Live Biotherapeutic Products (LBPs) are biological products that contain live organisms, are applicable to the prevention, treatment, or cure of a human disease or condition, and are not vaccines. A U.S. clinical investigation evaluating a live microorganism for a drug use—including diagnosis, cure, mitigation, treatment, or prevention of disease—generally must be conducted under an Investigational New Drug application (IND), unless a specific exemption applies. This article explains how IND applicability is determined and outlines the phase-appropriate manufacturing, nonclinical, and clinical information FDA expects.
As microbiome science advances, more companies are moving beyond traditional probiotics and developing Live Biotherapeutic Products (LBPs) intended to prevent, treat, or mitigate disease. These products represent one of the fastest-growing areas of biopharmaceutical research, offering novel approaches to conditions ranging from gastrointestinal disorders to metabolic and immune-mediated diseases.
Unlike products marketed as conventional foods or dietary supplements, an LBP intended for therapeutic use is regulated as a biological product under section 351 of the Public Health Service Act and as a drug under the Federal Food, Drug, and Cosmetic Act. A U.S. clinical investigation subject to 21 CFR Part 312 must be conducted under an effective Investigational New drug (IND) application. Commercial distribution of an LBP for therapeutic use requires approval of a Biologics License Application (BLA); an IND does not authorize commercial marketing. Understanding when an IND is required—and what FDA expects during the application process—is critical for avoiding development delays and ensuring a successful regulatory strategy.
FDA defines a Live Biotherapeutic Product (LBP) as a biological product that:
Unlike traditional pharmaceuticals, LBPs may act through transient persistence or colonization, competition with pathogens, production of biologically active substances, or modulation of host or microbial pathways. The relevant mechanism is product-specific, and permanent colonization is not required for a product to qualify as an LBP. Because these organisms remain biologically active after administration, FDA places significant emphasis on manufacturing consistency, product characterization, and clinical safety.
This distinguishes LBPs from conventional probiotic foods and dietary supplements, which are generally intended to support normal body structure or function rather than treat disease. FDA has consistently stated that a product’s intended use—rather than simply the microorganism itself—determines its regulatory pathway.
“Probiotic” is not itself a regulatory product category under U.S. law. A product described as a probiotic may be regulated as a conventional food, dietary supplement, drug, or biological product depending on its intended use, composition, and the statutory requirements applicable to the product category.
FDA’s LBP CMC guidance does not apply to microorganisms used as gene therapy vectors, oncolytic bacteria, or oncolytic viruses. Recombinant LBPs may also raise additional product-specific requirements, making early engagement with CBER particularly important.
FDA’s primary objectives in reviewing an IND are, in all phases of development, to protect the safety and rights of research participants and, in Phases 2 and 3, to help ensure that the scientific evaluation is adequate to assess the product’s safety and effectiveness. For Live Biotherapeutic Products, FDA evaluates whether:
Unlike conventional drugs, LBPs introduce living organisms into the body, creating additional considerations related to viability, genetic stability, microbial persistence, and host interactions.
Not every study involving a product marketed as a probiotic requires an IND. For example, a study intended only to evaluate a dietary supplement’s effect on the normal structure or function of the body generally does not require one. FDA also currently does not expect an IND for certain studies intended to support disease-risk-reduction health claims, subject to the limitations described in FDA’s 2015 partial stay. By contrast, a study intended to evaluate a product’s ability to diagnose, cure, mitigate, treat, or prevent disease generally requires an IND. When the classification is uncertain, sponsors may request FDA’s advice under 21 CFR 312.2(e).
For LBPs, FDA’s review extends well beyond the clinical protocol. Sponsors must demonstrate that both the investigational product and the proposed study meet appropriate standards for quality and participant safety.
Product Characterization
One of the first questions FDA asks is:
“Exactly what organism is being administered?”
Product characterization should be tailored to the organism and generally includes:
Unlike conventional pharmaceuticals, two microorganisms within the same species may exhibit very different biological properties. As a result, efficacy and safety data generated for one strain cannot simply be applied to another.
CMC information is a central component of an LBP IND. FDA expects phase-appropriate information sufficient to assure the identity, quality, purity, and strength—including potency—of the investigational product for the proposed clinical study. The required level of detail increases as development progresses, and FDA recognizes that manufacturing processes, analytical methods, and specifications may evolve. Manufacturing changes should nevertheless be evaluated for their potential effect on product comparability and clinical data. CMC documentation may include:
Because LBPs contain living microorganisms, maintaining viability throughout manufacturing, shipping, storage, and clinical use is often significantly more challenging than for traditional pharmaceuticals.
Phase 1 investigational drugs are exempt from the specific requirements of 21 CFR Part 211 under 21 CFR 210.2(c), but they remain subject to the statutory CGMP requirement and applicable IND controls. Once a product is made available for Phase 2 or Phase 3 studies, Part 211 requirements apply.
Before initiating human studies, sponsors should provide evidence supporting the product’s anticipated safety.
Depending on the product and indication, this may include:
The necessary package depends on the strain, formulation, route of administration, dose, treatment duration, target population, proposed mechanism, and identified risks.
A history of safe food or supplement use can be relevant, but safety evidence for a related species, strain, formulation, or dose cannot automatically be bridged to the investigational LBP.
FDA considers the totality of available evidence when determining whether a product can safely advance into clinical evaluation.
The proposed clinical protocol should demonstrate that the study is capable of answering the research question while protecting participant safety.
FDA reviews elements such as:
The protocol should align with both the product’s intended therapeutic indication and its long-term regulatory strategy.
Although many probiotic strains have long histories of safe use, therapeutic LBPs require a more comprehensive safety assessment because they are administered to patient populations and intended to influence disease processes.
Key safety considerations often include:
Safety assessment should consider the strain, dose, formulation, route, duration of exposure and vulnerability of the proposed study population. Relevant risks may include microbial translocation and systemic infection, pathogenicity or toxigenicity, antimicrobial resistance and its potential transferability, gastrointestinal intolerance, immune effects, persistence, shedding, and potential transmission to close contacts or the environment where applicable.
Genetic stability should be addressed through defined cell banks, passage limits, process controls, and targeted testing of engineered modifications or genetic loci relevant to identity, safety, activity, or potency. Clinical monitoring for shedding, persistence, translocation, infection, or recovered-organism characteristics should be included when justified by the product and study risks; it is not a universal requirement for every LBP trial.
| Development consideration | Typical small-molecule drug | Live Biotherapeutic Product |
| Product identity | Defined molecular structure | Strain-defined live organism or consortium, supported by source and cell-bank history |
| Dose and Potency | Mass, concentration and/or functional activity | Viable organisms per dose, often CFU, with additional functional assays where appropriate |
| Disposition | Conventional absorption, distribution, metabolism and excretion | Persistence, clearance, shedding, biodistribution and colonization when relevant |
| Stability | Chemical and physical degradation | Viability, identity, purity and potency during storage, shipping and administration |
| Manufacturing | Chemical synthesis or conventional biological processing with impurity controls | Cell banks, passage controls, fermentation, harvest, downstream processing and extraneous-organism controls |
| Safety | Pharmacologic and toxicologic effects | Also includes translocation, infection, toxigenicity, antimicrobial-resistance transfer and population-specific microbial risks |
Because LBPs are living products, manufacturing and quality systems play an even larger role throughout development.
Manufacturing Readiness
Many early-stage developers underestimate the amount of manufacturing documentation required before clinical trials can begin.
Developing robust CMC documentation early often reduces regulatory delays later in development.
Regulatory Classification
Products containing the same microorganism may fall within different regulatory categories, but there are many factors that determine the pathway. The intended use, product composition, route of administration, prior marketing history, and statutory requirements for the proposed category must all be considered.
Use in a conventional food requires an appropriate food-safety basis, such as GRAS status or an applicable food-additive authorization. Use in a dietary supplement requires that the microorganism qualify as a dietary ingredient and that any applicable New Dietary Ingredient Notification requirements be addressed. Medical-food status is limited to products formulated for the dietary management of a disease with distinctive nutritional requirements, consumed or administered enterally under physician supervision; it cannot be selected merely by changing the product’s claims. A product studied or marketed for therapeutic use is regulated as a drug and, when it meets FDA’s LBP definition, as a biological product.
Designing Studies That Support Regulatory Goals
Clinical trials should be designed with the final regulatory objective in mind.
Sponsors should ensure alignment between:
As discussed in our previous articles on probiotic clinical trial design and endpoint selection, early alignment between regulatory strategy and study design can significantly improve the long-term value of the resulting evidence.
Transitioning from Probiotic to Therapeutic Development
Many companies begin by developing probiotic foods or dietary supplements before pursuing therapeutic indications.
The sequence of food, dietary-supplement, and drug development can affect future market options. Under section 201(ff)(3)(B)(ii) of the FD&C Act, an article may be excluded from the dietary-supplement definition when it is authorized for investigation under an IND, substantial clinical investigations are instituted and made public, and the article was not marketed as a dietary supplement or conventional food before the IND became effective. Section 301(ll) creates a related restriction for adding certain investigated drugs or biological products to food. Companies seeking to preserve both therapeutic and food or supplement pathways should therefore assess market-entry sequencing before the IND and substantial clinical-investigation milestones.
An IND and an NDI notification serve different purposes. An IND permits clinical investigation of a drug; it does not establish that an organism may lawfully be marketed in a dietary supplement. Conversely, an NDI notification addresses the “reasonably expected to be safe” standard for specified supplement conditions of use; it does not authorize therapeutic claims or a disease-treatment study. If a microorganism is a new dietary ingredient and no exemption applies, an NDIN must be submitted at least 75 days before the supplement is introduced into interstate commerce.
However, once a sponsor seeks claims involving disease treatment, prevention, or mitigation, regulatory expectations change substantially.
Planning this transition early allows sponsors to build clinical, manufacturing, and regulatory programs that support future therapeutic development without unnecessary duplication of effort.
Although timelines vary, a typical LBP development program follows this progression:
Early planning at each stage can help reduce regulatory questions and streamline development.
1. Intended Use Primarily Determines the Regulatory Pathway
FDA regulates products based on their intended use—not simply the microorganism they contain. Therapeutic claims generally place an LBP within the biological product drug pathway requiring an IND for clinical investigation and an approved BLA for commercial marketing.
2. Product Characterization Is Critical
Sponsors should establish robust genomic characterization, manufacturing controls, and product consistency well before clinical development begins.
3. Clinical Strategy and Regulatory Strategy Should Be Developed Together
Study populations, endpoints, safety monitoring, and manufacturing plans should all support the intended regulatory pathway from the outset.
4. Manufacturing Can Become the Long Pole
For LBPs, demonstrating consistent production, viability, purity, and stability is often as important as demonstrating clinical efficacy.
5. Early Regulatory Planning Reduces Risk
Addressing FDA expectations during product development rather than after protocol completion can significantly reduce costly delays and improve the likelihood of a successful IND submission.
Developing a Live Biotherapeutic Product requires the integration of microbiology, clinical research, manufacturing, and regulatory science. Establishing the right strategy early can help sponsors avoid unnecessary delays while generating evidence that supports long-term commercialization.
At dicentra, our multidisciplinary teams support sponsors throughout every stage of LBP development, including:
Whether you are advancing a novel Live Biotherapeutic Product or transitioning a probiotic into therapeutic development, dicentra can help build a regulatory strategy that supports efficient clinical development and successful market access.