Communication of Nonefficacy Benefits of New Drugs Approved on the Basis of Noninferiority Trials Alone

Abstract

This cohort study of FDA- and drug sponsor–written communications evaluates the communication of nonefficacy benefits of new drugs approved on the basis of noninferiority trials alone.

About one-third of new therapeutics are tested in head-to-head, active-controlled trials prior to licensure.¹ Some of these trials test noninferiority hypotheses, which by design allow for some potential loss of efficacy in exchange for potential nonefficacy benefits.

The literature specifies several hypothetical nonefficacy benefits that new interventions approved based on noninferiority trials may offer, including decreased adverse events, less invasiveness, more convenient formulation, and reduced cost.^2,3,4,5 However, empirical evidence of actual benefits is lacking. We sought to characterize the nonefficacy benefits of new molecular entities (NMEs) approved based on noninferiority trials.

Methods

We identified NMEs approved by the US Food and Drug Administration (FDA) between January 2011 and September 2017 using the FDA’s yearly Novel Drug Approvals website (Novel Drug Approvals, 2017). We identified all indications approved based solely on noninferiority pivotal trials (ie, trials that included active control groups with stated noninferiority margins or stated objectives evaluating noninferiority hypotheses) using FDA and sponsor communications (press releases at market entry and FDA Drug Trials Snapshots), and statistical and medical officer reports. New indications for previously approved NMEs were excluded.

For each indication, FDA and sponsor communications were read by 2 investigators. All statements that expressed a nonefficacy benefit were extracted. Extracted statements were classified into categories (1) derived from the literature^2,3,4,5 regarding the nonefficacy purposes of noninferiority trials and (2) categories we developed through inductive reasoning. Categorizations were independently reviewed; disagreements were resolved through consensus.

Direct drug cost comparisons were made using average unit prices obtained from IBM Micromedex Red Book.

Results

Between January 2011 and September 2017, the FDA approved 262 indications for 238 NMEs. We excluded 242 indications (220 NMEs) not approved exclusively on noninferiority pivotal trials, leaving 20 indications (18 NMEs) for analysis.

Overall, 15 (75%) of FDA or sponsor communications mentioned a nonefficacy benefit. Sponsors mentioned nonefficacy benefits more often (n = 15; 75%) than the FDA (n = 6; 30%). The most common nonefficacy benefits mentioned by FDA were decreased adverse events (n = 3; 15%) and simpler dosing/administration (n = 3; 15%). Sponsors most often mentioned simpler dosing/administration (n = 10; 50%), reduced nondrug health care cost (n = 6; 30%), and decreased adverse events (n = 6; 30%). Noncomparative benefits were reported for all NMEs by sponsors or the FDA with “new treatment option” being the most common expression, appearing in 19 (95%) sponsor and 14 (70%) FDA communications (Table 1).

Table 1. Sponsor and FDA Statements Regarding Nonefficacy Benefits of 20 NME Indications Approved Exclusively on the Basis of Noninferiority Trials.

Statement	No. (%)
	FDA (n = 20)	Sponsor (n = 20)	FDA or Sponsor (n = 20)
Nonefficacy benefits over already approved treatments	6 (30)	15 (75)	15 (75)
Formulation benefita	0	2 (10)	2 (10)
Simpler dosing/administration benefitb	3 (15)	10 (50)	10 (50)
Lower direct drug cost	0	0	0
Reduces nondrug health care costs	0	6 (30)	6 (30)
Decreased need for hospitalization	0	3 (15)	3 (15)
Improved efficacy on nonprimary end point	1 (5)	3 (15)	3 (15)
Decreased adverse events	3 (15)	6 (30)	6 (30)
Explicit statement	2 (10)	2 (10)	2 (10)
Implicit statement	1 (5)	4 (20)	4 (20)
Noncomparative benefits	17 (85)	19 (95)	20 (100)
Safe	4 (20)	2 (10)	6 (33)
Effective	11 (55)	8 (40)	14 (70)
“New treatment option”	14 (70)	19 (95)	19 (95)
Fills unmet medical need	1 (5)	6 (30)	7 (35)

Abbreviations: FDA, US Food and Drug Administration; NME, new molecular entity.

^aFormulation benefit refers to change in the chemical composition of what is administered to patients that may result in nonefficacy benefit (eg, removal of preservatives).

^bSimpler dosing/administration benefit refers to change in the way the intervention is administered to patients (eg, less frequently, fewer pills, or lower volume of administration).

A treatment course with the NME was less expensive in 8 (35%) and more expensive than the active control in 13 (57%) comparisons (Table 2).

Table 2. Costs and Benefits of NMEs Approved Based on Noninferiority Studies.

NME vs Trial Comparator	Benefits of NME According to Sponsor	NME Cost Relative to Control Intervention (Cost, NME vs Comparator), $a
Tedizolid phosphate vs linezolid	New treatment option, simpler dosing/administration	1252 to 5790 less expensive (2408 vs 3660 to 8197)
Dolutegravir vs atripla	New treatment option	1215 less expensive (1843 vs 3058)
Aflibercept vs ranibizumab	New treatment option, fills unmet medical need, simpler dosing/administration	109 to 1143 less expensive (1295 vs 1404 to 2438)
Dolutegravir vs raltegravir plus background tenofovir/emtricitabine	New treatment option	872 less expensive (1843 vs 2715)
Dolutegravir vs raltegravir plus background abacavir/lamivudine	New treatment option	384 to 541 less expensive (1843 vs 2227 to 2384)
Peginesatide vs epoetin alfa	Simpler dosing/administration	486 less expensive (374 vs 860)
Elvitegravir/cobicistat/emtricitabine/tenofovir vs boosted tazanavir + truvada	Simpler dosing/administration, new treatment option	221 less expensive (3708 vs 3929)
Rilpivirine vs efavirenz	Implied decreased adverse events, safe, effective, new treatment option	17 less expensive (1160 vs 1177)
Sodium picosulfate, magnesium oxide and citric acid vs polyethylene glycol plus electrolytes solution and two 5-mg bisacodyl tablets	Simpler dosing/administration	1 less expensive to 26 more expensive (77 vs 51 to 79)
Tafluprost vs timolol	Effective, new treatment option	133 to 174 more expensive (221 vs 47 to 88)
Tafluprost vs latanoprost	Effective, new treatment option	131 to 215 more expensive (221 vs 6 to 89)
Edoxaban vs warfarin (stroke)	Improved efficacy on nonprimary outcomes, new treatment option, fills unmet medical need	265 to 360 more expensive (377 vs 17 to 112)
Edoxaban vs warfarin (venous thromboembolism)	New treatment option, fills unmet medical need, simpler dosing/administration, lower nondrug health care cost, decreased adverse events	265 to 360 more expensive (377 vs 17 to 112)
Elvitegravir/cobicistat/emtricitabine/tenofovir vs efavirenz/emtricitabine/tenofovir	Simpler dosing/administration, new treatment option	650 more expensive (3708 vs 3058)
Ceftolozane/tazobactam vs meropenem (cIAI)	New treatment option, effective	842 to 1292 more expensive (1447 to 2533 vs 156 to 1691)
Oritavancin vs vancomycin	Simpler dosing/administration, new treatment option	2786 to 3424 more expensive (3480 vs 56 to 694)
Fidaxomicin vs vancomycin	Improved efficacy on nonprimary outcomes	983 to 3938 more expensive (4418 vs 480 to 3435)
Ceftolozane/tazobactam vs levofloxacin (cUTI)	New treatment option, effective	2410 to 4728 more expensive (2533 to 5066 vs 123 to 338)
Isavuconazonium sulfate vs voriconazole	New treatment option, fills unmet medical need	282 less expensive to 4494 more expensive (5929 vs 1435 to 6211)
Dalbavancin vs vancomycin	Simpler dosing/administration, new treatment option	4831 to 5469 more expensive (5525 vs 56 to 694)
Belatacept vs cyclosporin	New treatment option	6147 to 7285 more expensive (8175 vs 890 to 2028)
Meropenem/vaborbactam vs piperacillin/tazobactam	New treatment option	11 606 to 15 413 more expensive (11 880 to 16 632 vs 274 to 1219)
Miltefosine vs amphotericin B	No benefit statements made by sponsor	56 221 more expensive (57 600 vs 1379)

Abbreviations: cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; NME, new molecular entity.

^aPrices extracted from the IBM Micromedex Red Book (https://www.ibm.com/us-en/marketplace/micromedex-red-book) on November 3, 2017; average wholesale price per unit was not available for delafloxacin at the time of Red Book extraction; nonefficacy benefits listed are the benefits mentioned in the first 2 statements from the sponsors’ press releases.

Discussion

Our analysis of NMEs approved on the basis of noninferiority trials found that sponsors generally named nonefficacy benefits (n = 15; 75%), while the FDA did so in a minority of cases (n = 6; 30%). This is concerning because potential nonefficacy benefits form the ethical and scientific justification for choosing noninferiority hypotheses, which allow potential loss of efficacy relative to older effective, often less expensive therapies.

The FDA’s most frequently cited benefit was “new treatment option.” However, all NMEs are by definition new treatment options. Novelty alone carries no intrinsic therapeutic value, is known before initiation of studies, and neither explains added benefits for patients of new interventions nor justifies harms to participants enrolled in trials. We found that some nonefficacy benefits were based on assumptions not evaluated in trials themselves (eg, reduced nondrug costs).

The study had several limitations. The FDA Snapshots, which always include a section on drug benefits, existed for only 7 of 20 indications. Also, we did not evaluate whether named nonefficacy benefits were worth the trade-off for potential reduced efficacy, which requires evaluating the efficacy results.

Future noninferiority trials should present potential nonefficacy benefits in protocols and consent forms.⁶ Potential nonefficacy benefits that can be formally studied, such as decreased adverse effects, should be required by regulators to be evaluated in trials and clearly communicated in study results.