Human/animal use considerations

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Human/animal use considerations

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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

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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

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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

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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

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Protection of Human Subjects

• Study needs
• Purpose
• Background
• Location
• Duration
• Research plan
• Economic considerations
• Justification of subject population
• Inclusion / exclusion criteria

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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?

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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?

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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?

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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?

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Protection of Human Subjects

• Subject population
• Must describe and justify
• Number of subjects
• Ages
• Gender
• Inclusion of minorities
• Children
• Vulnerable groups

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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

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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

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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

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Informed Consent

• Key components
• Process
• Voluntary
• Informed of all aspects
• Decision
• Documentation

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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 subjects
  satisfaction

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Informed Consent

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

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Informed consent

• Information about the consent procedure
• Consent to be given under subjects 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

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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

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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

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Informed Consent

• Information about study and treatment
• Procedures to be followed
• Experimental procedures
• Randomization procedures

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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

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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

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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

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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

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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

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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

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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

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Informed Consent

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

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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

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Informed Consent

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

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Informed Consent

• Readability
• 4th 6th grade
• You dont 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 doctors 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.

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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

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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

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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

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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

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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

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Documentation

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

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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

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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

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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

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Animal welfare

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

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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

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Budgets/Justification

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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

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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

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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

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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

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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

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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

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Budgets/justification

• Common elements of a study budget
• 2) Screen failures
• NB to review the complete process required to
  assess whether a patient is eligible
• Assess ratio of screened patients required to
  find each eligible patient
• Include cost of consent
• 3) Per patient fees
• Entry consent process, registration,
  randomization, preparing timelines for treatment,
  patient education, documentation, sample
  submission, supplies
• Treatment
• Follow-up

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Budget/justification

• Common elements of a study budget
• 4) Taxes / currency
• 5) Termination all startup payments should be
  non-refundable
• 6) Payee
• All payments should run through an institutional
  account

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Budgets/justification

• Issues
• Define study costs vs standard of care
• A priori determination works best
• Specify major study costs in consent form
• If grant will not support, notify subject they
  are responsible

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Budgets/justification

• Issues
• Clinical trial budgets are usually fixed
• Usually broken into per subjects payments
• Payments prorated based on subject completion
• Overhead / indirect costs may be included in
  fixed budget
• Study costs increase over the time the study is
  underway

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Budget/justification

• Challenges
• Accounting for subjects screening costs
• May be unpredictable
• Screening failures
• Reimburse as a ratio of enrolled subjects
• Reimburse only a fixed number
• ?Payments for partial or nonevaluable subjects
• Study delays
• Study on hold
• Accounting for residual dollars

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Budgets/justification

• Strategies
• Budget development process
• Understand costs at site
• Use standardized templates
• Define research costs for procedures
• Know break even point
• How long can you go without enrolling 1st subject
  ie cost of co-ordinator
• Get insight from experienced clinical research
  staff

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Budgets/justification

• Strategies
• ?Budget cost per subject
• Overhead or indirect costs included?
• Understand one time costs
• IRB fee etc.
• Have flexibility to cover prn costs
• ie follow-up imaging
• Consider start-up costs
• Have a payment schedule

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Budgets/justification

• Summary
• Identify all study-related costs a priori
• Address the issues that are specific to your site
  that may result in hidden costs
• Work with experienced people in designing budget
• Make sure the budget matches the work plan
• Ask for what you need, not too little and not too
  much