Introduction to Clinical Research

Introduction to Clinical Research

What is Clinical Research? Clinical research is medical research that involves people like you. People volunteer to participate in carefully conducted investigations that ultimately uncover better ways to treat, prevent, diagnose, and understand human disease. Clinical research includes trials that test new treatments and therapies as well as long term natural history studies, which provide valuable information about how disease and health progress. The idea for a clinical research study also known as a clinical trial often originates in the laboratory. After researchers test new therapies or procedures in the laboratory and in animal studies, the most promising experimental treatments are moved into clinical trials, which are conducted in phases. During a trial, more information is gained about an experimental treatment, its risks, and its effectiveness. National Institute of Health, 2015

What is a Clinical Trial? Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Treatments might be new drugs or new combinations of drugs, new surgical procedures or devices, or new ways to use existing treatments. The goal of clinical trials is to determine if a new test or treatment works and if it is safe. Clinical trials can also look at other aspects of care, such as improving the quality of life for people with chronic illnesses. People participate in clinical trials for a variety of reasons. Healthy volunteers say they participate to help others and to contribute to moving science forward. Participants with an illness or disease also participate to help others, but also to possibly receive the newest treatment and to have the additional care and attention from the clinical trial staff. Clinical trials offer hope for many people and an opportunity to help researchers find better treatments for others in the future. National Institute of Health, 2015

Clinical Research 101: Trial Process Long & Lengthy Process to Develop Drug or Device: Approximately 10-12 years for a drug to receive FDA Approval (Chow & Liu, 2004) Average cost $2.6 billion (Tufts Center for the Study Drug Development, November 2014) Several stages along the path of drug development Laboratory Research on Animals and Human Cells Investigational New Drug Application (IND) Submission Human Trials (Phases I-IV) New Drug Application (NDA) Submitted Final FDA Approval / Marketing

Clinical Research 101: Trial Phases A clinical trial is the process of testing a new treatment for safety and efficacy, with the ultimate goal of bringing it to market There are 4 phases of drug development, each with different objectives Omega Research has successfully completed trials in all 4 phases Phase Phase I Phase II Aim First In Human or First In Indication Proof of Concept / Dose Response Subject Population Healthy Volunteers or Specific Morbidity Disease Under Study Number of Subjects Approx. Duration (years) 10-100 1 or Less 100-300 1-2 Phase 1 trials are the trials that often involve overnight stays and healthy volunteers, but not always Phase III Phase IV Efficacy Post Approval Disease Under Study Disease Under Study 1000-5000 2-3 Variable Variable

Clinical Research 101: Trial Design Trials are designed to answer specific questions regarding safety and efficacy and are governed by regulatory requirements Key Elements In Trial Design Key Issues Faced When Designing a Trial: Study Populations Age, Gender, Health Status End Points Time-point or event based Choice of Comparator Bioequivalent/Placebo, or both Inclusion/Exclusion Criteria What subjects will qualify? Statistical considerations Will this trial lead to strong enough data to prove theory? Number of Subjects Taking in to account drop outs, lost to follow ups Randomization and blinding/masking

Clinical Research 101: Treatment Common Treatment Sequences Open label vs. Double-blind: What s the difference? Open label both the researchers and subjects know which treatment is being administered. Double-blind subjects and researchers are not aware of what treatment they are receiving.

Clinical Research 101: Treatment Randomization Using chance methods (random number tables, flipping a coin, etc.) to assign subjects to treatments Subject Number Randomization Assignment 1 B 2 A 3 A 4 B 5 A Stratification Subjects are assigned to treatment based on another variable, such as smoking status. Subject# Smoking Status Treatment Subject# Smoking Status Treatment 1S A 1N B 2S B 2N B 3S A 3N A

Clinical Research 101: Protocol vs. IB The Protocol Basis/rationale for study Contains: Objectives Procedures and Analysis Treatment Information Regulatory Requirements The Investigator Brochure (IB) Summary of properties of the investigational product Results of nonclinical studies Known effects in humans Summary of data and guidelines for the investigator Basically, IB is for the drug while the Protocol is for the trial. The Protocol is essentially the study Bible

Typical Protocol Table of Contents 1. Protocol Cover Sheet 2. Signature Page 3. Background 4. Objectives Primary / Secondary 5. Study Plan Study Design Subject Inclusion Subject Exclusion 6. Study Drugs Dose and Route Method of dispensing Methods and time of administration Description of controls Methods of randomization and blinding Package and labeling Duration of treatment Concomitant medications Concomitant procedures 7. Measurements and Observations Efficacy endpoints Safety endpoints Screening, baseline, treatment periods, and post treatment follow-up 8. Statistical Methods 9. Adverse Events Serious adverse events Adverse events attributions Adverse events intensity Adverse event reporting Laboratory test abnormalities 10. Subject withdrawal and discontinuation Subject withdrawal End of treatment End of study 11. Flow Chart of Studies (Schedule of Events) 12. References 13. Appendix

Defining the Trial: The Study Hierarchy FDA Sponsor IRB CRO Site

History of Food and Drug Administration Subcabinet organization within the Department of Health and Human Services (HHS) FDA is the Scientific, Regulatory, and Public Health Agency for the United States. Oversees the following: Food Products Human and animal drug Therapeutic Agents of biological origin Medical Devices Radiation emitting products for consumer, medical, and occupational use Cosmetics Animal Feeds Monitors the manufacture, transport, storage and sale of about 1 trillion USD worth of products More than 16,000 facilities are visited by Investigators and Inspectors (FDA.gov)

Federal Codes of Regulation Federal Code of Regulation (CFR) General and permanent rules published in federal register by departments and agencies for the federal government 50 Titles represent broad areas subject to federal regulation Title 21 is reserved for food and drug administration Title 21 CFR Part 11 (Electronic Records, Electronic Signatures) Part 50 (Protection of Human Subjects) Part 54 (Financial Disclosure) Part 312 (Investigational New Drug Application IND) Part 314 (Applications for FDA Approval to Market New Drug) Part 600 (Biologic Products) Part 812 (Investigational Device Exemption) Part 814 (Premarket Approval of Medical Devices)

Institutional Review Board (IRB) Any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects Primary Purpose Such review is to assure the protection of the rights and welfare of the human subjects Review of the following: Protocol/Amendments Investigator Brochure/Updates Written Informed Consent Any Subject Facing Materials Available Safety Information Subject SAEs/Site Deviations Payments and compensation available to subjects (21CFR56.102) (ICH E6 3.2) Common IRBs Conduct continuing review of each trial at least once a year Receives close-out documentation at the end of the trial

Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management and/or financing of a clinical trial (International Conference on Harmonization (ICH) E6 GCP Guidance Section 5)

Sponsor Responsibilities Quality Assurance and Quality Control Selecting Investigators Medical Expertise for Trial Overall Trial Design Keeping Investigators Aware of Trial Changes/Updates Review of Ongoing Investigations (Audits) Information on Investigational Product Manufacturing, Packaging, Labeling, and Coding Investigational Product(s) Supplying and Handling Investigational Product(s) Disposition of Unused Supply of Investigational Drug Financing Notification/Submission to Regulatory Authority regarding Study Status Confirmation of Review by IRB/IEC Providing Record Access to Regulatory Authorities Safety Information/Adverse Drug Reaction Reporting Clinical Trial/Study Reports (ICH E6 Section 5)

Contract Research Organization (CRO) A person or an organization that a Sponsor may transfer any or all of the sponsor s related duties and functions to a CRO (ICH 5.2.1) Engage in site selection activities, organize ancillary vendors (labs), etc. CROs implement quality assurance and quality control (ICH 5.2.1) Employ monitors, provide training, conduct audits etc.

Defining the Trial: The Site Hierarchy Principal Investigator Sub- Investigator Lead Study Coordinator Regulatory Specialist Medical Assistant Back-up Study Coordinator Study Nurse

Principal Investigator (PI) Responsible for Protecting the rights, safety, and welfare of subjects Investigator must be qualified by education, training, and experience to assume responsibility of the trial (ICH 4.1) Investigator should be familiar with investigational product (ICH 4.1.20) Investigator should be aware of, and comply with, GCP and applicable regulatory Sub-Investigator Any individual member of the clinical team designated and supervised by the investigator at a trial site to perform critical trial related procedures and/or to make important trial related decisions (ICH 1.56) Investigator should permit monitoring and auditing by sponsor, and inspection by appropriate regulatory authority (ICH 4.1.4) The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial related activities (ICH 4.1.5) Investigator must agree to sign 1572

Regulatory Specialists Ensures all initial essential documents are completed and submitted to Sponsor/IRB, as well as ensures all required updates to essential documents are completed and submitted in a timely manner Assists SC by: Tracking and completing all continuing review reports for each trial Documenting initial and continued protocol training and staff delegation Helping resolve regulatory issues noted on IMV follow up letters Filing documents in regulatory binder How can we help prevent this? Anytime a new Protocol, IB, or any manual comes through please forward to regulatory Either print any correspondence or forward to regulatory for filing. Anytime ANY training is completed please forward a copy of the certificate to regulatory. A note saying which protocol it was completed for would be helpful also. Make sure to update conductor with Reasons for subject withdrawal or screenfail

Medical Assistants Support Study Coordinators Discuss study protocol with Study Coordinator to ensure understanding Provide required assistance to ensure teamwork and success on study Prep for Subjects Visit Confirm patients appointment at least the day before and update in Clinical Conductor Prep lab kit for next day s appointment at least the day before and keep in designated daily kit area Day of Visit Obtain patient vitals (BP, Pulse, O2, Weight) for every visit using vitals form Perform Urine dipstick, pregnancy test, ESR, ECG, QFT-G or PPD Test if required per protocol Perform and process lab draws per protocol requirements for shipping Ensure exam room/lab remains clean and organized Handling of Lab Kits Each MA is responsible for removal, break down and disposal of all expired study related kits Maintain study kits inventory to show minimum and on-hand quantities Order kits as required and based on enrolled patients to maintain inventory levels Add dry ice needed to clinical conductor Lab Redraw Work with SC to ensure labs are obtained per SOP and protocol to prevent unnecessary lab redraws. If redraw is indicated, work with SC to rectify quickly

Administrative Responsibilities Assess & Manage the Trial Training of Auxiliary staff Preparing and submitting documents to the IRB (SAE reports, deviations) Maintaining regulatory files Documenting communication, study progress, overall subject status Resolving queries on study data Transcribing source information to ecrfs Coordinating, preparing for, and participating in monitoring visits, audits and inspections Ensure patient charts and source documents adhere to study protocol prior to IMV Correct any findings identified from monitor visits within 72 hours Ensure all IMV Follow Up Letters (FUL) issues are completed prior to the next IMV visit Ordering study supplies as needed Overview of the Role of the Clinical Research Coordinator (CRC/SC) Responsibilities Related to Subjects Recruiting & Screening subjects for eligibility Discussing study and conducting informed consent process with subject Properly obtain/document informed consent Scheduling study assessments and visits Ensuring all visits, tests, and procedures are completed in required time intervals Reviewing lab and clinical information for signs of adverse events Dispensing investigational product per protocol Maintaining drug accountability and investigational product per protocol Obtaining, preparing, and shipping biological specimens Coordinating study subject s reimbursements Ensure all Inclusion/Exclusion criteria is met before subject is randomized

Overview of the Role of the Clinical Research Coordinator (CRC/SC) Subject Contact Verify patient contact information sheet is completed Ensure patient signs HIPAA form / request patient records Interview and evaluate subject for eligibility Study Team Training Lead discussion with MA/back up coordinators to ensure understanding and adherence to study protocol Document Communication and Study Progress Ensure progress notes for all patient visits are specific to the visit date and document AE/SAE, compliance issues, re-education, and/or changes in con meds and study status Patient Visits Ensure patient visits are properly prepped the day before including source and any other needed supplies/devices Identify, document, report and follow up on adverse events Keep PI/Dr. Harry informed about any patient safety issues Data Entry and Queries Ensure all source for the study visit has been completed Ensure ecrf data entry is complete & entered within 24 hours Resolve all Sponsor queries within 48 hours

Click Here to receive your certificate. Please print your certificate and be sure to sign and date it before returning to your supervisor.