nda 21-399 zd1839 for treatment of nsclc fda review division of oncology drug products
DESCRIPTION
NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products. FDA ZD1839 NDA Review Team. Outline of FDA Presentation. Regulatory Overview and Critical Issues Grant Williams, MD Medical Review Findings Martin Cohen, MD Statistical Review Findings - PowerPoint PPT PresentationTRANSCRIPT
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NDA 21-399NDA 21-399 ZD1839 for Treatment of ZD1839 for Treatment of
NSCLCNSCLC
FDA ReviewFDA ReviewDivision of Oncology Drug Division of Oncology Drug
ProductsProducts
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 22
Project Managers Amy BairdDotti Pease
Medical Martin Cohen, M.D.Grant Williams, M.D.Richard Pazdur, M.D.
Statistics Rajeshwari Sridhara, Ph.D.Gang Chen, Ph.D.
Chemistry & Manufacturing Chengyi Liang, Ph.D.Richard Lostritto, Ph.D.
Pharmacology & Toxicology William McGuinn, Ph.D.David Morse, Ph.D.
Clinical Pharmacology Sophia Abraham, Ph.D.Atiqur Rahman, Ph.D.
Division of Scientific Investigations Khin U, M.D.
FDA ZD1839 NDA Review TeamFDA ZD1839 NDA Review Team
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 33
Outline of FDA PresentationOutline of FDA Presentation Regulatory Overview and Critical IssuesRegulatory Overview and Critical Issues
Grant Williams, MDGrant Williams, MD Medical Review FindingsMedical Review Findings
Martin Cohen, MDMartin Cohen, MD Statistical Review FindingsStatistical Review Findings
Rajeshwari Sridhara, PhDRajeshwari Sridhara, PhD Summary and Introduction of QuestionsSummary and Introduction of Questions
Grant Williams, MDGrant Williams, MD
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 44
Study ResultsStudy Results1. Claim of symptom improvement from a 1. Claim of symptom improvement from a
study without a control armstudy without a control arm2. Response rate (RR) of 10% in 139 2. Response rate (RR) of 10% in 139
patients with refractory NSCLCpatients with refractory NSCLC3. No clinical benefit in two large controlled 3. No clinical benefit in two large controlled
studies of first-line treatment of NSCLCstudies of first-line treatment of NSCLC4. In view of #3, is the 10% RR in 4. In view of #3, is the 10% RR in
refractory NSCLC refractory NSCLC reasonably likely to reasonably likely to predict clinical benefitpredict clinical benefit??
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 55
Efficacy requirement for Efficacy requirement for regular approvalregular approval
1962 law: substantial evidence of 1962 law: substantial evidence of efficacy from well controlled clinical efficacy from well controlled clinical trialtrialss
Efficacy is defined as clinical benefitEfficacy is defined as clinical benefit
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 66
DODP: Endpoints for DODP: Endpoints for Approval Approval
Approvals not based on SurvivalApprovals not based on Survival: : 67% (37/55) excluding accelerated 67% (37/55) excluding accelerated
approvalsapprovals 73% (48/66) of all approvals73% (48/66) of all approvals
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Examples of Approvals Examples of Approvals Based on Tumor-Related Based on Tumor-Related
SymptomsSymptoms Symptoms from obstructive Symptoms from obstructive
esophageal cancer or lung cancer esophageal cancer or lung cancer Symptomatic prostate cancerSymptomatic prostate cancer Symptomatic cutaneous KS or Symptomatic cutaneous KS or
CTCLCTCL Bone morbidity from metastatic Bone morbidity from metastatic
cancer cancer
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Problems with AZ symptom Problems with AZ symptom benefit claimsbenefit claims
No concurrent controlNo concurrent control Confounding palliative medicationsConfounding palliative medications Response correlation:Response correlation:
Patient and observer biasPatient and observer bias Assessment biasAssessment bias Shared baseline prognostic factors Shared baseline prognostic factors
(known and unknown)(known and unknown)
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 99
Accelerated approval Accelerated approval Serious or life-threatening diseaseSerious or life-threatening disease Drug must provide benefit over Drug must provide benefit over
available therapyavailable therapy Surrogate endpoint may be usedSurrogate endpoint may be used Surrogate endpoint must be Surrogate endpoint must be reasonably reasonably
likely to predict clinical benefitlikely to predict clinical benefit Post marketing studies must verify Post marketing studies must verify
clinical benefitclinical benefit
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DODP Accelerated Approval Using DODP Accelerated Approval Using Response RatesResponse Rates
Drug Indication
Liposomal doxorubicin Kaposi's sarcoma, second lineDocetaxel Breast cancer, second lineIrinotecan Colon cancer, second lineCapecitabine Breast cancer, refractoryLiposomal cytarabine Lymphomatis meningitisTemozolomide Anaplastic astrocytoma, refractoryLiposomal doxorubicin Ovarian cancer, refractoryGemtuzumab ozogamicin AML, second line, elderlyImatinib mesylate CML: blast phase, accelerated
phase, or after failing interferonOxaliplatin Colon cancer after failing 5FU/LV
and irinotecan
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 1111
Evidence for Accelerated Evidence for Accelerated ApprovalApproval
Substantial evidenceSubstantial evidence from well from well controlled clinical trials regarding a controlled clinical trials regarding a surrogate endpointsurrogate endpoint
NOT: NOT: Borderline evidenceBorderline evidence regarding a regarding a clinical benefit endpoint clinical benefit endpoint
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Accelerated approvalAccelerated approval Serious or life-threatening diseaseSerious or life-threatening disease Drug must provide benefit over Drug must provide benefit over
available therapyavailable therapy Surrogate endpoint may be usedSurrogate endpoint may be used Surrogate endpoint must be Surrogate endpoint must be reasonably reasonably
likely to predict clinical benefitlikely to predict clinical benefit Post marketing studies must verify Post marketing studies must verify
clinical benefitclinical benefit
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Drug must provide benefit Drug must provide benefit over available therapyover available therapy
Single arm trial design (all patients receive Single arm trial design (all patients receive ZD1839) dictates study of patients with no ZD1839) dictates study of patients with no available therapyavailable therapy
Drugs are currently available for first-line Drugs are currently available for first-line and second-line treatment of NSCLC and second-line treatment of NSCLC
The single arm design of Study 039 restricts The single arm design of Study 039 restricts the accelerated approval analysis to third-the accelerated approval analysis to third-line NSCLC (139 patients)line NSCLC (139 patients)
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 1414
Reasonably likely to Reasonably likely to predict clinical benefitpredict clinical benefit
This is a judgement based on all This is a judgement based on all available evidenceavailable evidence
A response rate of about 10% has A response rate of about 10% has supported some AA’s (e.g., irinotecan)supported some AA’s (e.g., irinotecan)
Lack of clinical benefit in large, Lack of clinical benefit in large, randomized first-line studies must be randomized first-line studies must be consideredconsidered
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Medical Review FindingsMedical Review Findings
Martin Cohen, MDMartin Cohen, MD
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 1616
FDA Approved Drugs: FDA Approved Drugs: NSCLC Stage IIIB/IV NSCLC Stage IIIB/IV
First line - paclitaxel/cisplatinFirst line - paclitaxel/cisplatin
gemcitabine/cisplatingemcitabine/cisplatin vinorelbine vinorelbine ++
cisplatincisplatinSecond line - docetaxelSecond line - docetaxel
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NSCLC Stage IIIB/IVNSCLC Stage IIIB/IVSubmitted ZD1839 Clinical Submitted ZD1839 Clinical
TrialsTrialsTrial 39 - Third-line trial for Trial 39 - Third-line trial for accelerated approvalaccelerated approval
Trial 16 - Supporting second-line Trial 16 - Supporting second-line trialtrial
INTACT 1 and 2 - First-line trials to INTACT 1 and 2 - First-line trials to demonstrate clinical benefitdemonstrate clinical benefit
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Trial DesignsTrial DesignsPhase II, Randomized, Double-Phase II, Randomized, Double-
BlindBlindZD1839 250 mg/dayZD1839 250 mg/day
versusversus ZD1839 500 mg/day ZD1839 500 mg/day
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Trial 39 - Efficacy Trial 39 - Efficacy EndpointsEndpoints
Co-primary:Co-primary: Response rateResponse rate Disease related symptom Disease related symptom
improvementimprovement(Assessment difficulty was (Assessment difficulty was recognized) recognized)
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 2020
Trial 39 ITT Population Trial 39 ITT Population n=216n=216
Characteristic % of PatientsPerformance status 0-1 80Tumor Histology Squamous Adenocarcinoma Squamous & Adenocarcinoma
15667
Months from Dx (median) 20Stage IV at diagnosis 50Metastases at study entry 89
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 2121
Trial 39 Pts refractory or Trial 39 Pts refractory or intolerantintolerant
Platinumrefractory/intolerant
Yes No
Yes 139 58Docetaxelrefractory/intolerant No 11 8
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 2222
Trial 39 Responder Trial 39 Responder CharacteristicsCharacteristics
Characteristics of 22responders N (%)
Female sex (43%)* 18 (82)Adenocarcinoma (66%) 19 (86)Stage IV at diagnosis 13 (59)Dx to Randomization (mo)<1213-24>25
3 (14)12 (55) 7 (32)
3 to 5 prior chemo regimens 15 (68)* Percent of study population
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Trial 39 Responder Trial 39 Responder CharacteristicsCharacteristics
Pt characteristic N Response rate
Platinum &Docetaxelrefractory/intolerant
14/139 10.1%
Not refractory/intolerant to both
8/77 10.4%
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Symptom Assessment Symptom Assessment ProblemsProblems
- Patients and caregivers are - Patients and caregivers are unblinded unblinded
- Patients are informed of - Patients are informed of response response
- No prospective plan for - No prospective plan for managingmanaging
concomitant medicationconcomitant medication
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Concomitant MedicationConcomitant Medication NarcoticsNarcotics BronchodilatorsBronchodilators Antidepressants/Antidepressants/
AnxiolyticsAnxiolytics OxygenOxygen PrednisonePrednisone Transfusions/Transfusions/
ErythropoietinErythropoietin AntibioticsAntibiotics Cough SyrupCough Syrup
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Trial 16 ITT Population Trial 16 ITT Population n=209n=209
Characteristic % of PatientsPerformance status 0-1 87Tumor Histology Squamous Adenocarcinoma
2163
Months from Dx (median) 12Stage IV currently 79Caucasian/Japanese 49/49
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Trial 16: Prior Trial 16: Prior ChemotherapyChemotherapy
Previous chemotherapy All patients (%)(n=209)
Platinum, 1st or 2nd line 100Progression on either 1st or2nd line
35
No progression on chemo 65
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Trial 16 Objective Response Trial 16 Objective Response RateRate
Best Response Number (%)
CR 1 (0.5)
PR 38 (18.2)
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Responder CharacteristicsResponder CharacteristicsCharacteristic NSex Male Female
18/148 (12)21/61 (34)
Origin Caucasian Japanese
11/102 (11)28/102 (27)
Histology Adeno Squamous
34/132 (26)3/43 (7)
Months from Dx Median (range)
14.9 (1.8 - 84.6)
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Response Rate and Response Rate and Chemotherapy ProgressionChemotherapy Progression
No Progression Progression
Caucasian 9/62 (15%) 2/40 (5%)
Japanese 19/69 (28%) 9/33 (27%)
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Trials 39 & 16 AE’sTrials 39 & 16 AE’sAE 250 mg/d (%) 500 mg/d (%)
Diarrhea 44 62Rash 45 61Acne 30 24Dry skin 20 28Nausea 13 20Vomiting 9 14
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Response RatesResponse Rates
Number %Trial 39 Doubly refractory < doubly refractory
14/1398/77
10.1*10.4
Trial 16 Caucasian Japanese
11/10228/102
10.827.5
* 95% CI 5.6%,16.3%
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Trial 39 Responding PatientsTrial 39 Responding Patients Responders constitute a patient Responders constitute a patient
population enriched for slowly population enriched for slowly growing, relatively non-biologically growing, relatively non-biologically aggressive cancers. aggressive cancers.
Median time from diagnosis to Median time from diagnosis to randomization was 19.5 months randomization was 19.5 months
Responders were predominantly P.S. Responders were predominantly P.S. 0-1 females with adenocarcinomas. 0-1 females with adenocarcinomas.
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Symptom ImprovementSymptom Improvement Problems in Interpretation Problems in Interpretation
Not blinded (no comparator regimen)Not blinded (no comparator regimen) Concomitant medicationsConcomitant medications
Drug dose and schedule Drug dose and schedule information information not collectednot collected
? bias in responders? bias in responders
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NDA 21-399: ZD1839 for NDA 21-399: ZD1839 for NSCLCNSCLC
Statistical Review FindingsStatistical Review Findings
Rajeshwari Sridhara, Ph.D.Rajeshwari Sridhara, Ph.D.
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Major Concerns in Trial IL0039Major Concerns in Trial IL0039
Trial Design: Single Arm Trial to Eliminate Trial Design: Single Arm Trial to Eliminate < 5% Response; Trial sized to < 5% Response; Trial sized to independently evaluate efficacy in the two independently evaluate efficacy in the two ZD1839 treatment arms (250 mg and 500 ZD1839 treatment arms (250 mg and 500 mg)mg)
Heterogeneity of patient population (third Heterogeneity of patient population (third and second line patients)and second line patients)
No Comparative Control Arm (no non-No Comparative Control Arm (no non-ZD1839 arm)ZD1839 arm)
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Objective Tumor ResponseObjective Tumor Response
250 mg + 500 mg ZD1839 Treatment 250 mg + 500 mg ZD1839 Treatment Arms (Third Line Patients Only):Arms (Third Line Patients Only):
Total 14/139 ( 10.1 %) responses Total 14/139 ( 10.1 %) responses 95% C.I.: 5.6 %, 16.3%95% C.I.: 5.6 %, 16.3%
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Symptom Improvement - LCS Symptom Improvement - LCS ScoreScore
Not atNot at A littleA little Some-Some- QuiteQuite VeryVery allall bit bit what what a lota lot muchmuch
1. I have been short of breath1. I have been short of breath 0 0 1 1 2 2 3 3 4 42. I am losing weight2. I am losing weight 0 0 1 1 2 2 3 3 4 43. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 3 3 4 44. I have been coughing4. I have been coughing 0 0 1 1 2 2 3 3 4 45. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 3 3 4 46. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 3 3 4 47. Breathing is easy for me7. Breathing is easy for me 0 0 1 1 2 2 3 3 4 4
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 3939
Symptom Improvement - LCS Symptom Improvement - LCS ScoreScore
Not atNot at A littleA little Some-Some- QuiteQuite VeryVery allall bit bit what what a lota lot muchmuch
1. I have been short of breath1. I have been short of breath 0 0 1 1 2 2 3 3 4 42. I am losing weight2. I am losing weight 0 0 1 1 2 2 3 3 4 43. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 3 3 4 44. I have been coughing4. I have been coughing 0 0 1 1 2 2 3 3 4 45. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 3 3 4 46. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 3 3 4 47. Breathing is easy for me7. Breathing is easy for me 0 0 1 1 2 2 3 3 4 4
00 2828
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Symptom Improvement - LCS Symptom Improvement - LCS ScoreScore
Not atNot at A littleA little Some-Some- QuiteQuite VeryVery allall bit bit what what a lota lot muchmuch
1. I have been short of breath1. I have been short of breath 00 1 1 2 2 3 3 4 42. I am losing weight2. I am losing weight 0 0 1 1 2 2 33 4 43. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 33 4 44. I have been coughing4. I have been coughing 00 1 1 2 2 3 3 4 45. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 33 4 46. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 33 4 47. Breathing is easy for me7. Breathing is easy for me 0 0 1 1 2 2 3 3 4 4
00 2828
Baseline Score = 24
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9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 4141
Symptom Improvement - LCS Symptom Improvement - LCS ScoreScore
Not atNot at A littleA little Some-Some- QuiteQuite VeryVery allall bit bit what what a lota lot muchmuch
1. I have been short of breath1. I have been short of breath 00 1 1 2 2 3 3 4 42. I am losing weight2. I am losing weight 0 0 1 1 2 2 33 443. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 33 444. I have been coughing4. I have been coughing 00 1 1 2 2 3 3 4 45. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 33 4 46. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 33 4 47. Breathing is easy for me7. Breathing is easy for me 0 0 1 1 2 2 3 3 4 4
00 2828
Baseline Score= 24 Improved Score = 26
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Symptom Improvement RateSymptom Improvement Rate 250 mg and 500 mg ZD1839 Treatment 250 mg and 500 mg ZD1839 Treatment
Arms (Third line patients only):Arms (Third line patients only):
45/139 (32.4 %) with symptom 45/139 (32.4 %) with symptom improvement per sponsor definition of improvement per sponsor definition of improvement on the LCS scaleimprovement on the LCS scale
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Patient LCS Profile - An ExamplePatient LCS Profile - An Example
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Patient LCS Profile - An ExamplePatient LCS Profile - An Example
1. Short of Breath2. Losing Weight3. Thinking is Clear4. Been Coughing5. Good Appetite6. Tightness in Chest7. Breathing Easy
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% of Patients Evaluated Over % of Patients Evaluated Over TimeTime
0102030405060708090
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
WEEKS
% o
f PAT
IENT
S
250 mg
500 mg
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Critical IssuesCritical Issues Efficacy with respect to Objective Tumor Efficacy with respect to Objective Tumor
Response with ZD1839 could be as low Response with ZD1839 could be as low as 5.6% (lower 95% CL = 5.6%).as 5.6% (lower 95% CL = 5.6%).
Symptom Improvement not Symptom Improvement not interpretable without control data.interpretable without control data.
Symptom Improvement possibly Symptom Improvement possibly confounded by concomitant medication confounded by concomitant medication effect and patient characteristicseffect and patient characteristics
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Results of Randomized, Controlled, Results of Randomized, Controlled, Phase III Studies in First-line Phase III Studies in First-line
NSCLC PatientsNSCLC Patients Study IL0014: Study IL0014:
Gemcitabine + Cisplatin + ZD1839 250 mg; N Gemcitabine + Cisplatin + ZD1839 250 mg; N = 365= 365
Gemcitabine + Cisplatin + ZD1839 500 mg; N Gemcitabine + Cisplatin + ZD1839 500 mg; N = 365= 365
Gemcitabine + Cisplatin + Placebo; N = 363Gemcitabine + Cisplatin + Placebo; N = 363
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250 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.4382
500 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.3041
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250 mg vs. Placebo: HR 1.0 (0.8, 1.2)
500 mg vs. Placebo: HR 0.9 (0.8, 1.1)
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Tumor Response and One-year Tumor Response and One-year Survival Rates in Trial IL0014Survival Rates in Trial IL0014
Treatment Arm Response Rate(95% C.I.)
% KM Survival Estimate at 1 yr
(S.E.)Chemo + ZD1839 250 mg
50.1%(44.7%, 55.6%)
43.75 (2.61)
Chemo +ZD1839 500 mg
49.7%(44.2%, 55.2%)
41.51(2.59)
Chemo + Placebo
44.8%(39.3%, 50.4%)
44.87 (2.64)
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Results of Randomized, Controlled, Results of Randomized, Controlled, Phase III Studies in First-line Phase III Studies in First-line
NSCLC PatientsNSCLC Patients Study IL0017: Study IL0017:
Taxol + Carboplatin + ZD1839 250 mg; N = Taxol + Carboplatin + ZD1839 250 mg; N = 347347
Taxol + Carboplatin + ZD1839 500 mg; N = Taxol + Carboplatin + ZD1839 500 mg; N = 345345
Taxol + Carboplatin + Placebo; N = 345Taxol + Carboplatin + Placebo; N = 345
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250 mg vs. Placebo: HR 1.0 (0.9, 1.2), P-value 0.6429
500 mg vs. Placebo: HR 1.0 (0.8, 1.2), P-value 0.6710
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250 mg vs. Placebo: HR 0.85 (0.70, 1.03)
500 mg vs. Placebo: HR 0.86 (0.72, 1.04)
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Tumor Response and One-year Tumor Response and One-year Survival Rates in Trial IL0017Survival Rates in Trial IL0017
Treatment Arm Response Rate(95% C.I.)
% KM Survival Estimate at 1 yr
(S.E.)Chemo + ZD1839 250 mg
35.0%(29.6%, 40.6%)
37.57 (2.60)
Chemo +ZD1839 500 mg
32.1%(27.0%, 37.7%)
41.89 (2.67)
Chemo + Placebo
33.6%(28.1%, 39.3%)
42.22 (2.66)
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Results of Phase III StudiesResults of Phase III Studies No Statistically Significant Difference with No Statistically Significant Difference with
respect to Overall Survival between ZD1839 respect to Overall Survival between ZD1839 treated group and Placebo treated group in treated group and Placebo treated group in the two well conducted, placebo controlled, the two well conducted, placebo controlled, randomized studies in over 2000 patients. randomized studies in over 2000 patients.
No difference between ZD1839 treated arm No difference between ZD1839 treated arm and Placebo treated arm with respect to and Placebo treated arm with respect to secondary endpoints including response rate secondary endpoints including response rate and time to progression in both the studies.and time to progression in both the studies.
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Summary of FDA FindingsSummary of FDA Findings
Grant Williams, MDGrant Williams, MD
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Study ResultsStudy Results1. Claim of symptom improvement from a 1. Claim of symptom improvement from a
study without a control armstudy without a control arm2. Response rate (RR) of 10% in 139 2. Response rate (RR) of 10% in 139
patients with refractory NSCLCpatients with refractory NSCLC3. No clinical benefit in two large controlled 3. No clinical benefit in two large controlled
studies of first-line treatment of NSCLCstudies of first-line treatment of NSCLC4. In view of #3, is the 10% RR in 4. In view of #3, is the 10% RR in
refractory NSCLC refractory NSCLC reasonably likely to reasonably likely to predict clinical benefitpredict clinical benefit??
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Questions to the Questions to the CommitteeCommittee
1. Can symptom improvements claimed for 1. Can symptom improvements claimed for ZD1839 be adequately assessed without ZD1839 be adequately assessed without a control arm?a control arm?
2. Given negative studies in first-line 2. Given negative studies in first-line treatment of NSCLC, is the 10% RR in treatment of NSCLC, is the 10% RR in refractory NSCLC reasonably likely to refractory NSCLC reasonably likely to predict clinical benefit?predict clinical benefit?
3. Discuss expanded access3. Discuss expanded access4. Discuss design of additional trials.4. Discuss design of additional trials.