Considering the End before the Beginning: Choosing the Correct EndpointsChoosing the Correct Endpoints

Andreas Grauer, MDExecutive Medical DirectorActing Therapeutic Area Head Global Development – Bone and NephrologyGlobal Development LeaderpAmgen Inc

Disclaimer

• The views expressed herein represent those of the t d d t il t th ipresenter and do not necessarily represent the views or

practices of the presenter’s employer or any other party.

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…to get from Bench to Bedside requires to keep the end in mind…p

Research /Research / Academia &

IndustryTranslational

SciencesGlobal

Development Commercialization

Formulate a hypothesis based on insights into

biology

Test hypothesis in people

Take the best to market

Ensure patients have access to the

medicine

The Drug Development Processg p

A tremendous number of

discoveries are tested against a

range of questions across the

process from bench to bedsidebedside

Post-LaunchLaunchFilingPhase 3Phase 2Phase 1Pre-

ClinicalLead

OptimizationHit-to-LeadScreenDiscovery

The Drug Development Process…only a few candidates make it through approval...…only a few candidates make it through approval...

Post-LaunchLaunchFilingPhase 3Phase 2Phase 1Pre-

ClinicalLead

OptimizationHit-to-LeadScreenDiscovery

The Drug Development Process…to get one drug approved ...…to get one drug approved ...

• 10000 candidates enter the funnel• 10 years of development time• 2.6 Billion $ investment

Post-LaunchLaunchFilingPhase 3Phase 2Phase 1Pre-

ClinicalLead

OptimizationHit-to-LeadScreenDiscovery

Pharmaceutical Research and Manufacturers of America (PhRMA). Drug discovery and development: understanding the R&D process. Washington, DC: PhRMA; 2014Grabowksi H, Long G, Mortimer R. Recent trends in brand‐name and generic drug competition. J Med Econ. 2014;17(3):207‐214. doi:10.3111/13696998.2013.873723. Accessed March 2014Tufts Center for the Study of Drug Development (CSDD). Cost of developing a new drug. Briefing. Boston, Mass.: CSDD; November 2014. Accessed March 2015.

The Drug Development Process…what do we need to prove...…what do we need to prove...

• Legal Basis for Drug Approval (US) • 1906 Pure Food and Drugs Act –– prohibited interstate trade of1906 Pure Food and Drugs Act prohibited interstate trade of

misbranded or adulterated food and drugs • 1938 Federal Food, Drug, and Cosmetic Act –– required that

drugs be shown safe prior to marketing g p g• 1962 Kefauver-Harris Amendments –– required that drugs be safe

and effective prior to marketing • Evidence of Effectiveness

• "substantial evidence" that a drug will have the effect it is claimed to have under proposed labeling.

• only source of substantial evidence are adequate and well- controlled studiesstudies

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The Drug Development Process…the goal: “global” approval”…

• Simultaneous global filing requires• Alignment on study design and key endpoints

…the goal: global approval …

• Usually obtained during an end-of-phase 2 meeting• Especially important for

• Indications with no approved products or no current guidance• First in class molecules

PMDAEMA

FDA

Health Canada

TGA

Post-LaunchLaunchFilingPhase 3Phase 2Phase 1Pre-

ClinicalLead

OptimizationHit-to-LeadScreenDiscovery

The Drug Development Process…challenges for global approval……challenges for global approval…

Key agencies have different expectations for important elements of the clinical trials e gthe clinical trials, e.g• Endpoint harmonization• Patient population• Trial Duration• PRO validation• Long term follow up• Pediatric study commitment• Administration/Device developmentDependent on disease area maybe less interested in p y• Placebo vs active comparator

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The Drug Development Process…why is it important to choose the right endpoint……why is it important to choose the right endpoint…

• Supports the indication

S t th ffi l i th t ill b d i th• Supports the efficacy claims that will be covered in the product label

• Characterizes the products efficacy• Characterizes the products efficacy• Basis for promotional use • Inclusion in product monographs

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The Drug Development Process…once approved, time of exclusivity is limited……once approved, time of exclusivity is limited…

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Pharmaceutical Research and Manufacturers of America (PhRMA). Drug discovery and development: understanding the R&D process. Washington, DC: PhRMA; 2014Grabowksi H, Long G, Mortimer R. Recent trends in brand‐name and generic drug competition. J Med Econ. 2014;17(3):207‐214. doi:10.3111/13696998.2013.873723. Accessed March 2014Tufts Center for the Study of Drug Development (CSDD). Cost of developing a new drug. Briefing. Boston, Mass.: CSDD; November 2014. Accessed March 2015.

The Drug Development Process…the goal: access and reimbursement…

• US: • commercial payers/Medicare

…the goal: access and reimbursement…

commercial payers/Medicare• Part B/Part D

• Canada• Reimbursement negotiations in every province g y p

• Europe• Health Technology Assessment drives pricing and reimbursement (e.g.)

• UK (NICE), • Germany (AMNOG)• France (CT) • Italy (AIFA)• Spain

• Japan• Ministry of Health Labor and Welfare (MHLW)

• AustraliaAustralia • Pharmaceutical Benefits Assessment Committee (PBAC)

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The Drug Development Process…to get a good price you have to demonstrate added value……to get a good price you have to demonstrate added value…

• Degree of innovation• availability of existing productsy g p

• no adequate treatment to date • aimed at sub-groups of patients with absolute contraindications against

current medications• for whom new drugs represent the only feasible therapeutic option• which sub-groups of patients are resistant or non-responders to first line

therapy Wh i d t t t l d i t• When recognized treatments already exist• extent of therapeutic benefit will be evaluation

• Products offering better safety and efficacy or a better pharmacokinetic profilepharmacokinetic profile.

• Products that represent a pharmacological innovation - such as a new method of action - but no improvement over existing therapies.

• Products offering a technological innovation but not a therapeuticProducts offering a technological innovation but not a therapeutic advantage over existing products

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The Drug Development Process…demonstrate superiority….…demonstrate superiority….

• Study Designs• Double-blind active-controlled trials• Mixed treatment Network Meta-Analyses

• Choice of endpointsP ti t l t t• Patient relevant outcomes

• “Hard” outcomes (e.g. Mortality, cardiovascular events, fractures)• “relevant” patient reported outcomes (QoL)

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The Drug Development Process…start with designing an ambitious and realistic Target Product Profile (TPP)…Target Product Profile (TPP)…

Unmet need

Base case assumptions

Differen-tiation

Optimisticcase

Pessimistic case

Indication

Efficacy

SafetySafety

Tolerability

Dosing

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The Drug Development Process…let’s not forget why we are doing this……let s not forget why we are doing this…

• Focus• Serious illnesses• areas of high unmet medical need

• MissionT ti t• To serve patients

• Aspiration• use science and innovation to dramatically improve people's• …use science and innovation to dramatically improve people s

lives

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