Links to read the Root Room and The Informed online.

In Issue 009, 1,106 patients across 16 countries had said yes to the IRIS trial. The data safety monitoring board had reviewed the interim results and made a recommendation nobody expected: stop the trial early. Not because something went wrong. Because the evidence for Gleevec was too clear to keep patients waiting on the interferon arm.

Over in the Root Room track, Vera Santiago, a reader who had been following the Facebook Lab group since Issue 004, had just enrolled in her own Phase II trial. Her aunt had enrolled in a trial 12 years earlier for a drug that later became a standard treatment. She did not live to see it approved. She said yes anyway, because someone had to be first.

Vera said yes for the same reason.

The IRIS trial was done. The data was in. Now what?

When a Phase III trial closes early for efficacy, the drug company has a decision to make. They can file for approval.

Filing for approval is not pressing a button. It took Novartis years to compile the Gleevec application file. Every piece of data the company had generated went into it: the Phase I dose-finding results, the Phase II response data, the IRIS trial results, the manufacturing process documentation, the safety monitoring plan, and the proposed label language telling doctors and patients exactly what the drug was approved for and what the known risks were.

The file was submitted to the FDA on February 27, 2001.

The FDA granted approval on May 10, 2001.

72 days. That is 2.5 months.

Here is what that number does not mean.

It does not mean the FDA saw less data. It does not mean the review team skipped steps. It does not mean Novartis wrote a check and moved the calendar.

Here is what it does mean.

The FDA has a category called priority review. Standard drug review takes about 12 months. Priority review is for drugs that address serious conditions where no good treatment exists, or that offer a meaningful improvement over what is already available. The target timeline for priority review is 6 months.

Gleevec qualified. At the time of approval, the standard treatment for CML caused severe side effects and did not work for many patients. Gleevec worked better and was more tolerable. Priority review was the right category.

The 72-day timeline means the FDA reviewers worked through the file faster than the 6-month target. That happens when the data in the file is exceptionally clean. The evidence behind Gleevec was strong enough that reviewers did not spend months chasing inconsistencies.

Speed and standards are not the same thing.

People hear 'accelerated approval' and assume a lower bar. It is not. It is a different measuring point, with required follow-up work.

Standard drug approval requires evidence that a drug improves how a patient feels, functions, or survives. Accelerated approval allows approval based on a reliable proxy measurement that is expected to predict that benefit. For cancer drugs, that proxy is often something like tumor shrinkage rates, which can be measured now. Data on whether patients actually live longer takes years to accumulate.

The catch: companies that receive accelerated approval must complete confirmatory trials proving the proxy predicted real clinical benefit. That is a condition of approval, not optional follow-up.

Gleevec received accelerated approval based on response rates showing that leukemia cells were clearing from patients' blood and bone marrow. The long-term follow-up from the IRIS trial provided the confirmatory evidence.

This one is worth taking seriously, because it is not entirely invented. There is a real concern embedded in it. And there is a claim it makes that is not accurate.

The real concern: drug companies pay fees to the FDA to fund the drug review process. This is true. It is called the Prescription Drug User Fee Act, shortened to PDUFA. Passed in 1992, it allows the FDA to collect fees from companies submitting drug applications. Those fees fund the review operation: staffing, systems, the timeline infrastructure.

The inaccurate claim: those fees determine the outcome.

They do not. PDUFA fees fund the clock, not the verdict. The FDA employees who review drug applications are federal employees. They do not work for the companies whose applications they are reviewing. The review process, the advisory committee deliberations, the labeling negotiations: none of that is something a company buys by paying a fee.

A simple check: when FDA says no, the company does not get a refund. In 2016, the FDA approved a drug called olaratumab for a rare cancer called soft tissue sarcoma. The Phase II trial that got it approved showed something almost unheard of in that disease: patients who received it lived roughly 12 months longer than those who didn't. Twelve months. In a cancer where gains are typically measured in weeks, that result felt like a breakthrough. Eli Lilly priced it at around $19,000 a month, doctors started prescribing it, and patients started taking it with real hope. Then the confirmatory trial came back. This was the larger, randomized trial the FDA required before granting full approval. It enrolled more than 500 patients. The drug did nothing. Patients who received olaratumab did not live longer than patients who didn't. Eli Lilly withdrew it from the market in 2019. What likely happened in that first trial is that 66 patients is a small enough group that chance imbalances between the two arms, who was a little sicker, who had better access to follow-up care, can produce a survival signal that looks real and isn't. The drug didn't fail the confirmatory trial. The confirmatory trial revealed what the first trial was too small to tell us.

The FDA sends a document called a Complete Response Letter when an application is not approvable as submitted. The letter explains what is missing and what would need to change. Companies that receive one paid the fee. They did not get a yes.

That olaratumab story is also the toolkit in action. The FDA demanded the one thing that separates a real result from a lucky one: enough patients. The signal that won the first approval came from 66 people. The trial that overturned it enrolled more than 500.

There is a separate, legitimate debate about the revolving door: former FDA officials who later work for pharmaceutical companies, and former industry officials who move into regulatory roles. Those relationships matter for how regulations are written and how enforcement priorities are set. That is a real concern worth examining. It is a different claim from the question of whether individual drug approvals are purchased.

2 questions do the most work on the FDA approval myth.

Q4: Who funded this, and do they have a stake in the answer?

Apply this to both directions. Novartis funded the IRIS trial. That is disclosed in the public record, and structural safeguards exist precisely because funder interest is real. Apply the same question to the sources making the 'FDA is captured' argument. Who is making that claim, and what do they gain if it is believed? Some of those sources are legitimate regulatory scholars raising structural concerns. Some are platforms and companies selling alternatives to FDA-regulated products, for whom public distrust of the FDA is a business asset.

Q9: What do independent experts with no stake in the outcome say?

The FDA advisory committee that reviewed Gleevec was composed of clinicians and scientists without financial relationships with Novartis. Their vote was unanimous. FDA's own statistical reviewers ran an independent analysis of the submitted data. The data safety monitoring board that recommended stopping the IRIS trial had no financial relationship with the company.

Debby posted a question in the Facebook Lab this week that she had been sitting with for a while.

'When people say the COVID vaccine was rushed, do they mean this kind of rush?'

Sam said yes.

Then Debby did the part she could not have done a year ago. She ran the answer out herself.

Read the full scene in The Root Room on the web.

From 1960, when Nowell and Hungerford first identified the Philadelphia chromosome in CML cells, to May 10, 2001, when the FDA approved imatinib, was 41 years.

The FDA review that closed that gap took 72 days.

Gleevec launched at $2,200 a month.

That is not the end of the story.

Next issue: who actually got it.

What question did this issue answer for you? What are you still wondering?

Reply to this email or leave a comment on the newsletter. Every question that comes in shapes what we cover next.

Debby spent 3 weeks trying to prove the approval was bought.

She went looking for the bought reviewer, the rigged vote, the drug waved through because somebody paid. She found the opposite every time. She even found a drug the FDA pulled when the money could not save it.

She posted what it cost her to admit. Sam answered in 4 words.

Then Auntie Nani, the nurse and trial coordinator readers met at the oncology office, said what it actually costs to get a drug to approval day.

Links to read the Root Room and The Informed online.

Issue 003b: Vaccine Myths, Set Straight. The Skeptic's Toolkit, the 10 questions you will use on everything.

Issue 001: Why Your Distrust Is Rational. The founding argument. Why skepticism is healthy and how to channel it.

Issue 004: From Molecule to Medicine. The map of how drugs get built, tested, and approved.

Citations verified June 2026. Peer-reviewed trials confirmed via PubMed; regulatory items cite the primary FDA or statutory record.

[1] IRIS trial (the 1,106-patient Gleevec trial): O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. https://doi.org/10.1056/NEJMoa022457

[2] Gleevec FDA approval (NDA 21-335, accelerated approval granted May 10, 2001): U.S. FDA Drug Approval Package. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21335_Gleevec.cfm

[3] Priority review and accelerated approval (definitions and timelines): U.S. FDA expedited programs; accelerated approval regulation 21 CFR 314.500.

[4] PDUFA (fees fund the review, not the verdict): Prescription Drug User Fee Act of 1992, Pub. L. 102-571.

[5] Olaratumab, the hopeful phase 2 result (about 11.8-month median overall survival gain, 66-patient arm): Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497. https://doi.org/10.1016/S0140-6736(16)30587-6

[6] Olaratumab, the confirmatory trial that showed no benefit (more than 500 patients): Tap WD, Wagner AJ, Schoffski P, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020;323(13):1266-1276. https://pubmed.ncbi.nlm.nih.gov/32259228/

[7] Olaratumab (Lartruvo) withdrawal: after the phase 3 ANNOUNCE trial missed its overall-survival endpoint, FDA advised that no new patients start the drug (January 2019) and Eli Lilly announced market withdrawal (2019); FDA formally revoked the Lartruvo biologics license effective 2020 (Federal Register, July 17, 2020). https://www.federalregister.gov/documents/2020/07/17/2020-15516/eli-lilly-and-co-announcement-of-the-revocation-of-the-biologics-license-for-lartruvo

[8] Philadelphia chromosome first identified (1960): Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85-109. https://pubmed.ncbi.nlm.nih.gov/14427847/

[9] Gleevec 2001 launch price (about $26,400 per year, roughly $2,200 per month): Washington Post, March 9, 2016. https://www.washingtonpost.com/business/this-drug-is-defying-a-rare-form-of-leukemia--and-it-keeps-getting-pricier/2016/03/09/4fff8102-c571-11e5-a4aa-f25866ba0dc6_story.html

The views expressed on Root to Rx are my own and do not represent the views or positions of my employer, or any affiliated organization.

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