Some of the FDA's questions pretty clearly showed that MSB tried to gloss over significant deficiencies in the trial, and it was those deficiencies that led to a CRL.
The FDA has basic rules and guidance for applicants to follow and if they don't follow them their chances of success will be reduced.
Similar evidence was submitted to the Australian TGA and the Canadian regulator and they elicited similar responses. That the trial was deficient and they should conduct a new and better trial. The TGA also made the rather surprising statement that they had seen evidence that the trial was concocted as a way to provide access to the treatment that skirts drug approval regulations instead of conducting a proper randomised trail. That's a big problem right there and it suggests contempt by someone for the treatment approvals process.
Australian Therapeutic Goods Assessment of Remestemcel
Study 275 was a single arm study, and the absence of a placebo control arm makes
interpretation of the data difficult. Osiris stated that Study 275 did not include a placebo
control for ‘ethical reasons’, and instead a ‘historical control was employed for the
comparison of survival’. The historical control was used to evaluate the 180 day survival
data, and there was no historical control to aid evaluation of the pre specified primary and
secondary efficacy endpoints. In Study 280, the choice of the placebo control group was
justified by the sponsor because both active and placebo treatment groups also received
the institutionally defined standard of care (for example, a second line therapy in addition
to continued corticosteroid treatment).
However, Study 275 also allowed standardsupportive therapy for GvHD to be administered at the Investigator’s discretion and inaccordance with site specific policies.
As discussed above, it appears to be inconsistent to state that a placebo control was not considered to be an option for ‘ethical reasons’ in Study 275, but was permitted in Study 280.
There is information in the submissionsuggesting that Study 275 was initiated at the request of physicians who specifically wanted to treat their patients with Prochymal rather than enrol them in Study 280 andrisk randomisation to placebo.
The Canadian Regulator's assessment of Prochymal (Remestemcel)
The panel discussed the issues of determining the efficacy of Prochymal® at length. Given the limited efficacy data, it was challenging for the panel to draw definitive conclusions on the drug's efficacy. There were different views on the level of efficacy; most of these differences resulted from personal clinical experiences that panel members have had with either Prochymal® and/or the standard of care in their transplant centres.
The options for obtaining further efficacy data, as discussed by the panel are summarized below. Option 1:
A randomised controlled trial between the best standard of care (control) and Prochymal® should be conducted in adults and children at the same time. Due to the low incidence of severe refractory GvHD in children, there will not be sufficient patients enrolled in a randomised controlled trial. However, assuming that the disease is the same in adults and children, the trial can be opened to adult enrolment as well. The data can then be analysed for the pediatric population or independent of the age of the patients. Option 2:
A proper case-controlled study with concurrent or historical controls should be carried out. A 1:1 match does not require an exact match on all factors. The relevant factors to be considered are: gender, age, race, regimen that was given, and the type of GvHD. Exact age matching might not be required, so an age range could be used, such as matching within: 0 to 6 months, less than 3 years, 4 to 7 years, etc. The goal is not to find perfect matches, but to find matches that make biological sense and produce reasonably comparable groupings for new patients that will be entered in the post-market protocol 295. A statistical analysis can adjust for other factors that have prognostic importance but were not matched on.
The panel would like the company to submit a clear comprehensive explanation of why 1:1 matching cannot be implemented prospectively by peer-matching. In addition, all recommendations from the panel concerning the confirmatory post-market protocol 295 described in Option 2 should be considered when developing the study proposal in the Letter of Undertaking of the NOC/c.
The Chief Investigator and author was Joanne Kurtzberg.
It's clear that as far back as 2012 Dr Kurtzberg had decided that Prochymal was effective and initiated a single arm trial (Study 275) so that patients could be diverted into it to receive Remestemcel (see the underlined segment from the TGA evaluation). The reason she gave was that it was "unethical" to have a randomised study even though both studies eventually failed to achieve the primary end point.
She is in no way a neutral, unbiassed investigator and her reasoning isn't supported by the trial evidence.
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