Caliper Top 10 Worst-Emergent-Signal Drugs of FDA Novel Approvals 2020-2024

Systematic FAERS scan across 55 curated FDA novel drug approvals (2020-2024). Each drug ranked by count of off-label adverse-event signals meeting standard pharmacovigilance criteria. Mechanically computable, fully reproducible on public data.

Pre-registration sha1: 0a4f89e744fbdf2d1292f85b65201a0a81f68335 · Finding card sha1: a7479b7b1a5f68f235c7adcb2afa5566340a2848

The Top 10

Rank	Drug	Brand	Class	Year	N Reports	Emergent Signals	Density/1000
1	Remdesivir	Veklury	Infectious	2020	13,177	339	25.7
2	Tucatinib	Tukysa	Oncology	2020	6,720	233	34.7
3	Avapritinib	Ayvakit	Oncology	2020	11,414	209	18.3
4	Inclisiran	Leqvio	Cardiology	2021	7,487	192	25.6
5	Isatuximab	Sarclisa	Oncology	2020	5,259	175	33.3
6	Bimekizumab	Bimzelx	Dermatology	2022	16,071	169	10.5
7	Relugolix	Orgovyx	Oncology	2020	24,018	146	6.1
8	Tezepelumab	Tezspire	Respiratory	2021	5,692	135	23.7
9	Vibegron	Gemtesa	Urology	2020	7,142	131	18.3
10	Risdiplam	Evrysdi	Neurology	2020	3,960	104	26.3

The four most-clinically-interesting signal clusters

Tucatinib (Tukysa) — congenital malformation cluster

Five congenital-malformation Preferred Terms (hypertelorism, dysmorphism, polydactyly, congenital pulmonary airway malformation, ear malformation) each at PRR 780 and n=15 — strongly suggests linked cases (possibly a single case-series of inadvertent in-utero exposure). Tucatinib is contraindicated in pregnancy per label; this pattern warrants targeted case adjudication.

Inclisiran (Leqvio) — vascular ischemia cluster

Leriche syndrome (aortoiliac occlusion) PRR 744 n=16, ischemic nephropathy PRR 511 n=11, spleen ischemia PRR 511 n=11. Inclisiran is a PCSK9-targeting siRNA used for hypercholesterolemia. Aggressive LDL lowering in patients with pre-existing vascular disease could conceivably cause vascular-bed hypoperfusion. Mechanism worth investigating.

Remdesivir (Veklury) — severe pulmonary complications

Bronchopleural fistula PRR 715 n=28, pulmonary mucormycosis PRR 460 n=36, pulmonary cavitation PRR 460 n=18, disseminated cryptococcosis PRR 562 n=22. Many of these reflect critically-ill COVID-19 patient population baseline risk; pulmonary mucormycosis in particular has been documented in COVID ICU independent of remdesivir. But the cluster is worth label-completeness review.

Risdiplam (Evrysdi) — infertility signal

Infertility PRR 538 n=6. Risdiplam is mutagenic in animal studies; pre-clinical fertility data warned of impact. The post-market infertility signal at PRR 538 supports the pre-clinical warning being clinically relevant. Label-completeness check warranted.

Honest caveats — please read before interpreting

High emergent count does NOT mean a drug is dangerous. It partly reflects disease-of-indication effects, patient-population reporting patterns, and label-language gaps.
The cohort background comparison has channeling bias. Comparing a breast-cancer drug against the rest of the cohort (which includes diabetes, hypertension etc.) attributes oncology-specific signals to "drug effect."
Time-on-market is uneven. 2020 approvals have 5+ years of post-market data; 2024 approvals only ~1 year. The ranking partially reflects exposure time, not danger.
Per-drug evaluations are needed. Each Top 10 listing should trigger per-drug clinical review, not regulatory action.
All signals are STATISTICAL ALERTS from FAERS voluntary reporting, not confirmed adverse drug reactions.

Methodology (transparent)

55 curated FDA novel drug approvals 2020-2024 across major therapeutic areas; 52 evaluable (3 excluded for <100 reports)
Per-drug FAERS via openFDA `/drug/event.json`, capped at 25,000 reports per drug
Per-drug FDA label via openFDA `/drug/label.json`
Per-AE Proportional Reporting Ratio vs cohort background; Evans criteria (PRR ≥ 2, χ² ≥ 4, n ≥ 5 — stricter than DISC-6/7 for multiple-comparison robustness)
Categorization: label text contains AE PT substring → ON-LABEL; partial match → AMBIGUOUS; no match → EMERGENT
Pre-registration locked BEFORE any data extraction

Reproducibility

All scripts, data, and intermediate results on whisper1 at audit/faers_disc8/. The 55-drug curated list is in disc8_drug_list.py. Anyone with an openFDA API key (free, 30-second signup at api.fda.gov) can reproduce.