I have a few shares of a tiny biotech called Biovie(BIVI) that got much tinier this morning after they released results of a phase 3 Alzheimer’s trial for their NE3107 drug candidate. Trial failures are normal, they happen, and it’s why I have for many years bought biotechs in baskets. However, the company’s announcement of trial results is something that I don’t believe I have ever seen before.
The trial enrolled 439 patients at 39 sites, but data was only reported on 57. Why? Well the company claims something bad happened at 15 of the sites. It’s unclear what happened exactly, and the company steers clear of calling it fraud outright. But it does say the following:
Upon trial completion, the Company found significant deviation from protocol and Good Clinical Practice (GCP) violations at 15 sites (virtually all of which were from one geographic area). This highly unusual level of suspected improprieties led the Company to exclude all patients from these sites and to refer them to the U.S. Food and Drug Administration (FDA) Office of Scientific Investigations (OSI) for further action. After these exclusions, 81 patients remained in our Modified Intent to Treat (MITT) population, 57 of whom were in the Per-Protocol population which included those who completed the trial and were verified to take study drug from pharmacokinetic (PK) data.
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I am also very proud of the integrity our team displayed in taking immediate action to identify and report the potentially problematic sites to the FDA for independent investigation.
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“The unblinding of topline efficacy data from the trial confirmed an unusual pattern we saw with the blinded data – that patients in a particular demographic group within the trial seemed to have a data pattern different from historical evidence for this demographic group. Patients from this demographic group in this trial reportedly experienced cognitive improvements that were improbable scientifically, and inconsistent with the pathology of this disease,” stated Suzanne Hendrix, Founder & CEO of Pentara, a specialized biostatistics consulting firm that has assisted dozens of AD clinical trials. “When sensitivity analyses were performed, we determined that the anomalous demographic data were associated with the previously identified anomalous sites located in the same geographic area.”
Referring sites to the FDA for investigation is something I don’t recall having seen before. Further down, the release buries some more specific allegations:
In parallel, some sites started to complete their patient-facing activities in early summer 2023, which created the first opportunity for BioVie to start the data verification and assessment process. The process surfaced unusual data patterns and deviations from expectations (missing data, suspected copied/pasted MRI results, etc.), which led the Company to retain two new CROs to conduct a multi-step process that entailed quality control (QC) visits at all sites, performing source data verification (SDV) on 100% of the documents used in the clinical sites to ensure what was notated on paper during patient visits was accurately reflected in the EDC, and auditing the sites. This extensive, multi-month process concluded when the Company received the final report identifying six sites that appeared to have a large number of deviations from the study protocol and Good Clinical Practices (GCP).
Suspected copying and pasting of MRI data sounds like outright fraud. This was suspected at 6 sites. Further analysis yielded another 9 sites with results that did not make sense.
As the top-line efficacy data was unblinded and PK data became available, the pre-specified demographic subgroup analyses showed that patients in the identified demographic on placebo significantly improved cognitively without any intervention – a finding that cannot be explained scientifically. Furthermore, the pre-specified anomalous sites vs. others revealed a similar scientifically improbable and that these 9 sites are in the same single geographic area. It turned out that virtually all of the patients in the identified demographic group were associated with the 9 anomalous sites. Consistent with our pre-specified statistical plan, these 9 additional sites were also excluded to arrive at our Modified Intent to Treat population, which became underpowered with just 81 subjects. Out of an abundance of caution, we also referred these 9 additional sites to the FDA’s OSI. It should be noted that virtually all of the 15 sites referred to the FDA were in the same geographic area.
Fierce Biotech has a little analysis of the reported results here.
There is a lot to unpack here. Is the company a victim of unscrupulous or sloppy trial sites? Is the company complicit in some way? What does this actually say about the efficacy of the drug candidate? These are difficult questions to answer, though touting subgroup analysis of failed trails is usually an indication that there is no future. What we can state, unequivocally, is that the path forward just became harder, longer and more expensive. For a small company with no runway, this may be a death blow regardless as to whether the compound actually works. On the other hand, some of my most successful biotech investments have come on the heels of setbacks like this. What do you think- sell, or buy more?
Disclosure: The author owns shares in Biovie