Clinical Trials: What you need to know to study diet and nutritional variables - PowerPoint Presentation

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Clinical Trials: What you need to know to study diet and nutritional variables (emphasis on fruits and vegetables and their components)

Steven K. Clinton, M.D., Ph.D.

The Ohio State University

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Introduction

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What is a Clinical Trial:

Essential Characteristics

“a

prospective

study involving

human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, devices, or behavioral or nutritional strategies”

- NIH / NCI Definition

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Fragment of

Daniel’s Protocol

Biblical Description of a Clinical Trial

Daniel 1:12-16

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The “First” Clinical Trial in Nutrition

“Please test your servants for ten days:

Give us nothing but vegetables to eat and water to drink. Then compare our appearance with that of the young men who eat the royal food, and treat your servants in accordance with what you see.

So he consented them and tested them for ten days. At the end of the ten days they looked healthier and better nourished than any of the young men who ate the royal food.

So the guard took away their choice food and the wine they were to drink and gave them vegetables instead.”

Daniel 1:12-16

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The “First” Clinical Trial in Nutrition

It’s often difficult to translate clinical trial results into practice, but in Daniel’s case, we remember it today:

“Eat your vegetables!”

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ChemopreventionPharmaceuticals (chemically defined pure agents)Natural

Synthetic

Nutrients

Pharmacologic dosages (acting like a drug)

Nutritionally relevant dosages (acting like a nutrient)

Dietary prevention

Dietary pattern (orchestration of your entire diet)

Foods (complex mixtures of bioactives)Traditional foodsFunctional foodsStrategically altered and composed to target a disease process

Definitions

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Ideas, Opinions

Case Reports

Case Series

Case Control Studies

Cohort Studies

Randomized

Controlled Studies

*

Randomized Controlled Double Blind Studies

*

Levels of the Evidence

* Buttressed by basic science

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WCRF/AICR Report

-

Released Nov. 1-2, 2007

Judging the evidence

CHAPTER 3

PART 1 • BACKGROUND

The task of expert committees responsible for reports such as this is to collect, discuss, and judge scientific evidence, as a basis for recommendations made in the public interest. The purpose of this third introductory chapter is to summarize the process the Panel has used …

Evaluating the Evidence

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Policies and actions

CHAPTER 8

PART 3 • RECOMMENDATIONS

The prevention of cancer worldwide is an urgent and feasible task of great importance. It requires concerted and integrated international, national and local action...

Figure 8.1

The nine actors: impact of concerted action

Translating

the Evidence

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Controversy

and

Wisdom

wis·dom  (wzdm)

n.

The sum of learning through the ages; knowledge: "In those homely sayings was couched the collective wisdom of generations" (Maya Angelou).

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Human Research / Clinical Trials

Human Research

Observational

Studies

Clinical

Trials

Uncontrolled Trials

Controlled Trials

Cohort Studies

Case-Control

Cross-Sectional

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Team Building

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Team Building: Everyone Deserves Credit!

Principle investigator and team

Clinical collaborators

Laboratory collaborators (agent development, analytics, …)

Biological sample procurement

Biostatistics

Single institution / multi-institution investigators

Institutional support / shared resources / NIH or USDA

General Clinical Research Center (GCRC)

Clinical and

Tanslational

Science Award (CTSA)

Comprehensive Cancer Center (NIH CCC)

Funding agencies

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Biostatisticians should be involved in your study from the beginning.

Design and writing of a clinical trial

Help write a grant to fund the trial

Necessary for IRB process

Collect, store, monitor & analyze data quality

Interim analysis in large studies

Data

andSafety

Monitoring Board (DSMB)

Help write / review abstracts, reports, or publications

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Remember this Model:

A,B,C and Ds of a

Dietary or Nutritional Clinical Trail

Agents

Diet pattern, specific food item

Nutrient or phytochemical (pure)

ExtractConcentrateNeutricuetical (manipulated, processed)

Biomarkers and Outcomes

Cohort

Dollars

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The Agent

Working with whole foods is more complex.

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Agent: Key IssuesStandardization

of study intervention

EZ for “drug” or “nutrient” or “phytochemical”

Form, safety, dose response, placebo possible.

Complex for “food product”

Variation due to source, cultivar, season, growing conditions, soil, processing, cooking, stability over time.

Placebo and double blinding may be

problematicDietary PatternsHeterogeneity among participants, complianceControl group is problematic.

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Known composition of a food is criticalHomogeneous and equal for all participantsOver the time of the study (batch to batch)During storage

Reproducible by others (report methods)

Quality control

Composition and ingredients

Microbial and toxic contaminants

Agent: Key Issues

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Example:Berries

Acai

Berry, Baneberry, Barbados Cherry, Barberry, Bearberry, Bilberry, Bittersweet, Blackberry, Blueberry, Black Mulberry, Black Raspberry, Boysenberry, Buffalo Berry, Bunchberry, Chokeberry, Chokecherry, Cloudberry, Cowberry, Cranberry, Currant, Dewberry, Elderberry,

Farkleberry

,

Goji

Berry, Gooseberry, Grape, Holly Berry, Huckleberry, Indian Plum, Ivy Berry,

Juneberry, Juniper Berry, Lingonberry, Logan Berry, Mistletoe Berry, Nannyberry, Oregon Grape, Persimmon, Pokeberry, Privet Berry, Raspberry, Red Mulberry, Salmonberry, Strawberry, Sugarberry, Tayberry, Thimbleberry, White Mulberry, Wineberry, Wintergreen, Yew Berry, Youngberry

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Phylogeny of Black RaspberriesSpecies: Rubus

occidentalis

Native to eastern North America

Different in composition and taste compared to the red raspberry and blackberry.

High in

anthocyanins and ellagic acidLow yield per acre  expensive to grow.

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Challenges for Berry Studies

Standardization of intervention agent

Variable chemical composition

Genetics

Environment (temperature, water, pests….)

Harvest (maturity,

sensecence

,…..)Storage and shippingProcessingWhat is the critical bioactive(s) to measureComplex mechanism(s) of action and uncertaintly about desired composition of food product.

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Components of Black Raspberries by Season (mg/100 g)

BR Components

LBR 1998

LBR 1995

LBR 1997

Minerals

Calcium

Copper

Iron

Magnesium

Manganese

Phosphorus

Potassium

Sodium

Zinc

Selenium

170.00

0.74

4.95

147.00

5.85

168.00

1060.00

<10.00

2.12

<5.00

245.00

0.52

13.20

169.00

3.60

222.00

1200.00

<10.00

2.69

<5.00

215.00

0.55

10.1

153.00

4.68

170.00

1300.00

<10.00

2.12

<5.00

Vitamins

Folic acid

Vitamin C

0.51

<1.00

0.07

<1.00

0.06

4.14

Sterols

ß

-

sitosterol

Campesterol

Cholesterol

Stigmasterol

72.40

4.60

<1.00

<3.00

89.1

4.30

<1.00

<3.00

80.10

3.40

<1.00

<3.00

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Components of Black Raspberries (mg/100g)

Components

a

LBR 1998

b

LBR 1995

c

LBR 1997

d

Phenolics

Ellagic acid

Ferulic

acid

p

-

coumeric

acid

200.00

21.00

6.72

185.00

32.40

7.94

166.30

17.60

9.23

Carotenoids

α

-carotene

ß

-carotene

Lutein

Zeaxanthin

<0.02

0.12

<0.02

<0.02

<0.02

<0.02

<0.02

<0.02

<0.02

<0.02

<0.02

<0.02

a Concentration of components is expressed as mg/100g : selenium is expressed as ug/100g

b Cultivar used for inhibition of oral tumors in HCP

c Cultivar used for inhibition of esophageal tumors in rats (complete chemoprevention assay)

d Cultivar used for inhibition of esophageal tumors (post-initiation assay)

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What are the

bioactive compounds

in black raspberries?

Steven Schwartz, Ph.D. and Ken Riedl, Ph.D.

Dept. Food Science and Technology

OSUCCC Nutrient and Phytochemical Analytic Shared Resource

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Anthocyanins in Black Raspberry Fractions

Cyanidin 3-O-glucoside

Cyanidin 3-O-rutinoside

Cyanidin 3-O-(2

G

-xylosylrutinoside)

Cyanidin 3-O-sambubioside

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Many anthocyanin chemical structures

Anthocyanidin + Sugar + Acid =

Anthocyanin (acylated)

Anthocyanidin + Sugar =

Anthocyanin (non-acylated)

Anthocyanidin

From Monica Giusti, Ph.D.

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Berry Ellagitannins and Ellagic Acid

From : Ken Riedl, Ph.D.

Hydrolysis of Ester Bonds

Liberates HHDA which Lactonizes to EA

Ellagitannins –

high MW polyphenols with hexahydroxy-diphenic acid or ellagic acid attached to glucose core.

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The analytical chemist is critical to your success. Careful documentation of chemical composition is essential.

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Application of Food Science and Technology is Critical

Enhanced delivery of bioactives

Target tissue

Systemic distribution

Improved compliance

Quality control.

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Several Berry Clinical Trials

Authors

Subjects

Product/Dose

Design

Outcome

Stoner et al, 2005

Healthy n=1145 g BRB x 7 days

Phase

1:

Pharmaco

-kinetic study

Well-tolerated.

<1% of compounds were absorbed and excreted in urine.

Kresty

et al, 2006

Barrett’s esophagus n=10

32-45g BRB x 6 months

Phase 1: Pilot study

Berries modulate markers

of oxidative stress

Mallery

et al, 2011

(

Ugalde

, 2009; Shumway, 2008) Oral neoplastic lesions and normal n=2710% BRB topical gel 4x/d x 6wksPhase 1: Pilot StudyNo toxicity.Preventative

effects histology and biomarkersWang et al, 2011(Wang, 2007)Colorectal Cancer n=20(Wang, 2007 n=50)60 g/day BRB x 1-9 wks SlurryPhase 1: Pilot study.

4 wks of tx was associated with protection of disease. Proliferation and angiogenesis biomarkers were reduced and apoptosis was enhanced.Chen et al, 2011

Barrett’s esophagus n=72Freeze-dried strawberry slurry 30-60g/dayPhase IIReduction in Ki-67 expression,

iNOS, COX-2, pS6, p-NF-kB-p65

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Human Clinical Trials:

Strawberries and Esophageal Cancer

Esophageal Squamous Cell Dysplasia in China

Tong Chen, M.D., Ph.D.

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Esophageal Cancer

6

th

most common malignant neoplasm worldwide

Squamous cell carcinoma-

arises in the proximal and mid-esophagus from dysplastic lesions in the squamous epithelium

Adenocarcinoma

- arises distally from from Barrett’s esophagus (metaplastic precancerous lesion) The incidence of esophageal SCC shows marked variation in its geographic distribution.Males have a 3- to 4- fold greater risk for developing esophageal SCC than females.

In the United States, African Americans have more than a 5-fold higher incidence of esophageal SCC than Caucasians.

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Tobacco AlcoholIngestion of salt-pickled, salt-cured and moldy food

Nutritional deficiency (Zn, etc)

Consumption of temperature hot beverage

Human

papilloma

virus infection

Etiology of Esophageal SCC

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Esophageal SCC in China

Peking Union Medical College Hospital

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Peking Union Medical College Hospital

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Randomized Phase II Trial of Lyophilized Strawberries in

Patients with Dysplastic Precancerous Lesions of the

Esophagus

Chen et al.

Cancer Prev Res; 5(1); 41–50. 2011

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Nutricuticals:Combination Agents

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Preclinical Study45

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Preclinical Results46

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Tomato-soy food products for cancer prevention studies

Bohn et al. Phase I Trial (Nutrition and Cancer, 2013)

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Department of Horticulture

Selection of Tomato Cultivar

Phytochemical content

Growth characteristics

Disease resistance

Processing issues

OSU Farms

Plant and harvest

Department of Food Science and Technology

Process into paste

Phytochemical analysis

Soy protein and extracts

Phytochemical analysis

Reconstitution and Formulation

Solubility

Taste

Texture

Taste Panel

1 can = 150 ml juice (6 oz)

22.5 mg lycopene and 33 mg isoflavones

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Bioavailability of phytochemical constituents from a novel soy fortified lycopene rich tomato juice developed for targeted cancer prevention trials.

Bohn T

,

Blackwood M

,

Francis D

, Tian Q,

Schwartz SJ

,

Clinton SK

.

Nutr

Cancer.

2013;65(6):919-29.

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Agent

Bioavailability Studies

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Pre-prostatectomy Trial

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Soy tomato Juice and Serum Carotenoids

(CLINTON PRELIMINARY DATA)

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Lycopene Phytoene Phytofluene

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Urinary Isoflavone Excretion

(CLINTON PRELIMINARY DATA)

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The Agent and Cohort:

Consideration of Dose is Essential

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Considerations of dose are critical.As

Paracelcus

noted in the 1500s:

“Poison is in everything, and no thing is without poison.

The dosage makes it either a poison or a remedy.”

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Example:Many nutrients show U-shaped risk relationship

Greatest benefit when increase those in lowest group

Harm when increase those in highest groups?

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Is this relevant to phytochemicals ?

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Plasma



-Carotene Concentrations in Large Population Studies

U.S. 5th to 95th%

0.09–0.9

(5–49)

“Threshold”

>0.4



mol/L

(>20



g/dL)

1.9

(100)

5.6

(300)

3.8

(200)

7.5

(400)

Linxian

(15 mg/day)

PHS

(50 mg every

other day)

CARET

(30 mg/day)

ATBC

(20 mg/day)

Blood

-carotene concentration µ

mol

/L (µg/

dL

)

(

Mayne, PPO Updates 1998

)

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The Cohort:Baseline status may be critical to results.

Pick your participants carefully.

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Linxian County, China Cancer Prevention Trial (Blot et al., JNCI 1993)

Micronutrient deficient

population from rural China (n = 29,584).

4 nutrient combinations evaluated.

Primary analysis:

beta-carotene (15 mg/d) + vitamin E (30 mg/d) + Se (50



g/d) reduced cancer deaths (13%), especially gastric cancer (RR = 0.79, 95% CI 0.64 - 0.99).

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Effect of Baseline Selenium Status on Chemopreventive EfficacyProtective effect of selenium on total cancer incidence evident only in those who were in the lowest 2

tertiles

of plasma selenium at entry

Hazard ratios based upon plasma Se at entry into trial(adjusted)

First

tertile

HR =

0.50 (0.30-0.80)Second tertile HR = 0.70 (0.44-1.12)Third tertile HR = 1.19 (0.75-1.90) P for interaction 0.007

Duffield-

Lillico

et al.,

CEBP,

2002

.

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Effect of Baseline Folate Status on Chemopreventive EfficacyRCT on supplemental

folate

(1 mg/day) for recurrent adenoma (3 - 6.5 years of evaluation).

Hazard ratios (adjusted)

Overall HR = 0.82 (0.59-1.13)

Low baseline

folate

HR = 0.61 (0.42-0.90)High baseline folate HR = 1.28 (0.82-1.99) P for interaction 0.01

Wu et al.,

AJCN,

2009.

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“

Calcium supplementation and vitamin D status appear to act largely together, not separately, to reduce colorectal adenoma recurrence”. JNCI 2003

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The Agent:Contextof Diet is Important

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The Cohort:Lifestyle variables may be critical.

Pick your participants carefully.

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Smoking (and drinking) are key effect modifiers of chemopreventive efficacy…

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Beta-Carotene Risk Ratios:Antioxidant Polyp Prevention Trial

J Natl Cancer Inst 2003

Neoplastic and Antineoplastic Effects of -Carotene on Colorectal Adenoma Recurrence: Results of a Randomized Trial

John A. Baron, Bernard F. Cole, Leila Mott, Robert Haile, Maria Grau, Timothy R. Church, Gerald J. Beck, E. Robert Greenberg

RR adenoma recurrence

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The Cohort:

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CohortsBroad and “generalizable” / public health model

Focused and “personalized” / medical model

Host

Genetics

Carcinogen exposure (tobacco)

Premalignancy (dysplasia, CIS, polyps)

Nutritional criteria (deficiency)

Infection (HepB, HPV)Immune suppressed (post-organ transplant)Cancer (recurrence of primary)Genomic signatureHistopathology subtype

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Outcomes:Biomarkers

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BiomarkersExposure

Validated analytic technology.

Dose response (linear, nonlinear)

Bio accessibility.

Pharmacokinetic / pharmacodynamic modeling.

Context (meal and composition).

Efficacy

Surrogate endpoints (polyps, intraepithelial neoplasia)Mechanisms -omics miRNA, mRNA, proteins, epigenetics, genomics, metbolomicsTargeted approach.“Hallmarks of Cancer”

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Enough !

Read the Rest!

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Classification of Clinical Intervention TrialsPhase I, II, III

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Traditional Clinical Trial Sequence in

Drug Development

(progression is less clear for diet and nutritional intervention)

Phase 0 (analytic/feasibility)

Phase I

Phase II

Phase IIIPhase IV

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What is a Phase I Trial ?

Common answers

“First in human” study

Mechanism of action

Show promise in animal studies

Find the ‘best dose’ in humans

Dose, Route, ScheduleSingle agent (nutrient) and combination therapyNot hypothesis driven

No comparisons

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Phase I Trials :

Typical Characteristics

Objective:

d

ose

f

inding (DF)Endpoints: safety and toxicitySingle arm: all pts treated with study agentDose escalation until toxicity is achieved

Small number of patients: 15-25 pts

Patients often have advanced disease with no effective therapy remaining (novel drug trials)

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Phase II Trials:

Typical Characteristics

Objective:

S

afety

and

Efficacy (SE)Endpoints: objective disease response (surrogate marker)Typically one “disease”Single arm (typically): all pts treated alike

Dose: typically one or limited number of intervention arms

Modest number of patients: 25-100 pts

Pts often have advanced disease with suboptimal therapy (drug trials) available.

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Phase III Trials:

Typical Characteristics

Objective: to compare outcome to standard

[

C

omparative

Treatment Efficacy]Endpoints: disease prevention, objective response, survival, time to progression/failureMultiple arms: 2 (control vs

intervention) or more

Randomized treatment allocation

Large numbers of patients: 10

2

-10

5

Pts may have high risk (prevention), early disease, and advanced disease as appropriate

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Basic Comparative Trial Designs: Parallel Group

95% of Phase III trials follow this design

Defined Pt

Population

R

A

N

D

O

M

Treatment A

Treatment B

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Phase III:

Randomized Clinical Trial

The

GOLD

Standard

Minimizes / eliminates bias

Requires clinical equipoiseDifficult to ‘sell’ to some physicians and patientsNo one wants to be the controlComplex mechanics & administrationPlacebo administration may be difficult

Dietary “drift” of your controls over time

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Stratification

Patient population may be

heterogenous

Male and female, age, smoking, obesity, exercise……

Differences in pre-existing conditions

Differences in prognostic factors

Stratification balances treatment groups to insure equitability

Stratification does not insure adequacy of sample for post-hoc analysis

Stratification

vs

Covariate Adjustment

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Blinding or Masking

Unblinded

- “Open Label”, typical in diet or food based interventions.

Single Blind – Patient

Double Blind - Patient & physician

Triple Blind - Patient, physician, & DSMB

“Double Dummy” –

when treatment is difficult to blind

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“Double Dummy”Double dummy is a technique for retaining the blind when administering “agents” in a clinical trial, when the two treatments cannot be made identical. Agents are prepared for Treatment A (active and indistinguishable placebo) and for Treatment B (active and indistinguishable placebo). Subjects then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active).

Double dummy is a method of blinding where both treatment groups may receive placebo. For example, one group may receive Treatment A and the placebo of Treatment B; the other group would receive Treatment B and the placebo of Treatment A.

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The figure above is a double-dummy example for a two treatment arm scenario.

To maintain the blinding, subjects in each arm will be assigned to take one tablet and one capsule.

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Blinding or Masking Issues

Ethics: No harm or risk to patient

Methods in place for

unblinding

in case of patient management emergency

DSMB

blindedness – some require DSMB to remain unblinded

Complicated mechanics

Subject/patient/investigator intent to discover allocation

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The Protocol

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The Protocol – An Action Plan

A formal written document detailing all aspects of a clinical study

Spells out how each patient is to be treated and how the study is to be conducted

Uses “standard” format / outline

Written by local investigator or outside (academic, agency, or company)

Must be reviewed and approved by an Institutional Review Board [IRB]

May be reviewed by NIH/NCI, FDA, or industry sponsors as necessary

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The Protocol Template

Schema

Objectives

Background

Patient Selection

Treatment Plan

Agent InformationStudy CalendarMeasurement of EffectEfficacy

Toxicity

Statistical Considerations

Regulatory and Reporting

References

Informed Consent Form

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Compliance

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Patient Compliance

Anticipate and consider how to cope

Define methods of compliance and monitor

Non-compliance

Adverse events – too frequent or severe

Financial – too costly / insurance problems

Prefer another treatmentDisappointing results

Great results

Inconvenience

Did not understand instructions

Too far to travel

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Adverse Events

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Adverse Events [AE’s] / Toxicity

An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a treatment or procedure

regardless of whether it is considered related to the medical treatment or procedure.

The term ‘toxicity’ has no regulatory definition;

use ‘adverse event’ instead

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Grading severity of AE’s

The NIH/NCI developed a standardized system of categorizing and grading AE’s

Common Terminology Criteria for Adverse Events v3.0 [CTCAE v3]

> 350 terms

Developed in collaboration by USA, EU, Japan

Used by all cooperative oncology groups

Available on-line at:http://ctep.info.nih.gov/reporting/ctc.html

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Grading Severity of AE’s

Most AE’s can be graded 0-5:

0 – none

1 – mild

2 – moderate

3 – severe

4 – life threatening5 – death

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AE’s – Severity

Not all AE’s are serious

Not all require immediate reporting

Reporting requirements are dictated by law and study sponsors

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Other Data on AE’s

Onset date or ‘baseline’

Resolved date or ‘ongoing’

Attribution [unrelated > definitely related]

Action [none > treatment discontinued]

Therapy [none > vigorous supportive]

Outcome [recovered > died]DLT / SAE [yes/no – SAE type]Apex/Nadir

In addition to grade, for each AE, we record:

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Serious Adverse Events [SAE’s]

Fatal or life-threatening

Requires or prolongs hospitalization

Permanently or substantially disabling

Congenital anomaly / birth defect

Requires intervention to prevent permanent impairment or damage

All AE’s are not alike

Required reporting: no general guidelines, but must report to IRB within 10 days (If death, within 72 hrs.

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Who/where do you report AE’s?

OSU IRB

OSU Cancer Center Clinical Trials Office

Study Sponsor

FDA

NIH

The ‘matrix’ of reporting will vary by study,

agency, type of treatment/device, and sponsor.

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How do you report AE’s?

NCI-sponsored trials use:

Adverse Event Expedited Reporting System

Clinical Data Update System

FDA Medwatch 3500 form

Pharmaceutical industry forms

OSU IRB forms

At OSUCCC, we use 14-15 different forms

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RULES, RULES, and more RULES !

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What kind of rules are we talking about?

Patient eligibility

Informed consent

Treatment

Laboratory parameters

Evaluation

ReportingEarly stopping

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Negative Reasons for Early Trial Termination

Adverse events

Lack of treatment benefit / futility

Inability to accrue patients

Lack of access to drug/agent

Inadequate patient/investigator compliance

New findings or publications render study mootFinancial reasons

Loss of interest

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Positive Reasons for Early Trial Termination

Patient benefit

However, must assure that the quantity and quality of data will be convincing to clinicians and statisticians

[ = Good Science]

Usually makes it impossible to conduct similar studies in the future

Examples: beta blockers, AZT

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ETHICS

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Time

April 14, 2002

Human Guinea Pigs

At a conference in DC last year, Alice Park, Time’s Senior Reporter, said the cover was a mistake !

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Clinical Trial Ethics

Clinical trials are governed by international codes and laws to protect human subjects

Hippocratic Oath: to do no harm

The Nuremberg Code of Ethics in Medical Research - 1947

Declaration of Helsinki - 1964

Belmont Report - 1978

OHRP – Office for Human Research Protections at NIH – covers human subjects and laboratory animals

Many new regulations and guidelines on protection of human subjects are being developed

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Evolution of Human Research

Celsius, first century AD

“it is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries”

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Development of Modern Science

Edward Jenner (1700s)

Smallpox vaccination

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Royal Commission of Vivisection (1908)

Commission (evaluating Dr. Walter Reed and yellow fever studies)

I understand that in the case of yellow fever the recent experiments have been on man

Dr. William Osler

Yes, definitely with the specific consent of these individuals who wnet into the camp voluntarily

Commission

We were told by a witness that in his opinion to experiment upon man with possible ill result was immoral. Would that be your view?

Dr. William Osler

It is always immoral, without a definite, specific statement form the individual himself, with a full knowledge of the circumstances. Under these circumstances, any man, I think is at liberty to submit himself to experiemnts.

Commission

Given voluntary consent, you think that entirely changes the question of morality or otherwise?

Dr. William Osler

Entirely

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Nuremberg

At the end of world War II, 23 Nazi doctors and scientists were put on trial for the murder of concentration camp inmates who were used as research subjects. 15 were convicted, 7 were condemned to death by hanging, 8 received prison sentences from 10 years to life, and 8 were acquitted.

The Nuremberg Code was developed.

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Nuremberg Code

Informed consent is essential

Research should be based on prior animal work

The risks should be justified by the anticipated beneftis

Only qualified scientists must conduct research

Physical and mental suffering must be avoided.

Research in which death or disabling injury is expect should not be conducted.

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Nuremberg Code

Did not have strength of law

Created post hoc

Applied only to non-therapeutic research

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Declaration of Helsinki

In 1964 the

World Medical Association

developed a code of research ethics that came to be known as the

Declaration of Helsinki

.

It was a reinterpretation of the Nuremberg Code, with an eye to medical research with therapeutic intent.Subsequently, journal editors required that research be performed in accordance with the Declaration. In principle, this document set the stage for the implementation of the Institutional Review Board (IRB) process.

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Ethical Problems

The Beecher article (1996) and increased public awareness brought to light problems (22 studies reviewed) with ethics in research.

He stated that “medicine is sound and most progress is soundly attained”…..if unethical research is not prohibited it will “do great harm to medicine”

Beecher HK, NEJM June 16, 1996

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Ethical Problems

The Beecher article (1996) brought to light problems (22 studies reviewed) with ethics in research such as the following:

Lack of informed consent

Coercion or undue pressure on volunteers (or on a parent to volunteer their child)

Use of a vulnerable population

Exploitation of a vulnerable population

Withholding information

Withholding information about risks

Putting subjects at risk

Risks to subjects outweigh benefits

Deception

Violation of rights

Beecher HK, NEJM June 16, 1996

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Willowbrook Hepatitis Study

In 1956, at an institution for mentally retarded children in Staten Island, New York, a study was initiated to determine the natural history of viral hepatitis and to test the effectiveness of gamma globulin as an agent for inoculation against hepatitis. Children were deliberately infected with a mild form of hepatitis.

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The investigators defended the study by stating that most new children would become infected with hepatitis within their first 6 – 12 months at the institution.

Although permission was obtained from parents, the parents were not fully informed of the possible hazards involved in the study.

There is evidence that the parents were led to believe that the child would not be enrolled at the school unless the parents signed the consent form.

Ethical problems: exploitation of a vulnerable group of subjects, withholding information about risks, coercion or undue pressure on parents to volunteer their children.

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Jewish Chronic Disease Study

In 1963 live cancer cells were injected into senile patients with their knowledge as part of a study of immunity to cancer.

Since the investigators believed that the cells would be rejected, the researchers did not inform the patients or seek consent because they did not want to frighten them.

Ethical problems:

lack of informed consent, use of a vulnerable group of subjects, risks to subjects outweighed benefits.

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San Antonio Contraception Study

In San Antonio, Texas, a number of Mexican-American women participated in a 1971 study to determine side effects of an oral contraceptive. The women came to a clinic seeking contraceptives.

Unbeknownst to them, the study was designed so that half the women would receive oral contraceptive for the first half of the study, then switched to placebo. The women initially receiving placebo were placed on the oral contraceptive for the second half of the study. Ten of the 76 participants became pregnant while using placebo.

Ethical problems:

lack of informed consent, use of a vulnerable group of subjects, risks to subjects outweighed benefits.

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The Public Health Service Syphilis Study (1932-1971)

Initiated by the Public Health Service, this study was designed to document the natural history of syphilis in African-American men.

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At the time the study began there was no known treatment for syphilis.

Hundreds of men with syphilis and hundreds of men without syphilis (serving as controls) were enrolled into the study.

The men were recruited without truly informed consent. They were deliberately misinformed about the need for some of the procedures. For example, spinal taps were described as necessary and special “free treatment.”

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Even after penicillin was found to be a safe and effective treatment for syphilis in the 1940’s, the men were denied antibiotics.

The study continued to track these men until 1972 when the first public accounts of the study appeared in the national press. The study resulted in 28 deaths 100 cases of disability, and 19 cases of congenital syphilis.

Ethical problems:

lack of informed consent, deception, withholding information, withholding available treatment, putting men and their families at risk, exploitation of a vulnerable group of subjects who would not benefit for participation.

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The Belmont Report

The National Commission met and in 1979 published the

Belmont Report.

The

Belmont Report

is “required reading” for everyone involved in human subject research.

The Belmont Report identifies three basic ethical principles that underlie all human subject research. These principles are commonly called the Belmont Principles. The Belmont Principles are respect for person, beneficence, and justice.

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Informed Consent

Information:

pts must be informed of aims, methods, anticipated benefits, and potential hazards & discomforts; right not to participate or withdraw at any time

Comprehension:

pts must understand these rights and give written consent

Voluntariness:

pts must give voluntary consent without coercionRisks and Benefits:

must be clearly presented in plain English

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Institutional Review Board - IRB

IRB’s are administrative bodies established to protect the rights and welfare of human research subjects

OSU has 3 IRB’s: Biomed, Cancer, & Behavioral

Cancer IRB meets biweekly to review all trials

The 12 members are required to represent multiple disciplines and include scientists, non-scientists, non-OSU members, and represent diverse racial, gender, & cultural backgrounds

Above all, it must be fair and impartial

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Data and Safety Monitoring Board

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Data and Safety Monitoring Boards

or Committees [DSMB/DSMC]

All clinical trials require some form of monitoring

Degree of monitoring commensurate with:

Risk of participation

Size of trial – number of patients

Complexity of trial

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What studies need a formal DSMB?

Randomized

Phase III

More than 100 patients

Data is blinded

More than one site/institution

Proposes a high risk interventionProtocol uses gene transfer / gene therapy

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DSMB Responsibilities

Become familiar with protocol and plans for data and safety monitoring

Review interim analyses of outcome and cumulative adverse event data

Review reports/papers of related studies

Review major proposed study modifications

Make recommendations in meeting report

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DSMB Membership

6+ members

Clinicians, biostatistician, regulatory officer, lay patient advocate

All represent the interests of patients, not investigator, institution, or sponsor

Must disclose all real or perceived conflicts of interest

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DSMB Recommendations

Termination [toxicity or benefit]

Continuation

Modification

Suspension

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Trial Statistician Reports to DSMB

Prior to DSMB meeting, the trial statistician prepares a full data summary

Summary includes patient demographic data, outcome data, adverse events, and protocol-specified interim analyses

If specified in the protocol, a futility analysis may be included

DSMB may be blinded or unblinded

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DSMB

The DSMB plays a unique and vital role in ensuring the safety of patients during their participation in a therapeutic clinical trial offering potential risks to their health and safety

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Other issues

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Inclusion of Women, Minorities and Children in Clinical Trials

NIH Revitalization Act of 1993:

Guidelines that require inclusion of women & minorities in clinical studies and stipulate that:

Women & minorities are to be included in all human subject research

They are to be included in Phase III trials to allow sufficient power to note differences

Cost cannot be a barrier

Outreach activities must take place to include & follow these groups

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DHHS/NIH Mandatory Education in Protection of Human Subjects

Required for NIH-supported staff involved in the design and conduct of clinical trials to include:

PI’s & Assoc Investigators

Nurse Coordinators

Data Managers

Statisticians!

How to protect the rights and welfare of all human participants in clinical research

No grants funded until completed!

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DHHS/NIH Mandatory Education in Protection of Human Subjects

Course includes concepts, history, principles, and issues

Bioethics and basic legal standards

Uses case studies and exercises

On-line web-based or formal course

Institution maintains roster of those completing the course

No grants are funded until all key personnel

of the grant have completed the course!

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HIPAA: Health Insurance Portability and Accountability Act of 1996

HIPAA protects patient information

HIPAA Privacy Rule went into effect on April 14, 2003

Privacy Rule in 45 CFR 160 / 164

Covers individually identifiable health information known as Protected Health Information [PHI]

Requires data to be de-identified

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HIPAA:

Health Insurance Portability and Accountability Act of 1996

Names

Addresses

Dates [< year]

Telephone #

Fax #Email addressSocial Security No.

Medical Record No.

Health Plan No.

Account No.

Vehicle Identifiers

URL’s / IP addresses

Fingerprints

Voiceprints

Full face photographs

Any other unique identifier

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What’s HIPAA have to do with me?

HIPAA affects everyone involved in the conduct of clinical research

Regulates use of data for research and disclosure of PHI

Use and sharing of data within and outside the Covered Entity [CE]

HIPAA introduces new ways by which CE’s handle PHI

Violators are subject to criminal prosecution

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Clinical Trial Ethics / Patient Protection

Violations of patient rights and patient abuse in clinical research have led to a proliferation of regulations designed to protect patients

Patients are protected as never before from unnecessary risks from participating in clinical research

Clinical biostatisticians have a key role in the process of patient protection in the ethical design, conduct, and analysis of clinical trials

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Thank you !