Premarketing Risk Assessment

Risk Assessment Public Meeting - 4Risk Assessment Public Meeting - 4/9/03/9/03

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Premarketing Risk AssessmentPremarketing Risk Assessment

Robert J. Meyer, MDRobert J. Meyer, MDDirector, ODE II / OND / CDERDirector, ODE II / OND / CDER

Chair of RA Working GroupChair of RA Working Group


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Group 1 - Premarketing Risk Group 1 - Premarketing Risk Assessment WG:Assessment WG:

Bob Meyer*Bob Meyer* Barbara Gould – PMBarbara Gould – PMMary Willy*Mary Willy* Ellis Unger *Ellis Unger * George Rochester George Rochester Mark AviganMark AviganDavid GrahamDavid Graham Jerry PhillipsJerry PhillipsDonna Griebel Donna Griebel Robert TempleRobert TempleZili Li Zili Li Judy RacoosinJudy RacoosinPeter Lee Peter Lee David ChoDavid ChoTrish RohanTrish Rohan

Janice Newcomb, Aileen Ciampa, Lois ChesterJanice Newcomb, Aileen Ciampa, Lois Chester


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Premarketing Risk AssessmentPremarketing Risk Assessment• Presentations:Presentations:

– Generating Risk InformationGenerating Risk Information• General Considerations - General Considerations - Bob MeyerBob Meyer• Special Considerations - Special Considerations - Bob TempleBob Temple

– Reporting Risk InformationReporting Risk Information• Analyzing and Presenting Risk Information - Analyzing and Presenting Risk Information - Ellis UngerEllis Unger


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Premarketing Risk AssessmentPremarketing Risk Assessment• For Each Topic:For Each Topic:

– FDA presentationFDA presentation– Public Comment PeriodPublic Comment Period– Panel Discussion (with questions from the Panel Discussion (with questions from the

attendees)attendees)


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• What is Risk Assessment?What is Risk Assessment?– Risk assessment is the process of identifying, Risk assessment is the process of identifying,

estimating and evaluating the nature and estimating and evaluating the nature and severity of risk from a productseverity of risk from a product

– Good risk assessment underlies good risk Good risk assessment underlies good risk management and pharmacovigilancemanagement and pharmacovigilance


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• Concept Paper and Talk Does NOT Concept Paper and Talk Does NOT cover:cover:– Pre-clinical and clinical pharmacology Pre-clinical and clinical pharmacology

aspects of developmentaspects of development– Efficacy considerationsEfficacy considerations– Post-marketing risk assessmentPost-marketing risk assessment


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Premarketing Risk AssessmentPremarketing Risk AssessmentAppropriate size of safety databaseAppropriate size of safety database• Ideal Size depends on:Ideal Size depends on:

– Novelty of the productNovelty of the product– Proposed IndicationProposed Indication

• life-sustaining vs. symptom relieflife-sustaining vs. symptom relief– Intended duration of useIntended duration of use– Safety concern from pre-clinical, early Safety concern from pre-clinical, early

clinical findingsclinical findings


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• ICH E-1 has guidance on long-term ICH E-1 has guidance on long-term treatments (chronic or intermittent, treatments (chronic or intermittent, recurrent) for non-life threatening recurrent) for non-life threatening conditionsconditions– 1500 patients total, with1500 patients total, with– 300 - 600 for 6-months, 100 for one year300 - 600 for 6-months, 100 for one year


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• ICH E-1 does NOT specify what patients ICH E-1 does NOT specify what patients should be regarded as contributing to should be regarded as contributing to this 1500 patient targetthis 1500 patient target– For chronic use drugs, should come from For chronic use drugs, should come from

multiple dose studies of reasonable duration multiple dose studies of reasonable duration (e.g., 4 weeks or more)(e.g., 4 weeks or more)

– Should be exposed to doses at or above Should be exposed to doses at or above lowest proposed doselowest proposed dose


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• Rule of Three tells us that for a 1,500 Rule of Three tells us that for a 1,500 patient database, we have a reasonable patient database, we have a reasonable chance of identifying chance of identifying aa particular event particular event that occurs at a rate of 1 / 500!that occurs at a rate of 1 / 500!

• Yet, drugs commonly are used by Yet, drugs commonly are used by thousands to millions of patients shortly thousands to millions of patients shortly after releaseafter release


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• When are ICH targets not enough? When are ICH targets not enough? ICHICH::

– Cause for concern for time related effect on Cause for concern for time related effect on safetysafety

– Need to quantify low-frequency eventsNeed to quantify low-frequency events– Limited or unknown efficacy Limited or unknown efficacy – Where there is concern that a product may add Where there is concern that a product may add

to a background rate of morbidity/mortalityto a background rate of morbidity/mortality


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• When are ICH targets not enough? When are ICH targets not enough? FDAFDA::

– Preventive treatmentsPreventive treatments– A very safe alternative already existsA very safe alternative already exists– There is a potential for a large market and very There is a potential for a large market and very

fast uptake into the marketplace, particularly fast uptake into the marketplace, particularly for a drug for a non-life-threatening, non-for a drug for a non-life-threatening, non-serious conditionserious condition


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Premarketing Risk AssessmentPremarketing Risk Assessment• For acute use therapies and/or those for For acute use therapies and/or those for

life-threatening diseases, no ICH or FDA life-threatening diseases, no ICH or FDA guidance exitsguidance exits

• For life-saving products with mortality For life-saving products with mortality trials, these data alone may be enough to trials, these data alone may be enough to demonstrate acceptable risk/benefitdemonstrate acceptable risk/benefit

• Accelerated approval - definitive efficacy Accelerated approval - definitive efficacy and full safety may come laterand full safety may come later


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• What are the Characteristics of an ideal What are the Characteristics of an ideal safety database?safety database?– Controlled trials performed throughoutControlled trials performed throughout– Diverse population (age, race/ethnicity, Diverse population (age, race/ethnicity,

concomitant disease, drugs….)concomitant disease, drugs….)– Range of doses explored throughout Range of doses explored throughout

development development


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• What are the Characteristics of an ideal What are the Characteristics of an ideal safety database?safety database?Controlled trials performed throughoutControlled trials performed throughout– essential for detecting treatment relation to common essential for detecting treatment relation to common

outcomes in the populationoutcomes in the population– helps address confounding by indicationhelps address confounding by indication– With active comparator, opportunity to judge safety With active comparator, opportunity to judge safety

vs. accepted (approved) therapyvs. accepted (approved) therapy


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Premarketing Risk AssessmentPremarketing Risk Assessment• What are the Characteristics of an ideal What are the Characteristics of an ideal

safety database?safety database?Diverse PopulationDiverse Population– Only patients with obvious contraindications Only patients with obvious contraindications

excluded in late phase trialsexcluded in late phase trials– Allows for better generalizability of safety findingsAllows for better generalizability of safety findings– Develop better clinical data on Rx-demographic, Rx Develop better clinical data on Rx-demographic, Rx

- disease and Rx - Rx interactions- disease and Rx - Rx interactions


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Premarketing Risk AssessmentPremarketing Risk Assessment• What are the Characteristics of an ideal What are the Characteristics of an ideal

safety database?safety database?Range of doses studied throughout Range of doses studied throughout developmentdevelopment– Better characterize Better characterize clinicalclinical exposure-response exposure-response

relationship (dose finding not complete at EOP-2)relationship (dose finding not complete at EOP-2)– May help provide important E-R data for dose May help provide important E-R data for dose

adjustments in subpopulationsadjustments in subpopulations– (Also may add important information on the assessment (Also may add important information on the assessment

of efficacy - maximizing benefit vs. risk)of efficacy - maximizing benefit vs. risk)


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• To detect potential interactions not To detect potential interactions not previously identified, sponsors should:previously identified, sponsors should:– Be vigilant for drug-drug interactions, Be vigilant for drug-drug interactions,

particularly for likely concomitant particularly for likely concomitant medications (e.g., binding resins and HMG-medications (e.g., binding resins and HMG-CoA reductase inhibitors)CoA reductase inhibitors)

– Product -demographic interactions (diverse Product -demographic interactions (diverse population studied)population studied)


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• To detect potential interactions not To detect potential interactions not previously identified, sponsors should:previously identified, sponsors should:– Product-disease interactions (study range of Product-disease interactions (study range of

disease and concomitant diseased patients)disease and concomitant diseased patients)– Product-food interactionsProduct-food interactions– Product-dietary supplement interactions (for Product-dietary supplement interactions (for

popular supplements for the disease in popular supplements for the disease in question)question)


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Premarketing Risk AssessmentPremarketing Risk Assessment• To help detect potential interactions:To help detect potential interactions:

– An important way of providing data to inform An important way of providing data to inform about unanticipated interactions is to perform about unanticipated interactions is to perform drug level (e.g., population PK) assessments in drug level (e.g., population PK) assessments in phase 3 trailsphase 3 trails

– Could help define E-R relationship for S+E Could help define E-R relationship for S+E (help validate biomarkers)(help validate biomarkers)

– Could help define drug level relationship to Could help define drug level relationship to any unusual, rare AEany unusual, rare AE


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• When would comparative safety data be When would comparative safety data be useful?useful?– Expected with some classes of products (e.g., Expected with some classes of products (e.g.,

preventive vaccines)preventive vaccines)– Need to characterize background ratesNeed to characterize background rates– When there is a well established, well-When there is a well established, well-

characterized low toxicity productcharacterized low toxicity product


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Premarketing Risk AssessmentPremarketing Risk Assessment• When would comparative safety data be When would comparative safety data be

useful?useful?– Where there is a well-established, related Where there is a well-established, related

therapytherapy– Where there is an established therapy with Where there is an established therapy with

effect on survival or altering irreversible effect on survival or altering irreversible morbiditymorbidity

– When the sponsor wishes to make comparative When the sponsor wishes to make comparative claimsclaims


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• ConclusionConclusion– Pre-marketing Risk Assessment relatively Pre-marketing Risk Assessment relatively

mature, but still evolvingmature, but still evolving– Public Health, Industry and FDA would all Public Health, Industry and FDA would all

benefit from optimizing Risk Assessment benefit from optimizing Risk Assessment allowing for approval of safe drugs with fully allowing for approval of safe drugs with fully informative labelinginformative labeling

Premarketing Risk Assessment

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