ISBHT - Clinical Trials

CLINICAL TRIALS
(A Certificate Course)

The Institute of Strategic Biotechnology, Health and Training (ISBHT), Bangalore, India, has launched a long-distance partnership with the National Institutes of Health (NIH), United States, to offer a comprehensive training course in “Clinical Research and Clinical Trials.” The key objective of this partnership is to foster a cGCP-based curriculum for building the infrastructure, training and standards for conducting clinical research/trials in India. The extraordinary scientific and technological advances that we have seen over the last 10 years in biomedical research have energized the pharmaceutical and biotechnology discovery sector(s) around the globe.

The NIH is the world premier organization that supports discovery-and translational-based medical and health research, which improves health and save lives around the globe. It provides extraordinary global leadership, direction and support to programs and technologies that provide great impetus to tackle human diseases. The broader theme of the NIH research support involves:

• The causes, diagnosis, prevention, and cure of human diseases;
• The processes of human growth and development;
• The biological effects of environmental contaminants;
• The understanding of mental, addictive and physical disorders; and
• Directing programs for the collection, dissemination, and exchange of information in medicine and
   health, including the development and support of medical libraries and the training of medical
   librarians and other health information specialists.
• Providing global leadership and support for research in areas of significant public health
importance such as HIV/AIDS, malaria and tuberculosis, bioethics and other training programs in
developing countries, including India.

Translational Medicine

One of the greatest accomplishments of modern sciences and at the end of the 20th century is the ‘Human Genome Project,’ which has revolutionized how we can diagnose and treat diseases. The Human Genome Project has transformed biology, which is now referred to ‘Systems Biology.’ We now have the ability to look for differences and similarities between all the genes of multiple species. From these studies (comparative genomics), we can draw specific conclusions about genetic susceptibility and pre-disposition, differences between the species and about the evolution. DNA microarrays technologies designed to measure the relative number of copies of a genetic message (levels of gene expression) at different stages in development or disease or in different tissues have gained highly significant importance in Translational Medicine.

Elias A. Zerhouni, M.D., NIH Director, states that we are in a revolutionary period of medicine that calls for the four Ps: Predictive, Personalized, Preemptive and Participatory. He believes that this new concept requires patient involvement well before disease strikes. In his opinion, the future is going to be patient-centric and proactive as opposed to the doctor-centric, curative model of the past. It must be based on education and communication. This model also applies to developing countries, including India.

What is Clinical Research?

In general, “clinical research” is defined as that either directly involves individual people or uses materials of human origin, such as behavior or tissue samples, that can be linked to a particular living person. Since it deals with individual people and/or materials of human origin, very complex issues often arise, including the protection of human subjects, standard of health care and personal data. Further, more complexities arise when human subjects are used for “clinical trials” as defined by the regulatory framework, and standards.

NIH Definition

At NIH, “Clinical Research” is defined as “Patient-Oriented Research” and it involves human subjects and/or materials from human subjects and can include:

• Studies of mechanisms of human disease;
• Studies of therapeutic interventions;
• Clinical trials;
• Development of new technology;
• Epidemiological and behavioral studies: These types of studies examine the factors that affect
health and health-related decisions;
• Outcomes and health services research: These studies seek to identify the most effective and
most efficient interventions, treatments, and services.

Clinical Research Training at NIH

At NIH, a formal annual training course in clinical research is offered at its clinical research hospital. The program trains researchers in how to design a successful clinical trial by focusing on epidemiologic methods, study design, protocol preparation, patient monitoring, ethical issues, including human subjects’ protection and informed consent, Institutional Review Boards (IRBs), data management, quality assurance, Food and Drug Administration (FDA) regulatory issues, and international clinical trials.

Standards are developed and approved by the NIH for performing clinical research at the NIH. All clinical principal investigators with a protocol approved through the NIH Clinical Center are required to take this course and successfully complete a final exam. Many US prominent medical schools, including Duke University, access this course offered by the NIH. A certificate is awarded upon successful completion of the course, including a final exam. The NIH has also added an online discussion board for student’s use. This forum will allow students to post questions and discuss topics with classmates. This activity should be of interest to physicians and other health professionals training for a career in clinical research and FDA-approved Trials.

Clinical Trials in India

Although India does have the all the prerequisites and hospital base for clinical research, it desires to improve further its infrastructure and training for clinical research/trials that can meet cGCP requirements as required by global companies. Such a “Clinical Research Enterprise”, will help India become more competitive in drug development areas and also, take advantage of the opportunities for global clinical trials that could be outsourced by companies. India does significant advantages, which include:

• A diverse patient population base;
• A therapeutic diversity;
• Expanding state of the art tertiary care hospitals;
• Trained and English-speaking physicians;
• Trained and English-speaking nurses and other support personnel;
• Excellent drug manufacturing facilities;
• Dominant generic drug makers;
• Presence of global pharmaceutical/Biotechnology firms;
• Expanding research and development infrastructure;
• Excellent computing infrastructure for bioinformatics;
• A new global regulatory environment.

In establishing this partnership with NIH in offering this course, the ISBHT has reviewed and carefully considered global standards, which we believe will benefit both clinical investigators and individuals, who may wish to pursue careers at the global level in clinical research/trials (FDA-approved and domestic). The goal of the Institute is to provide a well-structured and globally-competitive training program(s) that would meet the requirements of the trainees and the market place.

Course Objectives

• To make trainees understand the principals, practices, and methods in clinical research/trials,
   including study design, data collection, statistics, data analysis, data reporting and
   management;
• To teach trainees with the basic methods involved in epidemiologic clinical research that is
   necessary even for developing countries like India;
• To teach the principles of ethics, legal issues and regulations involved in clinical research/trials,
   including the role of IRBs in clinical research;
• To teach trainees in patient-oriented research, including monitoring, tracking, and reporting
   adverse events; and,
• To provide an overview of the infrastructure required for clinical research and of the steps
   involved in developing and funding research studies;
• To provide an understanding of the regulatory guidelines (European, US-FDA and Indian
   guidelines) for clinical trials (Phase I-IV).

This course is expected to meet global regulatory requirements on human subject issues, IRBs, Ethics and Informed Consent, Data Safety Monitoring, Data Collection, integrity and security and other related issues. The course is carefully structured to include faculty from NIH, other institutions from the US and India, and a combination effective teaching technologies and tools to create a great learning environment. A learning module would also involve a web-based discussion forum.

We believe that this course will be ideally suited to clinical investigators, who are and plan to be involved in clinical trials, practicing clinicians, medical graduates, allied health professionals (nursing and pharmacy graduates) and other graduates, who might be interested in clinical trials. It is also expected that the students who take this course will successfully complete a web-based exam to obtain a certificate from the Institute at the end of the program.

CLINCIAL TRIALS
Organization:               The Institute for Strategic Biotechnology, Health and Training (ISBHT)
                                   www.isbht.org

Venue:                         To be Announced
                                   Address

Course Duration:           Four Months-2 Full Days a Week
                                   Start Date: To be Announced

Course Fee:                  Rs. 45,000

Eligibility:                     Graduates of Life Sciences
                                   Biotechnology
                                   Professional Programs (Pharmacy/MBBS/BDS/Nursing)
                                   Pharmaceutical/Biotech Companies
                                   Contract Research Organizations (CRO’s)
                                   Other Related Organizations

Course Faculty

Carolyn Anne Carroll, Ph.D.
Mahadev Murthy, Ph.D., M.B.A.

Other US Faculty

Introduction

1. John I. Gallin, M.D., Clinical Research Center, National Institutes of Health, Bethesda, MD
2. Susan Lowell Butler, National Institutes of Health, Bethesda, MD
3. Miriam F. Kelty, Ph.D., National Institutes of Health, Bethesda, MD
4. Martin L. Brown, Ph.D., Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD
5. Kathryn C. Zoon, Ph.D., Acting Director, DIR/NIAID, National Institutes of Health, Bethesda, MD
6. Phillip L. Gomez, Ph.D., M.B.A., Director, Vaccine Production, National Institutes of Health, Bethesda, MD
7. Christopher P. Austin, M.D., Senior Advisor to the Director for Translational Research, National Human Genomics Research Institute, National Institutes of Health, Bethesda, MD
8. Mitchell Max, M.D., Joanne Lynn, M.D., M.A., M.S., National Institutes of Health, Bethesda, MD
9. Joanne Lynn, M.D., M.A., M.S., National Institutes of Health, Bethesda, MD
10. Stephen E. Straus, M.D., Director, National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
11. Marc R. Blackman, M.D., Chief, Endocrine Section, Laboratory of Clinical Investigation, National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
12. Jack Spiegel, Ph.D., Senior Advisor for Technology Transfer Operations, Office of Technology Transfer, National Institutes of Health, Bethesda, MD
13. Bruce Goldstein, J.D., M.S., Technology Transfer Policy Specialist, Office of Technology Transfer, National Institutes of Health, Bethesda, MD
14. John T. Burklow, Associate Director for Communications, National Institutes of Health, Bethesda, MD
15. Josh Duberman, MLIS, Informationist/Research Librarian, National Institutes of Health, Bethesda, MD

Data Management

1. Bon Nussenblatt, M.D., National Institutes of Health, Bethesda, MD
2. David W. Mailhot, National Institutes of Health, Bethesda, MD
3. Anne Tompkins, National Institutes of Health, Bethesda, MD
4. Frederick L. Ferris, III, M.D., National Institutes of Health, Bethesda, MD
5. Jack M. Guralnik, M.D., Ph.D., Laboratory of Epidemiology, Demography and Biometry, National Institutes of Health, Bethesda, MD

Project Management

1. Charles Grudzinskas, Ph.D., NDA Partners, LLC, Center for Drug Development Science (CDDS), UCSF, Washington Center, Presented this talk at the National Institutes of Health, Bethesda, MD
2. Margaret Matula, R.N., M.G.A., Branch Chief, Clinical Research Management Branch, Therapeutics Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD

Epidemiological Studies

1. Jack M. Guralnik, M.D., Ph.D., Laboratory of Epidemiology, Demography and Biometry, National Institutes of Health, Bethesda, MD
2. Jack M. Guralnik, M.D., Ph.D., Laboratory of Epidemiology, Demography and Biometry, National Institutes of Health, Bethesda, MD
3. Meta Analysis, Secondary Data Analysis, Participant Selection and Ads., Tamara Harris, M.D., M.S., National Institutes of Health, Bethesda, MD
4. Audrey Thurm, Ph.D., Pediatric and Developmental Neuro- Psychiatry, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
5. Laura Lee Johnson, Ph.D., National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
6. Laura Lee Johnson, Ph.D., Statistician, National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
7. Laura Lee Johnson, Ph.D., Statistician, National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
8. Laura Lee Johnson, Ph.D., Statistician, National Center for Complimentary and Alternative Medicine, National Institutes of Health, Bethesda, MD
9. Jack M. Guralnik, M.D., Ph.D., Laboratory of Epidemiology, Demography and Biometry, National Institutes of Health, Bethesda, MD

Ethics

1. Ezekiel J. Emanuel, M.D., Ph.D., Department of Clinical Bioethics, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD
2. Christine Grady, Ph.D., Department of Clinical Bioethics, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD

Legal Issues and Other General Videos

1. Valerie H. Bonham, J.D., Office of the General Counsel, National Institutes of Health, Bethesda, MD
2. John E. Ware, Jr., Ph.D., Quality Metric Incorporated, RI Health Assessment Lab., Waltham, MA, Tufts University of School of Medicine, National Institutes of Health, Bethesda, MD
3. Olivia Bartlett, Ph.D., Chief, Research Programs Review Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
4. Guidelines for the Conduct of Research in the Intramural Research Program at NIH, National Institutes of Health, Bethesda, MD

MODULE I
• Introduction
• Welcome and a Historical Perspective
• Economic Analysis in Clinical Research
• Opportunities for Innovation in Clinical Research: From Molecule to Medicare – Part I
• Opportunities for Innovation in Clinical Research: From Molecule to Medicare – Part II
• Evaluation of Alternative and Complementary Therapies
• Technology Transfer – Part I
• Technology Transfer – Part II
• Scope of Clinical Trials in India
o Why India? Why is the demand?
o What are the opportunities?
o What are the challenges in working with global trials?
o Are these clinical trials conducted to develop drugs for the Indian and outside markets?
o Are there any common issues (ethics, recruitment and data collection) that need to be
     recognized in the conduct of clinical trials in India?
o What are the potential concerns in Phase I, II, III, and post market studies? If so, why?
o Other related issues

MODULE II: ETHICS
The fundamental ethical principles for research involving human subjects, including the concepts of respect for persons, beneficence, and justice, will be discussed. The general principles of ethics in human investigation are also addressed in such documents as the Nuremberg Code of 1946, The Helsinki Declaration of 1964 (revised in 1975 and again in 1983), in guidelines from professional organizations, such as the American Psychological Association. This module will address key ethical issues and their governing international guidelines in human subject research.

• Ethical Principles in Clinical Research
• Researching an Ethics Question
• Legal Issues in Clinical Research
• Scientific Conduct

MODULE III: CLINICAL RESEARCH AND REGULATIONS
The US FDA guidelines serve as the basis for many sponsors and pharmaceutical/ biotechnology companies. For any FDA-approved clinical trials, the regulations generally require IRB review and approval of research involving FDA regulated products (e.g., investigational drugs, biological products, and medical devices) (21 CFR Part 56). FDA’s Bioresearch Monitoring (BIMO) Program ensures the protection of the rights, welfare, and safety of human subjects and the quality and integrity of data submitted to the Agency. In this module, the structure, operation and the role of the IRB’s that are relevant to the US FDA and US NIH will be discussed. In addition, Informed Consent Issues will be discussed based on what US FDA and US NIH require for clinical trials and studies. Local issues relating to this section will also be covered. Informed consent is the key element in clinical research. Among other things, the FDA BIMO Program involves site visits to IRBs, clinical investigators, sponsors, monitors, contract research organizations, non-clinical (animal) laboratories, and bioequivalence analytical laboratories.

• General Introduction
o Oversight on FDA-regulated Clinical Trials
o Oversight on Clinical Trials by Office of Drug Control, India
• Clinical Trial Designs (US-FDA Descriptions)
o Choosing a Research Question
o Product Development: Moving from the Bench to the Clinic
o Definition of Phases (I to IV)
o Randomized Clinical Trials (RCT’s)
o Multi-Center Clinical Trials
o Alternative Designs
o Institutional Review Board (IRB)
o Inclusion of Women and Children in Clinical Trials
o Post-Marketing Studies
• Overview of Medical Product Research and Development
o Drug Discovery and Pre-Clinical Research
o The Cliical Research and New Drug Application Approval Process
o The Biologics Research, Development and Licensing Process
o Medical Device Research, Development and Marketing Approval/Clearance
• US-FDA Product Regulation
• Communications with the FDA
• Investigational New Drug Applications (FDA)
o Exploratory IND studies
o FDA Guidance for Industry, Investigators, and Reviewers
• CMC Review and Manufacturing Issues

MODULE IV: CONTROLLED CLINICAL TRIALS – AIMS AND DESIGNS
Controlled clinical trials provide scientifically valid evidence. But, in order to give valid information, trials and are designed around a set of aims and hypotheses. This module will cover some of the basic designs, special trial management and data collection issues arising from the design, typical types of analysis, and the resulting statistical report.

• Study Aims and Hypotheses
• Basic Concepts in Design of Clinical Trials
• Measurements
• Trial Planning, Blinding, Placebos, Control
• Randomization: Blinding, Placebo, Control, etc.
• Measurement and Study Variables
• Statistical Report
• Practical Exercise

MODULE V: DATA COLLECTION, STATISTICS, ANALYSIS AND MANAGEMENT

• Trial Planning, Management & Data Requirements
o Consolidated FDA Guidance and Supporting Data Requirements
o Bioresearch Monitoring (BIMO) Program
o Data Requirements in FDA inspections
• Basic Concepts
o Study Aims and Hypotheses
o Basic Concepts in Design of Clinical Trials
o Measurement
o Randomization, Blinding, Placebos, Control
o Issues in Randomization
o Practical Exercise
• Data Support Trials
o Good Clinical Practices (cGCP), guidance, CFR title 21 part 11 (electronic records, signatures)
o Data and Safety Monitoring Boards
o Reporting and maintaining, clinical data, adverse events
• Statistics
• Quality Control and Preparatory to Analysis
o Data checking
     Missing data
     Logical checks
     Outliers and “normal” values
     Data screening – how suitable are the data for planned analysis
     Departures from normality
     Other matters
     Hidden time effects
     Practical exercise
o Data monitoring
o Requirements for recording, confirming, tracking changes
     Requirements
     Managing and reporting changes
     Practical exercise
• Computer usage:
o Design and Use of Case Report Forms
o Multiple Sites, Forms, Language
o Remote Data Capture
o Statistical programs, evaluation, and use
     Epi info and similar programs
o Computer aided reporting, analysis, and tracking
     Oracle Clinical
     Data collection, entry, checking, screening, analysis
     Practical Exercise
• Information Resources for Clinical Research
• Clinical Data Interchange Standards Consortium
o Data Domain Models
o Metadata Models
o Naming Conventions
o Practical exercise
• Statistical Principals, Data Analysis and Reporting
o ICH Guidelines – ICH Topic 9
o Trial purpose, population, and guidelines
o Variables
o Clinical Endpoints
o Pre-specified analysis plan
o Analysis sets
o Interim analysis and early stopping
o Sample size
o Accrual rates
o Treatment effect, center effect
o Adverse events and reporting
o Per protocol subjects or valid cases and all randomized subjects
o Practical exercise
o Safety and tolerability evaluation
     Variables
     Data collection
     Set of subjects to be evaluated and presentation of data
     Practical exercise
o Reporting (ICH Guidelines – E3
     Summarizing the Clinical Database
     Efficacy
     Safety
     Adverse events
     Practical exercise

MODULE VI: PROJECT MANAGEMENT

• Concepts in the Management of Projects
• Prototype and Protocol Mechanics
• Quality Control
• Clinical Endpoints
• Adverse Events and Patient Safety
• Compensation to Patients and Doctors
• Case Studies
• Practical Exercise

MODULE VII: EPIDEMIOLOGICAL STUDIES
Epidemiology is the study of disease in human populations. This branch of science has been essential in saving the lives of millions of people by discovering the causes of many diseases. By identifying what causes certain diseases, epidemiology has prompted advances in medicine and better ways of controlling and preventing disease. The analytic tools and technologies available to epidemiologists should be helpful to respond to emergent events, be they newly emerging infections, natural disasters, or terrorism, and will continue to study public health problems, such as unintentional injuries, environmental exposures, cardiovascular disease, obesity, tobacco use, and violence domestically and internationally. This module will cover some of the tools that essential for these studies.

• Participant Selection
• Using Secondary Data and Meta Analysis
• Design of Epidemiologic Studies
• Study Development
• Measures
• Randomization in Eepidemiologic Research
• Overview of Hypothesis Testing
• Ethical Concerns in Epidemiologic Studies
• Designing and Testing Questionnaires
• Practical Exercise