Clinical Trials and Good Clinical

PracticeM Suzanne Stratton, PhD

Research Assistant Professor of MedicineDirector, Prostate Cancer Prevention

ProgramCo-Chair, Institutional Review Board

Lecture objectives

• Become familiar with clinical trial types/phases

• Gain familiarity with government oversight of clinical trial practices

• Learn about what it takes to bring a drug from ‘bench to bedside’

• Learn about Good Clinical Practice using the example of an ongoing Phase III trial testing selenium as a chemopreventive agent

What is a clinical trial?

• A clinical trial (also clinical research) is a research study in human volunteers to answer specific health questions

• Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health.

• Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments.

• Observational trials address health issues in large groups of people or populations in natural settings.

• What are the steps to drug approval or (in the clinic)?

Types of clinical trials• Treatment trials test experimental treatments, new

combinations of drugs, or new approaches to surgery or radiation therapy.

• Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.

• Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.

• Screening trials test the best way to detect certain diseases or health conditions.

• Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

Interventional clinical trial phases

• Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions:

– In Phase I trials, researchers test a experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

– In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

– In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

– In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

Phase I Trials

• First time in humans – May not be required if drug is well-known dietary supplement, e.g. Vitamin E or selenium for chemoprevention

• Primary objective is safety– Pharmacokinetic data is often obtained

• Small numbers of subjects– Usually healthy subjects (not in cancer)

• Identifies likely dose range– Dose tolerance/escalation performed especially if dose is to be based on toxicity (cancer therapeutic drugs)

Phase I Trials (Continued)

• Length: several days to several weeks

• Closely monitored

• Special indications (Cancer, HIV) – Performed in subjects with condition for whom conventional therapies have failed or are not an option

Phase II Trials

• Safety & efficacy in select population– Larger than Phase I (50-200 subjects)– Usually no comparator arm

• Chemoprevention Phase IIa– Dose-finding based on efficacy in small # of patients

• Chemoprevention Phase IIb– Efficacy study of one dose, often compared to placebo in larger # of patients

• Seeking maximum benefit with minimal side effects

Phase III Trials

• Definitive studies, Multicenter, $$

• Confirm safety & efficacy in large population (100 – 2500 subjects/study)

• Randomized comparison is drug vs. placebo (or current standard of care)

• 2 ‘pivotal’ studies generally required

• Demonstrates reproducibility of results

• NDA approval will be based on data from these studies

Phase III Trials (Continued)

• Provides adequate basis for labeling

• Therapeutic market advantages

• Broad demographics required for generalization

• Ethnic & geographic representation required

Phase IV

• Studies often compare a drug with other drugs already in the market

• Studies are often designed to monitor a drug's long-term effectiveness and impact on a patient's quality of life

• Many studies are designed to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies.

Clinical trial oversight

• FOOD AND DRUG ADMINISTRATION (FDA): The U.S. Department of Health and Human Services agency responsible for ensuring the safety and effectiveness of all drugs, biologics, vaccines, and medical devices

• http://www.fda.gov/oc/gcp/default.htm

• Center for Drug Evaluation and Research (CDER)– Assures safe drugs in the US

CDER History

• 1902 - Harvey Wiley, the Chief Chemist of the Bureau of Chemistry, announced the formation of a Drug Laboratory within his organization.

• 1906 Pure Food and Drugs Act (one-man operation) – ‘FDA”

• 1910 – First challenge to enforce regulation when a bogus cancer drug was sold with false advertising

• 1926 – First standardized manufacturing testing in response to several deaths from impurities in anesthetics

• 1937 – FDA requirement of NDA

• 1940s – FDA assumed oversight for testing of penicillin, insulin and use labeling

• 1966 – Reformed organization– Office of New Drugs – Office of Drug Surveillance – Office of Medical Review – Bureau of Veterinary Medicine

CDER History• 1962 - Kefauver-Harris Amendments in response to the

narrowly missed disaster of thalidomide

• To comply with the new amendment, previously approved drugs were tested for efficacy– Of 3,443 products, 2,225 were found to be effective, 1,051

were found not effective (1984)

• 1972 – the results of the ongoing review were published in a monograph entitled the Code of Federal Regulations (CFR)– specifying the active ingredients, restrictions on

formulations, and labeling by therapeutic category

• 1980 – Center for Drugs and Biologics was formed

• 1987 – Broken into two Centers– Center for Biologics Evaluation and Research (CBER)– Center for Drugs Evaluation and Research (CDER)

• 1995 – CDER broken into divisions by indication type

Executive Branch:

PresidentVice PresidentExecutive office of the president

Dept. of Health & Human Srvcs

DHH

S

Mike Leavitt

Andy Voneschenbach

Office of New Drugs

‘Bench to Bedside’

Shows activity

Potential mechanism

IN VITRO Pharmacodynamics

Pharmacokinetics

Safety

Effectiveness

Mechanism

IN VIVO

Investigational New Drug (IND) Application

Investigational New Drug (IND) Application

All data

Clinical plan

Basic scientist with an idea

Epidemiology

Mechanistic lab studies

IND Application

• There can be exemptions • Provides a means of advancing from pre-

clinical to clinical testing• Required for unmarketed/unapproved products • May be required for already marketed

products• Formal application to study an intervention

in patients• Commercial - sponsor usually a

pharmaceutical company• Non-commercial

– investigator IND– treatment IND

IND contents

• Should include the following data– Chemistry, manufacturing, and control information – animal pharmacology / toxicology– prior human use if applicable– clinical protocol(s) and investigator information

• Other required documents– Cover Sheet (Form 1571 or 2)– Table of Contents– Introductory Statement and General Investigational

Plan– Investigational Brochure– Informed Consent Form

IND review

• 30-day review clock

• Clinical hold – Safety concerns (e.g., known risk, inadequate

information, Investigator’s Brochure (IB) misleading, Principal Investigator (PI) not qualified)

– Design will not allow protocol objectives to be met

– Teleconference with sponsor and division director about what is required to lift the hold

‘Bench to Bedside’

Institutional Review Board (IRB)

Human Subject Protection Committee (HPSC)

Good Clinical Practice

• Relationship between Sponsor and Investigators

• Focuses on the investigator commitments signed for on the FDA Form 1572

• Inspection and audits usually announced in advance

• Inspections are either routine or directed

• Compliance classifications– NAI – No Action Indicated. In compliance– VAI – Voluntary Action Indicated. – OAI – Official Action Indicated. Serious non-compliance:

Warning Letter, study rejection, investigator disqualification

Sponsor investigator responsibilities

• Selecting qualified investigators

• Providing the investigators with the information they need to conduct an investigation properly

• Ensuring proper monitoring of the investigation

• Ensuring that the investigation is conducted in accordance with the general investigational plan and protocols

• Ensuring that the FDA, IRB, and other investigators are promptly informed of significant new adverse events or risks with respect to the drug

• Documentation– Updated versions of Investigator’s Brochure– Updated versions of the protocol– Keep investigators aware of any safety issues

Study conduct• Make sure that the study is conducted as outlined in

protocol

• Provide protocol amendments to IRB, FDA, and site investigators

• Report adverse events to IRB, FDA and site investigators

• Provide updated IB to IRB, FDA and site investigators

• Monitor site investigator’s compliance with protocol– Remove non-compliant investigators– Maintain records

• Permit FDA inspection

• Dispose of unused drug

• Provide reports to the FDA – annual reports, safety reports, final study report, financial disclosure

Required safety reporting

• Any AE associated with a drug that is both serious and unexpected

• Any findings from tests in laboratory animals that suggests a significant risk for human use (e.g., positive mutagenicity, carcinogenicity, or tetratogenicity) within 15 days of initial notification

• Any unexpected fatal or life-threatening AE that is associated with use of the drug within 7 days

New Drug Application (NDA)

• Formal application to market a new product (drug)

• Requirement since 1938 (FD & C Act)– safety information

• Kefauver-Harris Amendments 1962– evidence of efficacy and risk/benefit assessment

• NDA classification– New Molecular Entity– New Indication for Already Marketed Drug– New Formulation – New Combination of Two or More Drugs– Others

Basis for NDA approval• Demonstration of efficacy with acceptable safety

in adequate and well-controlled studies

• Ability to generate product labeling that– Defines an appropriate patient population for

treatment with the drug– Provides adequate information to enable safe and

effective use of the drug

• Accelerated approval

• Commonly used endpoints for approval– Survival (the gold standard)– Prolongation in time to recurrence or disease-free

survival (commonly used in adjuvant studies)– Prolongation in time to progression – Palliation (objective response with reduction in

tumor-related symptoms)– Prevention of disease or surrogate endpoint

Why NDAs fail

• Poor Drug Development– Inadequate early development

• Study Design– Populations, endpoint definitions, analysis plan

• Study Execution– Failure to maintain adequate records (dose, drug

disposition, adverse events)– Failure to adhere to regulations

IND Safety Reporting: Shared Responsibility

• Sponsor – Collect & submit all safety data in a timely manner

– Must update IB– Must notify PIs and IRB

– Initiate, audit, terminate clinical site

• FDA– Review, analyze reports– Require changes to

protocol or consent as needed to protect patient safety

• PI– Evaluate and report

toxicities

• IRB– Independently review

toxicities and recommend changes

• Patient– Education, adequate

informed consent– Repeat consent if

necessary

Phase III Study Testing Selenium as a Chemopreventive Agent for Prostate Cancer in

High-Risk Men

How did we get up and running?How do we run?What are some of the regulatory issues?How will it end?

Why selenium?

• Some cancer prevention studies work ‘backwards’

• Preclinical studies were not done before study initiation

• Mechanistic studies are now ongoing– In vitro– In vivo

• This is now rare and preclinical studies are required for natural products (vitamins and supplements)

Selenium background

• Discovered in 1817 by Jons Jakob

• Named after Selene, the Greek Moon Goddess

• Initial interest due to toxicity– Alkali disease, staggers, hoof deformaties

• Prevented liver necrosis in rats

• Livestock white muscle disease

• Low intake associated with Kashin-Beck and Keshan’s disease

• Deficiencies reported in New Zealand

Inverse *Forage cropUSAClark, 1985

Inverse *Forage cropChinaYu, 1985

Inverse *Diet27 countriesSchrauzer, 1976

Inverse *Grain/forageBlood

USA/CanadaShamberger and Frost, 1969

ResultsSe MeasurePopulation Study Study

EpidemiologicalEpidemiological

Selenium and overall cancer risk

Results ‡Se Measuren=Population Study

‡‡ Relative Risk in highest versus lowest quartile.

1.27 (0.70-2.20) 0.84 (0.43-1.67)

DietSelf suppl.

317FinlandHartman et al., 1998

0.37 (0.18-0.71) *

Se suppl.13USAClark et al., 1996

0.69 (0.03-2.5)Se in water

27ItalyVinceti et al., 1995

Inv (p trend 0.44)

Plasma60USACriqui et al., 1991

1.15 (p trend 0.71)

Serum51FinlandKnekt et al., 1990

0.30 (p trend 0.18)

Plasma13USACoates et al., 1988

Epidemiological studies and prostate cancer

‡‡ Relative Risk in highest versus lowest quantile. Source: Vinceti, M. et al., The Epidemiology of Selenium and Human Cancer. Tumori, 86: 105-118, 2000.

0.35 (0.16-0.78) *Toenail181USAYoshizawa et al., 1998

1.14 (0.46-2.83)

Toenail83CanadaGhadirian et al., 2000

0.50 (p trend 0.02) *

Serum249Japan-AmNomura et al., 2000

Results ‡Se Measuren=PopulationStudy

Epidemiological studies and prostate cancer

Chinese

Results ‡

0.87 (0.75-1.00) *

0.63 (0.47-0.85) *

81

‡‡ Relative Risk in selenium exposed versus selenium unexposed.

200 gUSAClark et al., 1986

50 gBlot et al., 1985

Treatmentn=PopulationStudy

77

Clinical studies with selenium

IND submitted and approved

NPC Study Design

• Double-blind

• Randomized

• Placebo-controlled

• 1312 participants with a history of nonmelanoma skin cancer

• Randomized to receive 200g selenized yeast daily or placebo

• Clinics in the Eastern U.S.

NPC Study Design

Primary endpointsPrimary endpoints

Recurrence of nonmelanoma skin cancer

Recurrence of nonmelanoma skin cancer

Secondary endpointsSecondary endpointsAll cause mortality

Specific site cancers (colon, breast, lung, prostate)

All cause mortality

Specific site cancers (colon, breast, lung, prostate)

Summary of primary analyses

Baseline plasma selenium levelBaseline plasma selenium levelLower baseline – more chemopreventive

effectLower baseline – more chemopreventive effect

GenderGenderGreater effect in menGreater effect in men

AgeAgeNo apparent differenceNo apparent difference

Smoking statusSmoking statusNo apparent differenceNo apparent difference

JAMA. 1996 Dec 25;276(24):1957-63.

0.440.24-1.880.670.440.19-2.070.6696Other car.

AdjustedUnadjustedCase No.

0.260.44-1.24

0.740.180.40-1.210.703525Lung

0.0050.28-0.800.480.0090.29-0.880.514222Prostate

0.0570.21-1.02

0.460.0550.19-1.080.46199Colorectal

p(95% CI) HR ‡p(95% CI) RR*PlacSeSite

62% decrease in incidence in prostate cancer

JAMA. 1996 Dec 25;276(24):1957-63.

Site specific cancer incidence

Years of follow-upYears of follow-up

Log-rank, p=0.009Log-rank, p=0.009analysis timeanalysis time

00 55 1010

0.000.00

0.050.05

0.100.10

0.150.15

PlaceboPlacebo

Cumulative incidence

Cumulative incidence

SeSe

JAMA. 1996 Dec 25;276(24):1957-63.

Cumulative hazard ratio by treatment group

p

AdjustedUnadjustedNo. CasesBaseline

0.020.13-0.82

0.330.030.14-0.990.39167106.8-123.2

0.0090.03-0.61

0.140.0020.02-0.590.14152≤ 106.4

0.750.51-2.591.140.660.50-2.971.201113> 123.2

p(95% CI) HR ‡(95% CI) RR*PlacSeSe ng/ml

* RR indicates relative risk; CI indicates confidence interval. P values derived from log rank tests.‡ HR indicates hazard ratio. P values from the Cox proportional hazard model adjusted for gender, age (continuous) and smoking (never, former, current) at randomization.

BJU Int. 2003 May;91(7):608-12

Prostate Cancer Incidence by Tertile of Baseline Plasma Selenium

AdjustedUnadjustedNo. CasesBaseline

0.010.330.010.13-0.870.35207≤ 4.0

0.09

0.14-0.79

0.42-2.140.950.860.36-2.130.881311> 4.0

p(95% CI) HR ‡p(95% CI) RR*PlacSePSA ng/ml

* RR indicates relative risk; CI indicates confidence interval. P values derived from log rank tests.‡ HR indicates hazard ratio. P values from the Cox proportional hazard model adjusted for gender, age (continuous) and smoking (never, former, current) at randomization.

BJU Int. 2003 May;91(7):608-12

Prostate Cancer Incidence by Baseline PSA

• Lower biopsy rate in the treatment group

• Lower incidence in two lower tertiles of baseline selenium

• Lower incidence with baseline PSA ≤4

• Smoking status and age – No effect

Summary of Prostate Data

Follow-up up to 5 years or prostate cancer

Primary endpoints:Prostate cancerPSA velocity

Secondary endpoints:Tissue biomarkers IHCKaryometric analyses

400g selenium400g selenium

200g selenium200g selenium

PlaceboPlaceboRANDOMIZATION

RANDOMIZATION

80% compliance

80% compliance

Run-inRun-in

Enrollment

Screening

Biopsy negative for HGPIN and prostate cancer

Anticancer Drugs. 2003 Sep;14(8):589-94

The Negative Biopsy Study (NBT)

Adjusted (95%)

Adjusted (95%)

pp RR RR

0.030.031.05-2.121.05-2.12

1.591.59

105.3-122.0105.3-122.0

0.420.420.62-1.220.62-1.220.870.87≤ 105.2≤ 105.2

0.010.011.11-2.301.11-2.30

1.491.49

> 122.0> 122.0

Baseline Se (ng/mL)Baseline Se (ng/mL)

Placebo 196

Selenium 244

Cases

JNCI 95(19). Oct 1, 2003.

Final analyses of primary endpoint (SCC recurrence)

How did this affect trial conduct?• Before data were published

• Contact the external Data Safety Monitoring Board (DSMB for recommendations )

• Contact IRB

• Contact NCI– DSMB dictated to add information into the Informed

Consent Form (ICF)

• Rreconsent patients

• FDA report

GreatGreat Expe

ctations

Expectatio

ns

Drug Discovery1-5 years$1 Million

Preclinical Dev1-4 years

$250k-850k

IND ApplicationPhase I Clinical

1 year$100k – 1 Million

Phase II Clinical1-2 years

$10-100 Million

Phase III2-8 years

$10-500 MillionRea

lity

Realit

yNew DrugApplication

(NDA)

~ 10,000~ 10,000 CompoundsCompounds

250250 CompoundsCompounds

15%15%

40%40% 80%80%

55 CompoundsCompounds

1 New Drug1 New Drug

Topics for discussion

• What are examples of patient compliance issues and how are they handled?

• What are the differences between treatment and a clinical trial?

• What are ways to change trial conduct to reduce risk if a new toxicity is discovered?

• Why are studies blinded?

• What are the disadvantages of cancer prevention trials with regard to trial conduct?– How can some of the disadvantages be circumvented?