Clinical research protocol

Protocols for Clinical Research

1. Presented By Dr. Puneshwar Keshari , 1 st Year PG Scholar, Guided By Dr. Prakash L. Hegde Professor DEPT. OF DRAVYAGUNA PROTOCOL FOR CLINICAL RESEARCH

2. Definition of Research Clinical Research and Clinical Trial Clinical Research Protocol Why Protocol Parts of Protocol Formats of Clinical Research Protocol Clinical Research in Ayurveda Discussion Conclusion Refer ences CONTENT

3. Research is Systematic collection, Analysis and Interpretation of data WHAT IS RESEARCH? to answer a certain question or solve a problem

4. Clinical research Clinical trial Branches of medical science Part of clinical research Systematic, observational and biomedical studies Systematic experimental biomedical studies Ultimate goal is to improve the quality of life To evaluate the effectiveness and safety of medications or medical devices or biologics CLINICAL RESEARCH & CLINICAL TRIAL

5. “ A complete written description of, and scientific rationale for, a research activity involving human subjects.”

6. To clarify the research question To compile existing knowledge To formulate a hypothesis and objectives To decide about a study design To clarify ethical considerations To apply for funding To have a guideline and tool for the research team

7. Introduction Abstract Objectives (including study scheme) Background Rationale Eligibility criteria Study design/methods (including drug/device info) Criteria For Evaluations Study Treatments Clinical Assessment PARTS OF THE PROTOCOL

8. Clinical Laboratory Measurements Evaluations by visit Adverse experience reporting and Documentation Discontinuation and Replacement of subjects Protocol violations Statistical section (including analysis and monitoring) Administrative, Ethical , Regulatory Considerations Reference/ Appendices Publication Contd …

9. INTRODUCTION Study Subject / hypothesis should be clearly identified and briefly described in introduction.

10. Abstract is a summary of the information in a document. Abstract must be: Accurate - which correctly reflects the purpose and content of manuscript. Concise and specific – to make sentence informative and as possible as brief. Non evaluative – to report information objectively ABSTRACT

11. Objectives should be clearly mentioned as hypotheses to be tested. It should have a corresponding discussion in the statistical section. Objectives are of two types: Primary objective & Secondary objective OBJECTIVE OF THE STUDY

12. All protocols require a section detailing the scientific rationale for a protocol and the justification in medical and scientific literature for the hypothesis being proposed. BACKGROUND

13. Describe why it makes sense to study this product in this patient population or in the event of an observational study, why the information is needed. Risk / benefit assessment – how the specific risks of the product will be alleviate in the study and why the potential benefits outweigh the risks should be clearly mentioned STUDY RATIONALE

14. Subjects with a diagnosis of the specific disease intended to take in the study, who meet the inclusion and exclusion criteria will be eligible for participation in this study. Reasons for imposing eligibility criteria can include scientific rationales, safety concerns, regulatory issues, and practical considerations. ELIGIBILITY CRITERIA

15. The number of eligibility criteria should be kept to a minimum. Criteria should include only those absolutely necessary to ensure scientific validity and patient safety. Eligibility criteria should be clearly defined and verifiable by an external auditor. Contd ..

16. The study design section of the protocol should contain a stepwise description of all procedures required by the study. STUDY DESIGN Parts of the study design section may include: Initial evaluations Screening tests Required lab tests Details of treatment and supplementary procedures Agent information or device specifications Dose scheduling and modification Calendars

17. Types of study design used in clinical research Observational study Interventional study Descriptive study Analytical study Cross sectional study Cohort study Contd..

18. Study characteristics Type of study design to be used The way in which study will be conducted Single center Double blind Placebo control Randomized / non randomized GENERAL PRINCIPLES OF STUDY DESIGN

19. Methodology Sampling Collection of data Statistical analysis Merits and demerits of particular study Contd …

20. Safety evaluation Evaluation of LFT, RFT etc. Incidence of adverse events The Safety (or Adverse Events) section should include: Detailed information for reporting adverse events Lists of expected adverse events CRITERIA FOR EVALUATION

21. Concurrent Medication Formulation of Test and control products Packaging and labeling Dose/Dosage regimen Dispensing Administration Supply/Storage Complications STUDY TREATMENT

22. All subjects should be maintained on the same medications throughout the entire study period, as medically feasible, with no introduction of new chronic therapies. Standard therapy for specific disease is allowed except for treatments noted in the exclusion criteria. CONCURRENT MEDICATION

23. Identify the test and control product, manufacturer, specify the formulation of the test article. If drug must be reconstituted or otherwise prepared indicate in this section FORMULATION OF TEST & CONTROL PRODUCTS Control Test Active ingredient, mg/ml Other ingredient , mg/ml pH

24. Brief explanation of how the drug will be packed and labeled and by whom. It should also explain how labeling will maintain blinding for blinded studies. PACKAGING AND LABELING

25. Information of Dose Route of administration Dosing schedule Optimal timing between doses Adjustments for weight, age, meals and other pertinent information and Treatment periods DOSAGE/ DOSAGE REGIMEN

26. Dispensing Administration instructions Supply of drug at the site Storage Study drug accountability Measures of treatment compliance AN IDEAL CLINICAL RESEARCH PROTOCOL SHOULD EXPLAIN ABOUT

27. Concomitant medications all concomitant medications and concurrent therapies will be documented. Demographics date of birth, gender, race Medical history Physical examination Vital signs Other clinical procedures CLINICAL ASSESSMENT

28. Adverse events Duration (start /stop dates and times) Severity/ grade Mild Moderate Severe Life threatening Information regarding occurrence of adverse events will be captured throughout the study and reported accordingly. ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION

29. Treatment and relation of adverse experience to study drug will be recorded on the case report form as Definitely Probably Possibly Unrelated Contd..

30. Hematology Bio-chemistry profile Pregnancy test Urinalysis Pharmacokinetic measurements Others CLINICAL LABORATORY MEASUREMENTS

31. Visit 1 (Day/Week/Month ) Visit 2 (Day/Week/Month ) Visit 3 (Day/Week/Month ) Visit 4 (Day/Week/Month ) Visit 5 (Day/Week/Month ) Informed Consent x Medical History x Complete Physical Exam x x Abbreviated Physical Exam x x x Height x X X X X Weight x x x x x Vital Signs x x x x x Oximetry x x x x x Spirometry x x x x x Pharmacokinetics x Chemistry x X X EVALUATION BY VISIT

32. Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Pregnancy Test ( Urine or Serum ) X X x Hematology x x x ESR x x x C-Reactive Protein x x x Urinalysis x x x Randomization x Dispensing or Administration of Study Drug X X X X Counting of Returned Study Drug X X X X Initiate Subject Diary x Subject Diary Review X X X X Concomitant Medication Review X X X X X Adverse Experiences Contd ..

33. All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified and without prejudice Researcher should keep proper record of Time Reason Adverse experience Consent from to withdraw DISCONTINUATION & REPLACEMENT OF SUBJECTS

34. A protocol violation occurs when the subject, investigator or sponsor fails to adhere to significant protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria. PROTOCOL VIOLATIONS

35. Protocol violations of the study include Failure to meet inclusion / exclusion criteria Use of a prohibited concomitant medication Failure to follow good clinical practice. Contd …

36. To ensure the continued scientific validity and merit of the study DATA SAFETY MONITORING

37. The data which may be subjected to statistical analysis may be specified with specific processes tests, formulae, and which may be adopted for analysis of data, may be proposed in blue prints in advance. Sample size should be clearly mentioned and reasons for selecting such number for study also be clearly defined. STATISTICAL METHODS & CONSIDERATIONS

38. Data will be entered into a validated database All procedures for the handling and analysis of data will be conducted by using good computing practices. DATA COLLECTION, ANALYSIS RETENTION & MONITORING

39. The investigator is responsible for all information collected on subjects enrolled in this study. All data collected during the course of this study must be reviewed and verified for completeness and accuracy by the investigator. A copy of case report form should be with investigators at the completion of study. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS

40. The study should be conducted according to Declaration of Helsinki Protection of Human Volunteers Institutional Review Board Institutional Ethics Committee Obligation of Clinical Investigators Good Clinical Practices ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS

41. The protocol, consent form and protocol amendments should be reviewed and approved by the IRB/IEC. Serious adverse experiences regardless of causality should be reported to the IRB/IEC. INSTITUTIONAL REVIEW BOARD & INDEPENDENT ETHICS COMMITTEES

42. Informed consent should be prepared in accordance with the declaration of Helsinki, ICH GCP (International council for harmonization good clinical practices), FDA (Food and Drug Administration, USA), health insurance portability and accountability act (HIPAA) and local regulations. INFORMED CONSENT FORM

43. A proper executed, written, informed consent will be obtained from each subject prior to entering the subject into the trial. Information should be given in both oral and written form in their native language to subjects/ or their legal representatives about the study. Contd ….

44. In order to maintain subject confidentiality, only a site number, subject number and subject initials will identify all study subjects on CRFs and other documentation. SUBJECT CONFIDENTIALITY

45. All laboratory specimens, evaluation forms, reports and other records should identified by a coded number and initials only All study records should be kept in a locked file cabinet TO MAINTAIN CONFIDENTIALITY

46. Code sheets linking a patients name to a patient identification number should be stored separately in another locked file cabinet Clinical information should not be released without written permission of the subjects, except as necessary for monitoring by the authorized agency. Contd..

47. All references cited in the protocol and/or relevant to the study should be listed properly Supplemental documents such as data collection form, surveys, questionnaires, advertisements, and flyers should be included to the protocol. REFERENCE/APPENDICES

48. The publication or presentation of any study results should be according to the privacy laws, agreement with sponsor, health insurance portability and accountability act. PUBLICATION

49. Article

50. Abstract: Cosmetic Dermatology is a growing subspecialty. High-quality basic science studies have been published; however, few double-blind, randomized controlled clinical trials, which are the major instrument for evidence-based medicine, have been conducted in this area. Clinical research is essential for the discovery of new knowledge, improvement of scientific basis, resolution of challenges, and good clinical practice. Some basic principles for a successful researcher include interest, availability, persistence, and honesty. It is essential to learn how to write a protocol research and to know the international and national regulatory rules. How To Design And Write A Clinical Research Protocol In Cosmetic Dermatology An Bras Dermatol . 2013;88(1):69-75 Ediléia Bagatin Helio A. Miot

51. A complete clinical trial protocol should include question, background, objectives, methodology (design, variable description, sample size, randomization, inclusion and exclusion criteria, intervention, efficacy and safety measures, and statistical analysis), consent form, clinical research form, and references. Institutional ethical review board approval and financial support disclosure are necessary. Publication of positive or negative results should be an authors' commitment . Keywords : Clinical protocols; Clinical trial; Comparative study; Cosmetics; Epidemiologic research design; Research design

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55. DISCUSSION

56. Research as may be defined as attempt to find out/ discover facts in a systematic and scientific manner with statistical support. Clinical research refers to the entire bibliography of drug/device/biology or in fact any test article from it’s inception in the lab to it’s introduction to the consumer market and beyond. Clinical trials are parts of clinical research in which experiments are done on human participants.

57. Clinical research must be always conducted within the frame work of prevailing relevant laws of country & state. A properly planned & executed clinical study is a powerful experiment technique for assessing the efficacy of an intervention. Contd ….

58. Protocol is a systematic & complete Performa of research activity, needed for clarify research question & ethical consideration & useful to applying for funding. Problem identification, literature review, developing research question and statistical hypothesis are the main steps for preparing research protocol. Contd ……..

59. Project summary, general information, rationale and background, references, study goals and objectives, study design, methodology, safety considerations, follow up, data management and statistical analysis, quality assurance, expected outcome, dissemination of results and publication policy, duration, ethical considerations, budget and other support projects are the parts of protocol . Researcher can modify the content according to the types of study, Contd …

60. Chikitsha chatushpada dealt in Charak samhita and their individual characteristics of each pada should be considered as requirements and protocols for clinical research . Rog and Rogi Pareeksha vidhi and Pareekshya vishay should be considered as methodology for research protocol. Contd..

61. Clinical research protocol is a systematically structured scientific framework of guidelines for clarifying research question. Proper and appropriate solution should only be drawn by applying appropriate Protocol in clinical research study. CONCLUSION

62. COMMONLY USED PROTOCOL FORMAT

63. Protocol Number: Version Date: Investigational Product: IND Number: Development Phase: Sponsor: Name (please note – for academic studies, the sponsor is the Investigator, not the funding agency.) Address, City , State Funding Organization: Principal Investigator: Name: Telephone: Fax : E-mail : Medical Monitor: Name: Telephone: Fax : E-mail: Coordinating Center: If applicable SPONSOR NAME Clinical Research Protocol Protocol Name

64. Approval: PI or Sponsor Signature (Name and Title) Date This confidential information about an investigational product is provided for the exclusive use of investigators of this product and is subject to recall at any time. The information in this document may not be disclosed unless federal or state law or regulations require such disclosure. Subject to the foregoing, this information may be disclosed only to those persons involved in the study who have a need to know, with the obligation not to further disseminate this information.

65. PROTOCOL AGREEMENT I have read the protocol specified below. In my formal capacity as Investigator, my duties include ensuring the safety of the study subjects enrolled under my supervision and providing [Sponsor Name] with complete and timely information, as outlined in the protocol. It is understood that all information pertaining to the study will be held strictly confidential and that this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required to carry out the study in accordance with accepted GCP principles and to abide by the terms of this protocol. Protocol Number: Number Protocol Title: Title Protocol Date: TBD Investigator Signature Date Print Name and Title Site # Site Name Address

66. TITLE SPONSOR FUNDING ORGANIZATION NUMBER OF SITES RATIONALE This should be very brief – 2 paragraphs or so, just highlighting why it makes sense to study product X in these patients and that there is a medical need. STUDY DESIGN This is a randomized, double-blind, placebo-controlled phase 2 study. PRIMARY OBJECTIVE SECONDARY OBJECTIVES PROTOCOL SYNOPSIS

67. NUMBER OF SUBJECTS SUBJECT SELECTION CRITERIA Inclusion Criteria : Exclusion Criteria :   TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION Product XX at XX dose Product will be administered every XX hours (or days) for X length of time. Describe administration (orally, IV, or by inhalation). If inhalation describe delivery system. CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION Product XX (indicate if comparator or placebo) at XX dose Product will be administered every XX hours (or days) for X length of time. Describe administration (orally, IV, or by inhalation) If inhalation describe delivery system. dURATION OF SUBJECT PARTICIPATION AND DURATION OF STUDY Subjects will be on study for up to 28 days Screening: up to 7 days Treatment: 5 days (subjects to be admitted to the hospital) Follow-up: 16 days The total duration of the study is expected to be XXX. XXX months for subject recruitment and XXX for final subject follow-up.

68. E CONCOMMITANT MEDICATIONS Allowed: Prohibited: Efficacy Evaluations Primary endpoint Secondary endpoints Other Evaluations PK, research lab evaluations, etc., would go here Safety Evaluations Change in clinical safety labs from baseline to XXX Incidence of adverse events Planned Interim Analyses Fill in details of DMC. Please note: if this is a NIH-funded study, all references should be “DSMB”; for non-NIH funded studies, refer to the” DMC.” Sample text: When approximately 50% of patients have completed the study through Visit X , an interim analysis for safety will be conducted by an independent data monitoring committee. Serious adverse events will be monitored by the committee on an ongoing basis throughout the study. STATISTICS Primary Analysis Plan Describe plan for analyzing the primary endpoint. Rationale for Number of Subjects

69. WHO recommended format for clinical research protocol 1 and2 CCRAS Research Policy Research Methodology- C.R. Kothari . Gaurav Garg Research Methodology and Medical Biostatistics – DR.S.M. Sarpotdar , Dr. Santosh Bhor Charak Samhita Writing Research Protocol- Manubhakta PROTOCOL TEMPLATE- University of California, Sanfrancisco . REFERENCES