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'z% B{cIP0FbWҼϾy;3bM1e839+-[lA?88~>?uCKϽsZh '~WSd,iq{Oֆ➴Z㞾y'~~?Lnz1hO)Ӭ.DkAK3W(g6-iI= ޠ`&lsA=33s~ڨ~ѳw9]+rV`f/$w|Ѡ7dCV& vxLFdrâfLZdjAjYSI6)Dz@m@pdϏ,bn2Cjq62VRaal93{*Fz!r'tRUFVmIgc5]Y r֓hQ:[qg:Ge7FI=U)wtZ!O:tuTShF]v4Y蹑'F?nmDRy]qhX;g4ytkV're0kTD'h ;Kպ1Ǵ5/*8bTW*V{g3bQ{"'rѾ}K\)y:z=g7|vɞ3?[m!{vM&n&C+Zcw׻Ej̀þd î3g)ռBN\OIe7+YqWw+Gua7`/) BJMm#{5X͔pZUFfNkNcS榃G( U  +e0Document Word.Document.80.Microsoft Word Document0 Document Word.Document.80.Microsoft Word Document0!Document Word.Document.80.Microsoft Word Document}0#Document Word.Document.80.Microsoft Word Document 0$Document Word.Document.80.Microsoft Word Document 0%Document Word.Document.80.Microsoft Word Document/ 0LDTimes New Roman̳0~0   @n?" dd@  @@``  |_1$  2 .)), $!&,+&&)),+,-.1/,- $+#  (" #%  '$h$$$$$2$;nt0fA_uB.2$+H(Ÿn2$mMAK>I0$$$2$N$IK@8  2$"Y* w6h8rwp2$˫*;\DVg 0e0e     A@  A5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||@ g4TdTd~0ppp@ <4ddddtv<4!d!dtv g4dddd~0  p@ pp? %O =m.-Defining Success in Oncology Drug DevelopmentRichard Pazdur, MD CDER, FDA The views expressed are the results of independent work and do not necessarily represent the views or findings of the United States Food and Drug Administration or the United States $Basis for NDA ApprovalDemonstration of efficacy with acceptable safety in adequate and well-controlled studies Ability to generate product labeling that Defines an appropriate patient population Provides adequate information to enable safe and effective use Approval for an indication, not drug HW+oActivity vs. Benefit$    Biologic Activity--screening of a compound, phase II trial endpoint, an indication for further study Clinical benefit--what is meaningful to a patient The approval process is not a screening process for drug activityRegulatory TermsZAccelerated Approval--serious or life-threatening disease, benefit over available therapy. Use of surrogate; mandated phase IV trials Fast Track--life-threatening disease, potential to address unmet medical need. Rolling NDA, meetings Priority review--drug would be a significant improvement compared to available drugs. Review of NDA in 6 monthsn[G+ EGpOncology Trial ConcernsMinimize bias Blinding trials (few) Endpoints that minimize bias Internal consistency of subgroups, endpoints Magnitude of change of endpoint Clinical significance Underpowered trials--guessing treatment effect Isolating effect of drugZ` E` E ;y"Risks in Developing Oncology DrugspIndication--lack of predictive models  Creative Indications --progressively more refractory patient, market share Two trials versus one trial Dose ranging studies--moving away from MTDEndpoints in OncologySurvival and improvement in patient reported symptoms considered clinical benefit Objective Response Rate and Time to Progression usually viewed as surrogates Exceptions : relatively non-toxic products such as hormonal therapies or some biologics nEndpoints 1990 to 200152 regular approvals; 10 accelerated 43/62 oncology drug applications were approved on endpoints other than survival Tumor response was basis in 27/52 supported by relief of tumor specific sxs in 10/27 Relief of tumor symptoms provided support in 13/52 regular approvalsNqTraditional Endpoints: SurvivalNon-inferior or improved survival constitutes  patient benefit after consideration of toxicity and the magnitude of the benefit Non-inferior outcome ensures that a survival advantage associated with an approved drug will not be lost with a new agent mVTraditional Endpoints: SurvivalDrawbacks Requires large sample size and long follow-up Confounder--Cross-over therapy may  wash out a survival effect 6 n n8 7-Time to Progression--AdvantagesCould use a smaller sample size and shorter follow-up than trials that require a survival endpoint Differences will not be obscured by secondary therapy if cross-over effect exists  Time to symptomatic progression 0" TTP: Problems*Unblinded trials introduce bias Must evaluate all patients on a regular basis Must evaluate all sites of possible disease Complete ascertainment of all sites at baseline and follow-up (i.e., look for new sites) Same type of assessment tool at each follow-up Should use same evaluation schedule $OO !3% TTP: Problems, How much improvement constitutes benefit? c Response RateUnique endpoint--treatment is  entirely responsible for tumor reduction In contrast, survival and TTP have an effect of the natural history PLUS treatment effect Must consider duration of response Does not include stable disease Pick your criteria and stick with itoYComplicated Picture of RR(Number of CRs vs PRs? Duration of responses? Location of responses (e.g., liver vs skin)? Association with symptom improvement? Extent or bulk of metastatic disease? H@T> ;?   ) Palliation and Patient Reported OutcomesBlinding and associated antitumor effects (response rates) lend credibility Use simple instruments Hypothesis-driven Avoid multiple endpoints Example: Photofrin PDT and dysphagia scale .LoLn P u  P==Potential palliative endpoint: Health-related quality of life.Pro: Patient s perspective on treatment Con: Blinding is essential, but difficult to do Careful serial assessments Missing data makes interpretation problematic Multiple endpoints and comparisons to baseline must be adjusted for in the statistical analysis plan Clinical significance of score changes may be unclear Is additional information gained, compared to a careful recording of toxicity/symptom data?X-F-F+Accelerated Approval- Subpart H (21CFR 314)For serious or life-threatening diseases Where the drug appears to provide benefit over available therapy Approval based on a surrogate that is reasonably likely to predict clinical benefit21CFR314 (continued)Subject to the requirement that the applicant verify and describe benefit Post-marketing studies would usually be underway The applicant shall carry out such studies with due diligence Withdrawal ProceduresConditions postmarketing study fails to verify benefit applicant fails to perform required study with due diligence postmarketing restrictions inadequate to assure safe use failure to adhere to postmarketing restrictions promotional materials false/misleading Requires a hearing6  > [@IEndpoints Utilizedp Single arm trials : ORR Randomized Setting : Cytologic response, number of polyps, ORR, TTP, DFS, LVEF ; CHF , 9RR in Single Arm TrialsRR in Single Arm TrialsRR in Single Arm TrialsRandomized Trials(Randomized Trials (contd)*Uncertainty of Benefit to Ultimate OutcomeAAmifostine (Ethyol) Dexrazoxane (Zinecard) Anastrozole (Arimidex)l   5 Timing of Confirmatory Trials Converted Indications&6 ($,Issues Related to the AA Program As a Whole0The importance of confirmatory trials being underway at the time of AA The approach of studying slightly different populations in the confirmatory setting than the AA population Relative merits of different trial designs single arm in refractory populations randomized trials in less refractory patients$SSy^Scientific Challenges Re-define diseases; surrogate validation Greater efficacy in selected population may result in smaller patient populations Dosing aimed at target rather than MTD Dose studies, chronic administration Exclude pts who would benefit due to unrecognized mechanisms1xRegulatory ChallengesDifferences in oncology drug development/regulation compared to other therapeutic areas Coordination of Agency s Centers (Drugs, Biologics, Devices) regarding oncology therapeutics Scientific foundation must precede regulatory decision-making    /P~!#()-125w ` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@,|?" dd@   " @ ` p?" dd@  @@``PR    @ ` ` p>> c(    6Tv P  T Click to edit Master title style! !  0v   RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0v ``  =*  0tv `   ?*  0v `   ?*H  0޽h ? n 0 .&@(    0 P   v =*   0     ?* d  c $ ?    0T  @  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  6 `P   =*   6 `   ?* H  0޽h ? ̙33 0`4( y@ ` ` 0 P    =*  ` 0t     ?*  ` 6ԕ `P   =*  ` 64 `   ?* H ` 0޽h ? ̙33  (  l  C p  l  C TP   H  0޽h ? ̙33 5 % 0(Pl( , l l # lԘgֳgֳ ?    l # l?gֳgֳ ?Pp   H l 0޽h ? 3  `0( w 0l 0 C AP   l 0 C 4B  H 0 0޽h ?   px$(  xr x S CP   r x S D  H x 0޽h ? 3  4( w 4l 4 C FP   l 4 C G  H 4 0޽h ?   d( Ow@ dl d C GP   l d C 4H@`  H d 0޽h ?   $(  @ r  S IP   r  S J  H  0޽h ?   ,$( Ow@ ,r , S P   r , S   H , 0޽h ?  2 8$( Ow@ 8r 8 S 4P   r 8 S   H 8 0޽h ?  ! $( Ow@ r  S P   r  S t@`0  H  0޽h ?   (  l  C 4P   l  C   H  0޽h ?   (  l  C T   l  C    H  0޽h ?   (  l  C    l  C 4p  H  0޽h ?  1 ( w l  C P   l  C   H  0޽h ?  #  $( w r  S t`   r  S @`  H  0޽h ? 3 ( 0L$( < Lr L S  `   r L S  P@`  H L 0޽h ? 3 ) @L( 8 WH  Ll L C     l L C $   H L 0޽h ?   P$( [BlBA r  S D P   r  S  p  H  0޽h ? ̙33  `$( h r  S $ P   r  S    H  0޽h ?   p$(  r  S  P   r  S    H  0޽h ?   T$( 4p/ Tr T S $ P   r T S    H T 0޽h ?   H4( , Hr H S  P    H0 6A #? # H H 0޽h ?   L4(  Lr L S  P    L0 6A $?_) $ H L 0޽h ?   P4(  Pr P S d P    P0 6A %?j % H P 0޽h ?   ,4( k$VԞ ,r , S  P    ,0 6A ?  H , 0޽h ?   04(  0r 0 S $ P    00 6A  ?h  H 0 0޽h ?   8$( l$l[X 8r 8 S  P   r 8 S i 0P  H 8 0޽h ?   <4(  <r < S $j P    <0 6A !?so ! H < 0޽h ?   $(  r  S j P   r  S j   H  0޽h ?  - ,( w ,l , C l P   l , C $m    H , 0޽h ?    \( ) \l \ C o P   l \ C do   H \ 0޽h ?   0$( LMdcx< r  S p P   r  S Dq   H  0޽h ?  @t0( ll lX8l tH t 0޽h ?   P$(  r  S q P   r  S r   H  0޽h ?  0 x`@( f @R @ 3    ~ @ C r  @    H @ 0޽h ? ̙33n% 0 .&P( @ X@ PR P 3    G, P C DyG @  G Other problems with the TTP endpoint is the consideration of the magnitude of difference which would constitute clinical benefit. Since most measurement are performed every 3 months and the differences in TTP may be of similar benefit, the clinical relevance of relatively small differences, especially in unblinded trials, may be questioned. In addition, prolongation of TTP may not impact survival. Other problems with this endpoint include the handling of missing data and censoring issues, especially for long periods between loss to follow-up and death or the introduction of new therapies in the absence of documented progression.,6 (H P 0޽h ? ̙33" 0 T2( @ X@ TR T 3    G T C du  @  G @Most oncology trials are unblinded potentially introducing bias into decision-making regarding TTP. Patients must be evaluated on a regular basis on all treatment arms for this endpoint to be meaningful and must evaluate all sites of possible disease and ideally measure all lesions. There must be complete ascertainment of all sites of disease at baseline and follow-up. The same assessment technique must be used at each follow-up and the same evaluation schedule should be used.> YoH T 0޽h ? ̙33 0 ~\(  \R \ 3     \ C u  @   $ Time to progression is defined as the time from randomization to time of progressive disease or death. This endpoint has been used for the approval of hormonal therapies and certain biologics because of the more favorable toxicity profile. Differences in TTP will not be obscured by secondary therapies if a cross-over effect exists. We have been interested in improving this endpoint by potentially correlating radiographic changes with a delay of new symptoms or of worsening of symptoms.H \ 0޽h ? ̙33V 0 p'( |@|@ pR p 3     p C t  @   5!Although a preferred endpoint, survival has drawbacks. Since most active agents in oncology are associated with small incremental survival benefits, large sample sizes may be required to demonstrate comparatively small differences. An increasing concern is the effect of cross-over therapy in randomized trials which may obscure a survival effect. This issue was discussed in a June, 1999 ODAC meeting with a consensus that survival should remain the primary endpoint for first-line breast cancer trials. Despite significant cross-over, trials have demonstrated survival advantages. An example of this is use CPT-11 in 5-FU refractory patients. Nevertheless, the issue of cross-over and its effect on survival remains an issue of concern and will be reviewed in subsequent advisory committees.H p 0޽h ? ̙33Y 0 {sx ( 7 xR x 3    Gy x C dzG @  G The evaluation and comparison of response rates may be difficult. Methodological questions include --Were lesions to be measured prospectively identified? -- Was the same imaging techniques including scan and types of cuts used? In comparing RR, one must analyze the relative number of CRs vs PRs, duration of responses, location of responses, and correlation with symptom imporvment, and extent or bulk of metastatic disease.P: M   H x 0޽h ? ̙33  0 xp( 7 R  3    Gv  C zG @  G Palliation or relief of symptoms are traditional endpoints corroborating clinical benefit. These endpoints are usually reported as patient reported outcomes. Credibility of these endpoints can be enhanced by blinding and an association with a biologic effect of the drug--e.g. response rate. Instruments used to measure these endpoints should be relatively simple, prospectively designed and tailored around an expected outcome. Examples include relief of dysphagia, and pain  H  0޽h ? ̙33 = 0 Z(  R  3    G  C ${G @  G h2Health-related quality of life are included in many registration trials and may provide the patient s perspective on the treatment. However, their interpretation is complicated by the lack of blinding, missing data leading, multiple endpoints and multiple comparisons to baseline which must be adjusted in the statistical analysis plan. In addition, clinical significance of score changes may be unclear. SFH  0޽h ? ̙33^ 0 NF( 7 R  3    GL  C {G @  G Novel agents pose new challenges. Rather than conventional histological criteria for diagnosis, we may need to re-define how we classify cancers based on the mechanism of pathogenesis and therapy. This may allow greater efficiency in the clinical trial process by selecting populations with a greater liklihood of responding to treatments. Novel surrogates will need validation and acceptance by the scientific community. Starting doses of agents may need to be aimed at inhibiting or interacting with a target rather than the MTD. Dose ranging studies, accepted as a norm in most other therapeutic areas, may be accepted by oncologists to avoid toxicities and optimize the therapy s interaction with targets.>;  R 5H  0޽h ? ̙33?c 0 (  R  3    G  C yG @  G 1Whereas, the endpoints of survival and TTP are comprised of the effect of the natural history plus an increment produced by treatment, tumor size reduction can usually be attributed entirely to treatment. Duration of the response must be included. Response rates are comprised of partial and complete responses. Stable disease and minor response patients are excluded. Although several criteria exist for response rate measurement, a single criteria should be adopted and uniformly applied. We have accepted the RECIST criteria for registration trials. Pl:{@H  0޽h ? ̙33q 0 <,(  <X < C     < S Dt  @   . Patient benefit can be described as improved survival or a non-inferior survival after consideration of toxicity and the magnitude of benefit.A survival duration is comprised of a component of a natural history effect plus a treatment effect. A non-inferiority analysis ensures that a survival advantage,  the control effect associated with an approved drug will not be lost with a new agent.H < 0޽h ? ̙33C 0 pp(  p p  N1 ?     p 3 rs gֳgֳ ? @   The requirement to demonstrate safety and efficacy before drugs are marketed stems from two Congressional actions. The safety requirement comes from the Federal Food and Drug and Cosmetic Act of 1938. The efficacy requirement stems from a 1962 amendment. The FDA has interpreted the 1962 amendment to require in most cases at least two trials for drug approval and to require claims to represent clinical benefit. For drug and indication to receive approval sufficient information must be available to define an appropriate patient population for drug use and enable safe and effective use.The product label represents a licensing agreement between the sponsor and the Federal government. Marketing and advertising claims are derived from the product label. 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CDER, FDA .Times New Romanww0- .R2 {2The views expressed are the results of independent            . .R2 2work and do not necessarily represent the views or            . .H2 +findings of the United States Food and Drug            . .<2 #Administration or the United States           .-- "System 0-&TNPP &՜.+,D՜.+,X     On-screen Show FDA.CDER Sh9" 1 %Times New RomanDefault DesignMicrosoft Word Document.Defining Success in Oncology Drug DevelopmentBasis for NDA ApprovalActivity vs. BenefitRegulatory TermsOncology Trial Concerns#Risks in Developing Oncology DrugsEndpoints in OncologyEndpoints 1990 to 2001 Traditional Endpoints: Survival Traditional Endpoints: Survival Time to Progression--AdvantagesTTP: ProblemsTTP: ProblemsResponse RateComplicated Picture of RR* Palliation and Patient Reported Outcomes>Potential palliative endpoint: Health-related quality of life,Accelerated Approval- Subpart H (21CFR 314)21CFR314 (continued)Withdrawal ProceduresEndpoints UtilizedRR in Single Arm TrialsRR in Single Arm TrialsRR in Single Arm TrialsRandomized TrialsRandomized Trials (contd)+Uncertainty of Benefit to Ultimate Outcome6 Timing of Confirmatory Trials Converted Indications-Issues Related to the AA Program As a WholeScientific Challenges Regulatory ChallengesNo Slide TitleNo Slide TitleNo Slide Title  Fonts UsedDesign TemplateEmbedded OLE Servers Slide Titles" 6> _PID_GUIDAN{ED9F3643-41C4-4C21-8FB8-0BB0C223D97B}Root EntrydO) I4@PicturesCurrent User,SummaryInformation(_XLuoXLuoRoot EntrydO)ЍS@PicturesCurrent User2SummaryInformation(_VinuriVinuri  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root EntrydO)PicturesCurrent UserSummaryInformation(PowerPoint Document(DocumentSummaryInformation8