Human Research Protection Program Training

Human Research Protection Program Training Michael Thomas, CIP Assessment Manager, HRPP Michael.Thomas@ucsf.edu 415-476-9837 Megan Sullivan Assistant Coordinator, Assessment Team, HRPP Megan.Sullivan@ucsf.edu 415-502-6880 CHR Training: Modifications and Renewals Melanie Mace, MA, CIP Education Coordinator, HRPP Melanie.Mace@ucsf.edu 415-476-9839 July 16, 2009

Renewals Overview Re-review of all projects involving human subjects is required at least annually (see 45 CFR 46.109(d) (DHHS) and 21 CFR 56.109(d) (FDA))

Modification Overview All changes to a study, even minor ones, must receive CHR approval before they are implemented.

Modification Approval Exception • The only exception to the requirement for prior CHR review and approval is when the changes are “necessary to eliminate apparent immediate hazards to the subject” (45 CFR 46.103.b.4, 21 CFR 56.108.a). • In such cases, the actions taken should be reported to the CHR within 5 working days, and approval should be sought for permanent changes to prevent the hazards in the future.

Types of Modifications • Administrative Modifications • Minor Modifications • Major Modifications

are Minor Modifications or changes that do not affect study participants (subjects) in any way. Administrative Modifications

Changing procedures that do not affect participants (e.g., method of shipping samples) Fixing typographical, grammatical, or spelling errors Changing personnel (but PI and Co-PI stay the same) if no participant-contact documents are affected. Not changing procedures that affect participants Not changing risks Not changing information on the CHR application form or protocol beyond fixing typographical, grammatical, formatting, or spelling errors Not changing CHR consent form beyond fixing typographical, grammatical, formatting, or spelling errors Administrative Modifications Examples

1 set of the following: Cover letter (optional) CHR Modification Request for Minor and Administrative Changes Revised Versions of All Previously Submitted Documents that Contain Information Affected by the Modification Additional Documents Needed to Explain or Implement the Modifications What to submitAdministrative Modifications

Noted and approved in database No Approval Letter sent Administrative Modifications:Type of Review

to previously approved research are changes in which any increase in risk to participants is no more than minimal and all additional activities or procedures would be eligible for review using the expedited procedures if submitted as part of new research and either the research itself involves minimal risks or the changes do not significantly alter the study design. Minor Modifications

Changing minor procedures (e.g., adding small-volume blood draws, ultrasounds, visits with noninvasive procedures) Reducing risks Adding minor risks (e.g., risks of small blood draws) Changing wording in CHR consent form, application, or other documents Revising questionnaires unless the new questions are more likely than the old ones to evoke responses that would reasonably place subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing if the answers became known outside of the study context Minor Modification Examplesfor Full Committee Studies

Adding or changing advertisements or notices Changing or deviating from eligibility criteria if the change creates no serious risks to participants Changing the Principal Investigator or Co-Pl Changing other Key Personnel (in some circumstances) Minor Modification Examples (cont.)for Full Committee Studies

Changing major procedures or activities without adding more-than-minimal risks (e.g., adding participant contact to a record-review study, adding a new round of participant contact and interviews, changing from review of past patients’ records to review of current patients’ records) Changing study design without adding more-than-minimal risks Changing method of contacting participants Changing, adding, or deleting approved drugs, devices, or other standard treatments that are being used in standard ways Adding vulnerable populations (e.g., minors, patients unable to consent) as long as risks remain minimal and other criteria for expedited review are still met. Adding prisoners is almost always a major modification requiring full committee review. Minor Modification Examplesfor Expedited Studies

Changing wording in CHR consent form, application, or other documents Changing or adding questionnaires or other study instruments Adding or changing advertisements or notices Changing or deviating from eligibility criteria if the change itself creates no more than minimal risks to participants Changing Principal Investigator or Co-PI Changing other Key Personnel (in some circumstances) Minor Modification Examplesfor Expedited Studies (cont.)

6 identical collated sets of the following: Cover letter (optional) CHR Modification Request for Minor and Administrative Changes Revised Versions of All Previously Submitted Documents that Contain Information Affected by the Modification Additional Documents Needed to Explain or Implement the Modifications (including application supplements [e.g. Surrogates, Minors, Prisoners, Stem Cells], consent and assent documents, questionnaires, advertisements, HIPAA documents, letters of support, etc.) What to submitMinor Modifications

2 copies of the following (ONLY if revised): Questionnaire/Instruments/Focus Group Guides 1 copy of the following (ONLY if revised): Sponsor’s protocol (or “full” or “multicenter” protocol) Investigator’s Brochure What to submitMinor Modifications (cont)

To facilitate review, specific changes in the modified application (or Cover Page and Protocol, if originally submitted using those forms), consent form(s), and other documents must be bolded, highlighted, or struck through as appropriate. All revised documents should be based on the version most recently approved by the CHR. All revised documents should include a new version date. Additional Instructions for all Modifications

Additional Tips: • Make double-sided copies of large documents (e.g., sponsor’s protocol, investigator brochures, exceptionally long surveys or questionnaires). • Please use a single staple in collating the copies of the submission. • DO NOT edit documents using “balloons.” You can turn balloons off in the “Track Changes” tab in “Options” under the “Tools” pull down menu.

Reviewed by a subcommittee (using “expedited” review procedures) Approval letter sent when approved Expiration date does not change Minor Modifications:Type of Review

you currently have an expedited (no subject contact) application approved for a study that involves retrospective medical record review of patients visiting the ER. The PI now wants to modify the study to include a survey that will be sent to a small subset of patients. The survey does not include any questions that might increase risk to the subjects. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

you currently have an approved Full Committee study that involves a Phase I drug. The PI now wants to add key personnel who will consent research subjects. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

you currently have an approved expedited review study that involves conducting anonymous surveys at fast food restaurants. The PI now wants to include subjects under 18 years of age. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

to previously approved research are changes in which Any increase in risk to participants is more than minimal or any additional activity or procedure would not be eligible for expedited review if submitted as part of new research or the research itself involves more than minimal risks and the changes significantly alter the study design. Major Modifications

Changing, adding, or deleting drugs, devices, or other treatments being studied (significant alteration of design of study) Adding or deleting major procedures or diagnostic tests (e.g., adding bronchoscopy or spinal tap; doubling duration of treatment; deleting adjuvant chemotherapy; deleting diagnostic MRI or liver function test) Increasing major risks or discomforts (e.g., risks from new procedures, deleted safety measures, or newly discovered serious risks; risks that are serious by themselves do not become minor even if subjects already have a terminal disease) Major Modification Examplesfor Full Committee Studies

Changing study design (e.g., eliminating 1 arm of a multi-arm study or going from placebo-controlled to open-label) Adding serious privacy risks (e.g., asking subjects about abusive behavior or illegal activities) Adding vulnerable populations (e.g., minors, prisoners, patients unable to consent) Re-starting study after a hold for safety concerns If sponsor or cooperative group specifically requires full committee review Major Modifications Examples for Full Committee Studies(cont.)

Any change that: Makes the study have more than minimal risks for participants or Makes the study no longer fit one of the Expedited Review Categories Major Modifications for Expedited Studies

Adding invasive procedures other than small-volume blood draws Adding use of experimental drugs or devices Adding serious privacy risks (e.g., asking participants about abusive behavior or illegal activities) Revising questionnaires if the new questions are more likely than the old ones to evoke responses that would reasonably place subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing if the answers became known outside of the study context Changing retrospective record review of standard care to randomized test of two standard regimens Major Modifications for Expedited Studies: Examples

Renewals Re-review of all projects involving human subjects is required at least annually (see 45 CFR 46.109(d) (DHHS) and 21 CFR 56.109(d) (FDA)) • even if no changes are made, • even if the only study activity is patient followup, and • even if the only study activity is data analysis. • The CHR may require more frequent review.

Renewals (cont.) If ApprovalExpires, ALL ACTIVITIES INVOLVING SUBJECTS MUST STOP. • The only exception is that activities needed for participant safety should continue. • No new subjects may be enrolled. • You should notify the CHR before any such research activities are done

REQUIRED - 6 identical collated sets of the following: CHR Status Report for Renewals and Major Modifications (Continuing Review) CHR Full Committee or Expedited Review Application (if using current forms) or CHR Cover Page, Protocol, and HIPAA supplement (if originally submitted using those forms). CHR Application Supplements that have been previously submitted or are now needed for proposed modifications All Consent Documents All Recruitment Letters All Flyers/Ads (only if revised) Adverse Event Summary Log (if applicable) Other Reports: serious or unexpected AERs, violations, incidents (if not previously submitted) Audit or Data and Safety Monitoring Board Report (if a report was issued) Other supporting documents if new or revised What to submitMajor Modifications / Renewals:

2 copies of the following (ONLY if revised): Questionnaire/Instruments 1 copy of the following (ONLY if revised): Sponsor’s (or “full” or “multicenter”) protocol Investigator’s Brochure OPTIONAL: Include with the 6 identical sets: Cover letter What to submit for Major Modifications and Renewals (cont):

Full Committee Review ALL major modifications Full Committee studies with ongoing subject contact Expedited Review Expedited studies Full Committee studies that qualify for expedited review Approval letter sent when approved New expiration date is given Major Modifications / Renewal: Type of Review

Studies Initially Reviewed as Full Committee can be reviewed under the Expedited Review procedures if one of the following apply: The research is permanently closed to the enrollment of new subjects and the research remains active only for long-term follow-up such as medical records review and telephone follow-up. (If one of the research follow-up procedures is an intervention such as a blood draw or an x-ray, the renewal is not eligible for expedited review). No subjects have ever been enrolled and no additional risks have been identified since the last Full Committee IRB review. Full Committee Studies Renewed through Expedited Review:

Studies Being Renewed for Data Analysis Only undergo expedited review Submit 6 copies of the CHR Status Report for Renewals And Major Modifications (Continuing Review) Renewals – Data Analysis Only:

you have a currently approved Full Committee study and the P.I. receives an updated sponsor's protocol that identifies additional minimal risks to the study? What type of modification request would you submit? What would you need to include in your submission? What would you do if…

you currently have a Phase II/III study approved. It is a randomized 3 arm study - Arm A is a higher dose of an experimental drug; Arm B is a lower dose of the same experimental drug; and Arm C is placebo. A scheduled interim analysis concludes that while Arm A has more frequent and severe side effects, there is no statistical difference in efficacy over Arm B. The study sponsor has revised the protocol to eliminate Arm A. All new subjects will be randomized to either Arm B or placebo, and all subjects originally randomized to Arm A will be switched to Arm B. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

you currently have a Phase III study approved. It is a randomized study comparing an experimental drug versus placebo. The study has reached its accrual goal and preliminary data suggests that the experimental drug provides a benefit. The study sponsor wants to modify the protocol to an open-label extension study so that the experimental drug is available to all participants. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

you currently have an approved study that takes place at Parnassus and Mt. Zion. The PI now wants to add the VAMC as a study site. What type of modification request would you submit? What would you need to include in your submission? What would you do if…

Changes are not bolded or highlighted and deletions are not struck through. Version dates are not revised The wrong version(s) is modified Affected documents are not submitted with modification request form Not all changes are stated explicitly in the modification request form 5 Common Problems with Modification Submissions:

Subject numbers do not add up and no clear explanation is given in the status report. Study status (page 2 of the status report) is wrong Modifications approved since the last renewal are not listed in Section J.1 of the status report If the study has expired or is about to expire, assurance that no study activity will occur is not given or the status report doesn’t fully discuss approval lapse including a corrective action plan. Required supplements are not included 5 Common Problems with Renewal Submissions:

Remember! IRB Review is required before initiating, modifyingor extending any research project that uses human subjects

Questions? www.research.ucsf.edu/chr/ • Ask your PI or Mentor • Call or email the CHR and ask for a screener of modifications and renewals • Main CHR Line: 415-476-1814 • Main CHR Email: chr@ucsf.edu

HRPP Training: Upcoming Sessions • Post-Approval Event Reporting • Tuesday, August 11, 10-11:30 a.m., N-225 • Lisa Voss, Assistant Director, HRPP Quality Improvement Unit

Human Research Protection Program Training