The authors reply

ABSTRACT

This is a reply to the commentary of Ossorio and Zhou.

KEYWORDS:

• microbiota
• transplant
• definition
• regulation

Ossorio and Zhou make several points that merit consideration. First, they “are not convinced that minimally manipulated microbial products should receive minimal regulation.” We agree, and we did not intend to suggest that microbiota transplantations (MT) should not be adequately regulated. In fact, our article does not specify how we believe MT should be regulated. We do state that FDA should consider “whether FMT (fecal MT) is unique in ways that call out for treating it differently from drugs” and that an alternative regulatory pathway would be one that treats it as both a “product and a procedure” incorporating aspects of drug and human tissue regulation. For our opinion on regulation, we refer readers to our subsequent article,¹ in which we propose a combination regulatory approach. The purpose of our article was to provide a starting point for a discussion about the regulation of MT. Before we started that conversation, our working group on regulation of MT, comprised of scientists, physicians, legal scholars, ethicists, and industry representatives, felt it critical to first agree upon a clear definition of MT.

Ossorio and Zhou take issue with the concept of “minimal manipulation” included in our proposed definition, raising two concerns: 1) that “minimally manipulated MT product for allogeneic transplant is likely the most dangerous type of microbial product for a recipient,” and 2) questioning the ability of regulators to determine when stool has been minimally manipulated, or not, and therefore their ability to operationalize the proposed definition. The first of these concerns is speculative. The human microbiota has evolved with humans over millennia and it is not clear that highly manipulated products would be safer, especially when carefully selected and screened donors are used for MT. In addition, the efficacy of more than minimally manipulated products largely remain unproven, thus the benefits of an effective therapy, such as FMT for Clostridium difficile infection, need to be accounted for when setting regulation. As to the second concern on the ability to determine what is minimally manipulated or not, we do agree that this is challenging. We defined minimal manipulation as processing that does not alter the original relevant characteristics of the transferred material. Given the complex nature of microbial communities, this definition does require regulators to exercise judgment. However, we believe it provides regulators with a guiding principal that also allows needed flexibility for a rapidly evolving field, while not limiting innovation.

The drug approval process, which Ossorio and Zhou appear to advocate for all microbiota-based products, does have limitations that make it poorly applicable to MT. First, it does not inherently require screening of donors or specify what should be screened for. We acknowledge that donor screening would likely be a required part of any Food and Drug Administration (FDA) investigational new drug (IND) application and institutional review board-approved clinical trial as part of the drug approval process. However, screening of a donor and specimen is not typically required of a drug after approval. Formal screening requirements are included in the regulations for blood and human tissue/cell donation, and we believe these regulatory frameworks provide a useful model that can be applied to MT donor screening. Second, the composition, strength, and purity of donor microbiota samples cannot be fully characterized, and these are expected components of an FDA IND application. Each sample is different, even if it is from the same person; thus, it could not go through the standard drug approval process without FDA making changes to regulatory requirements. Subjecting minimally manipulated, highly diverse microbiota products to the ill-fitting drug approval process could limit research on, and access to, a potentially low-cost, readily available, and, in some cases, life-saving alternative.

Ossorio and Zhou also propose “if MT products are regulated differently than more manipulated ‘stool-based products,’ the regulatory system will disincentive investment in research and development of more standardized, better characterized, higher quality microbial therapeutics.” We do not know if this is true, but we do believe that encouraging investment needs to be balanced with access to effective and affordable therapies, especially as patients can turn to (and have turned to) “do-it-yourself” microbiota transplants that carry major safety concerns, as no stringent screening is performed.

Finally, Ossorio and Zhou believe that regulators should not draw a line between MT and other microbial products intended to cure, mitigate, treat, or prevent disease. The continuum of manipulation that we included was not meant to be a scale of risk rather it was to indicate that things on the right hand side were more capable of being regulated as a drug, i.e., more likely to be able to be standardized from batch to batch or dose to dose. In our conclusion, we specifically state that we could not identify a “bright line” dividing the spectrum of microbial products. However, given the differences in composition and complexity of various microbiome products, e.g. from whole stool to defined cultures, we do not believe that all products should be regulated the same, and that nuance is required.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.