Clinical Trials

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“ CLINICAL TRIALS ”:

KULDEEP KINJA M.PHARMA ( Pharmacology) “ CLINICAL TRIALS ” 1 Department Of Pharmacology NIMS University

INTRODUCTION:

Clinical Research is a vital part of h ealth care. Clinical Trials is the testing the efficacy and safety of newly developed drugs on Humans. In drug research, the specific goals of Clinical Research include determining the efficacy (effectiveness) and safety of new drug as well as defining and adjuvant therapies. This is accomplished through careful planning and implementation of Clinical Research trials. Broadly we can classify Clinical Trials into 2 types:- 1) Pre-Marketing Clinical Trials ( Phase I.II & III ) 2) Post-Marketing Clinical Trials ( Phase IV) INTRODUCTION 2 Department Of Pharmacology NIMS University

PHASES OF CLINICAL TRIALS:

Clinical Research trials are the systemic investigations of the effects of an investigation agent; treatment modify (surgery, radiation); methods of prevention, detection (or) diagnosis of a disease state. Phases of Clinical Trials are:- 1) Phase- I 2) Phase- II 3) Phase- III NDA Approval 4) Phase IV (Post Marketing surveillance) PHASES OF CLINICAL TRIALS 3 Department Of Pharmacology NIMS University

PHASE- I ‘FIRST TIME IN MAN STUDIES’:

Purpose - Phase I trials are conducted to determine the SAFETY of an investigational agent. Length of Studies - Phase I trials are conducted over several months. Individual subject participation may be from one day to several weeks. Subjects -Generally, normal volunteers without confounding diseases or concurrent medications are recruited to participate in Phase I trials. Phase I trials usually enrol 20-60 subjects. PHASE- I ‘FIRST TIME IN MAN STUDIES ’ 4 Department Of Pharmacology NIMS University

PHASE- II (a) ‘PILOT TRIALS’:

Purpose- Phase II trials are conducted to demonstrate EFFICACY with a particular disease. Length of Studies- Phase II trials may be completed in a few months or take up to several years. Subject participation will vary but is usually of longer duration than in Phase I. Subjects- Subjects in Phase II trials are patients with the disease or clinical situation being examined. These trials are randomized, tightly controlled studies, using small numbers (60-200) of carefully selected patients. PHASE- II (a) ‘PILOT TRIALS’ 5 Department Of Pharmacology NIMS University

PHASE- II (b) ‘PIVOTAL TRIALS:

Purpose- Phase IIb trials (sometimes overlap with Phase IIIa ) are conducted to gain specific efficacy and safety information for submission of an NDA and are often referred to as pivotal trials. Two pivotal trials are typically required to file an NDA with the FDA. Length of Studies- Pivotal trials may last a few months to several years. Subjects- Subjects are generally patients with the disease without serious complications or other concurrent diseases. PHASE- II (b) ‘PIVOTAL TRIALS 6 Department Of Pharmacology NIMS University

PHASE- III (a) ‘EXPANDED CLINICAL TRIALS’:

Purpose- Phase llla trials are designed to gain safety and efficacy information in a large number of patients. Some variables include extended dosing, dose ranging, and patient characteristics more representative of the market situation. Length of Studies- Phase llla studies tend to be of longer duration, lasting one to four years. Subjects- Phase IIIa subjects are patients exhibiting the disease under study and are selected from a larger population of patients, although entry criteria are still stringent. Several hundred subjects are required in Phase llla studies. PHASE- III (a) ‘EXPANDED CLINICAL TRIALS’ 7 Department Of Pharmacology NIMS University

PHASE- III (b) ‘LARGE SCALE TRIALS’:

Purpose- The purpose of Phase lllb trials is to gain experience with the experimental agent in a large number of subjects that reflect the general population at risk. Length of Studies- Phase lllb studies last one to four years and are used to gather additional data about the investigational agent. Subjects- Phase lllb trial subjects come from a larger, heterogeneous patient population. More than 1000 subjects are taken. PHASE- III (b) ‘LARGE SCALE TRIALS’ 8 Department Of Pharmacology NIMS University

PHASE- IV ‘POST MARKETING TRIALS’:

Purpose- Phase IV trials are done for:- to place the drug in the market("seeding" studies) to make marketing claims, for surveillance for unexpected or rare adverse events. for pharmacoeconomic studies. Length of Studies- determined by the purpose of the study and may be indefinite. Subjects- are drawn from the general population with the specific disease. PHASE- IV ‘POST MARKETING TRIALS’ 9 Department Of Pharmacology NIMS University

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Department Of Pharmacology NIMS University 10

ABBREVATIONS-:

ACP- Association of Clinical Pharmacology (now ACRP ) ACRP- Association of Clinical Research Professionals ADR- Adverse Drug Reaction CFR- Code of Federal Regulations CRA- Clinical Research Associate CRC- Clinical Research Coordinator CRF- Case Report Form, Case Record Form CRO- Contract Research Organization CTA- Clinical Trial Agreement CTX- Clinical Trial Exemption DSMB- Data and Safety Monitoring Board ABBREVATIONS- 11 Department Of Pharmacology NIMS University

cont.…:

EIR- Establishment Inspection Report GCP- Good Clinical Practice IRB- Institutional Review Board PI- Principal Investigator SUD- sudden unexpected death TMO- trial management organization WHOART- World Health Organization Adverse Reaction Terminology ICF- information consent form IB- investigational brochure IEC- institutional ethical committee. cont.… 12 Department Of Pharmacology NIMS University

ELEMENTS OF CLINICAL TRIALS:

There are many elements to conducting a clinical trial, and understanding these critical clinical process. The basic elements are:- Protocol Investigator’s Brochure Investigational Agent Data Collection Forms/Case Report Form Study Files ELEMENTS OF CLINICAL TRIALS 13 Department Of Pharmacology NIMS University

PROTOCOL:-:

The study protocol is the blueprint for the study and is required by Good Clinical Practice (GCP) guidelines [2 1 CFR 3 l2.23(a)]. Generally it includes the following items : Objective Background and Rationale Subject Selection Criteria ( Inclusion/ Exclusion Criteria ) Treatment Plan Study Procedures Response Evaluation Criteria Administrative Items Bibliography Appendices PROTOCOL:- 14 Department Of Pharmacology NIMS University

INVESTIGATOR’S BROCHURE:-:

The Investigator's Brochure (IB) is a confidential document (sometimes referred to as CIB ) provided by the sponsor that summarizes all known information about the investigational drug. This includes preclinical data such as chemical, pharmaceutical , and toxicology data; pharmacokinetic and pharmacodynamics data in animals and in man; and the results of earlier clinical trials. IBs are updated periodically so that data resulting from clinical trials and further preclinical data can be incorporated. The IB and any revisions should be submitted to the Institutional Review Board (IRB). INVESTIGATOR’S BROCHURE:- 15 Department Of Pharmacology NIMS University

INVESTIGATIONAL AGENT:-:

The investigational agent is the item (drug, device) being studied. It may be an experimental drug, a new combination therapy of approved drugs, or an experimental drug combined with or compared to an approved drug . STUDY DRUGS ARE NOT SAMPLES . Materials supplied for the study are INVESTIGATIONAL AGENTS and must be stored, dispensed, and monitored as a study requirement (21 CFR 3 12.57, 3 12.59, 3 12.6, and 312.62). INVESTIGATIONAL AGENT:- 16 Department Of Pharmacology NIMS University

CASE REPORT FORM (or) DATA FLOW SHEETS:-:

Data in clinical trials must be identified and collected in a systematic fashion to assure the data can be analyzed to determine the outcome of the trial (21 CFR 312.62). The CRF or flow sheet should be designed to capture all of the data required by the protocol. The CRF is- completed by the investigator or the CRC, reviewed by the monitor and data management personnel, entered into the study database by a data entry specialist , analysed by statisticians. a nd at the end data is reported to the authority. CASE REPORT FORM (or) DATA FLOW SHEETS:- 17 Department Of Pharmacology NIMS University

STUDY FILES:-:

FDA regulations require that all documents pertinent to the conduct of the clinical trial be maintained (21 CFR 312.62). Items included in the study files are as follows: Protocol Investigator's Brochure Form FDA 1572 (Statement of Investigator (SOI )) Financial Disclosure Curriculum Vitae (CV) IRB Approval and Correspondence Informed Consent Correspondence Telephone Contacts STUDY FILES:- 18 Department Of Pharmacology NIMS University

Slide 19:

Laboratory Certification Laboratory Normal Value Ranges Case Report Forms Investigational Agent Records Serious Adverse Event (SAE) Reports IND Safety Reports Study Procedures Manual Final Study Report Monitoring Log Budget Information Study file records must be retained for- two years after FDA approval of the compound for the listed indication, OR two years after all investigations have been completed and the IND is terminated. 19 Department Of Pharmacology NIMS University

THE ROLE OF THE CLINICAL RESEARCH COORDINATOR:

The primary responsibility of the CRC in clinical research is to ensure smooth, accurate progress of the project from the planning stage through study end (and often beyond) by acting as liaison to the investigator, the subject, the institution , and the company or government sponsor. Clinical research studies can be fun, exciting, and professionally satisfying, but research isn't for everyone. During the planning phase of clinical trials, it is very important for the investigator to evaluate the coordinator's qualifications for the job and for the candidate to do some self-evaluation. THE ROLE OF THE CLINICAL RESEARCH COORDINATOR 20 Department Of Pharmacology NIMS University

IDEAL CHARACTERSTICS OF CRC:-:

Scientific/Medical background. Interest in research methodology. Detail oriented. Good organizational skills. Ability to work independently. Innovative and creative. Availability per study requirements. Flexibility. People oriented. Good interaction skills with patients. Certification in clinical research. IDEAL CHARACTERSTICS OF CRC:- 21 Department Of Pharmacology NIMS University

RESPOSIBILITIES OF CRC:-:

Note that the CRC's responsibilities can vary tremendously from institution to institution. The investigator can delegate specific responsibilities to the CRC when appropriate . Some of the common responsibilities of CRC are- Assist in preparation of IRB documents including the Informed Consent Document Prepare a study budget. Assure all study documentation is maintained. Assure all study documentation is maintained. Interact with sponsor. Interact with Principal Investigator and sub investigators. Coordinate and participate in monitoring visits with sponsor. Complete CRFs and submit to sponsor/resolve data queries . RESPOSIBILITIES OF CRC:- 22 Department Of Pharmacology NIMS University

Slide 23:

Facilitate inspections/audits . Interact with IRB, lab staff, clinic staff, pharmacy, other departments in the institution such as radiology and nursing . Document study progress . Recruit study subjects. Assess subjects for eligibility. Discuss study with subject and assist in obtaining informed consent . Schedule subject assessments/visits. Provide information for treatments and reactions. Promote subject compliance by providing patient support and education. Arrange for study subject compensation. Comply with FDA regulations for conducting clinical trials. 23 Department Of Pharmacology NIMS University

CERTIFICATION OF CRC’S:-:

Two organizations currently certify clinical research professionals: the Association of Clinical Research Professionals (ACRP ) the Society of Clinical Research Associates ( SoCRA ). ACRP certifies both Clinical Research Coordinators (CCRC) and Clinical Research Associates (CCRA) as two separate test processes. SoCRA certifies both CRAs and CRCs but as a single process, and the title is Certified Clinical Research Professional (CCRP). Both certifications require a minimum amount of on-the-job experience plus passing an exam. CERTIFICATION OF CRC’S:- 24 Department Of Pharmacology NIMS University

INSPECTION OF CLINICAL TRIAL SITES:-:

All Clinical Trials are subject to review by a higher authority. The authorities which audit the Clinical Trials sites are- Food and Drug Administration (FDA) Sponsor Office for Human Research Protection (OHRP) National Institute of Health (NIH) Other Cooperative group/grants management auditing team. Some institutions & IRBs also have internal auditing committees to look after their own trials. INSPECTION OF CLINICAL TRIAL SITES:- 25 Department Of Pharmacology NIMS University

Slide 26:

Blinding- Characteristic of a controlled study design to deter bias in interpretation of reported results . Following types- In a single-blind study , the patient or observer does not know which treatment is being received. In a double-blind study , neither the patient nor the investigator knows which treatment the patient receives . In a triple-blind study , the investigator, patient, and sponsor all are blinded to the study medication. Compliance- Patient : A term referring to the degree to which the patient has followed the instructions and dosing requirements of the protocol. Protocol: Refers to adherence to the procedures defined in the study protocol. 26 Department Of Pharmacology NIMS University

Slide 27:

Clinical Research Associate (CRA) - A qualified individual working with the sponsor to oversee the progress of a clinical trial; the liaison between the sponsor and the investigator/site . Also referred to as Clinical Research Scientist (CRS), Medical Research Associate (MRA), and Monitor. Clinical Research Coordinator (CRC)- this individual is the study site's organizer of day-to-day conduct of study activities, including completing Case Report Forms, maintaining study files, and assisting the investigator. 27 Department Of Pharmacology NIMS University

REFERENCES:

Certified Clinical Research Coordinators. L. Stephens and A. Papke, Applied Clinical Trials, Vol . 4 (9), pp. 58-63, September 1995 . Improving Performance in Clinical Trials. Edward Fuchs, Research Practitioner; Vol. 1 (3), pp. 81-86, 2000 . Clinical Trial Design. G. Keith Chambers and Mary Sue Fairborn , Applied Clinical Trials, Vol . 7 (9), p. 60, 1998 . Challenges in the Design of Phase I and Early Phase I1 Studies. George S. Hughes, Jr ., Drug Information Journal, Vol. 23, pp. 693-697, 1989. How Drugs Are Developed: A Practical Guide to Clinical Research. Josh Cochr, Applied Clinical Trials Vol. 5 (3, p. 63, 1996. REFERENCES 28 Department Of Pharmacology NIMS University

Slide 29:

The PF (Pitfalls) of B (Brevity). A. Papke, Journal of Clinical Research and Drug Development, Vol . 7 (2), pp. 77-86, 1993 . Medical Abbreviations: 5500 Convenience at the Expense of Communications and Safety, 4th ed. Neil M. Davis, Neil M. Davis Associates, Huntingdon Valley, Penn. Reasonable Possibility: Causality and Post marketing Surveillance. Joyce Johnson, Drug Information Journal, Vol . 26 (4), pp. 553-558, 1992 . Clinical Trial Adverse Events: The Case for Descriptive Techniques. William Huster, Drug Information Journal, Vol . 25 (3), 1991 . http://www.fda.gov/medwatch Auditing a Clinical Trial, B. Spilker, D N & P, Vol. 3 (5), pp. 280-286, 1990. 29 Department Of Pharmacology NIMS University

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ANY DOUBTS ???? 30 Department Of Pharmacology NIMS University THANK YOU