On 6 September 2013, the US Food and Drug Administration (FDA) released an Untitled Letter to a manufacturer of amniotic/chorionic-based products, saying it had run afoul of "minimal manipulation" regulations under 21 CFR 1271. Now the company is in effect conceding to FDA's contentions, suspending enrollment in a US-based clinical trial meant to support an eventual regulatory filing and commercialization of its products.
On 5 September 2013, FDA's Center for Biologics Evaluation and Research (CBER) released the text of four Untitled Letters sent to separate manufacturers of amniotic and/or chorionic-based products, explaining that all four had failed to comply with "minimal manipulation" regulations under 21 CFR 1271.
FDA explained that under its understanding of the regulations, these companies' products would be human cells, tissues or cellular and tissue-based products (HCT/Ps) regulated under 21 CFR 1271.
However, that section of the CFR contains a sub-section, 1271.3(f), which states that any HCT/P can only undergo "minimal manipulation," or else it is considered a biological product. FDA defined minimal manipulation in two ways:
- for structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement
- for cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues
If a product does undergo non-minimal manipulation, it is technically regulated under 21 CFR 201-that is to say, as biological products requiring the submission of a biologic licensing application (BLA) under Section 351 of the Federal Food, Drug and Cosmetic Act (FD&C Act).
Similar Problems for OvaScience
That same "minimal manipulation" distinction has also reportedly been applied to an investigational product being advanced by Cambridge, MA-based OvaScience, a company working on developing fertility treatments.
The company said it was in receipt of an Untitled Letter from FDA on 6 September 2013-just one day after CBER released the text of the other minimal manipulation letters-indicating that its fertility treatment process was in fact a HCT/P product under 21 CFR 361, and thus required an FDA-approved investigational new drug (IND) to conduct clinical trials in the US.
The company said it has "chosen to suspend enrollment" in its main US trial (AUGMENT) while it holds further discussions with FDA. "OvaScience continues to believe that AUGMENT qualifies as a 361 HCT/P," it said.
In the meantime, the company said it would continue to move forward with plans to expand enrollment outside of the US.
Uncertainty Leads to Untitled (Not Warning) Letter
As Focus reported at the time of the initial letters, the distinction between a "Warning Letter"-a formal denunciation of a practice indicating further action if a company fails to act-and an "Untitled Letter"-a less formal admonishment that does not indicate further enforcement action-is not a minor one.
The legal distinction of "minimal manipulation" has been fraught with legal uncertainty (2), which likely explains why FDA opted to use Untitled Letters instead of the more formal Warning Letters: It's possible the companies are on firm legal footing despite FDA's assertions to the contrary.
One company in receipt of a similar Untitled Letter said it was "surprised" at the letter since FDA had recently inspected its facility and had no findings to report, resulting in a No Action Indicated (NAI) inspection report. The letter could be based on a misunderstanding of the processes involved in handling the tissue products, the company speculated.
Which is to say, it's still possible OvaScience has a chance to make its case to FDA. The company has not shut down the trial (just halted new enrollments), and flush with $35 million in private equity raised in March 2013, the company may just have the time it needs to argue with FDA.
However, as noted by Fierce Biotech, the company's 2012 S1 filing contains an ominous reminder that adopting a risky commercialization strategy was not without risk for the company: "If the FDA disagrees with our interpretation of the applicable regulations, disagrees with our characterization of the AUGMENT procedure or changes its position with respect to such rules and regulations, we may not be able to commercialize AUGMENT on the timeline or with the resources we expect, if at all."