Gardasil (human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant): what was done before first-in-human, and what came after?

Precedia/Protein and VLP vaccines/Gardasil/Tox package

Gardasil: what was done before first-in-human, and what came after?

human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPs

Before first-in-human

First-in-human: where

Not stated in public reviews

Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.

Repeat-dose tox before first-in-human

Not stated in public reviews

Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.

First-in-human starting dose

Not stated in public reviews

Why it's blank

The public FDA and EMA reviews of Gardasil don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.

How it's usually set for oncology vaccines (ICH S9)

HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.

“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

This product's starting point

NOAEL / key findings: No systemic toxicity; iliac lymph node enlargement/hyperplasia and injection-site inflammation in mice (EMA assessment report, p. 8)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

10-week IM BALB/c mouse study (1 or 3 doses); recovery phase not stated

“A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received 1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs.”

✓ VerifiedEMA assessment report, p. 8Source ↗

Pivotal GLP studies

10-week IM repeat-dose study in BALB/c mice (1 or 3 doses); single-dose mouse and rat; rat DART; rabbit local tolerance

✓ VerifiedEMA assessment report, p. 8Source ↗

DART package

Species: DART

Rat (female Sprague-Dawley; all phases of reproduction and development)

“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”