[2026.04.04 | Philadelphia]

The journal, Botanical Drugs, published a review article on the CMC Challenges and Solutions in Botanical IND & NDA [https://botanicaldrugs.org/index.php/pub/article/view/7]

The FDA approved its first botanical prescription drug in 2006. Nearly two decades later, only three more have followed. To many in the pharmaceutical industry, that number tells a story of failure — a pathway too difficult, too uncertain, and too risky to pursue. In a review article, we analyzed the challenges and solutions each approved botanical drug went through and summarized their successful approaches.

The Problem Is Not the Pathway

Botanical drugs are complex, multi-component preparations derived from plant materials. Unlike single-molecule drugs, they cannot be fully characterized at the molecular level. Their chemical profiles vary with cultivar, geography, harvest season, and processing conditions. By every measure of conventional pharmaceutical quality control, they are difficult products.

The FDA recognized this decades ago. Through two successive guidance documents in 2004 and 2016, and the establishment of a dedicated Botanical Review Team within the Center for Drug Evaluation and Research, the agency built a regulatory framework specifically designed for this complexity. At its core is a principle called the totality-of-evidence approach: rather than requiring the complete molecular certainty demanded of new chemical entity drugs, the FDA accepts aggregate evidence drawn from upstream raw material controls, chemical characterization, mechanistic bioassays, and multi-batch clinical data to assure product quality and therapeutic consistency.

The framework is sound. The four approvals prove it works. So why have so few botanical drugs made it through?

Lessons from Four Approved Drugs

Our review examines each of the four FDA-approved prescription botanical drugs — Veregen, Fulyzaq/Mytesi, NexoBrid, and Filsuvez — with a specific focus on the CMC challenges each program faced and the solutions that enabled approval.

• Veregen, a green tea catechin ointment for genital warts, could not achieve batch-to-batch consistency through conventional specifications because no correlation existed between individual catechin levels and clinical response. The solution was to restrict raw material to specific cultivars under Good Agricultural and Collection Practices, derive acceptance ranges from clinical trial batch data, and demonstrate through a dual-dose Phase 3 program that natural compositional variability did not affect clinical outcomes.

• Fulyzaq/Mytesi, an oligomeric proanthocyanidin for HIV-associated diarrhea, presented even greater characterization uncertainty — its oligomers could not be individually separated or quantified by any available analytical technique. The FDA required the development of a clinically relevant bioassay measuring chloride channel inhibitory activity as the primary quality specification, grounding quality assurance in what the drug does rather than what it contains.

• NexoBrid, a proteolytic enzyme concentrate from pineapple stems for burn debridement, took this a step further by electing the Biologics License Application pathway, where process-defines-product and functional activity assays are the established quality paradigm.

• Filsuvez, a birch bark triterpene gel for epidermolysis bullosa, leveraged orphan drug designation for commercial viability and quantitative triterpene fingerprinting as its quality anchor, supported by European clinical data demonstrating therapeutic consistency across the controlled compositional range.

Each program was different. Each product posed unique challenges. But five generalizable patterns emerge across all four: upstream raw material control as the quality foundation, characterization depth calibrated to product complexity, functional assays as compensatory evidence when chemistry alone is insufficient, clinical data as the ultimate quality anchor, and strategic regulatory pathway alignment as a CMC decision rather than merely an administrative one.

The Real Barrier: Predictability

If the framework works, why has uptake been so limited? Our review identifies several structural barriers.

1. The 10-to-15-year drug development timeline means that programs initiated under the mature 2016 Guidance are only now approaching the window for NDA submission. Most botanical drug sponsors are small companies whose development programs are interrupted by funding gaps, extending timelines further. Regulatory expertise specific to botanical drug INDs is scarce and largely resides outside the established contract research organizations that serve conventional pharmaceutical sponsors. And major pharmaceutical companies, despite evaluating the pathway, held back by short-term financial reporting pressures, institutional entrenchment in single-molecule thinking, lack of botanical science expertise, underdeveloped supply chains for pharmaceutical-grade botanical raw materials, and a perceived intellectual property disadvantage.

2. That last point deserves particular attention. The conventional view is that botanical drugs are harder to protect than single-molecule drugs because they lack composition-of-matter patents. Our review argues the opposite. The totality-of-evidence framework itself creates a multi-layered body of proprietary knowledge — specific raw material sources, specific manufacturing processes, specific analytical methods, specific bioassays, specific clinical datasets — that a generic competitor would need to independently reconstruct in its entirety. In practical terms, this barrier may exceed the protection of a single patent that can be designed around through molecular modification. The totality-of-evidence framework functions as a de facto intellectual property shield. It does not protect a molecule. It protects the entire integrated system that delivers the drug to patients.

The Gold Standard We Already Have

The central argument of our review is this: the totality-of-evidence principle, already articulated in the FDA Guidance and validated by four successful approvals, should serve as the gold standard for both regulators and sponsors.

• For sponsors, that means building development programs around the totality-of-evidence architecture from day one — investing in upstream raw material control during the IND phase, initiating bioassay development early when characterization limitations are foreseeable, and designing clinical programs that generate CMC-relevant data including multi-dose and multi-batch analyses.

• For the regulatory side, that means ensuring consistency across all disciplines of the IND review team. The Botanical Review Team possesses specialized expertise, but the complete review team includes clinical, nonclinical, and clinical pharmacology reviewers who may apply interpretive frameworks rooted in single-molecule expectations. When all reviewers apply the totality-of-evidence principle and calibrate CMC expectations to the appropriate IND stage, the process becomes predictable. When review comments default to conventional new chemical entity requirements for inherently complex botanical products, the resulting unpredictability discourages sponsors and reinforces the misperception that the pathway itself is flawed.

The Framework Exists. The Precedent Exists.

Four approved botanical drugs is not a story of failure. It is a proof of concept — for the regulatory framework, for the totality-of-evidence principle, and for the proposition that complex botanical products can meet modern FDA standards of quality, safety, and efficacy through a different but equally rigorous evidentiary architecture.

What is most needed now is alignment. Sponsors who build their programs on the principles the four approved drugs have demonstrated. Reviewers who apply the Guidance they helped create. When both sides of the table operate from the same framework, the botanical drug IND process becomes not only predictable but achievable — and more botanical drugs will reach the patients who need them.

The full article, "CMC Challenges and Solutions in Botanical Drug IND & NDA Development — Lessons Learned from Four Approved Botanical Drugs," is available in the Journal of Botanical Drugs.

Scientific Paper Revew-U.S. FDA Botanical Cancer Drug Current INDs

SILVER SPRING, MD - A recent analysis, published in Therapeutic Innovation & Regulatory Science, by researchers including Jin-Young K. Park, Daniel Lee, Lixin Rui, Xiaoyue Gao, M. Scott Furness, and Charles Wu, examines botanical investigational new drug applications (INDs) submitted to the U.S. Food and Drug Administration (FDA) for cancer management. The study provides a comprehensive overview of regulatory submission profiles and review experiences for oncologic botanical drug research and development

The FDA has received over 700 botanical INDs across various therapeutic areas since 1984, with the largest number pertaining to cancer management. This study specifically analyzed 254 botanical INDs with oncologic indications and 485 non-oncologic botanical INDs received by the FDA between March 1984 and December 2020.

Key findings from the analysis include:

• Initial 30-Day Actions: A higher percentage of oncologic botanical INDs (69%) received an initial 30-day "safe-to-proceed" designation compared to non-oncologic botanical INDs (58%). This action permits the initiation of clinical investigations.

• Current Regulatory Status: As of December 2020, 82 (32%) of the oncologic botanical INDs and 171 (35%) of the non-oncologic botanical INDs were active, indicating ongoing clinical investigations.

• Clinical Trial Phases: Of the oncologic botanical INDs, 137 were submitted for Phase 1 trials (46 active), 111 for Phase 2 trials (33 active), and 6 for Phase 3 trials (3 active).

• Primary Purpose of Trials: The primary purposes for oncologic botanical INDs were basic research (38%), treatment (26%), supportive care (20%), and prevention (14%).

• Specific Tumor Types Investigated: The majority of oncologic botanical INDs (71%) focused on specific solid tumors, with prostate and breast tumors representing more than one-third of these cases. Hematologic malignancies accounted for 9% of the submissions.

The authors note that the FDA's regulatory approach for botanical drugs considers their inherent complexity, including challenges in identifying active components and ensuring quality consistency. The agency's 2016 Guidance for Industry for the Development of Botanical Drugs provides recommendations for facilitating drug development and ensuring batch-to-batch consistency.

The study concludes that over 80 active botanical oncologic INDs were identified, with several in the late phases of drug development. This indicates a pipeline of botanical drug products under investigation for cancer management, encompassing basic scientific research, various cancer treatments, supportive care, and cancer prevention.

ABSTRACT:

The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. Between 2016 and 2019, 195 botanical drug clinical trials were registered, of which 81 are phase 2. By the end of 2018, over 600 IND applications were in clinical development under the botanical drug category. Two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals’ chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.

Authors: Charles Wu, Botanical Review Team, Science Staff, Immediate Office, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States

Source: J. Nat. Prod. 2020, 83, 2, 552–562

[2023.12.31 | Filver Spring, MD]

In a significant breakthrough for the medical community and patients suffering from rare diseases, Chiesi Global Rare Diseases, a division of the Chiesi Group dedicated to the development of treatments for rare disorders, has announced a critical milestone. The U.S. Food and Drug Administration (FDA) has granted approval to FILSUVEZ®, a topical gel containing birch triterpenes, aimed at treating partial thickness wounds in patients aged 6 months and older with Junctional Epidermolysis Bullosa (JEB) and Dystrophic Epidermolysis Bullosa (DEB).

Epidermolysis Bullosa (EB) is a group of rare genetic conditions that cause the skin to be very fragile. Any trauma or friction to the skin can lead to painful blisters and skin erosions. JEB and DEB are among the most severe forms of EB, with symptoms appearing in infancy or early childhood. These conditions not only cause extreme physical discomfort but also present emotional and psychological challenges to patients and their families.

The approval of FILSUVEZ® is a beacon of hope for those affected by JEB and DEB. This is the first FDA-approved treatment specifically targeting the wounds associated with these forms of EB. Prior to this development, treatments were limited and primarily focused on wound care and pain management, without addressing the underlying cause of the blisters and wounds.

FILSUVEZ® is a sterile botanical drug product, derived from a dry extract of two species of birch bark. Its unique formulation aims to promote healing of the wounds associated with EB. The approval is based on extensive clinical trials that demonstrated the effectiveness and safety of the medication in patients aged 6 months and older.

In addition to providing a new treatment option, the approval of FILSUVEZ® also signifies a step forward in the recognition and understanding of rare diseases like EB. It reflects the commitment of pharmaceutical companies and regulatory agencies to invest in research and development for conditions that affect a small percentage of the population but have a profound impact on the quality of life of those who suffer from them.

This advancement is not just a medical milestone; it's a message of hope for the EB community. It represents the potential for improved quality of life, reduced pain, and better wound management for patients. The approval of FILSUVEZ® encourages further research and development in the field of rare diseases, potentially leading to more innovative treatments in the future.

For the families and individuals dealing with EB, this news brings a sense of relief and optimism. The journey of living with EB is fraught with challenges, but developments like this offer a light at the end of the tunnel. The approval of FILSUVEZ® is a testament to the progress being made in the treatment of rare diseases and a reminder of the importance of continued research and innovation in this field.

Importance Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials.

Objective To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design, Setting, and Participants Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021.

Interventions Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments.

Main Outcomes and Measures The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year.

Results Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], −1.8% [95% CI, −3.2% to −0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, −1.2% [95% CI, −2.5% to −0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, −3.0% [95% CI, −4.6% to −1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, −1.6% [95% CI, −3.1% to −0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms.

Conclusions and Relevance In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI.

Trial Registration ClinicalTrials.gov Identifier: NCT03792035

Source: Yang Y, Li X, Chen G, et al. Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial. JAMA. 2023;330(16):1534–1545. doi:10.1001/jama.2023.19524

Importance Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials.

Objective To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design, Setting, and Participants Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021.

Interventions Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments.

Main Outcomes and Measures The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year.

Results Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], −1.8% [95% CI, −3.2% to −0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, −1.2% [95% CI, −2.5% to −0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, −3.0% [95% CI, −4.6% to −1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, −1.6% [95% CI, −3.1% to −0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms.

Conclusions and Relevance In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI.

Trial Registration ClinicalTrials.gov Identifier: NCT03792035

Source: Yang Y, Li X, Chen G, et al. Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial. JAMA. 2023;330(16):1534–1545. doi:10.1001/jama.2023.19524

At the forefront of groundbreaking research, Coacillium, a plant-based drug developed by Legacy Healthcare, has emerged as a potential game-changer in the treatment of alopecia areata. The revelations come from research findings unveiled at the 2023 annual meeting of the European Academy of Dermatology and Venereology (EADV), where the unique properties of Coacillium took center stage.

The research indicates that the application of Coacillium can lead to significant hair regrowth in children grappling with alopecia areata. The plant-based drug presents a novel approach to addressing this challenging condition, offering hope to families and individuals affected by hair loss.

During a recent radio interview, Saad Harti, the CEO of Legacy Healthcare, provided insights into the Phase 2/3 data. Harti highlighted the distinctiveness of Coacillium, stating, "Coacillium is among the first drugs to show sustained remission off-treatment in an autoimmune and inflammatory disease, with no immune-altering side-effects." This characteristic sets Coacillium apart in the realm of autoimmune therapies, promising a unique and well-tolerated solution for patients.

The significance of these findings extends beyond the scientific community, reaching individuals who seek effective and sustainable solutions for alopecia areata. Coacillium's potential to induce hair regrowth in children and its ability to maintain remission without the need for continuous treatment represent a beacon of hope for those affected by autoimmune and inflammatory diseases.

As Legacy Healthcare continues to pave the way in pharmaceutical innovation, the spotlight on Coacillium intensifies. The plant-based drug not only signifies a breakthrough in dermatological treatments but also underscores the commitment of Legacy Healthcare to bring transformative and patient-centric solutions to the forefront of medical advancements.

Botanical drugs are plant-derived, complex mixtures which may have synergistic effects. In order to understand this disparity between human use and drugs approved by regulatory agencies, we analyzed botanical drug clinical trials registered at ClinicalTrial.gov to detect trends in current trials and guide future trials. A total of 195 botanical drug clinical trials were registered from 2016 to 2019, of which 81 are phase II or phase II/III. 95% of all phase II and II/III studies were designed with 100 or less participants per arm, indicating a more observational nature due to the limited power to detect differences in outcomes between treatment and control groups. Due to the limited number of participants, efficacy outcome from results may be highly subjective. 14% of the total trials were phase I studies. For botanical drugs with well-documented or extensive history of human use, phase I may not provide significant additional information, and may, therefore, not be necessary. For the trial design, we suggest added-on studies when botanical drugs are used as part of a combination treatment. Additionally, we believe standardized data collection methods and criteria are critical to utilizing the vast collection of human experience as quality evidence to support regulatory approval.

ABSTRACT

Coronavirus disease 2019 (COVID‑19) pandemic has caused the millions of deaths worldwide. Much of the mortality has been associated with a cytokine storm syndrome in patients admitted to the hospital with acute respiratory distress syndrome.Vast arrays of anti‑inflammatory therapies are being explored to decrease the cytokine storm to save the lives. None of these therapies have demonstrated efficacy at all stages of the disease thus underlining its complexity. The current vaccine approach is challenged by the emerging virus variants. A multi‑target approaches have been used with success for human immunodeficiency virus and some types of cancer. It has been recently proposed to use the same strategy for COVID‑19.

Scott Gottlieb, M.D. “Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes. We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products. But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims. Marketing unapproved products, with uncertain dosages and formulations can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.”