6
Full records
2
Approved
4
Declined
6
Impact dimensions each
Contents
- About These Records
- CR-01 — Add an Asian-population cohort to Phase 2
- CR-02 — Add a cardiovascular outcomes sub-study to Phase 3
- CR-D1 — Add a head-to-head comparative tolerability trial
- CR-D2 — Extend Phase 3 to a third pivotal in an adolescent population
- CR-D3 — Switch the primary endpoint to proportion achieving ≥10% reduction
- CR-D4 — Qualify a second contract manufacturer for drug product
About These Records
Six change requests reached the Development Committee. This holds the full form behind each one; the Change Control Register summarizes them and links here.
| Ref | Change | Outcome | Record |
|---|---|---|---|
| CR-01 | Add an Asian-population cohort to Phase 2 | Approved | open the record |
| CR-02 | Add a cardiovascular outcomes sub-study to Phase 3 | Approved | open the record |
| CR-D1 | Add a head-to-head comparative tolerability trial | Declined | open the record |
| CR-D2 | Extend Phase 3 to a third pivotal in an adolescent population | Declined | open the record |
| CR-D3 | Switch the primary endpoint to proportion achieving ≥10% reduction | Declined | open the record |
| CR-D4 | Qualify a second contract manufacturer for drug product | Declined | open the record |
Every record states the option of not doing it, and the build fails if one does not.
A change request without a do-nothing option is a proposal wearing a change request's clothes. It presents a decision that has already been made and asks for ratification, and a Committee reading it has nothing to weigh the proposal against.
The same applies to the impact assessment: all six dimensions — cost, schedule, scope, quality, risk and resource — are required on every record, including the ones where the honest answer is “none”. A blank is indistinguishable from a dimension nobody thought about.
A change request without a do-nothing option is a proposal wearing a change request's clothes. It presents a decision that has already been made and asks for ratification, and a Committee reading it has nothing to weigh the proposal against.
The same applies to the impact assessment: all six dimensions — cost, schedule, scope, quality, risk and resource — are required on every record, including the ones where the honest answer is “none”. A blank is indistinguishable from a dimension nobody thought about.
The two declined records with the most weight are CR-D1, the head-to-head trial that would have generated the comparative evidence the program now lacks, and CR-D4, the second manufacturer declined three weeks after the method transfer failed. Both were declined for defensible reasons that are stated in full.
CR-01 — Add an Asian-population cohort to Phase 2
Approved Raised by Dr. P. Raghunathan, SVP Regulatory Affairs on 2024-08-22 · decided 2024-10-09 · authority tier 4 (Development Committee) · status: Closed
| Field | Content |
|---|---|
| Description | Add 50 participants of East Asian ancestry to the Phase 2 dose-ranging study, enrolled at two additional sites, with the same protocol, endpoints and visit schedule as the existing cohort. |
| Driver | Regional regulators increasingly expect ethnic-sensitivity data for a systemic agent before accepting a foreign dossier. Generating it inside Phase 2 is far cheaper than a standalone bridging study later. |
| Traceability | Touches T-10 only (indication population). No endpoint, analysis or claim changes. ⚠ Verified against the traceability matrix before routing. |
| Decision | Approved by the Development Committee. Funded from contingency; ceiling unchanged. |
| Verification | Both sites activated and the cohort fully enrolled before the Phase 2 enrolment window closed 31 December 2024. Request closed. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing | Accept a probable bridging-study requirement at the point of any future EU or Asia-Pacific filing. Cost deferred, not avoided, and on a worse timeline. |
| Add the cohort to Phase 2 (recommended) | Enrolment is open; marginal cost per participant; no protocol amendment to the endpoints. |
| Add it to Phase 3 instead | ⚠ Rejected. Phase 3 is powered for efficacy; adding a sub-population there complicates the analysis of the primary endpoint for no additional benefit. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | $1,900,000, within contingency |
| Schedule | None — enrolment window absorbs it |
| Scope | Population widened; endpoints unchanged |
| Quality | None |
| Risk | Reduces a future regulatory risk; adds no new one |
| Resource | Two additional sites for Clinical Operations to activate |
CR-02 — Add a cardiovascular outcomes sub-study to Phase 3
Approved Raised by Dr. A. Okoye, Chief Medical Officer on 2026-02-16 · decided 2026-04-20 · authority tier 4 (Development Committee) · status: Approved — implementation in progress
| Field | Content |
|---|---|
| Description | Nest a 640-participant cardiovascular outcomes sub-study within Pivotal 301, with its own endpoint set, its own statistical analysis and a standalone clinical study report. |
| Driver | ⚠ A cardiovascular outcomes post-marketing requirement is likely to be imposed at approval for a systemic agent in this class. Generating the data during Phase 3 pre-empts it, and a PMR imposed at approval must be completed on the agency's timetable rather than the sponsor's. |
| Traceability | ⚠⚠ Creates an entirely new chain (T-09) end to end — new endpoint, separate analysis, standalone CSR, §5 label target — without touching any existing chain. This is why it was tractable eighteen months into Phase 3. |
| Decision | Approved by the Development Committee, 20 April 2026. Held as work package 1.6.5, not absorbed into the Phase 3 clinical account. |
| Verification | Sub-study protocol issued to the Data Monitoring Committee 12 August 2026, closing gate condition GC-02 on 25 September 2026. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing | ⚠ Accept a probable PMR. Post-approval studies are run under regulatory deadline, cost more, and a missed PMR deadline is a compliance matter rather than a program one. |
| Nest the sub-study in Pivotal 301 (recommended) | Shares infrastructure, sites and participants. Held as a discrete work package so its cost stays visible. |
| Run a standalone CV outcomes trial | ⚠ Rejected. Roughly four times the cost and it would not complete before the filing date. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | $6,400,000 from contingency |
| Schedule | Six months added to the Phase 3 window; float absorbed it |
| Scope | New endpoint set, new analysis, standalone CSR |
| Quality | Additional DMC review scope |
| Risk | Retires a post-marketing exposure; adds execution risk |
| Resource | Biostatistics and Clinical Development capacity in Stage 4 |
CR-D1 — Add a head-to-head comparative tolerability trial
Declined Raised by J. Barrington, SVP Market Access on 2025-09-30 · decided 2025-11-14 · authority tier 4 (Development Committee) · status: Declined — closed
| Field | Content |
|---|---|
| Description | A dedicated randomized trial against the leading approved comparator, powered on gastrointestinal-attributed discontinuation, to support a comparative tolerability claim. |
| Driver | ⚠⚠ Payers ask for comparative effectiveness first. The program has no head-to-head data and an indirect comparison is materially weaker — a fact every payer understands. |
| Traceability | Would have created a direct, dedicated chain for T-04 rather than leaving it dependent on three endpoints above it in the hierarchy. |
| Decision | ⚠ Declined by the Development Committee. Cost outside contingency; the schedule cost fell on patent life; and the tolerability endpoint was already positioned to generate the data within Phase 3. |
| Verification | Not applicable. ⚠⚠ Recorded in full because it is the program's largest what-if: positioned to produce and able to claim turned out to be different things. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing (adopted) | Rely on the tolerability endpoint already positioned in the Phase 3 hierarchy, and construct an indirect comparison for payers. |
| Run the head-to-head trial | ⚠ ~$34,000,000 and roughly eighteen months. The eighteen months come off commercial life at the far end, against a patent expiring on a fixed date. |
| Run it post-approval | Too late for the first formulary cycle, which is the decision that matters most. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | $34,000,000 — outside contingency; a ceiling matter for the Board |
| Schedule | ~18 months, directly against patent life |
| Scope | A new trial, not an extension |
| Quality | None |
| Risk | ⚠ Would have retired the differentiation risk (R-04, R-06) |
| Resource | A second clinical operations team |
CR-D2 — Extend Phase 3 to a third pivotal in an adolescent population
Declined Raised by Dr. A. Okoye, Chief Medical Officer on 2025-12-08 · decided 2026-02-03 · authority tier 4 (Development Committee) · status: Declined — closed
| Field | Content |
|---|---|
| Description | A third pivotal trial in participants aged 12–17, run concurrently with the adult pivotals. |
| Driver | Pediatric obligations under PREA, and a possible earlier pediatric indication. |
| Traceability | No new chain. The adolescent population is out of the sought indication. |
| Decision | Declined. The obligation is deferred and the deferred study is the route to pediatric exclusivity — running it early forfeits nothing and costs both. |
| Verification | Not applicable — no implementation to verify. ⚠ The obligation it would have discharged early is tracked instead as PMR-1 in the post-marketing register, with a final report due 2034. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing (adopted) | The agreed iPSP satisfies PREA with a post-approval deferral. PMR-1 covers ages 12–17 with a final report due 2034. |
| Run it now | ⚠ Adds cost and calendar to satisfy an obligation already deferred, and adolescent enrolment is materially slower. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | ~$18,000,000 |
| Schedule | 12+ months |
| Scope | A third pivotal |
| Quality | None |
| Risk | ⚠ Adds enrolment risk to a program already dependent on adult enrolment |
| Resource | Beyond current Clinical Operations capacity |
CR-D3 — Switch the primary endpoint to proportion achieving ≥10% reduction
Declined Raised by Dr. F. Achterberg, Biostatistics and Data Management on 2025-12-19 · decided 2026-01-20 · authority tier 4 (Development Committee) · status: Declined — closed
| Field | Content |
|---|---|
| Description | Promote the ≥10% responder endpoint from key secondary to co-primary, replacing the ≥5% responder co-primary. |
| Driver | A ≥10% threshold is more clinically meaningful and more marketable, and the Phase 2 data suggest it is achievable. |
| Traceability | Would reorder T-01, T-02 and T-03 — the testing hierarchy is shared state, so a change to one position moves every position below it. |
| Decision | ⚠ Declined. The endpoint is already collected and reported as a key secondary at hierarchy position 3; promoting it buys marketing language at the cost of regulatory certainty. |
| Verification | Not applicable — no implementation to verify. ⚠ The endpoint remains collected and reported at hierarchy position 3, so the data this request wanted to promote is generated either way. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing (adopted) | Retain the co-primaries agreed at End-of-Phase-2. |
| Promote ≥10% to co-primary | ⚠⚠ Reopens a question settled with the agency at EOP2. A sponsor changing an agreed co-primary after alignment invites a new discussion and signals the original agreement was not carefully made. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | Minimal directly |
| Schedule | ⚠ Potential Type C meeting, 75 days |
| Scope | Endpoint definitions and the SAP |
| Quality | None |
| Risk | ⚠⚠ Reopens regulatory alignment; risks the efficacy claim |
| Resource | Biostatistics re-analysis |
CR-D4 — Qualify a second contract manufacturer for drug product
Declined Raised by Dr. K. Oyelaran, Technical Operations / CMC on 2026-03-16 · decided 2026-04-28 · authority tier 4 (Development Committee) · status: Declined — closed
| Field | Content |
|---|---|
| Description | Technology transfer to a second contract manufacturer, with full process validation, to remove the single-source dependency on Aldergate. |
| Driver | ⚠ Raised three weeks after the analytical method transfer failed acceptance at Aldergate (issue I-02). Single-source risk had stopped being theoretical. |
| Traceability | No chain affected. This is a supply-continuity change, not an evidence change. |
| Decision | Declined. Recorded in the RAID log as an accepted single-source risk, with the technology-transfer clause as the standing remedy. |
| Verification | Not applicable. ⚠ Method 2 re-qualified 28 Aug 2026 and method 3 re-run 30 Sep 2026, which is what the decision was betting on. |
Options considered
| Option considered | Assessment |
|---|---|
| Do nothing (adopted) | Carry the single-source risk explicitly, and rely on the unexercised technology-transfer clause negotiated at award. |
| Qualify a second manufacturer | ⚠ Technology transfer, a second validation and a second pre-approval inspection — roughly two years against a filing date that does not move. |
| Dual-source drug substance only | Partial protection, most of the cost, and ⚠ comparability between two substance sources is itself a regulatory exercise. An unresolved comparability question at filing is worse than the single-source risk. |
Impact assessment
| Impact dimension | Assessment |
|---|---|
| Cost | ~$22,000,000 |
| Schedule | ⚠ ~24 months — beyond the filing date |
| Scope | A second validated supply chain |
| Quality | ⚠ A second inspection exposure |
| Risk | Would retire a named risk and create a comparability one |
| Resource | CMC capacity already committed to PPQ |