principles and practice of clinical research · principles and practice of clinical research ......

Principles and Practice of Clinical Research

C. Sola Olopade, MD, MPH, FCCP Professor of Medicine Clinical Director, Global Health Initiative University of Chicago

THE UNIVERSITY OF CHICAGO

G L O B A LH E A L T HINITIATIVE

NIH Clinical Center



Mission

Science

Patient Care

Training



NIH Training Curriculum In Clinical Research

Ethical and Regulatory Aspects of Human Subjects Research >3,700 participants since course began in 1999

Introduction to the Principles & Practice of Clinical Research >8,900 participants since course introduced in 1995

Principles of Clinical Pharmacology >5,300 registrants since course began in 1998

http://clinicalcenter.nih.gov/training/training/ippcr.html



Workshop Format

•  1-3 lecture(s) per faculty member •  Discussion of research topics and ideas with

faculty •  DVDs received by all participants contain

additional lectures to supplement presentations



Course Overview

•  Daily lectures – The need for research – Ethics and responsible conduct of research –  Study design and Biostatistics –  Importance of team science and collaboration – Discussion of research ideas – Grant opportunities



Expectations

•  Above 80% attendance with active participation

•  Completion of Program Evaluation

•  Success in Final Examination on 09/30/11

•  Certificate awarded for passing grade of 75%



Learning Objectives •  Provide overview of history of research •  Why conduct research? •  Define:

–  Human Subject –  Research –  Clinical Trial

•  Summarize the phases of clinical research •  Name the essential activities that are

conducted during a clinical trial



What is Research?

“Research” is “a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge”

(45 CFR46).



Definition of Clinical Research

• Patient-Oriented Research

Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects…includes: - Development of new technologies - Mechanisms of human disease - Therapeutic interventions - Clinical Trials

• Epidemiologic and Behavioral Studies • Outcomes Research and Health Services Research

*From NIH Director’s Panel on Clinical Research, 1996



History of Clinical Trials

“Then Daniel said to the steward…

Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let our appearance and the appearance of the youths who eat the king’s rich food be observed by you, and according to what you see, deal with your servants.

So he harkened to them in this matter; and tested them for ten days.

At the end of ten days it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s rich food. So the steward took away their rich food and the wine they were to drink, and gave them vegetables.”

Daniel 1:11 – 16c. 530 BC (Courtesy John Gallin, MD)



• Scurvy was a major health problem for the British Navy in the 1700’s.

• William Harvey had recommended lemons to treat scurvy, but had argued that the therapeutic effect was a result of the acid in the fruit.

• James Lind, a naval surgeon, conducted a clinical trial in 1747 to assess the utility of three therapies for scurvy.

James Lind

Born in Edinburgh, Scotland (1716 – 1794)




• 12 sailors with classical scurvy, divided into six groups of two each; all given identical diets, the various groups supplemented with: - vinegar - diluted sulfuric acid - cider - sea water - nutmeg, garlic, and horseradish mixture - two oranges and one lemon, daily


James Lind - Experimental Design




James Lind - Experimental Design (cont’d)

Treatment Arm Cured P Value*

Sulfuric Acid 0/2 NS

Vinegar 0/2 NS

Sea Water 0/2 NS

Cider 0/2 NS

Physician’s Remedy 0/2 NS

Citrus Fruit 2/2 NS!!!!

*Compared to patients in the other 5 arms of the trial; no placebo group



Ancient Chinese Medicine

2737 B.C. Emperor Shen Nung experimented with poisons and classified medical plants. He is reputed to have eaten 365 medicinal plants over the course of his life, turned green and died.

Shen Nung (c. 2800 B.C.)



Global Successes

•  Identification of new microorganisms (Mokola virus) • Pioneering efforts in characterizing Lassa virus •  Isolation of distinct strains of HIV clustered in W. Africa •  Significant contributions to malaria research

•  Clinical trials demonstrating efficacy of treatment with pyrimethamine-sulphonamide and pyrimethamine-dapsone combinations

• HIV research and treatment program at Ibadan and Jos are models for Nigeria



Poverty and Life Expectancy

Institute of Medicine



Today’s Challenge

UNDP 2009



Why Revamp Research Locally?

•  The 95/10 disequilibrium •  Sub-Saharan Africa and other developing

countries bear over 90% of the global burden of disease

•  Capacity to do research is limited Less than 5% of human capacity needed Brain drain Inadequate funding



What is Clinical Research?

Clinical research, as defined by the National Institutes of Health (NIH), is research performed on human subjects or on material or information obtained from human subjects as part of human experimentation.



Research may include * •  Administration of drugs •  Removal of body tissues or fluids •  Exposure to various forms of radiation •  Alteration of diet or environment •  Interviews or surveys •  Simple observation •  Administration of questionnaires •  Review of medical records

*…(but is not limited to)



What is Clinical Research? The Process

Includes a set of activities meant to test a hypothesis, permit conclusions to be drawn and thereby contribute to generalizable knowledge useful to others.



Goals of Clinical Research?

To generate knowledge useful to improving medical care or the public health and thus serve the common or collective good.



What is Human Subject Research? •  "a living individual about whom an investigator

conducting research, obtains –  (1) data through intervention or –  (2) interaction with the individual, or identifiable private

information." (45 CFR 46.102(f))

•  Human subject research, therefore, does not require direct contact with a subject but may include the systematic collection of private information about individuals, such as review of medical records.



Types of Clinical Research •  Patient oriented research

– Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects -- includes:

•  Development of new technologies •  Mechanism of human disease •  Therapeutic interventions •  Clinical trials



Patient Oriented Research

•  Epidemiological and behavioral studies •  Outcomes research and human services

research



Clinical Trial Definition

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s) , and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. ICH GCP 1.12



Clinical Research Responsibilities

It is the responsibility of the investigator, the institution and the Sponsor to establish an institutional culture where studies are conducted in an ethical and scientifically rigorous manner and where safeguards to subjects who participate in clinical trials are of paramount importance.



Phases of Clinical Research

•  Phase I •  Phase II •  Phase III •  Phase IV



Phase I Objective

•  To determine safe dose, toxicity and pharmacology NOT EFFICACY

•  Introduction of an investigational new drug into humans

•  Small numbers of subjects participate-closely monitored •  Dose escalation •  Eligible patients-Generally Hem/Onc and healthy

volunteers •  Dose limiting toxicity (DLT), Maximum tolerated dose

(MTD)

The purpose is not therapeutic benefit to subjects



Phase II Objective

•  To determine outcome or disease response •  Larger number of subjects participate •  Researchers build on what was learned in phase I-

continue to learn about safety and less common side effects

•  Used in a specific disease or disorder that fits limited eligibility criteria



Phase III Objective

•  To determine if study treatment is as effective or more effective than standard of care

•  Usually involves thousands of subjects •  Multiple centers are involved •  Study treatment is compared to and/or combined with

standard treatment •  Subjects randomized to either “treatment group” or “control group/placebo”



Phase IV

•  Post-marketing •  Monitors long term usage •  Can study affects on certain populations or economic

outcomes •  If dangerous side effects are found, the drug is taken

off the market •  The best example is COX-2 inhibitors and cardiac

events



The Protocol



Protocol=Recipe

•  When participating in a clinical trial, it is of the utmost importance to follow all protocol related specifications written in the text of the study.

•  It should not be difficult to determine what the protocol is designed to measure and what needs to be collected in order to make that measurement.



Essential Elements of a Protocol

•  Objectives: The objectives should be clearly states and generally should be stated as the hypotheses to be tested.

•  Background and Rationale: Sufficient background information should be included so that the rationale for the study is clear. In addition, rationale should be provided and if extensive, an appendix should be attached.

•  Patient Eligibility Criteria: Who is eligible to participate in the trial?

•  Pharmaceutical Information (if

appropriate): Product description, solution preparation, storage requirements, stability, route of administration and toxicity information.



Elements, cont.

•  Treatment Plan •  Dose Modification Information •  Criteria for Response •  Monitoring of Patients/Visit Schedule and Require

Exams or Procedures •  Off-Study Criteria •  Statistical Considerations •  Data Collection Procedure •  Reference List



Regulatory Process

•  Approvals needed at the clinical site: – Feasibility – Budget/Contract – Other Committees

• Pharmacy • Radiation • Conflict of interest

– IRB/Ethics Boards



Study Evaluation/Feasibility

Principal Investigator responsibilities 1.  Protocol review for evaluation of research

design and ability to conduct study 2.  Accrual goals 3.  Identification of study personnel 4.  Ensuring suitable environment is present 5.  Assess budget template for appropriate funding



Adequate Resources for Clinical Research

•  The investigator should be able to demonstrate a potential for recruiting the required number of suitable subjects within the agreed recruitment period. ICH GCP 4.2.1

•  The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period. ICH GCP 4.2.2



Adequate Resources for Clinical Research

•  The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely. ICH GCP 4.2.3

•  The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions. ICH GCP 4.2.2



Study Management

•  Essentials for Study Implementation – Clearly defined roles/responsibility –  Start-up –  Screening – Consenting – Visits – Data Collection/Reporting – Adverse events



Other Regulatory Documents Needed Prior to Starting a Clinical Trial: (Critical Documents)

•  CVs for all research staff in

study •  Medical Licenses •  Protocol •  Amendments •  Investigator’s Brochure •  Protocol Signature Pages •  Correspondence •  Current IRB Membership list •  Test Article Records/Drug

Accountability

•  Delegation of Responsibility forms

•  IND Safety Reports •  Laboratory Information

Certifications Reference Ranges Lab Director’s CV and License

•  Telephone Logs •  Site Signature Log •  Monitoring Log •  Financial Disclosures



Essential Steps for Trial Management

•  Subject Screening & Recruitment

•  Obtaining Informed Consent

•  Follow schedule of events related to research intervention

•  Data Collection

•  Case Report Form Completion

•  Screen for adverse events •  Monitoring Visits •  Query resolution •  Data Analysis •  Publication of data



Conclusion

•  Clinical research is serious business!!! •  Clinical research is essential for addressing local

health challenges •  An investigator should have sufficient time,

knowledge and support to properly and safely conduct and complete a clinical trial.

•  Research cannot be conducted without collaborators and highly trained and organized staff.