Table 1.
Characteristics of single pivotal trials supporting the approval of novel therapeutic drugs
| Novel therapeutic drug | Study population (disease or condition) | Study design | Treatment arms | Number of randomized patients | Primary end point | Results of the primary efficacy analysis for the approved dosage(s) |
|---|---|---|---|---|---|---|
| Aclidinium bromide (AB) | Chronic obstructive pulmonary disease | Randomized, double‐blind, placebo‐controlled |
Grp 1: AB 200 μg Grp 2: AB 400 μg Grp 3: placebo |
828 | Change in forced expiratory volume |
Mean difference from placebo: Grp 1: 0.099 L (95% CI: 0.057, 0.141); Grp 2: 0.128 L (95% CI: 0.085, 0.170); P < 0.0001 (both groups) |
| Cangrelor | Coronary artery disease | Randomized, double‐blind, active‐controlled |
Grp 1: cangrelor Grp 2: clopidogrel |
11,145 | Death or CV event |
Grp 1: 4.7%; Grp 2: 5.9%; OR = 0.78 (95% CI: 0.66−0.93); P = 0.005 |
| Ceftolozane/tazobactam (C/T) | Complicated intra‐abdominal infections | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: C/T + metronidazole Grp 2: meropenem |
993 | Clinical cure rate |
Grp 1: 94.1%; Grp 2: 94.0%; 0.0% (99% CI: −4.16%, 4.30%) |
| Complicated urinary tract infections including pyelonephritis | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: C/T Grp 2: levofloxacin |
1,083 | Microbiological response rate |
Grp 1: 84.7%; Grp 2: 75.4%; 9.4% (99% CI: 1.54%, 17.12%) |
|
| Cobicistat (COBI) | HIV | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: COBI/ATV/ FTC/TDF/placebo Grp 2: RTV/ATV/FTC/TDF/placebo |
698 | Proportion of subjects with HIV‐1 RNA below predefined cutoff |
Grp 1: 85.2%; Grp 2: 87.4%; −2.2% (95.2% CI: −7.4%, 3.0%) |
| Conjugated estrogens/bazedoxifene (CE/B) | Vasomotor symptoms associated with menopause | Randomized, double‐blind, placebo‐controlled |
Grp 1: CE/B Grp 2: placebo |
332 | Change from baseline in frequency and severity of hot flushes (coprimary end points) |
Mean difference from placebo: Frequency: W4: −3.1 (95% CI: −4.4, −1.7); W12: −2.7 (95% CI: −3.8, −1.6); Severity: W4: −0.5 (95% CI: −0.7, −0.3); W12: −0.6 (95% CI: −0.9, −0.4); P < 0.001 (all primary end points) |
| Daclatasvir | EU: Hepatitis C virus infection genotypes 1, 2, and 3 | Randomized, open label | 10 groups stratified by prior treatment, viral genotype, and treatment regimen | 211 | Rate of sustained virologic response | > 90% in all treatment arms |
| US: Hepatitis C virus genotype 3 infection | Single arm, open label | Daclatasvir/sofosbuvir | 152 (treated) | Proportion of treated subjects with sustained virologic response | 89% (95% CI: 83%−93%) | |
| DTG + 3TC/ABC | HIV | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: DTG + 3TC/ABC Grp 2: EFV/FTC/TDF |
844 | Proportion of subjects with HIV‐1 RNA below predefined cutoff |
Grp 1: 88%; Grp 2: 81%; 7.4% (95% CI: 2.5%, 12.3%); P = 0.003 (superiority) |
| Edoxaban (EDOX) | Stroke and systemic embolism in pts with nonvalvular atrial fibrillation | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: 30 mg EDOX Grp 2: 60 mg EDOX Grp 3: warfarin |
21,105 | All strokes and systemic embolic event |
Grp 2: 1.18%/year; Grp 3: 1.50%/year; HR = 0.79 (97.5% CI: 0.63, 0.99) (Grp 2) |
| Venous thromboembolism and/or pulmonary embolism | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: 60 mg EDOX Grp 2: warfarin |
8,292 | Symptomatic recurrent venous thromboembolism |
Grp 1: 3.2%; Grp 2: 3.5%; HR = 0.89 (95% CI: 0.703, 1.128) |
|
| Elvitegravir | HIV | Randomized, double‐blind, active‐controlled (noninferiority) |
Grp 1: elvitegravir Grp 2: raltegravir |
724 | Proportion of subjects with HIV‐1 RNA below predefined cutoff |
Grp 1: 59%; Grp 2: 57.8%; 1.1% (95% CI: −6.0%, 8.2%) |
| Ivabradine | Chronic heart failure | Randomized, double‐blind, placebo‐controlled |
Grp 1: ivabradine Grp 2: placebo |
6,558 | Time to first adjudicated CV death or hospitalization |
Incidence rates: Grp 1: 24.5%; Grp 2: 28.7%; HR = 0.82 (95% CI: 0.75, 0.90); P < 0.0001 |
| Lomitapide | Homozygous familial hyper‐cholesterolemia | Non‐randomized, single‐arm, open label | Lomitapide | 29 (treated) | Change from baseline in low‐density lipoprotein cholesterol | −3.8 mmol/L mean change from baseline, i.e., −40% (P < 0.001 on the mean percent change from baseline) |
| Netupitant (NETU)/palonosetron (PALO) | Emesis associated with highly emetogenic chemotherapy | Randomized, double‐blind, placebo‐controlled |
Grp 1: PALO alone Grp 2: PALO + NETU 100 mg Grp 3: PALO + NETU 200 mg Grp 4: PALO + NETU 300 mg Grp 5 (exploratory): combination of licensed agents |
694 | Complete response rate |
Grp 1: 76.5%; Grp 4: 89.6%; P = 0.004 |
| Emesis associated with moderately emetogenic chemotherapy | Randomized, double‐blind, active‐controlled |
Grp 1: PALO + NETU 300 mg Grp 2: PALO alone |
1,455 | Complete response rate |
Grp 1: 76.9%; Grp 2: 69.5%; OR = 1.48 (95% CI: 1.16, 1.87); P = 0.001 |
|
| Patiromer | Chronic kidney disease with hyperkalemia |
Part A: single arm, single‐blind, open‐label Part B: randomized, single‐blind, placebo‐controlled |
Part A: patiromer Part B: Grp 1: patiromer Grp 2: placebo |
Part A: 243 (treated) Part B: 107 |
Change in serum potassium from baseline |
Part A: −1.01 mEq/L (95% CI: −1.07, −0.95) Part B: Difference from placebo: −0.72 mEq/L (95% CI: −0.46, −0.99); P < 0.001 |
| Peginterferon beta‐1a (PEG) | Relapsing remitting multiple sclerosis | Randomized, double‐blind, placebo‐controlled |
Grp 1: placebo Grp 2: PEG Q4W Grp 3: PEG Q2W |
1,516 | Annualized relapse rate at 1 year |
Grp 1: 0.397; Grp 3: 0.256; RR = 0.644 (95% CI: 0.500, 0.831); P = 0.0007 |
| Peramivir (PRV) | Acute uncomplicated influenza | Randomized, double‐blind, placebo‐controlled |
Grp 1: PRV 300 mg Grp 2: PRV 600 mg Grp 3: placebo |
300 | Time to alleviation of symptoms |
Difference from placebo: Grp 1: −22.7 hours; Grp 2: −21.9 hours; P = 0.001 (pooled doses) |
| Pimavanserin (PIMV) | PD with psychosis | Randomized, double‐blind, placebo‐controlled |
Grp 1: PIMV Grp 2: placebo |
199 | PD‐adapted scale for the assessment of positive symptoms |
Difference from placebo: −3.06 (95% CI: −4.91, −1.20); P = 0.001 |
| Sacubitril/valsartan (SBT/VAL) | Heart failure with reduced ejection fraction | Randomized, double‐blind, active‐controlled |
Grp 1: SBT/VAL Grp 2: enalapril |
8,442 | Time to first occurrence of either CV death or heart failure hospitalization |
Incidence rates: Grp 1: 21.8%; Grp 2: 26.5%; HR = 0.80 (95% CI: 0.73, 0.87); p = 0.0000002 |
| Selexipag | Pulmonary arterial hypertension | Randomized, double‐blind, placebo‐controlled |
Grp 1: selexipag Grp 2: placebo |
1,156 | Time to first Critical Event Committee ‐confirmed morbidity and/or mortality event |
Incidence rates: Grp 1: 24.4%; Grp 2: 36.4%; HR = 0.60 (99% CI: 0.46, 0.78); P < 0.0001 |
| Sucroferric oxyhydroxide (SUC) | Chronic kidney disease on maintenance dialysis | Randomized, open label (stage 1: active‐controlled; stage 2: “surrogate placebo”‐controlled) |
Stage 1 (non‐inferiority): Grp 1: SUC Grp 2: sevelamer Stage 2 (superiority): Grp 1: SUC maintenance dose Grp 2: SUC low dose |
Stage 1: 1,059 Stage 2: 99 |
Change in serum phosphorus levels from baseline |
Stage 1: Grp 1: −0.7 mmol/L; Grp 2: −0.8 mmol/L; 0.08 mmol/L (97.5% CI: ‐infinity, 0.15); P = 0.011 (superiority) Stage 2: Grp 1: 0.08 mmol/L; Grp 2: 0.62 mmol/L; difference between doses: 0.54 mmol/L (95% CI: 0.37, 0.71); P < 0.001 |
| Susoctocog alfa | Hemophilia A with serious bleeding episode | Open label, single arm | Susoctocog alfa | 29 (treated) | Proportion of serious bleeding episodes responsive to therapy | 100% |
| Teriflunomide (TER) | Relapsing multiple sclerosis | Randomized, double‐blind, placebo‐controlled |
Grp 1: TER 7 mg Grp 2: TER 14 mg Grp 3: placebo |
1,086 | Annualized relapse rate |
Grp 1: 0.370 (95% CI: 0.318, 0.432); P = 0.0002; Grp 2: 0.369 (95% CI: 0.308, 0.441); P = 0.0005; Grp 3: 0.539 (95% CI: 0.466, 0.623) |
| Vedolizumab (VDZ) | Ulcerative colitis | Randomized, double‐blind, placebo‐controlled (induction and maintenance) |
Induction: Grp 1: VDZ Grp 2: placebo Maintenance: Grp 1: VDZ Q4W Grp 2: VDZ Q8W Grp 3: placebo |
Induction: 374 Maintenance: 373 |
Induction: % patients with clinical response Maintenance: % patients in remission |
Induction: Difference from placebo: 21.7% (95% CI: 11.6, 31.7); P < 0.0001
Maintenance: Difference from placebo: Grp 1 (EU only): 29.1% (95% CI: 17.9−40.4); Grp 2: 26.1% (95% CI: 14.9, 37.2); P < 0.0001 (both dose regimens) |
| Vorapaxar | Atherosclerosis | Randomized, double‐blind, placebo‐controlled |
Grp 1: vorapaxar Grp 2: placebo |
26,449 | Time to the first CV event |
Grp 1: K‐M = 11.2%; Grp 2: K‐M = 12.4%; HR = 0.88 (95% CI: 0.82, 0.95); P = 0.001 |
3TC, lamivudine; ABC, Abacavir; ATV, atazanavir; CI, confidence interval; CV, cardiovascular; DTG, dolutegravir; EFV/FTC/TDF, efavirenz/emtricitabine/tenofovir; EU, European Union; FTC/TDF, emtricitabine/tenofovir; Grp, group; HR, hazard ratio; K‐M, Kaplan‐Meier event rate; OR, odds ratio; PD, Parkinson's disease; RR, rate ratio; RTV, ritonavir; US, United States; Q2W, Once every two weeks; Q4W, Once every four weeks; Q8W, Once every eight weeks; W12, week 12; W4, week 4.
Characteristics and outcomes of the pivotal trials supporting the approval of novel therapeutic drugs based on a single pivotal trial. Trial characteristics comprised overall trial design including study population, randomization, blinding, treatment arms, and number of randomized (or enrolled in case of no randomization) patients as well as nature and result of the primary outcome measure. Color shading signifies drugs fulfilling study selection criteria in the EU only (blue shading), in both regions (no shading); and US only (red shading).