journal, 21, 457-465.

The Restricted Procedure

  • Tiaprofenic acid and indomethacin in osteoarthritis. Whitehead and Thomas (1997). Journal of Biopharmaceutical Statistics, 7, 333-353.
  • Comparison of radiotherapy regimens in Hodgkin's lymphoma. Engert et al. (2003). Journal of Clinical Oncology, 21, 3601-3608.

Safety Monitoring

  • Examples for severe head injury, stroke and heart disease. Bolland and Whitehead (2000). Statistics in Medicine, 19, 2899-2917.

Open Top Design

  • Rilozole in amyotrophic lateral sclerosis. Lacomblez et al. (1996). The Lancet, 347, 1425-1431.