Are There Better Alternatives to Phase III Clinical Trials: Con

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Are There Better Alternatives to Phase III
Clinical Trials Con

• Nevin Murray

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A Short History of Clinical Trials

• Theoretical rationale sufficient.
• Case Reports.
• James Lind A Treatise of the Scurvy, 1753.
• Claude Bernard 1813-1878 observations in groups
  rather than case reports.
• Oslerian Era Results of treatment of a series of
  patients by Professor A versus Professor B.

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Van Helmonts Wager 1662Theory versus Experience

• Let us take out of the hospitals, out of the
  camps, or from elsewhere, 200, or 500 poor people
  that have fevers and pleurisies. Let us divide
  them into half, let us cast lots, that one half
  of them may fall to my share, and the other to
  yoursWe shall see how many funerals both of us
  shall have. But let the reward of the wager be
  300 florens, deposited on both sides.

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Theory Based Treatments

• Middle Ages
• Purging the System of Toxins.
• Bloodletting leeches, phlebotomy etc.

• 2003
• Purging the System of Toxins
• Boosting the Immune System

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A Short History of Clinical Trials

• Theoretical rationale sufficient.
• Case Reports.
• James Lind A Treatise of the Scurvy, 1753.
• Claude Bernard 1813-1878 observations in groups
  rather than case reports.
• Oslerian Era Results of treatment of a series of
  patients by Professor A versus Professor B.

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Fibigers Trial of Serum Treatment for Diphtheria

• Johannes A G Fibiger 1867-1928
• Nobel Laureate 1927 Spiroptera carcinoma and
  gastric cancer.
• Diphtheria trial 1896-7, Blegdamhospitalet
• Roux, Paris benefit versus serum sickness
• To compensate for the large seasonal variation
  in mortality, the study should last one year

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Fibigers Trial of Serum Treatment for Diphtheria

• Random allocation central methodological
  principle.
• May 1896-May 1897 484 pts randomized
• Serum versus No Serum by admission day.
• Planning, conduct, reporting high quality.
• No statistics (statistical analysis later)
• Efficacy of serum Rx for diphtheria shown
• First properly conducted clinical trial.

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Controlled Trials The 1948 Watershed

• Concurrent versus historical.
• Alternate patients method selection bias.
• Two Groups then coin flip gambit groups not
  comparable.
• Austin Bradford Hill recommended randomization of
  individual patients 1946
• Provided an estimate of random error and
  eliminated bias of selection of pts in trial.
• MRC Streptomycin in TB 1948

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A Comparative Study of Two Regimens of
Combination Chemotherapy in Acute Leukemia

• Frei E III, Holland JF, Schneiderman MA, et al
  Blood 131126-1147, 1958

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Classification of Evidence

• I. Adequately powered, high quality randomized
  trial, or meta-analysis of randomized trials
  showing statistically consistent results.
• II. Randomized trials inadequately powered,
  possibly biased, or showing statistically
  inconsistent results.
• III. Non-randomized trials with concurrent
  controls.
• IV. Non-randomized studies with historical
  controls
• (ie typical single arm phase II studies).
• V. Expert committee review, case reports,
  retrospective studies.

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Quality of Medical Evidence in Oncology

• Between 1966-1996 783 controlled trials
  pertaining to 24 common decisions or
  interventions (level 1)
• Additional 21 of decisions/interventions
  supported by (level 2)
• 55 supported by level III, IV, V
• Djulbegovic et al. Am J Med 1999,106198-205.

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Quality of Medical Evidence in Oncology

• Investigation of evidence-based oncology project
  examined the level I evidence in solid tumors by
  an in-depth review of the papers published since
  1975.
• 1967 randomized clinical trials.
• 1238 clinical endpoints.
• 130 (11) ranked as contributing to level I.
• Brooks et al. Evidence-based Oncology Project.
  Surg Oncol 2002.

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Do we always need randomised controlled trials?
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Res ipsa loquitur

• 1. Childhood Leukemia
• 2. Hodgkins Lymphoma
• 3. Testicular Cancer
• 4. Gastrointestinal Stromal Tumors

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How large should the trials be?

• As of today, there has not been a single
  systematic review of randomised trials in solid
  tumors that has shown an absolute long-term
  survival improvement of gt10.
• Many trials have targeted gt 15.
• Controversy until meta-analysis.

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British Medical Journal 1995311899-909
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IALT Trial DesignOpen Design Phase III
PE 56 PVin 27 PVlb 11 PVnd 6
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Summary
4.1 absolute benefit from 40.4 to 44.5 at 5
years for overall survival plt0.03

• 5.1 absolute benefit from 34.3 to 39.4
• at 5 years for disease-free survival (plt
  0.003)
• No treatment interaction identified
• Lethal toxicity 0.8

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Overall Survival
Chemotherapy
Control
Years
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Adjuvant Chemotherapy of Resected NSCLC the
Difference

• 1. Relative Risk Reduction 14
• 2. Absolute difference 4
• 3. Number Needed to Treat 25 patients

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A difference is not a difference unless it makes
a difference.

• Gertrude Stein

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Corynebacterium parvum

• Shake and Bake

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CODE Regimen
Week
Chemotherapy 1
2 3 4 5 6 7 8 9 Cisplatin 25
mg/m2 IV x x x x x x
x x x Vincristine 1 mg/m2 IV
x x x x
x Doxorubicin 40 mg/m2 IV x x x
x x Etoposide Day 1 - 80 mg/m2
IV x x x x x
x Day 2 - 80 mg/m2 PO x x
x x x Day 3 - 80 mg/m2 PO x
x x x x
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High Dose Chemotherapy in Breast Cancer

• 1990s Phase II trials of high dose chemotherapy
  with bone marrow transplantation made public.
• Compared to historical controls, high dose
  chemotherapy suggested a 40 improvement compared
  to historical controls at 3 years.
• 41,000 women treated before phase III trials
  reported in 1999.

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NCIC CTG MA.16 Overall Survival
100
80
60
Percentage
40
20
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
High-Dose Standard
112
99
76
56
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23
11
0
111
101
76
54
40
17
5
1
Time from Randomization (years)
Log-Rank test for equality of groups p0.9558
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ALLEGED Harms and Benefits

• Breast cancer
• Endometrial cancer
• VTE
• cholelithiasis

• Menopausal Sx
• Lipid lowering
• Ischemic cardiac disease
• Alzheimers
• Osteoporosis
• Colorectal cancer

H
B
Where does the balance rest?
HRT
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Sources of Information

• Observational Studies
• Case-control Cohorts
• Consensus Reports
• Randomized trials

HRT
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ALLEGED Harms and Benefits

• Breast cancer
• Endometrial cancer
• VTE
• Cholelithiasis

• Menopausal Sx
• Lipid lowering
• Ischemic cardiac disease
• Alzheimers
• Osteoporosis
• Colorectal cancer

?
B
H
HRT JAMA, 2002
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Concurrent Chemoradiation of Locally Advanced
Epithelial Ca

• Stage III Non-small Cell Lung Cancer
• Limited Stage Small Cell Lung Cancer
• Head and Neck Cancer
• Esophageal Cancer
• Anal Cancer
• Cervical Cancer

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Phase III Randomised Clinical Trials

• Hallmark is to expose trial participants to
  exposures based on the play of chance.
• Reduces likelihood of biases (known and unknown)
  in determination of outcome.
• Amenable to statistical analysis
• Especially useful for the examination of small
  and moderate treatment effects.

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Opposition to Phase III Randomized Clinical
Trials

• Rebuttal from the 1940s

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T. Lewis Clinical Science Illustrated by
Personal Experience. London Shaw and Sons
1934178-83

• It is to be recognised that the statistical
  method of testing treatment is never more than a
  temporary expedient, and that but little progress
  can come of it directly for in investigating
  cases collectively, it does not discriminate
  between cases that benefit and those that do not,
  and so fails to determine criteria by which we
  may know beforehand in any given case that
  treatment will be successful.

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Bradford Hills Reply 1946

• Tell me the criteria to distinguish patients
  who will respond from those who dont and we will
  build this into the trial.

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Bottom Line

• The Randomized phase III trial will continue to
  be the best method to test new treatments for
  patients within strata defined by clinicians.
• If scientists can enhance clinical strata with
  appropriate genomic/proteomic parameters that are
  of practical value, this information will be
  incorporated into a new generation of more
  sophisticated clinical trials.