SF Coordinating Center. AEs SF Coordinating Center Issues re: Adverse Events Elicited vs. volunteeredElicited vs. volunteered Nuisance AEsNuisance AEs

SF Coordinating Center


AEs


Issues re: Adverse EventsIssues re: Adverse Events

• Elicited vs. volunteeredElicited vs. volunteered

• Nuisance AEsNuisance AEs

• Attribution of causeAttribution of cause


AEs for FAT?AEs for FAT?

• The company’s standard approach: The company’s standard approach:

Record any symptoms or conditions the subject Record any symptoms or conditions the subject has experienced:has experienced:

__________________________________________________________________

__________________________________________________________________


AEs for FAT?AEs for FAT?

• The company’s standard approach: The company’s standard approach:

Record any symptoms or conditions the subject Record any symptoms or conditions the subject has experienced:has experienced:

__________________________________________________________________

__________________________________________________________________

• What’s wrong with this approach?What’s wrong with this approach?


An alternative?An alternative?

““Since your last visit, has a doctor told you you Since your last visit, has a doctor told you you had (check all that apply)”had (check all that apply)”

� � A blood clot in the leg (venous thrombosis)A blood clot in the leg (venous thrombosis)

� � A blood clot in the lung (“P.E.”)… A blood clot in the lung (“P.E.”)…

(for all possible diseases)(for all possible diseases)

……ditto for all possible symptomsditto for all possible symptoms


An alternative?An alternative?

““Since your last visit, has a doctor told you you Since your last visit, has a doctor told you you had (check all that apply)”had (check all that apply)”

� � A blood clot in the leg (venous thrombosis)A blood clot in the leg (venous thrombosis)

� � A blood clot in the lung (“P.E.”)… A blood clot in the lung (“P.E.”)…

(for all possible diseases)(for all possible diseases)

……ditto for all possible symptomsditto for all possible symptoms• What’s wrong with this approach?What’s wrong with this approach?


The Aspirin Myocardial Infarction StudyThe Aspirin Myocardial Infarction Study

1.3 1.3

2.8

4.9

0.7 0.5

1.7

3

0

1

2

3

4

5

Tarry Bloody Tarry Bloody

AspirinPlacebo


Which approach is most likely to Which approach is most likely to find real AEs? find real AEs?

• Eliciting AE’s increases rates in placebo and Eliciting AE’s increases rates in placebo and treatment groupstreatment groups

• Not clear whether one approach is more likely Not clear whether one approach is more likely to detect AEs as statistically significantto detect AEs as statistically significant


Approaches to AEsApproaches to AEsVolunteered vs. elicitedVolunteered vs. elicited

Pro Pro elicitedelicited• More sensitive?More sensitive?• Easier to codeEasier to code

Pro Pro volunteeredvolunteered• Catch unexpected AEs Catch unexpected AEs • Fewer AEs?Fewer AEs?


Approaches to AEsApproaches to AEsVolunteered vs. elicitedVolunteered vs. elicited

Pro Pro elicitedelicited• More AEsMore AEs• Easier to code; cheaperEasier to code; cheaperCon:Con:• Miss unexpected AEs Miss unexpected AEs

Pro Pro volunteeredvolunteered• Fewer AEs Fewer AEs • Finds unexpected AEsFinds unexpected AEsCon:Con:• Hard to code; costlyHard to code; costly







The Bunion ProblemThe Bunion Problem

• FIT Trial of alendronate in 6,400 women for 4 FIT Trial of alendronate in 6,400 women for 4 yearsyears

• Recorded over 20,000 episodes of URIs (and Recorded over 20,000 episodes of URIs (and thousands of reports of bunions!)thousands of reports of bunions!)

• Enormous data management effort and costEnormous data management effort and cost

• How could this be avoided?How could this be avoided?


How to minimize ‘nuisance’AEsHow to minimize ‘nuisance’AEs

• Elicit uncommon, plausible and important AEsElicit uncommon, plausible and important AEs

• Limit collection of minor AEs to samples of Limit collection of minor AEs to samples of subjectssubjects







FDA AE classificationsFDA AE classifications

• Serious AEsSerious AEs– DeathsDeaths

– HospitalizedHospitalized

– Cancer (except skin cancer)Cancer (except skin cancer)

– Birth defectsBirth defects

• SAEs “definitely or probably” due to study SAEs “definitely or probably” due to study drug must be reported to company and by drug must be reported to company and by the company to FDA in 24°the company to FDA in 24°


The problem of attributionThe problem of attribution

• AEs must be classified asAEs must be classified as– DefinitelyDefinitely

– ProbablyProbably

– Possibly, orPossibly, or

– Not... Not...

...related to the study drug...related to the study drug


The problem of attributionThe problem of attribution

• 67 year old FAT volunteer starts 67 year old FAT volunteer starts taking the study drug. taking the study drug.

• At 1 month visit she reports an itchy At 1 month visit she reports an itchy rash on her forearms that started 7 rash on her forearms that started 7 days after starting and disappeared 2 days after starting and disappeared 2 days after stopping the drug. days after stopping the drug.

• Your attribution?Your attribution?


AttributionAttribution

• AEs must be classified asAEs must be classified as– DefinitelyDefinitely

– ProbablyProbably

– Possibly, orPossibly, or

– Not... Not...

...related to the study drug...related to the study drug

What is wrong with this system?


AttributionAttribution

• Attributions to drug may be as likely with Attributions to drug may be as likely with placebo as with active drug…placebo as with active drug…

• This could be studied using Coordinating This could be studied using Coordinating Center databasesCenter databases

Volunteer?Volunteer?


The FAT AE planThe FAT AE plan

• Elicit DVT, PE, hot flashes (etc) withElicit DVT, PE, hot flashes (etc) with– ““Has doctor told you that you have…?”Has doctor told you that you have…?”

• Open ended collection for other AEs Open ended collection for other AEs – in a sample?in a sample?

• Elicit serious AEs in allElicit serious AEs in all– Hospitalizations Hospitalizations


Multicenter trials Multicenter trials Industry-sponsored trialsIndustry-sponsored trials


Multicenter trialsMulticenter trials

• 2 to 1,000+ centers2 to 1,000+ centers– Usually individual practicesUsually individual practices– Sometimes professional research centersSometimes professional research centers

• Standard protocolStandard protocol– ““Case-report forms” (AKA “CRFs”)Case-report forms” (AKA “CRFs”)– Usually in addition to records for clinical careUsually in addition to records for clinical care

• Data management systemData management system– Paper forms, electronic entry (fax, web)Paper forms, electronic entry (fax, web)– Fed to a “Coordinating Center”Fed to a “Coordinating Center”


Multicenter trialsMulticenter trialsThe Cast of CharactersThe Cast of Characters

• Sponsor Sponsor – Provides the $Provides the $– Industry: designs the study and owns the dataIndustry: designs the study and owns the data

• Contract Research Organization (CRO)Contract Research Organization (CRO)– Does the sponsor’s biddingDoes the sponsor’s bidding– Collects clinical sitesCollects clinical sites– Develops the CRF’s (usually)Develops the CRF’s (usually)– Manages the data and provides to the sponsor or FDAManages the data and provides to the sponsor or FDA– (Usually) Hires and supervises the site monitors (Usually) Hires and supervises the site monitors

(CRAs)(CRAs)


Multicenter trialsMulticenter trialsSite MonitoringSite Monitoring

• To make sure every entry into the study data To make sure every entry into the study data system matches the paper CRF’s and entries system matches the paper CRF’s and entries into the medical recordinto the medical record

• Make sure that the clinical site is following Make sure that the clinical site is following instructionsinstructions

• Do Do notnot check or oversee the quality of exams check or oversee the quality of exams or interviews for data collectionor interviews for data collection

• Accounts for about 30% of the total cost of Accounts for about 30% of the total cost of multicenter trials!multicenter trials!


Multicenter trialsMulticenter trialsScientific StructuresScientific Structures

• Steering Committee (or Scientific Advisory Steering Committee (or Scientific Advisory Board)Board)

• ““Investigator Assembly”Investigator Assembly”• SubcommitteesSubcommittees

– Publications, Recruitment and Retention…Publications, Recruitment and Retention…

• Data Safety Monitoring Board (DSMB, DMC…)Data Safety Monitoring Board (DSMB, DMC…)• Universal in NIH-sponsored trialsUniversal in NIH-sponsored trials• Uncommon in industry-initiated trialsUncommon in industry-initiated trials



• Why organize them for research?Why organize them for research?



• Why organize them for your research?Why organize them for your research?• When you need the statistical power.When you need the statistical power.• Later stages of your career.Later stages of your career.



• Why participate?Why participate?



• Why participate?Why participate?• MoneyMoney• New treatments for your patientsNew treatments for your patients• Can be fun/interestingCan be fun/interesting• May be able to analyze data (NIH) or publish. May be able to analyze data (NIH) or publish.

– Depends on circumstance, sponsor, and your initiativeDepends on circumstance, sponsor, and your initiative


Multicenter trials Multicenter trials Industry-sponsored trialsIndustry-sponsored trials


Industry-sponsored research has Industry-sponsored research has become a commercial enterprisebecome a commercial enterprise

• ~70 to 80% of all industry-sponsored trials are ~70 to 80% of all industry-sponsored trials are done in private practices or commercial done in private practices or commercial research clinics and run by sponsors or CROsresearch clinics and run by sponsors or CROs

• <30% of industry-sponsored research is done <30% of industry-sponsored research is done “by academic centers”“by academic centers”

• About 2-3 dozen small university-based non-About 2-3 dozen small university-based non-profit coordinating centersprofit coordinating centers


Reasons to avoid industry-sponsored Reasons to avoid industry-sponsored trialstrials

• Bad reputation for biased resultsBad reputation for biased results• They control the money and dataThey control the money and data• Little or no value for academic promotionLittle or no value for academic promotion• Can lose moneyCan lose money• Can get into trouble at UCSFCan get into trouble at UCSF


Reasons for working with industryReasons for working with industry

• They have the drugs and resourcesThey have the drugs and resources– NIH usually will not fund trials involving one drug NIH usually will not fund trials involving one drug

from one companyfrom one company

– Example: Can PTH ‘cure’ osteoporosis?Example: Can PTH ‘cure’ osteoporosis?



• They have the drugs and resourcesThey have the drugs and resources

• The results of industry trials influence practiceThe results of industry trials influence practice

• MoneyMoney





• MoneyMoney– $3 to 20,000 per patient per year$3 to 20,000 per patient per year

– These are These are discretionary discretionary fundsfunds

– Opens the door to other types of fundingOpens the door to other types of funding

– Available in months (vs 1-2 years for NIH)Available in months (vs 1-2 years for NIH)





• MoneyMoney

• The experience can be impactful and The experience can be impactful and educational, if managed welleducational, if managed well


Individual CasesIndividual Cases


Dr. SDr. S

• Junior faculty, investigator on mentor’s grant from Junior faculty, investigator on mentor’s grant from Pfizer to test a drug for incontinencePfizer to test a drug for incontinence

• Invited to attend meeting at Miami resort to attend an Invited to attend meeting at Miami resort to attend an advisory board on a new ‘selective estrogen receptor advisory board on a new ‘selective estrogen receptor modulator’ that might influence incontinence. modulator’ that might influence incontinence. – Trip cost: $3,500; consultation fee: $1,500Trip cost: $3,500; consultation fee: $1,500

• Should you attend? Should you attend?


Vote on a UCSF PolicyVote on a UCSF Policy

• Academic Senate Committee is split on a UCSF-wide Academic Senate Committee is split on a UCSF-wide policy governing allowable payments from industry to policy governing allowable payments from industry to faculty for consulting and honoraria (for speaking) faculty for consulting and honoraria (for speaking) and related expenses.and related expenses.

1. Faculty should be allowed to receive ≤ $10,000/year 1. Faculty should be allowed to receive ≤ $10,000/year from sponsors of their researchfrom sponsors of their research

2. Faculty should not be allowed to receive any 2. Faculty should not be allowed to receive any payments from sponsors of their researchpayments from sponsors of their research


Vote on a UCSF PolicyVote on a UCSF Policy

• Academic Senate Committee is split on a UCSF-wide Academic Senate Committee is split on a UCSF-wide policy governing allowable payments from industry to policy governing allowable payments from industry to faculty for consulting and honoraria (for speaking) and faculty for consulting and honoraria (for speaking) and related expenses.related expenses.

1. Faculty should be allowed to receive ≤ $10,000/year 1. Faculty should be allowed to receive ≤ $10,000/year from sponsors of their researchfrom sponsors of their research

2. Faculty should not be allowed to receive any payments 2. Faculty should not be allowed to receive any payments from sponsors of their researchfrom sponsors of their research

3. This policy should be applied only to research 3. This policy should be applied only to research involving human subjectsinvolving human subjects


Is this the real issue?Is this the real issue?


A ScandalA Scandal

• Results of a trial of a new AIDS drug are negative Results of a trial of a new AIDS drug are negative (except in a small subgroup) (except in a small subgroup)

• A lead investigator on a trial of a new drug for AIDS A lead investigator on a trial of a new drug for AIDS writes a paper emphasizing the negative results. The writes a paper emphasizing the negative results. The company blocks publication insisting on including the company blocks publication insisting on including the results from the subgroup.results from the subgroup.

• The investigator publishes the paper over the The investigator publishes the paper over the objections of the sponsor. The sponsor sues.objections of the sponsor. The sponsor sues.

What is wrong with this approach?What is wrong with this approach?


MORE Trial ResultsMORE Trial Results

• 7,705 women treated with raloxifene. Primary 7,705 women treated with raloxifene. Primary outcome-reduced vertebral fractures 40%.outcome-reduced vertebral fractures 40%.

• Main paper in JAMA on 3-year resultsMain paper in JAMA on 3-year results– Graphs and tables regarding vertebral fractureGraphs and tables regarding vertebral fracture

– Mention in text: no effect on other fracturesMention in text: no effect on other fractures

• Paper on 4-year resultsPaper on 4-year results– ““Continued reduction in vertebral fracture”Continued reduction in vertebral fracture”

– No mention of other fracturesNo mention of other fractures


BiasBias

• Financial incentives bias the researchFinancial incentives bias the research– Biased analysis and reporting of results Biased analysis and reporting of results

• (Bekelman: industry sponsorship likelihood of ‘pro-industry (Bekelman: industry sponsorship likelihood of ‘pro-industry result about 3.6-fold.)result about 3.6-fold.)

– Biased trial designsBiased trial designs

– Biased selection of research questionsBiased selection of research questions


Fundamental problemsFundamental problems

• The sponsor hasThe sponsor has– datadata

– data analystsdata analysts

– medical writersmedical writers


Fundamental problemsFundamental problems

• The sponsor hasThe sponsor has– datadata

– data analystsdata analysts

– medical writersmedical writers

• Usually, sponsors have no checks on what they Usually, sponsors have no checks on what they can publish, except the first authorcan publish, except the first author– First authors often too busy or inexperienced First authors often too busy or inexperienced


A set of principlesA set of principles

AlwaysAlways

• Get the data (or unfettered access)Get the data (or unfettered access)

• Get a data analyst (and medical writer?)Get a data analyst (and medical writer?)

• Have a publications committee with a voting Have a publications committee with a voting majority from outsidemajority from outside

• Make your own slidesMake your own slides

• Report your sponsors and support in Report your sponsors and support in presentations and paperspresentations and papers


What is the responsibility of a What is the responsibility of a publicly sponsored university?publicly sponsored university?

• Work with industry to influence the rigor and Work with industry to influence the rigor and objectivity of researchobjectivity of research

• Be a model of ethical principles, uninfluenced Be a model of ethical principles, uninfluenced by ties to industry?by ties to industry?

Documents

SF Coordinating Center. AEs SF Coordinating Center Issues re: Adverse Events Elicited vs. volunteeredElicited vs. volunteered Nuisance AEsNuisance AEs