Regulation of Vaginal Seeding and the Vaginal Microbiome — Is it a Biologic or Drug (or Neither)?

An initial issue for any researcher conducting a clinical trial is whether submission of an Investigational New Drug Application (IND) to the US Food and Drug Administration (FDA) is required. While the practical requirement for an IND is to allow the testing of unapproved drugs and biologics in humans, the legal requirement for an IND is based on whether or not the treatment being tested is a biologic⁴³ or a drug that has a connection to interstate commerce. The Federal Food, Drug, and Cosmetic Act defines the term drug, in part, as any article “intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals” or a “substance (other than food) intended to affect the structure or any function of the body.”⁴⁴ Thus, the definition is tied to the researcher's or manufacturer's intent. FDA's authority to require an IND stems from its authority under the Food, Drug, and Cosmetic Act to prevent the distribution of adulterated or misbranded products in interstate commerce. An unapproved drug is considered misbranded.

When a novel substance is being tested in human clinical trials, FDA has on many occasions issued an Industry Guidance document informing the research community as to how the substance will be regulated and whether or not an IND is required.⁴⁵ FDA has not as yet issued public guidance on vaginal seeding; however, as they did in the early days with fecal micro-biota transplantation (FMT), the agency is handling requests by investigators on a case-by-case basis.

Both of the current US clinical trials on vaginal seeding are being conducted under an IND. In the case of the Inova Study, after the researchers submitted their study protocol to their institutional review board and the relevant data and safety monitoring board (DSMB),⁴⁶ members of the DSMB advised the study team to investigate whether an IND would be required by the FDA. The investigator team contacted FDA in November 2017 and provided background information on the proposed study, including the study's inclusion and exclusion criteria that incorporate comprehensive screening for infectious diseases. The FDA advised that an IND would be required for the study. In January 2018, the study team submitted an application request for a pre-IND meeting in order to discuss with FDA why an IND application was required for the study. In its response declining the meeting request, the agency noted that the study's “plan to use maternal vaginal flora applied to infants in a study to determine possible impact on obesity in young children, utilizes administration of live organisms to affect structure/function of the body” and falls within IND requirements as per Section VI.B of FDA's 2013 “Guidance for Clinical Investigators, Sponsors and IRBs — Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND.”⁴⁷ This decision by FDA appears to be based on the agency's decision that “maternal vaginal flora” meets the definition of a “drug/biologic” under the federal Food, Drug and Cosmetic Act. FDA's determination also presumes that FDA has jurisdiction over use of the substance/procedure.

Although FDA has claimed regulatory jurisdiction over FMT performed by a physician with donated stool from a patient's family or friends, some have argued it should be treated as the practice of medicine which is regulated by state medical boards and departments of health.

While FDA's authority under the Food, Drug, and Cosmetic Act is limited to drugs having a connection with “interstate commerce,” in passing the 1997 Food and Drug Administration Modernization Act (which amended the Food, Drug, and Cosmetic Act), Congress made clear that “the connection with interstate commerce required for [the agency's] jurisdiction … shall be presumed to exist.”⁴⁸ Since then, FDA has interpreted its jurisdiction as being extremely broad and in virtually all cases the courts have upheld FDA's decisions.

In United States v. Kaplan (2016), a physician was found criminally liable under the Food, Drug, and Cosmetic Act after reusing single-use plastic needle guides during prostate biopsy exams.⁴⁹ The physician/defendant appealed the lower court decision arguing that the Food, Drug, and Cosmetic Act did not apply. The 9th Circuit Court of Appeals' decision turned on its interpretation of Section 331(k) of the Food, Drug, and Cosmetic Act which prohibits any act “with respect to, a food, drug, [or] device … if the act is done while such article is held for sale … after shipment in interstate commerce and results in such article being adulterated or misbranded.”⁵⁰ A drug is misbranded if it does not include the proper labeling. The court referenced a prior 9th Circuit case, U.S. v. Geborde,⁵¹ in which a disc jockey distributed a home-made designer drug called gamma hydroxy butyrate to several teenagers and one of the teens drank it and died. This was the only 9th Circuit case addressing the “held for sale” provision, and the court sided with the defendant. It distinguished Geborde, however, from the facts of Kaplan by pointing out that Geborde “was not a physician, made his own recreational drugs and distributed them free of charge,” and, thus, the transaction was of a “noncommercial nature.”⁵² The defendant in Kaplan argued that the needle guides were not “held for sale” because there was no sale. The 9th Circuit, however, rejected this argument, relying on a number of out-of-circuit cases which have held that “a physician's use of a device on a patient is covered by the statutory phrase ‘held for sale.’”⁵³ The court ultimately sided with FDA concluding that Kaplan's medical practice was commercial in nature; he operated at a profit and what he charged patients for procedures also covered the products he used, therefore the needle guides were “held for sale.”

In US v. Regenerative Sciences (2014),⁵⁴ the U.S. Court of Appeals, District of Columbia Circuit, sided with FDA concluding that cultured stem cells, originating from a patient's bone marrow and sent to an in-state lab for processing and then injected back into the same patient, constituted a drug when combined with an antibiotic prior to injection. The District Court indicated that, in claiming jurisdiction under the Commerce Clause, the FDA must establish that the substance at issue had been both (1) “held for sale” and, prior to such sale, (2) “ship[ped] in interstate commerce.”⁵⁵ While the defendant agreed that the product was “held for sale,” it argued that the second requirement was not met because the entire process took place intrastate at the defendant's medical facilities. The Court relied on prior case law holding that “wholly intrastate manufacturers and sales of drugs” meet the interstate commerce requirement as long as “an ingredient used in the final product travelled in interstate commerce.”⁵⁶ In the Regenerative Sciences case, the stem cells were combined with the antibiotic doxycycline before they were administered to the patient. Because the doxycycline was shipped across state lines and was a component of the substance given to the patient, that substance constituted a drug subject to FDA's regulatory authority.

Based on the decision in Regenerative Sciences, it is likely that a court would find that stool administered to patients from donated stool from a friend of family member meets the second prong of the jurisdictional test, i.e., the product must be shipped in interstate commerce, as the stool is combined with saline solution, which is shipped across state lines for sale. Based on Kaplan and cases from other circuits,⁵⁷ it is likely that a court would find that the donor stool is “held for sale.” An argument can be made, however, that vaginal microbiota from a baby's mother is not being sold or distributed across state lines and therefore would arguably be the practice of medicine. In the case of vaginal seeding, the only material used in the vaginal seeding process, other than the mother's own vaginal secretions, is gauze. FDA might be able to argue that, because such gauze is sold in interstate commerce, the vaginal microbiota in combination with the gauze constitutes a drug or medical device/drug combination. FDA would further likely argue that the microbiota-soaked gauze would be considered “held for sale” as the hospital is charging the patient for the C-section and the gauze would be bundled into the hospital charge. If the facts were changed slightly, however, and the mother brought the gauze with her to the hospital, the gauze may no longer be considered “held for sale” and FDA may not have jurisdiction.

In addition to controversy about jurisdictional claims, just as the categorization by FDA of fecal matter as a drug/biologic has been controversial, the classification of vaginal secretions when administered to newborns from their mother shortly after birth is also likely to raise objections on the part of some researchers and possibly patients. There are several reasons for this. As others have noted, microbiota are not like “drugs” as traditionally understood. In the case of FMT, FDA is currently regulating the stool administered during the procedure as a biological / drug product. While FDA has not publicly addressed the regulation of vaginal seeding or vaginal micro-biota transplantation, the regulatory history of FMT may provide some insight as to how the agency may approach vaginal seeding or vaginal microbiota transplantation more broadly.

In the case of FMT, the FDA has changed its position regarding how it will regulate fecal microbiota over the past six years. After an initial determination in 2013 that fecal microbiota would be categorized as a “biological product” that would require an IND application, the agency reversed course in response to patient and provider opposition, opting to exercise enforcement discretion of the IND requirement for C. difficile infection that is non-responsive to traditional antibiotics. Then, in 2014 and 2016, the agency issued draft guidance that would require an IND application from stool banks that collect and distribute fecal material for FMT for C. difficile infections. While the agency has not yet finalized this guidance and has maintained its enforcement discretion posture for providers performing FMT on patients with recurrent C. difficile infections, the guidance gives some indication of FDA's current thinking on the matter of how it would prefer to regulate microbiota transplants.

Vaginal seeding, however, is distinct from FMT and vaginal microbiota transplantation in several ways. In the case of vaginal seeding, if a woman delivered her neonate vaginally, the neonate would naturally be exposed to her vaginal fluids and thusly the mother's vaginal microbiota. The C-section delivery constitutes a medical intervention that interrupts that process. Thus, there may be an argument that vaginal seeding is an attempt to replicate an exposure that occurs in the natural birthing process. While FDA may argue that it is being done to prevent disease or chronic conditions or tp affect the structure or function of the body, it seems very different from the typical drug as well as different from FMT and VMT.

In FMT the patient receives the fecal matter of a different individual. Outside of the context of the FMT, the patient would not otherwise be exposed to the other individual's fecal microbiota. Similarly, in a vaginal microbiome transplant, vaginal contents from one woman are transplanted into the vagina of another in an effort to alter the recipient's microbial composition (e.g., for treatment of bacterial vaginosis). Researchers and patients have made numerous arguments that fecal microbiota should not be classified as a drug or biologic and that the drug regulatory pathway is not appropriate for FMT. These arguments have included the difficulty of characterizing the active ingredients in FMT which is typically required of drugs, the cost of the drug approval process which may lead to an increase in unsafe “do-it-yourself ” FMTs, the inadequacy of the IND process to accommodate post approval changes to the manufacturing process, and the availability of off-label prescribing that may discourage research into the use of FMT for other indications.

Characterization, which refers to the use of external techniques to “characterize” a substance to ensure that the substance is what it claims to be, has been considered a particularly challenging stumbling block in treating fecal microbiota as a drug/biologic. The issue of characterization is particularly important for microbiota transplantation because, unlike most other regulated products, microbiome products include a microbial community and other elements that differ from person to person and within the same person at different times. This makes characterization extremely challenging.

Maternal vaginal secretions are a heterogeneous substance, composed primarily of bacteria and water, but also containing viral and fungal organisms, metabolic products of these organisms, salts, dead cells, and mucus from the cervix and vaginal tract. Lactobacillus spp. typically dominate the secretions; however, members of the genera Atopobium, Corynebacterium, Anaerococcus, Peptoniphilus, Prevotella, Gardnerella, Sneathia, Eggerthella, Mobiluncus, and Finegoldia are also less commonly found in vaginal secretions.

Similar to the fecal microbiome, the vaginal micro-biome differs between women and within the same woman over time. While typically less diverse than the fecal microbiome, the vaginal microbiome is dynamic and changes in response to multiple factors, such as pregnancy, hormonal fluctuations, intercourse, and environmental exposures.^{Reference MacIntyre, Chandiramani and Lee58} Defining the exact contents of donor vaginal seeding material is a major obstacle due to this variation. In addition, the intent of vaginal seeding is to restore exposure of an infant to its own mother's vaginal microbiota, and the vaginal seeding material may be very specific for each mother-infant dyad.

FDA has largely dealt with the “lot-to-lot” variability challenge in the context of stool-based products through the Good Manufacturing Practices framework for drugs and live biotherapeutic products. Whether this makes sense in the context of vaginal seeding done between mother and infant is not at all clear, as it would require major scaling up of the product to justify the cost of implementing Good Manufacturing Practices. Rather than defining what the exact contents of the transferred substance are, it may be more than sufficient to characterize the major bacteria species and what is not contained in the secretions (like pathogens) through a variety of clinical and laboratory tests.

In addition to the identity of the biological product, a critical part of the Chemistry, Manufacturing and Control information requirements for new drugs/biological products is to establish their safety, potency or strength, quality, and purity. Determining dose, potency, and purity are major hurdles for stool used for FMT and may also be for the vaginal secretions used in vaginal seeding.

Another concern about the drug regulatory pathway in the context of FMT has been the do-it-yourself phenomenon. This could also happen in the context of vaginal seeding. Mothers could place, or request that their physician or nurse place, a gauze pad or a swab in their vagina prior to their C-section procedure and then after the baby is born apply the gauze to their baby themselves without any physician intervention or the need for any product other than what they have produced from their own bodies. This makes it even less likely that a court would consider the “product” “held for sale.” Mothers could even perform vaginal seeding in their own home after discharge from the hospital (although the vaginal microbiome postpartum may not be similar to the vaginal microbiome just before birth). Such do-it-yourself practice might be safer in the context of vaginal seeding than in FMT if the mother asks her physician if there is any likelihood of an immediate risk to the baby if she exposes the baby to her vaginal fluids. However, trials would be needed to test such an approach if vaginal seeding in a controlled context first proves to be efficacious.

The most controversial regulatory issue in the context of FMT has been whether stool from stool banks should be regulated as drugs. This raises the question of whether vaginal microbiota for vaginal seeding might ever be banked. While the current research on vaginal seeding involves vaginal microbiota from the baby's mother, it is possible that researchers may find that certain mothers have vaginal microbiota that are more beneficial to health than others. This could ultimately lead to banking vaginal secretions and making them available for sale. It is also possible that researchers will identify particular microbial strains that offer infants born via C-section the protection of the mother's vaginal microbiota and will attempt to develop a probiotic based on vaginal microbiota for administration to these newborns. In both of these cases there is a stronger argument for regulating vaginal seeding as a drug than in the context of applying a mother's own vaginal microbiota directly to her newborn.

Because of the obstacles to approving stool or fecal microbiota as a drug, some have argued that other regulatory pathways may be more appropriate for FMT, such as those used for blood, human cells and tissues, or cord blood.^{Reference Sachs and Edelstein59} These alternative regulatory pathways may also be more appropriate for vaginal microbiota associated with vaginal seeding. These pathways are more flexible and allow for more rapid updating of screening protocols for donors and the product to be “transplanted.”^{Reference Khoruts, Hoffmann and Palumbo60}

Ethical Challenges Associated with Vaginal Seeding

In addition to the myriad legal and regulatory questions, vaginal seeding also implicates a number of ethical concerns with regard to clinical practice and research. The concept of informed consent and the regulations that require its use are intended to provide patients and research subjects with full information about a treatment or procedure, including its risks and benefits, so they can make educated and autonomous decisions about how to proceed. In the case of vaginal seeding, there is preliminary evidence that the practice may result in a C-section delivered infant microbiome that more closely resembles that of vaginally-delivered infants.⁶¹ To date, however, the scientific evidence of the benefits is very limited and little is known about the potential short- or long-term risks of the procedure on the infant.