Clinical Trials and Good Clinical Practice M Suzanne

Clinical Trials and Good Clinical Practice M Suzanne Stratton, Ph. D Research Assistant Professor of Medicine Director, Prostate Cancer Prevention Program Co-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 longterm effectiveness and impact on a patient's quality of life • Many studies are designed to determine the costeffectiveness 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 • 1940 s – 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: President Vice President Executive office of the president Dept. of Health & Human Srvcs

D S H H Mike Leavitt Andy Voneschenbach

Office of New Drugs

‘Bench to Bedside’ All data Epidemiology Mechanistic lab studies Basic scientist with an idea Investigational New Drug (IND) Application Clinical plan IN VIVO IN VITRO Pharmacodynamics Potential mechanism Pharmacokinetics Safety Effectiveness Mechanism Shows activity

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

Selenium and overall cancer risk Epidemiological Study Population Se Measure Results Shamberger and Frost, 1969 USA/Canada Grain/forage Blood Inverse * Schrauzer, 1976 27 countries Diet Inverse * USA Forage crop Inverse * China Forage crop Inverse * Clark, 1985 Yu, 1985

Epidemiological studies and prostate cancer Study Population n= Se Measure Results ‡ Coates et al. , 1988 USA 13 Plasma 0. 30 (p trend 0. 18) Knekt et al. , 1990 Finland 51 Serum 1. 15 (p trend 0. 71) Criqui et al. , 1991 USA 60 Plasma Inv (p trend 0. 44) Vinceti et al. , 1995 Italy 27 Se in water Clark et al. , 1996 USA 13 Se suppl. Finland 317 Diet Self suppl. Hartman et al. , 1998 ‡ Relative Risk in highest versus lowest quartile. 0. 69 (0. 03 -2. 5) 0. 37 (0. 18 -0. 71) * 1. 27 (0. 70 -2. 20) 0. 84 (0. 43 -1. 67)

Epidemiological studies and prostate cancer Study Yoshizawa et al. , 1998 Nomura et al. , 2000 Ghadirian et al. , 2000 Population n= Se Measure Results ‡ USA 181 Toenail 0. 35 (0. 16 -0. 78) * Japan-Am 249 Serum 0. 50 (p trend 0. 02) * Canada 83 Toenail 1. 14 (0. 46 -2. 83) ‡ Relative Risk in highest versus lowest quantile. Source: Vinceti, M. et al. , The Epidemiology of Selenium and Human Cancer. Tumori, 86: 105 -118, 2000.

Clinical studies with selenium Study Population n= Treatment Results ‡ Blot et al. , 1985 Chinese 81 50 mg 0. 87 (0. 75 -1. 00) * Clark et al. , 1986 USA 77 200 mg 0. 63 (0. 47 -0. 85) * ‡ Relative Risk in selenium exposed versus selenium unexposed. IND submitted and approved

NPC Study Design • Double-blind • Randomized • Placebo-controlled • 1312 participants with a history of nonmelanoma skin cancer • Randomized to receive 200 mg selenized yeast daily or placebo • Clinics in the Eastern U. S.

NPC Study Design Primary endpoints Recurrence of nonmelanoma skin cancer Secondary endpoints All cause mortality Specific site cancers (colon, breast, lung, prostate)

Summary of primary analyses JAMA. 1996 Dec 25; 276(24): 1957 -63. Baseline plasma selenium level Lower baseline – more chemopreventive effect Gender Greater effect in men Age No apparent difference Smoking status No apparent difference

Site specific cancer incidence JAMA. 1996 Dec 25; 276(24): 1957 -63. Case No. Site Unadjusted Adjusted Se Plac RR* (95% CI) p HR (95% CI) p Prostate 22 42 0. 51 0. 29 -0. 88 0. 009 0. 48 0. 28 -0. 80 0. 005 Lung 25 35 0. 70 0. 40 -1. 21 0. 18 0. 74 0. 44 -1. 24 0. 26 Colorectal 9 19 0. 46 0. 19 -1. 08 0. 055 0. 46 0. 21 -1. 02 0. 057 Other car. 6 9 0. 66 0. 19 -2. 07 0. 44 0. 67 0. 24 -1. 88 0. 44 ‡ 62% decrease in incidence in prostate cancer

Cumulative hazard ratio by treatment group JAMA. 1996 Dec 25; 276(24): 1957 -63. Cumulative incidence 0. 15 Placebo 0. 10 Se 0. 05 0. 00 0 5 analysis time Years of follow-up 10 Log-rank, p=0. 009

Prostate Cancer Incidence by Tertile of Baseline Plasma Selenium BJU Int. 2003 May; 91(7): 608 -12 Baseline No. Cases Se ng/ml Se Unadjusted Adjusted Plac RR* (95% CI) p HR ‡ (95% CI) p ≤ 106. 4 2 15 0. 14 0. 02 -0. 59 0. 002 0. 14 0. 03 -0. 61 0. 009 106. 8 -123. 2 7 16 0. 39 0. 14 -0. 99 0. 03 0. 33 0. 13 -0. 82 0. 02 > 123. 2 13 11 1. 20 0. 50 -2. 97 0. 66 1. 14 0. 51 -2. 59 0. 75 * 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.

Prostate Cancer Incidence by Baseline PSA BJU Int. 2003 May; 91(7): 608 -12 Baseline No. Cases PSA ng/ml Se Unadjusted Plac RR* ≤ 4. 0 7 20 0. 35 > 4. 0 11 13 0. 88 (95% CI) 0. 13 -0. 87 0. 36 -2. 13 Adjusted p HR ‡ (95% CI) p 0. 01 0. 33 0. 14 -0. 79 0. 01 0. 86 0. 95 0. 42 -2. 14 0. 09 * 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.

Summary of Prostate Data • 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

The Negative Biopsy Study (NBT) 80% compliance Screening Biopsy negative for HGPIN and prostate cancer Primary endpoints: Prostate cancer PSA velocity Run-in Enrollment R A N D O M I Z A T I O N Placebo 200 mg selenium Follow-up up to 5 years or prostate cancer 400 mg selenium Secondary endpoints: Tissue biomarkers IHC Karyometric analyses Anticancer Drugs. 2003 Sep; 14(8): 589 -94

Final analyses of primary endpoint (SCC recurrence) JNCI 95(19). Oct 1, 2003. RR Adjusted (95%) p ≤ 105. 2 0. 87 0. 62 -1. 22 0. 42 105. 3 -122. 0 1. 49 1. 05 -2. 12 0. 03 1. 59 1. 11 -2. 30 0. 01 Baseline Se (ng/m. L) > 122. 0 Cases Placebo 196 Selenium 244

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

ns o i t a ct e p x E t a Drug Discovery e Gr ~ 10, 000 Compounds Phase II Clinical 1 -2 years $10 -100 Million 40% 15% Phase III 2 -8 years $10 -500 Million 1 -5 years $1 Million 250 Compounds Phase I Clinical 1 year $100 k – 1 Million 80% Preclinical Dev 1 -4 years $250 k-850 k IND Application 5 Compounds New Drug Application (NDA) ty i l a Re 1 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?