Two things live here. Up top, the regulatory topics we’re grounding the agent on, organized by category. Below, eighteen items across three passes where your regulatory judgement is genuinely required — mostly confirmations rather than compositions, since we’ve pre-filled everything a public source can answer.
The compiled topics feeding the agent’s training — use the category cards above to filter.
Everything below is drawn from public FDA/EMA records and the topic list you and Franklin compiled. Please correct what is wrong rather than restate what is right — anything here becomes a fixed constant the agent cannot override.
Quoted or directly transcribed from FDA labels / approval summaries. If any is not how you want it framed, that is the most urgent thing on this page.
| Item | What the record says |
|---|---|
| Tovorafenib (Ojemda) | Accelerated approval 23 Apr 2024; patients ≥6 months; relapsed/refractory pLGG with BRAF fusion/rearrangement OR V600 mutation. ORR 51% (RAPNO-LGG, BICR, N=76); median DoR 13.8 mo. Type II pan-RAF inhibitor. Confirmatory FIREFLY-2 (NCT05566795) required. |
| Dabrafenib + trametinib (peds LGG) | Traditional/full approval 16 Mar 2023; ≥1 yr; BRAF V600E LGG requiring systemic therapy. Randomized Ph2 (N=110): ORR 47% vs 11%, mPFS 20.1 vs 7.4 mo (HR 0.31). Type I inhibitor. |
| Dab + tram (tumor-agnostic) | Accelerated approval 22 Jun 2022; ≥6 yr; unresectable/metastatic BRAF V600E solid tumors after prior treatment; excludes colorectal. Covers glioma. |
| Approval pathways | Traditional/regular = confirmed clinical benefit. Accelerated = surrogate endpoint (ORR/DoR); confirmatory trial required and (per FDORA 2022) generally must be underway at approval. |
| Response criteria | pLGG response assessed by RAPNO-LGG / RANO-LGG (T2/FLAIR-based), not RANO-HGG. Tovorafenib's FDA figure is RAPNO 51% — not the Nature Medicine RANO-HGG 67%. |
| US pediatric framework | PREA obligation; iPSP/PSP agreed with FDA prior to NDA; RACE for Children Act (FDARA molecular-target list) drives pediatric oncology study requirements. |
| EU pediatric framework | PIP agreed with the PDCO; class/condition waivers and deferrals; EMA conditional approval convertible to standard on confirmatory evidence. |
| Project ORBIS | FDA OCE framework for concurrent oncology review with international partners (Health Canada, TGA/Australia, Swissmedic, MHRA, ANVISA, HSA, others). |
| Post-marketing | PMR = required study/trial; PMC = commitment. Follow accelerated approvals and many rare-tumor approvals to verify clinical benefit. |
These are inferences shaping how the agent will operate. A single line of correction on any is worth more than a paragraph elsewhere.
| We have assumed | Because | Confirm? |
|---|---|---|
| Grounding is public-domain only — Drugs@FDA, FDA guidances/approval summaries, EMA EPARs, PubMed, ClinicalTrials.gov, open web | Matches our other tools; no licensed feed named | Yes / No — add sources: |
| The lens is Fore's pediatric BRAF-CNS program (plixorafenib) as the anchor | Your program focus | Yes / No |
| Every answer is a cited, HITL draft with verify-flags on anything unconfirmed | Regulatory strategy must be defensible | Yes / No |
| Topics split into on-demand precedent Q&A vs scheduled monitoring per the platform tags | Some topics are one-time deep dives, others recurring | Yes / No |
| Home is a standalone platform, later foldable into the FRED hub | Fastest path; reuses the agent pipeline | Yes / No |
| Tovorafenib's subgroup ORRs (fusion 52% / V600 50%) are exploratory, not powered | Label lists them as exploratory; V600 n=12 | Yes / No |
| The breadth rationale is mechanism (type II pan-RAF), NOT the RACE Act/iPSP | Primary sources do not state RACE/iPSP as FDA's reasoning | Yes / No |
| Outputs are decision support, never regulatory/legal advice | HITL review chain owns the decision | Yes / No |
Ticks and corrections against material we have already assembled. Please correct rather than recall — a remembered figure that hardens into the system is very hard to dislodge later.
Each becomes a fixed rule the agent cannot override.
Using the Facts table above — the anchored precedents — mark any that are not framed the way you want, or that you would not want the agent to state without a caveat.
The Assumptions table sets out grounding, lens, run-modes and the HITL bar. Correct anything wrong — particularly whether we may use only public-domain sources or you have licensed feeds to add.
Confirm the run-mode assignment for the 18 topics (on-demand precedent vs monitoring vs both), and give us the build priority order.
Below is the full set of rules we intend to write into the agent. Mark each keep / reword / not a rule, and add anything load-bearing we have missed.
| # | Rule as currently written into the agent | Keep / reword / not a rule |
|---|---|---|
| R1 | Approval type is stated precisely. Traditional/regular vs accelerated (surrogate endpoint, confirmatory trial pending). Never call an accelerated approval simply “approved” without the qualifier. | |
| R2 | Every regulatory claim is cited to a primary source (FDA label/guidance/approval summary, EMA EPAR, peer-reviewed article). No uncited assertions. | |
| R3 | Do not attribute a rationale to an agency unless a source states it. (E.g., RACE Act / iPSP is not FDA's stated basis for tovorafenib's breadth — mechanism is.) | |
| R4 | Endpoints/criteria stated as used. Name the response criterion (RAPNO-LGG vs RANO-HGG) and never conflate figures across criteria. | |
| R5 | Jurisdiction is explicit. FDA ≠ EMA ≠ MHRA/Health Canada/PMDA. Do not generalize one agency’s position to another without a source. | |
| R6 | Separate “approved” from “precedent/guideline” from “proposed/under review.” Never present a precedent as a rule or a proposal as settled. | |
| R7 | Flag exploratory / subgroup / small-N data as such (e.g., tovorafenib subgroup ORRs; V600 n=12). | |
| R8 | If a precedent or figure is not in a locatable source, it is unknown. Say so and route to the research-gap list. Never estimate or fabricate. | |
| R9 | Keep conditional/pending language conditional — “confirmatory trial ongoing,” “continued approval contingent” — never upgraded into settled fact. | |
| R10 | Decision support, not advice. Every output is a HITL draft for the regulatory review chain; it does not constitute regulatory or legal advice. | |
| R11 | Confidentiality boundary. Public precedents are public; Fore program specifics, strategy, and internal documents stay internal and are never echoed into a public-grounded answer. | |
| R12 | End with the single most decision-relevant open flag — the next thing a human should verify. | |
| + | Anything load-bearing we have missed: | |
The most common way a regulatory precedent gets misapplied.
For a precedent like tovorafenib’s broad accelerated approval, what makes it transferable to Fore’s program versus fact-specific — and where would leaning on it be indefensible?
Short prose. Two or three sentences each is genuinely enough.
Which of the 18 topics map to a live or near-term Fore filing decision (iPSP, PIP, extrapolation, confirmatory-evidence design) — where the agent’s output would actually feed a submission?
What is the honest regulatory positioning of plixorafenib’s pediatric BRAF-CNS path — the argument you would defend in a Type B/C meeting?
Where is cross-jurisdiction extrapolation (FDA↔EMA↔MHRA/HC) legitimate, and where does it become misleading?
What must the agent never do, even when a user pushes — e.g., predict an approval outcome, assert an agency will accept a design, or offer legal conclusions?
What language reliably signals over-reach in a regulatory answer? Specific words or constructions you flinch at (“FDA will require…,” “guaranteed pathway,” “equivalent to approval”).
Name three sentences — actual sentences, not categories — that would make you wince if the agent produced them.
How current must an answer be to be trustworthy — and what should the agent say when the most recent guidance/approval may post-date its sources?
For the BRAF/MAPK competitive and emerging-inhibitor monitoring, which competitors and assets must never be missed — and do our proposed keywords (exarafenib, NST-628, PF-07799933/RG6344, ABM-1310, ERK inhibitors, next-gen pan-RAF) match your intent?
What does a useful monthly brief look like to you — what would you actually read, and what is noise?
Give us five regulatory questions you expect to be asked (internally, or by a partner/board) about the pediatric BRAF-CNS path, with the answer you would want given.
Where is the line between a defensible precedent summary and a strategic recommendation that needs your sign-off? That boundary is what we most need to encode.
The highest-value thing you could give us, and the least urgent. It can wait weeks without holding anything up.
What is the single regulatory question you are asked most often — and roughly how do you answer it?
If you have half an hour at any point, four or five more real questions with your own answers would give us a proper calibration set.
Internal working copy — anyone reviewing this can add a topic or question. Submissions appear below and feed the next revision.
Added topics appear in Training topics near the top of the page.