Pivotal trial dossier · BioIntel

Roll-over Study to Collect and Assess Long-term Safety of Everolimus in Patients With TSC and Refractory Seizures Who Have Completed the EXIST-3 Study [CRAD001M2304] and Who Are Benefitting From Continued Treatment

Novartis Pharmaceuticals · Ph3 · NCT02962414 exact date enrolment complete

Readout due

2026-12-30

Ph3

Patients

206

actual

Sites

18 countries

Arms

Masking

None

blinding depth

Design

Allocation	Na
Masking	None
Primary purpose	Treatment
Arms	1
Planned duration	112 months
Started	2017-08-23

What is being measured

Endpoint class	safety
Primary outcomes	1
Stated as	Occurances of adverse events and serious adverse events

Endpoint class is inferred from the sponsor's own wording of the primary outcome. Hard endpoints such as survival are generally harder to hit than scales or laboratory surrogates.

Population

Condition	Tuberous Sclerosis Complex
Therapeutic area	neurology
Patient pre-selection	all-comers (no selection detected)
Modality	small_molecule_or_unspecified
Sex	ALL

Evidence trail

Linked references	0 on the registry record
Results posted	not yet
Stopped early	no

Reference-class base rate

46% – 51%

historical share of Phase 3 trials in this class that reached approval

This is a base rate, not a prediction about this trial. It is what happened to comparable trials historically. It is not a model fitted on outcomes — no outcome labels exist for trials that have not read out — and it uses none of this trial's own results.

How this number was reached

Published Phase 3 → approval rate for neurology: 51.1% (Wong/Siah/Lo 2019) and 46.0% (BIO/Informa 2011–2020).

Design flags

• Not randomised.
• Runs in 18 countries. Multi-country trials show higher termination odds (OR 0.65).
• Enrolment is complete, so the readout date carries less recruitment risk.

Flags are shown separately rather than folded into the number. Wood et al. (BMJ 2008) measured effect-size inflation, not approval probability, so multiplying it into an approval rate would misuse the finding.

Deliberately not adjusted for

Enrollment size	no evidenced association with Phase 3 success
Number of sites	no evidenced association
Endpoint type	no evidenced association with success once area is held
Phase 2 design	single-arm vs randomised Phase 2 does not predict Phase 3

Each of these is visible in the registry and each is evidenced to be null for Phase 3 success. Using them would add false precision.

Evidenced, but not in the registry

Sponsor approval track record	51%→81% (Danzon 2005) — not a registry field
Orphan designation	aOR 2.3 — zero CT.gov fields carry FDA designations
Phase 2 effect-size shrinkage	rHR 0.73 — requires prior-trial results

The standing criticism, stated plainly. Hampson et al. (Pharmaceutical Statistics 2022;21(2):439–459, eight of nine authors at Novartis) argue that starting from industry rates and applying subjective adjustments "lacks transparency and fails to make full use of data from previous clinical trials". That criticism applies to this figure. The response here is to show every input and to refuse unsupported adjustments, not to claim the objection does not apply.

Rates: Wong, Siah & Lo, Biostatistics 2019 (CC BY 4.0; corrigendum values) and BIO/Informa/QLS Clinical Development Success Rates 2011–2020 (cited, not reproduced). MIT Project ALPHA is not used — its terms restrict use to governmental, charitable or social purposes and bar redistribution.