Design of Clinical Drug Development Programs*

4/19/2012Design of Clinical DrugDevelopment Programs** For SmartiesDr Christopher D Breder 4/12 1DisclaimerThe views expressed in this talk represent myopinions and do not necessarily represent theviews of the FDA.2Objectives• To give the audience a general idea of thepharmaceutical development strategies usedin the process of submitting a US marketingapplication and of increasing the value of theapproved asset31

4/19/2012Where do New Drug Products come From?4Development Lead Selection.1New Molecular or ChemicalEntities *Chemical SynthesisStructure Activity Relationships“Fishing”Fortuitous FindsEtc…BiologicsAntibodiesOligonucleotidesEnzymesReplacement proteinsEtc…ReformulationsFormulation +Modified Release includingControlled andExtended releaseEtc…High Throughput Screening5* A drug where no active moiety has been approved through Sec.505(b) of the FD&CADevelopment Lead Selection.24 ChemicalCandidates, A, B, C & DOral (+/- SQ, IN?) Bioavail.B = ++++, C= +, D= +++Receptor BindingA = 23 nM; B=45 nM; C=67 nM;D=120 nMIn Vivo PD ScreenB = +++, C= ++, D= ++++Off target < 500nMA = 5HT2B Ag; B = M1; C = MuAg; D=CCKAPreliminary toxB ~ DCExtras…ADME, PgP, etcB “-”; D= CYP3A4 inh, PgP subs.DB goes to “IND enabling” program; SARfocus on B like molecules62

4/19/2012Conclusion 1. Efficacy Requirements• So, unless you have contributory evidence,you should plan on doing two adequate andwell controlled trials (AWCT).– “Phase 3”, “Pivotal”, “Registrational”, or“Confirmatory”• Exceptions?Coming soon….How to get to your 2 adequate and well controlled Phase 3trials.13Patient / Metabolism Specific Studies• Some studies you should do prior to Phase 3– Renal or Hepatic Impairment PK (RIPk or HIPk)• Depending on the metabolism, population• The results may effect whether you include this population or doseadjust in Phase 3– Drug Drug Interaction Studies (DDI)• Depending on the In Vitro Metabolic Profile• The results may effect whether you include this population or doseadjust in Phase 3• Very often these subjects are excluded from Phase 2because these studies have not been performed.– Usually dose not effect your overall dose / efficacy.safetyexploration• Often want to determine if drug efficacious before investing inthese studies14Clinical Development Path ….so far2 AWCTPh3NDARIPkHIPkDDIData from these studies obtained prior to Ph3 155

4/19/2012How do I get to my 2 AWCT• What do I need to know to conduct theseAWCTs?– Right dose in terms of efficacy and safety, from…• Phase 2b trials – effect of dose range on efficacy andsafety16Phase 2, the Lone UnlovedDevelopment Phase• Not strictly required by regulations– However, a case may be made for the safeconduct of Phase 3 based on thoroughunderstanding of the dose / efficacy orsafetyrelationship– E.g., for drugs with toxicities, may want toensure the lowest efficacious dose is used.• These trials are almost as long and expensive in certaindesigns as the Phase 3 studies– Can they be used as registrational?• In certain cases, you can make argument for not doing17– Modified release formulations with well behaved PKAim of Drug Development• CMC [21 CFR 312.23(a)(7)]:To assure the proper identification, quality, purity,and strength of the investigational drug.• Nonclinical [21 CFR 312.23(a)(8)]:To assure that it is reasonably safe to conduct theproposed clinical investigations.• Clinical [FD&C Act Sec. 505]:To establish efficacy and safety of a drug for use inhumans, in a dose range and schedule thatprovides an acceptable risk benefit relationship.186

4/19/2012Dose Response Rationale19Phase 2: The Dose Response• The most typically accepted study design isthe parallel fixed-dose study• What you should know about your doserange– The “maximum tolerated dose”– The minimum efficacious dose (MED) thatgives a significant effect– The shape of the curve leading up to the MED– The effect of titration on the drugs tolerability20Clinical Development Path ….so farPhase2b2 AWCTPh3NDARIPkHIPkDDIData from these studies obtained prior to Ph3 217

4/19/2012Clinical Pharmacology Trials Before Phase2• Multiple Ascending Dose Study (MAD)– Prerequisites: SAD, Nonclinical repeat dose studies ofappropriate duration and population (as applicable)– What it gives you• Maximal Tolerated Dose ~ top clinical dose• Tolerability/Safety data at or > clinical doses• Critical PK data – Cmin, accumulation etc.– Allows:• Dose selection for Phase 2,• Studies where you need to know the top clinical dose (e.g.,QT study, Food Effect study)25Multiple Ascending Dose Study• Objective: What is PK andtolerability when drug isdosed repeatedly as plannedonce marketed (MAD)?– Start dosing below anticipateddose; go to maximal tolerateddose– Informs you of tolerability,safety and steady state PK– Plan on 2 quarters from FPFV totopline data– Precedes Phase 2Multiple Dose (MD) PK Curve(open circle line)26Clinical Development Path ….so farSADMADPhase2b2 AWCTPh3NDARIPkHIPkDDIData from these studies obtained prior to Ph3 279

4/19/2012Other Supportive ClinicalPharmacology Studies• Thorough QT• Food Effect• Dose Linearity• Dose Proportionality• Mass Balance28Thorough QT Study (TQT)• A thorough QT study is performed to determinepotential of drug to prolong the QT interval of EKG.– This effect has been linked toa ventricular arrhythmia,Torsades de Pointes, which maylead to sudden cardiac death.– The study is done with the new drug, a placebo and apositive control known to induce QT prolongation– Primary endpoint: Upper bound of 90% confidence intervalin the change from baseline of a time series of EKGscannot include 10 mstorsades de pointes29Food-Effect Study• Objective – Determine effect of food(high fat meal) on drug absorption–A crossover study of fedvs fasted state–Primary endpoint - Thisis a bioequivalence study(Exposure in the fastedstate should be BE tothat in the fed state)• If not BE, labeling orreformulation dependinghttp://www.medicineonline.com/drugs/S/3503/SKELAXIN-Metaxalone-Tablets.htmlon circumstancesBE = bioequivalent or bioequivalence depending on the context3010

4/19/2012Timing Considerations of ClinicalPharmacology Studies• Thorough QT– often done after efficacy determined unless there is aprior signal of concern• hERG assay; CV safety pharmacology study, Ph1 EKG• Food Effect– Optimally precedes Ph2; trials prior done fasted– May consider doing a pilot study of one or twosubjects fed in early studies (SAD or SD in modifiedreleaseprogram) to check for gross food effects thatwould make one consider reformulatingDose Linearity• Objective – Linearity of dosing through theproposed clinical dose range– Ensure plasma levels increase linearly as doseincreases• Primary endpoint:xaction buttonDrugs Today 2000, 36(1): 55 Lornoxicam, a new potent NSAID with animproved tolerability profile Radhofer-Welte, S., Rabasseda, X.32Dose Proportionality• Objective – Proportionality of Dosing Units– E.g., compare 4x1 mg, 2x2mg and 1x4 mg– Needs to know from Ph-2 studies, what doserangeto be investigated in Ph-3 and how toescalate dosing (titration to higher doses); this willdetermine what dosage units are needed.• If one uses multiple tablets to make up a certain dose(your top clinical dose is greater than your top dosagestrength) , then this study should be done prior to Ph-2A.action button3311

4/19/2012Metabolism Studies• Objective – nonclinical metabolism in vivo– track metabolites in all PK studies oncemetabolites established• Objective in clinical Mass balance study– Characterize excretion– Same mass balance experiment as inanimals …but no cage– Only way to know what metabolites are formed inman and have measureable exposure — microsomesand hepatocytes don’t fully inform with respect tothis.– Essential for downstream studies34Timing of Other Clinical Pharm Studies.2• Mass Balance– "as early as possible"– Many advocate this study should be the 3rd study conducted(after FIH and MAD study). Due to improvements in analyticalcapabilities, this study is now usually done much later in thedevelopment program. Today, plasma and urine samples fromFIH can be analyzed for metabolites without 14C material asthey can utilize the mass spectrometer to scan for potentialmetabolites. However, it is important to confirm findings oncethe compound is worthy of Phase 3 development.• Dose Linearity– Before Phase 2A, you should have an idea of this information.• Dose Proportionality– Pivotal study with to be marketed formulation before Phase 35 3Distribution in Body and to its “Target” Organ• Objective: How is the drug distributed afteradministration?–Nonclinical• Tissue levels• Whole bodyAutoradiography–Clinical• Positron Emission Tomography• Tissue fluid levels3612

4/19/2012Clinical Development Path ….so farTQT *DL DPDDISAD(DLpreliminary)MADPhase2b2 AWCTPh3NDAMBRIPkHIPkDDIData from these studies obtained prior to Ph337Aim of Drug Development• CMC [21 CFR 312.23(a)(7)]:To assure the proper identification, quality, purity,and strength of the investigational drug.• Nonclinical [21 CFR 312.23(a)(8)]:To assure that it is reasonably safe to conduct theproposed clinical investigations.• Clinical [FD&C Act Sec. 505]:To establish efficacy and safety of a drug for use inhumans, in a dose range and schedule thatprovides an acceptable risk benefit relationship.38What is Ultimately Required for Safety• Number treated for 6 months at intended clinical dosesshould be adequate to characterize the pattern of ADEs overtime. Usually 300 to 600 patients adequate;• Some patients should be treated with drug for 12 months.100 patients for minimum of one-year is acceptable• It is anticipated that total number treated with drug,including short-term exposure, will be about 1500.• Filing for approval usually possible based on data frompatients treated 6 months. Data on patients treated through12 months should be submitted as soon as available andprior to approval in USA. In the USA, initial submission fordrugs designated as priority drugs must include the 12month patient data.• Reasons for exceptions [i.e larger databases] existhttp://www.fda.gov/downloads/Drugs/Guidance%20ComplianceRegulatoryInformation/Guidances/ucm0730833913

4/19/2012Conclusion 2. Safety Requirements• As a first approximation, you will need at least1500 subjects exposed to drug– 300 for 6 months– 100 for 1 year• If there are any of a variety of safety concerns,these numbers could go more (# subjects) orlonger (duration of exposure)Coming soon….How to get to your adequate exposure database.40Long Term Extension Studies (LTES)• Objective:– Long term safety data, more subjects for longer• Guideline for Industry The Extent of Population Exposure to Assess ClinicalSafety:http://www.fda.gov/downloads/Drugs/Guidance%20ComplianceRegulatoryInformation/Guidances/ucm073083• Allows observation of AEs that take longer or are less frequent than the durationand sample size of the RCT– Continuation of therapy from RCTs until marketing– Marketing claims – typically need controlled data (not OL)• Design– Usually open label• Allows Investigators to flexibly dose to effect or based on tolerance• Harder to characterize safety without control group– Can either be associated with a specific, blinded RCT or you can have oneLTES that “catches” subjects from multiple trials– Visits and evaluations usually less frequent than double blind (DB) RCT usedfor demonstrating efficacy41Schematic Diagram for LTESTreatmentActive, X mgEnd ofDB RCTActive, Y mgActiveWXYZPlaceboExtra drug naïvesubjects recruited intothe LTES to bolstersample size= study visit• In this example, subjects are enrolled in the LTES from a preceding DBRCT or are drug naïve•At the end of the DB RCT treatment period, subjects are titrated to acommon dose. After achieving that dose, the Investigator is allowed toflexibly change their dose level throughout the trial, to a dose that isusually between a subjects minimally effective (Z) and maximally tolerated(W) dose.•Various rules are applied as to the common dose, the frequency of dosechanges, the speed of titration and the minimum and maximum allowabledose. Note the study visits are less frequent.4214

4/19/2012Clinical Development PathTQT *DL DPDDISAD(DLpreliminary)MADPhase2b2AWCT.......Ph3OLES............. NDAMBRIPkHIPkDDIData from these studies obtained prior to Ph34344Extended Release (ER) versus Immediate Release(IR) Plasma Profiles4515

4/19/2012How does the Development Program For a ModifiedRelease Differ from An Immediate Release• Generally, if the excipients are Generally Recognized as Safe(GRAS) and the PK levels, are lower than the IR, you don’t needmore toxicology studies– Exceptions exist, e.g., reformulating drugs approved long ago• The dose range of the MR should be very close to the IR – IRdosing levels are usually used for planning Phase 3 trials (hencePh 2 not usual)• The goal in the tolerability comparison is often to showcomparison to the IR more so than Pbo.• The number of Phase 3 trials can be less than 2 since youalready have evidence the active ingredient works. The Phase 3trial must show the formulation has not rendered the moleculeineffective.46MR Clin Pharm Program AttributesStudy Objective DosingAlcoholdumpingTest for alcohol dumping in reactionvessel; May need human studydepending on resultsSDFPFV-Topline1Q eachSD Test a # formulations vs IR; Pilot fed arm SD, X-over 1 QMDRelativeBioavailabilityDose proportionalityDose linearityTest top 1-2 candidates vs IR; Finalcandidate choiceTop clinical dose MR vs IR; Gives goodpicture of tolerability; May add PboAs per IRAs per IRSteady State,X-overSteady State,X-overSD, X-overSD, X-over2Q+3-4Q1 Q1 QFood EffectAs per IRSD, X-over1 QBridgingGMPDetect changes in performance withscaleup; As per IRSD, X-over1 Q47Prototypic Clinical Development Plan(Modified Release Type)YearStudy2010 2011 2012 2013 2014 2015Pilot SD (wpilot Fed arm)Pilot MDINDRel BADose PropDose LinFood EffectBridge APIPeds PKPh3aNDALaunch4816

4/19/2012Logical Studies Flow - BiologicsFIH/SAD:Based on NOEL;Often in HNV(depends oneffect)MAD: Often inHNV (dependson effect)Duration ofEffect: Howoften do youneed to dose interms of EFFECTTitration: Howfast can you getthere; Can yougo higher ifslowerPhase 2 Phase 3Other Studies:TQT, DrugInteraction,Specialpopulations,etcHNV: Healthy Normal Volunteer; MTD: Maximaltolerated dose ; NOEL: No Observed Effect Level; TQT:Thorough QT Study49NewIndicationsFormulations/ Follow OnGenericThe After-Life: Postmarketing DevelopmentPediatricsPartner?OTC50How Companies Plan to Counter Generics0 10 20 30 40 50 60 70Litigation Citizen's Petition PricingOTC Authorized Generic Generic SubsidiaryNew Formulations New Indications Pediatric ExclusivityNext Generation DrugCombination Drughttp://www.pharmalot.com/2010/07/how-brand-name-drugmakers-fight-generics/ 5117

4/19/2012Life Cycle Management ROIDollars Earned Per $1 Spent140120100806040200Want To Milk A Cash Cow? Try Pediatric Exclusivity Pharmalot By Ed Silverman //October 7th, 2010 //52Pediatric Development• Best Pharmaceuticals for Children Act• Pediatric Research Equity ActThe Carrot and Stick of Pediatric Drug Development53• Studies mandatory• Studies required only onproduct & indicationbeing reviewed• Studies not required fororphan indications• Standard review – unlessit qualifies for priority• Drugs and biologicsPREA vs. BPCA• Studies voluntary• Studies on entire activemoiety• WR may be issued fororphan indications• Priority review• Drugs only• Both - Pediatric studies must be labeled5418

StudyDeferWaiver4/19/2012Pediatrics - 3 Flavors• Epilepsy• Asthma• Depression• Type 2Diabetes• ALS• Parkinson'sSome diseases have distinct Adult and Pediatric Indications but a pure adult programmay not be allowed if it is expected that pediatrics will be prescribed the medication 55Pediatric Programs• Nonclinical "Juvenile Tox Study (-ies)"– Designed in conjunction with review body includingitems of special interest given drugs mechanism• Clinical Program - An example (there are manyways to do this)– Phase 2A study• Main goal is PK, tolerability leading to dose selection withPharmacodynamic secondary endpoints– Phase 3– Issues• Weight based dosing• Placebo• Ethics - Subpart D56Over-The-Counter Drugshttp://www.chpa-info.org/pressroom/Sales_Category.aspx5719

4/19/2012OTC Drug ProductsGeneral Concepts• Need to ensure that consumers can:– Diagnose the underlying condition– Determine whether drug is appropriate for them– Self-administer safely and effectively– Avoid potential serious consequences– Recognize when to see a physician or seek emergencyassistance• Label comprehension is key to approval– All labeling directed to the consumer58Generic Drugshttp://www.themedica.com/articles/2009/04/the-us-generic-drugs-industry.html59Definition of Generic Drug• “Same” as a drug product listed in the Orange Book (“listed drug”)– active ingredient(s)– route of administration– dosage form– strength– conditions of use recommended in labelingOR. . .• Certain changes from a listed drug if FDA has approved a suitabilitypetition• Labeling same as reference listed drug except for– Manufacturer/distributor– Indications protected by patent or exclusivity60– “Voluntary” pieces of approved labeling20

4/19/2012Summary• Clinical Development is the portion of the programwith an aim to provide information about the doserelationship of safety and efficacy and to provideevidence for risk benefit considerations• The Clinical Pharmacology portion is driven byspecific questions about the drug:patientinteractions• The Efficacy considerations should be directed attesting a clinically meaningful hypothesis in thetarget population• Postmarketing planning should be in parallel with theregistrational program and execution and executionshould6121