Human/animal use considerations

1. Human/animal use considerations

2. Protection of Human Subjects • Basic principles • Clinical trials should be conducted in accordance with generally accepted ethical principles • Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society • A trial should only be initiated and continued if the anticipated benefits justify the risks

3. Protection of Human Subjects • Basic principles • The rights, safety and well being of trial subjects are the most important considerations and should prevail over interests of science and society • The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial • Clinical trials should be scientifically sound and described in a clear, detailed protocol

4. Protection of Human Subjects • Basic principles • A trial should be conducted in compliance with the protocol that has received prior IRB approval • The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician • Each individual involved in conducting a trial should be qualified by education, training and experience to perform their respective tasks • Freely given informed consent should be obtained from every subject prior to clinical trial participation

5. Protection of Human Subjects • Basic principles • All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification • The confidentiality of records that could identify subjects should be protected • Investigational products should be manufactured, handled and stored in accordance with good manufacturing practice and used with the approved protocol • Systems with procedures that assure the quality of every aspect of the trial should be implemented

6. Protection of Human Subjects • Study needs • Purpose • Background • Location • Duration • Research plan • Economic considerations • Justification of subject population • Inclusion / exclusion criteria

7. Protection of Human Subjects • Relevant issues to be addressed: • The need for the trial • 1) What is the problem to be addressed? • 2) What are the principle research questions to be addressed? • 3) Why is a trial needed now? • 4) Give references to any systematic review and discuss the need for a trial in this light • 5) How will the results of this trial be used?

8. Protection of Human Subjects • Relevant issues to be addressed • The proposed trial • 1) What is the proposed trial design • 2) What are the planned trial interventions • 3) What are the proposed practical arrangements for allocating participants to trial groups • 4) What are the proposed methods for protecting against sources of bias? • 5) What are the planned inclusion / exclusion criteria?

9. Protection of Human Subjects • Relevant issues to be addressed • The proposed trial • 6) What is the proposed duration of treatment period? • 7) What is the proposed frequency and duration of follow-up? • 8) What are the primary and secondary outcome measures? • 9) How will the outcome measures be measured at follow-up? • 10) What is the proposed sample size? • 11)What is the planned recruitment rate?

10. Protection of Human Subjects • Relevant issues to be addressed • The proposed trial • 12) Are there likely to be any problems with compliance? • 13) What is the likely rate of loss to follow-up? • 14) Give details of the planned analyses • 15) Are there any planned subgroup analyses? • 16) What is the proposed frequency of analyses? • 17) Will the trial address any economic issues? • 18) What is the estimated cost and duration of the trial? • 19) What are the details of the trial team?

11. Protection of Human Subjects • Subject population • Must describe and justify: • Number of subjects • Ages • Gender • Inclusion of minorities • Children • Vulnerable groups

12. Protection of Human Subjects • Information required when using human subjects: • 1) A description of all persons who will be involved in the research, including their roles and qualifications • 2) Information regarding who will have access to the personal health information • 3) A description of the anticipated public or scientific benefit of the study • 4) A description of all personal health information to be collected and how it will be used • 5) Justification of why research can not be accomplished without using personal health information

13. Protection of Human Subjects • Information required when using human subjects: • 6) A description of how personal health information is to be linked to other information • 7) A description of how long personal information will be retained and then disposed of • 8) A description of foreseeable risks and harms and how these will be addressed • 9) A description of any conflicts of interest

14. Informed Consent • A process by which a subject voluntarily confirms his or her willingness to participate in a clinical trial • Informed of all aspects of the trial that are relevant to their decision to participate • Documented by means of a written, signed and dated consent form

15. Informed Consent • Key components • Process • Voluntary • Informed of all aspects • Decision • Documentation

16. Informed Consent • Process of obtaining consent • Provide ample time and opportunity to: • Inquire about details of trial • Discuss and interact • Decide whether or not to participate • Have all questions answered to subject’s satisfaction

17. Informed Consent • Essential requirements • Information about the consent procedure • Information about study and treatment • Information about risks/benefits • Other essential information • Signatories • Readability

18. Informed consent • Information about the consent procedure • Consent to be given under subject’s free will • Right to withdraw at any time without prejudice or consequences • Adequate time allowed for subjects to decide on participation in study and to ask questions

19. Informed Consent • Information about the consent procedure • Explanation that participation is confidential, but records will be reviewed and may be disclosed to a regulatory authority • Description of circumstances under which participation will be terminated • Ethics committee approval obtained • Name of contact person on EC

20. Informed Consent • Information about study and treatment • Name of sponsor or sources of funding • Explanation that study is a research procedure • Research aims, purpose or objectives • Description of medication or devices

21. Informed Consent • Information about study and treatment • Procedures to be followed • Experimental procedures • Randomization procedures

22. Informed Consent • Information about study and treatment • Comparator treatment (including placebo where no other treatment exists) • Expected duration of participation in study • Number of other subjects participating • Reasons for selection of suitable subjects • Access to best proven treatment at conclusion of study

23. Informed Consent • Information about risks/benefits • Refusal to participate would involve no penalties or loss of usual benefits • Foreseeable risks, discomforts, side effects, inconveniences • Issues related to embryo, fetus or nursing infant • Known therapeutic benefits, if any • Availability of alternative therapies • Financial remuneration, if any

24. Informed Consent • Information about risks/benefits • Any new findings which might adversely affect safety of subject would be disclosed to subject • Any additional costs to subject that may result from study participation

25. Informed Consent • Information about risks/benefits • Assurance of compensation, if any, for medicine induced injury • Measures to be taken in the event of an adverse event or therapeutic failure

26. Informed Consent • Other information • Information (name, address, 24-hour telephone number) about contact person at study site for emergency • Requirements to disclose use (and any change in use) of any medicines (or alcohol, tobacco/other drugs) • Requirement to disclose details of medical history

27. Informed Consent • Other information • Requirement to disclose participation in other studies • Primary care physician to be informed of study participation and significant problems during study

28. Informed Consent • Other information • Medical records to clearly indicate study participation • Conditions as applicable to women of child bearing potential • Any possible conflicts of interest and institutional affiliations of the investigator

29. Informed Consent • Signatories • Date and time of providing information and obtaining consent must be documented in writing • All signatories must date their own signatures

30. Informed Consent • Signatories • Consent form should be signed and dated by: • Study subject or, where appropriate, a legally authorized representative • Investigator who provided information, obtained consent and assured that subject understood information

31. Informed Consent • Signatories • Other personnel (eg study site co-ordinator who assist in consent procedure • Witness or patient advocate

32. Informed Consent • Readability • 4th – 6th grade • “You don’t have to be in this research study. You can agree to be in the study now and change your mind later. Your decision will not affect your regular care. Your doctor’s attitude toward you will not change” • College • “You voluntarily consent to participate in this research investigation. You may refuse to participate in this investigation or withdraw your consent and discontinue participation in this study without penalty and without affecting your future care or your ability to receive alternate medical treatment at the University.”

33. Informed Consent • Consent form: Components • 1) Title: Consent to participate in a research study • 2) Title of research study • 3) Investigators • 4) Study sponsor • 5) Purpose of the research • 6) Description of the research • 7) Potential harms • 8) Women as research subjects

34. Informed Consent • Consent form: Components • 9) Potential Benefits • 10) Treatment options • 11) Confidentiality and privacy • 12) Publication of results • 13) Reimbursement • 14) Compensation for injury • 15) Participation and withdrawal • 16) Research ethics board contact • 17) Consent

35. Surrogate consent • Criteria • The research protocol has scientific merit • It would not be feasible to carry out the research relying on subjects who are capable to give free and informed consent • Any imposition on the individual is clearly outweighed by the potential benefit of the research to the group sharing the condition • The research is limited to the investigation of those conditions or aspects of behaviour which are directly related

36. Surrogate Consent • The procedures proposed by the research protocol involve no significant risk of either harm or more than trivial discomfort to the subject and would not be regarded by a reasonable person of full capacity as involving embarrassment or indignity or breach of confidentiality

37. Documentation • Requirements for Ethics Committee/IRB • Investigator name, qualifications and site address • Full protocol including case report forms • Subject information sheet and consent form • Investigator brochure • Insurance/compensation for subjects

38. Documentation • Requirements for Ethics Committee/IRB • Indemnity for investigator/institute • Financial agreements, if any • Advertisements • Regulatory submission and/or approval documents

39. Investigator responsibilities • 13 main obligations for the investigator • 1) Qualifications and agreements • 2) Adequate resources • 3) Medical care of trial subjects • 4) Communication with IRB • 5) Compliance with protocol • 6) Investigational product

40. Investigator responsibilities • 7) Randomization procedures and unblinding • 8) Informed consent of subject • 9) Records and reports • 10) Progress reports • 11) Safety reports • 12) Procedure termination or supervision of trial • 13) Final report by investigator

41. Animal welfare • Oversight by Animal Care and Use Committee • Need a complete description of research plan • Special considerations • Species, age, gender, numbers of animals, anaesthesia (terminal and survival experiments), discomfort, hazards (infectious, chemical, physical, infectious agents • Must justify use of animals vs in vitro techniques, analytical models, humans • Must justify species

42. Animal welfare • Veterinary care must be outlined • Minimization of discomfort • Anaesthesia • Analgesics • Antibiotics • Methods of euthanasia • Must use an accredited facility

43. Animal welfare • Common pitfalls • Reasons for rejection of proposal • Poor justification of animal numbers • Unclear animal care endpoints • When morbidity is expected, the severity, monitoring frequency and provisions for unexpected complications should be stated • Death and animal moribundity should be avoided

44. Budgets/Justification

45. Budgets/Justification • Preparing the Budget: Defining “Real” Costs • Common fixed costs: lab, xray etc • Related costs: phlebotomy fees, supplies, specimen processing fees • Drug costs: investigational drug management/dispensing, alternate or adjunct drugs • Subject costs: travel, parking, time compensation

46. Budgets/justification • Preparing the Budget: Defining “Real” Costs • Ancillary costs: travel, pager/phone, administrative (copying, long distance phone) • Marketing costs: radio, newspaper ads etc • Study personnel: research nurse/coordinator, investigator, technician • Budget by time estimate or milestone • Use actual salary values • Use significant detail in describing duties • Ensure there is someone to perform all needed tasks • Institutional fees • IRB, Contracting, Overhead or indirect costs • Record retention fees

47. Budget/justification • Preparing the Budget: Defining “Real” Costs • Equipment fees • Budget early and justify well • Supplies • Ask for enough money to buy what you need • For animal research justify expenses: purchase costs, surgery costs, housing per diem; what are costs over time

48. Budgets/justification • Preparing the Budget: Defining “Real” Costs • “Hidden costs” • Time/cost to obtain special reports • Copy cost for xrays, MRIs • Cost increases for studies that go on later than one year • Inflation, health system price increases etc • Personnel costs • Screening, training of staff, failed enrollment etc • Cost of starting enrollment late • Publication costs • Disposal costs • Service contracts / lab maintenance

49. Budgets/justification • Common elements of a study budget • 1)Administrative fees • Start-up: protocol review, consent preparation, budget review, regulatory requirements, meetings, staff training, site activation, clerical support • Pharmacy fees • REB fees • Patient advertising • Overhead: use of utilities, telephone, fax, internet, photocopying, use of maintenance staff, general administrative work, institutional opening and maintenance of a file, keeping records etc

50. Budgets/justification • Common elements of a study budget • 1)Administrative fees • Overhead: exclude start-up fees, pharmacy fees, REB fees, maintenance fees, close-out fees, storage fees patient advertising, screen failures, per patient fees, investigator fees • Maintenance fees: audits, storage costs, submission of protocol amendments, implementation of revisions, reporting etc • Close out fees • Storage /archiving fees