INTRODUCTION:

"Specially designed preparations" that are intended to address specific nutritional requirements and/or offer preventive healthcare are referred to as nutraceuticals. Nutraceuticals are specially designed nutrients that help prevent and treat specific diseases when added to a supplement diet^1,24.

Dr. Stephen De Felice, who founded the Foundation of Innovation Medicine in Crawford, New Jersey in 1989, coined the word "nutraceutical". It originated from the word’s "nutrition" and "pharmaceutical". Vitamins, minerals, amino acids, herbs, and botanicals are examples of nutraceuticals. These substances can be taken as liquids, pills, capsules, or tablets. The items may include probiotics, prebiotics, dietary supplements, protein supplements, functional foods, or herbal supplements alone or in combination^2.,22,32.

Hippocrates said in 400 BC, "Let food be thy medicine and medicine be thy food." This still applies in the modern era. The saying "a day without an apple keeps a doctor away" has evolved into "a day without a nutraceutical keeps a doctor away."^3,23,28.

However, a number of additional terms, such as "functional foods" and "supplements," make it unclear. One significant distinction is that nutraceuticals, which are supported by substantial scientific data, can help with immune enhancement or illness prevention.^4,26

Clinical trials offer data on a product's safety and effectiveness in humans and are considered the "gold standard" in clinical research⁵. medicine trials assess the safety and effectiveness of a medicine in a particular ailment, but nutraceutical studies record experiences of people eating particular meals within the background of a human diet. This makes nutraceutical trials potentially more practical. While drug trials contain patients with a particular ailment who need the therapy, Participants in these trials may be high-risk or healthy. Research with a robust experimental design facilitates the differentiation of unsubstantiated claims from those that are supported by evidence. This tendency will significantly contribute to the medical community's and consumers' perceptions of nutraceuticals' legitimacy.⁶

GLOBAL NUTRACEUTICAL MARKET ANALYSIS: CURRENT STATUS, GROWTH POTENTIAL, AND MARKET TRENDS IN INDIA:

The increased demand for functional foods and supplements that offer health advantages beyond basic nutrition is driving the rapidly expanding global nutraceuticals market. The nutraceuticals market was valued at USD 383.69 billion in 2022. It is anticipated to rise at a compound annual growth rate (CAGR) of 5.09% from USD 420.14 billion in 2023 to USD 488.41 billion in 2024. Finally, it is anticipated to reach USD 626.02 billion by 2029.^7,31

India Nutraceutical Market:

The aging population and the increased prevalence of chronic illnesses are two major factors driving the nutraceutical market in India. Nutraceuticals are a useful way to treat and avoid these persistent illnesses. The value of the Indian nutraceutical sector had expanded dramatically by 2019, despite its only 2% worldwide market share in 2017. India's pharmaceutical exports were valued at USD 15.86 billion as of November 2020, having reached a total of USD 16.3 billion in the fiscal year 2020.

Currently, the Indian Nutraceutical Market was valued at USD 6113.20 million in 2023, the Indian nutraceutical market is expected to develop impressively over the next several years, with a compound annual growth rate (CAGR) of 11.395 through 2029⁸.

By the end of 2025, the Indian nutraceutical market is expected to have grown to USD 18 billion. Since the manufacturing of food supplements and nutraceuticals is now open to 100% Foreign Direct Investment (FDI), foreign investors' interest in the nutraceutical market has increased significantly. These businesses can also sell their products through e-commerce, retail, or wholesale channels. As a result, from USD 131.4 million in 2012 to USD 584.7 million in 2019, FDI has grown. With such phenomenal growth, India is poised to be a global leader in nutraceuticals³.

Figure 1: Growth of the Indian Nutraceutical Market

REGULATION OF NUTRACEUTICALS IN INDIA:

The rules pertaining to health supplements and nutraceuticals are currently within the purview of the Food Safety and Standards Authority of India (FSSAI).

Nutraceuticals are defined as "foods for special dietary uses, functional foods, nutraceuticals, or health supplements" by the Food Safety and Standards Authority (FSSA). Nutraceuticals are hence referred to as "Foods for special dietary uses" in India^10,24.

FSSAI

It was not until the Food Safety and Standards Act of 2006 that the parliament passed the Food Safety and Standards Authority of India (FSSAI), which was established on September 5, 2008, with guidance from the Indian government. With 22 members and a chairwoman, the Indian government oversaw the FSSAI's establishment as a preeminent administrative expert. The fourth chapter of the 21-chapter legislation covers the production, distribution, marketing, sale, and importation of various functional foods, nutritional supplements, and nutraceuticals. Regulation guidelines were set by the FSSAI in order to license nutraceuticals in India^11,1,27,30.

On August 28, 2020, the FSSAI published a guideline note in an effort to clear up any misunderstandings regarding the various kinds of nutraceuticals. It is evident that the purpose of health supplements is to complement a person's regular diet with one or more nutrients that have been shown to provide health advantages. Foods for special dietary use (FSDU) are foods that have been specially processed or manufactured to satisfy specific dietary demands for specific conditions. Foods categorized as "special medical purposes," or "FSMPs," are intended to be given to people with digestive issues either whole or in part.3. The Food Safety and Standards Authority (FSSAI) unifies several laws and directives that addressed food-related matters across multiple Ministries and Departments. This means that nutraceuticals and dietary supplements fall under this category as well. After the FSS Act of 2006 was implemented, a number of central Acts were repealed, including the Prevention of Food Adulteration Act of 1954, the Fruit Products Order of 1955, the Meat Food Products Order of 1973, the Vegetable Oil Products Order of 1947, the Edible Oils Packaging (Regulation) Order of 1988, the Solvent Extracted Oil, the De-Oiled Meal and Edible Flour Order of 1967, the Milk and Milk Products Order of 1992, and others^9,25.

The Nutrition Labelling and Education Act (NLEA) of 1990 established guidelines for food labeling, including nutrition labeling, based on FDA standards that were later updated by the "Food Safety and Standards (Packaging and Labelling) Regulation, 2011." This legislation enabled a more stable environment and increased legal security. It promotes innovation and keeps producers who make false or misleading statements out of unfair competition¹².
2018 saw the implementation of the Food Safety and Standards (Advertising and Claims) Regulations. Its primary goal was to regulate the marketing and statements that food industry owners made about their products¹³.

NEED OF NUTRACEUTICALS CLINICAL:

Large-scale clinical studies must be carried out to produce useful clinical data. When extensive trials are conducted, the product's safety and tolerability are well established. The general public and the medical community must be convinced of the drug's efficacy and effectiveness before it can be trusted. For nutraceutical items, the pharmacodynamics data is obvious; but, the information regarding the product's pharmacokinetics—that is, how the substance is metabolized or removed from the body—is not. To learn more about the pharmacokinetics of nutraceuticals, more clinical research must be done to produce clinical proof. The ideal dosage for nutraceuticals is still up for debate. For all illness conditions and populations, the majority of dosages are prepared in a standard manner.

For nutraceuticals, topical and oral administration are the most used dosage forms. Since there is insufficient evidence to support the stability and efficacy of different dose forms, new formulations are not being created.

The most dependable method of educating the public about nutraceuticals is marketing, yet it can be difficult to promote these products among the general public in the absence of adequate clinical data and evidence. Between 2016 and 2020, clinical trials for pharmaceuticals were shown to be more prevalent than those for nutraceuticals in both Indian and global contexts. To develop the scientific proof of the nutraceutical profile, more trials and real-world experience are required. Clinical data, pharmacokinetics, and pharmacodynamics are crucial. Since there have been far fewer clinical trials on nutraceuticals than on pharmaceuticals, it is difficult to determine their applications and efficacy^12,1,28.

REGULATORY LANDSCAPE FOR NUTRACEUTICAL CLINICAL TRIALS IN INDIA:

Central Drugs Standard Control Organization (CDSCO): In India, the regulatory body in charge of licensing and monitoring clinical trials is called the CDSCO. It guarantees data integrity, patient safety, and adherence to ethical standards. Clinical studies for nutraceuticals adhere to the same regulatory framework as trials for pharmaceuticals, guaranteeing the trial's robustness and dependability.

Ethical Considerations: To ensure conformity with international scientific and ethical criteria, including getting informed consent, preserving participant rights, and ensuring privacy and confidentiality, nutritional studies conducted in India adhere to both national and international rules. This encourages the global scientific community to accept and recognize experimental outcomes.

Data Integrity and Quality: Data quality and integrity are given top priority by Indian regulatory bodies. To ensure that trials are carried out ethically, data is accurately collected, and results are reliably reported, trial sponsors are required to adhere to the Good Clinical Practices (GCP) principles.

Streamlined Approval Process: Clinical trials, particularly those using nutraceuticals, are subject to an accelerated approval procedure that India has put in place. It requires the Ethics Committee's and CDSCO's permission. For sponsors, this procedure saves time by minimizing delays and enabling trials to start soon¹⁴.

NUTRACEUTICALS TRIALS IN INDIA:

Clinical trial plays a vital role in evaluating the safety and effectiveness of nutraceutical products. Additionally, they offer a vital channel for initiating evidence-based clinical trials for nutraceuticals, investigating the possible advantages of these novel medicines, and verifying them. It is anticipated that clinical studies about nutraceuticals will increase in India. India has become a well-known location for conducting business in the upcoming years.

India's nutraceutical regulatory environment is now undergoing notable advancements. The nutraceutical business in India has a strong basis due to the creation of the Food Safety and Standards Authority of India (FSSAI) and the enforcement of laws about functional foods and nutraceuticals. India offers a favorable landscape for more research and development because of its advances in science, growing emphasis on preventive healthcare, and growing demand for evidence-based nutraceutical goods.

ADVANTAGES OF NUTRACEUTICAL CLINICAL TRIALS IN INDIA:

Diverse Population: India is renowned for having a diversified population that offers a wide range of illness profiles and genetic variants. Because of this diversity, study populations are more representative, which leads to more consistent and trustworthy trial outcomes.

Cost-Effective Trials: For nutraceutical companies on a tight budget, clinical trials performed in India are generally more affordable than those undertaken in Western nations. Trial costs can also be lowered by the availability of trained medical personnel and an affordable infrastructure.

Vast Patient Pool: The vast population of India presents a major benefit in terms of participant recruitment for clinical trials including nutraceuticals. Because many different health disorders are highly prevalent, it is easy for researchers to locate individuals who meet the parameters of a given study.

Collaborative Research Ecosystem: Numerous university institutes, research centers, and contract research companies (CROs) that specialize in nutraceutical trials may be found in India's thriving research ecosystem. Effective cooperation among industry, academia, and government entities promotes trial conduct efficiency and ensures access to the most recent scientific findings ¹⁴.

STATISTICAL EVIDENCE FROM THE LAST 5 YEARS:

Figure 2: Nutraceutical clinical trials in India

As per the last 5 years, the nutraceutical clinical trials in India were displayed in the above diagram.

In India, 2019-20, 2020-25, 2021-20, 2022-24, 2023-9, 2024-13 trials were registered.

EVIDENCE-BASED PRACTICE:

Clinical decisions made by medical practitioners using evidence-based practice are based on the product's or drug's clinical efficacy for specific patients. A client's perspective, observations, scientific literature, and expert opinion are all combined to form evidence-based medicine.

Features: Evidence-based practice offers several advantages. Evidence-based practice can help provide patients with effective care, which will ultimately lead to better patient outcomes. EBP provides a robust foundation for customized treatment plans. This strategy also enhances the standard of care that professionals give their patients. EBP keeps medical professionals informed about current procedures and developments.

Challenges: Implementing evidence-based nutraceutical practice may be hampered by an abrupt switch from traditional medicine. The management or co-workers may provide barriers to new implementations. It could be difficult to get teammates' approval when more than one healthcare provider is involved in a patient's care. There might not be enough time to teach all medical practitioners about evidence-based practice. Health professionals working in remote locations may face challenges related to inadequate access to resources for evidence-based procedures. The lack of resources to locate nutraceutical evidence to support the approach is another problem. Collaboration problems might be a hindrance to the evidence-based practice of nutraceuticals. Obtaining the necessary proof to back up the approach could be challenging. It can be difficult to study or explore the nutraceutical practice when one is pressed for time⁶.

The foundation of evidence-based nutraceutical practice consists of the following five steps:

1. Formulate an answered question.

2. Producing clinical data to support the query.

3. A critical evaluation of the available data.

4. Utilizing the proof.

5. Assessing how evidence-based medicine is practiced⁴.

CLINICAL EVIDENCE:

Clinical evidence serves as the cornerstone for evaluating the effectiveness of nutraceutical interventions in preventing, managing, or treating various health conditions. Unlike pharmaceutical drugs, which undergo rigorous testing and regulatory scrutiny before approval, nutraceuticals often enter the market with less stringent requirements. Consequently, there is a pressing need to bridge the evidentiary gap through well-designed clinical trials that adhere to rigorous scientific standards.

Efficacy:

he ability of a nutraceutical product or intervention to exhibit its intended effect or result under specific conditions is known as efficacy. Certain endpoints or metrics should be monitored to assess efficacy, such as the research methodology employed to assess the effectiveness of nutraceuticals is Observational Studies and Experimental studies

Safety:

Nutraceuticals also cause safety issues such as misidentifying the plants or adulterating them during manufacture, as well as safety problems because of pharmacological modification Drug-food, drug-drug, and nutraceutical-pharmaceutical interactions are examples of pharmacological problems. Safety issues have cast a shadow over the potential benefits of nutraceuticals in recent years. The list of products that regulatory bodies in different jurisdictions have recalled is getting longer⁶.

Complementary medication recalls have been caused by factors such as unknown active components and incorrect labeling⁹. Most side effects of nutraceuticals are minimal or non-existent. There are side effects such as vomiting, diarrhea, and constipation. Safety concerns arise because nutraceutical preparations are not as well-regulated as medications.

Studies on the pharmacological and toxicological effects of nutraceuticals are complicated since a single plant can contain several different phytochemicals. It's thought that because natural extracts are used to make them, there won't be any significant negative consequences. Plants have the potential to become contaminated with metals or alkaloids from other plants, which could lead to mild adverse effects such as gastrointestinal problems like vomiting and diarrhoea, etc⁶.

Figure 3: Clinical Evidence of Nutraceuticals

PATIENT-REPORTED OUTCOMES (PRO):

It is defined as a word that encompasses the clinical or health information that a patient reports about a study, product, or symptom, as well as the patient's satisfaction with the therapy. The patient is the only source of PRO. Patient-reported outcomes in clinical trials can reveal details regarding the adverse consequences of the novel medication under investigation. The use of patient-reported outcomes may help plan the best treatment and improve the quality of care. Also called PRO¹⁸. Physical functioning, social functioning, psychological well-being, pain, vital signs, disease-related symptoms, treatment-related symptoms, treatment satisfaction, and treatment adherence are the components of patient-reported outcomes. These elements are considered when evaluating a PRO.

PRO Measures Employed in Nutrition Research:

PRO metrics can also be used to evaluate nutrition-related outcomes. Research on the effects of diet plans or nutritional supplements typically concentrates on non-PRO clinical outcomes, such as energy intake, muscle strength, immune system response, blood glucose levels, liver function, body mass index, cholesterol, and vitamin levels.

For instance, by giving a clear indicator of patients' emotions and measuring the practical effects of nutrition on patients' lives, PROs can enhance clinical results. PRO measurements can also show whether patients experience any appreciable improvement from nutrition-based therapies and whether quality of life and functional status are affected by nutrition regimens or supplements^18.

PRO measurements are frequently divided into two categories: generic and condition-specific.

Generic PRO Measure Used in Nutrition Studies:

Furthermore, useful for characterizing healthy samples free of a particular medical problem, generic, measurements are intended for usage across a variety of demographics and a wide range of medical problems. The EQ-5D, created by Two frequently used generic PROs are the Euro QoL group and the Short Form (36), or SF-36, Health Survey, which was derived from the Medical Outcomes Study. The SF-36 is the PRO measure that is most frequently used to evaluate the results of dietary studies. With this generic instrument, the patient's views of their current health status are assessed in eight domains: physical functioning, social functioning, role limitations due to physical health issues, role limitations due to emotional health issues, pain, mental health, vitality, and overall health perceptions.

It is reasonable to assume that certain of these domain scores—like vitality—will be more susceptible to dietary modifications. Given its extensive scope across both psychological and physical domains, the SF-36 is frequently utilized as a gauge for health-related quality of life. The results of several nutrition interventions, such as dietary counseling and oral nutritional supplements, have been evaluated using the SF-36. These studies have involved a wide range of patient subpopulations, including healthy individuals and those with depression, cancer, and chronic renal disease¹⁸.

Condition-Specific PRO Measures Used in Nutrition Studies:

The results of dietary studies have also been evaluated using a range of condition-specific PRO measures. For instance, in studies conducted within these populations, the effects of oral nutritional supplements have been evaluated using instruments specific to depression (such as the Beck Depression Inventory) and cancer (such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy-General).However, rather than focusing on particular nutrition-related outcomes, the PRO instrument was created in each of these investigations to evaluate outcomes associated with the patient's medical condition¹⁸.

CHALLENGES OF NUTRACEUTICAL TRIAL DESIGNS:

For researchers, creating nutraceutical studies presents several special difficulties. For a variety of reasons, many businesses in this industry are not familiar with clinical trial designs.

Existing Generic Claims: There are already generic claims about vitamin and mineral content, which could reduce the need for more study.

Budget Constraints: Comprehensive research is difficult to conduct since food and ingredient firms frequently have limited funding for testing.

Generalized Health Benefits: Pharmaceutical medications tend to provide more concentrated and specific health advantages than nutraceuticals. Nutraceuticals are frequently advertised for general well-being, in contrast to medications, which are tested specifically for certain medical disorders. As such, their effects on health might be less strong and have not been thoroughly examined in as much rigorous clinical research.

Sample Size Requirements: Compared to traditional medication studies, nutraceutical trials require larger sample sizes. Nutraceutical clinical trials face significant challenges due to the increasing requirement for participants, which may result in greater expenditures, longer recruiting periods, and potential challenges in obtaining a representative and varied research population.

Defining Endpoints: Nutraceuticals frequently have complicated interactions and broader health claims than pharmaceutical trials, which typically have well-defined illness targets and methods of action. It can be difficult to choose endpoints that accurately represent the anticipated benefits of the product and to make precise, fact-based statements. Pilot studies are more expensive to conduct to obtain insights.

Subject Recruitment and Retention: It is difficult to get volunteers for nutraceutical trials since they need to have a healthy lifestyle and submit plenty of data. In contrast to drug trials, dropout rates are usually greater ^11,1.

STRATEGIES FOR EFFECTIVE NUTRACEUTICAL TRIAL DESIGN:

Nutraceutical trial designs can be successfully handled using structured procedures, even with their complicated challenges.

Surrogate Markers: Within a reasonable timescale, the preventative characteristics of a substance can be established with the aid of surrogate markers. Consumers should recognize and trust surrogate markers. For instance, a different strategy might be to state that a product “decreases levels of bad cholesterol linked to an elevated risk of strokes and heart attacks” in place of directly stating that it “lowers the risk of strokes or heart attacks."

Blinded Trials: Double-blinded trials with placebos are the gold standard, minimizing bias and maintaining the integrity of the study. When creating appropriate placebos is difficult, open-label trials might be taken into consideration.

Controlled Trials: Control groups enable comparisons between nutraceuticals and placebos in clinical trials, which improves comprehension of the changes in participants that are seen.

Inclusion Criteria: Nutraceutical trials must recognize lifestyle factors and apply stringent inclusion and exclusion criteria for participants. This guarantees that the chosen subjects will exhibit and demonstrate the effects of the nutraceuticals.

Generable Data: Trial data ought to be balanced between homogeneity and variety, and ought to be indicative of a larger population. Trials conducted at several locations capture a range of environmental conditions and demographics, improving the consistency and dependability of the results^19,1.

NUTRIVIGILANCE AND ITS IMPORTANCE:

The research and practices involved in identifying, evaluating, comprehending, and averting unfavorable consequences associated with the consumption of food, dietary supplements, or medicinal foods are known as nutrivigilance. Any comprehensive public health strategy must include nutrivigilance as a key component to ensure safety and efficacy. However, in the absence of regulations about purportedly nutritional products, consumers are compelled to depend on the assessment and presentation of the product by the sponsoring company or on outside organizations serving as watchdogs to make informed decisions about which products are safe and, perhaps more importantly, even useful²⁰.

NUTRIVIGILANCE IN THE INDIAN SCENARIO:

In India, nutrivigilance is a relatively new concept compared to pharmacovigilance, which is the reporting of adverse drug-related incidents. There are currently neither recommendations for dietary surveillance in India nor specific post-market surveillance programs for dietary supplements. Establishing protocols and tools for signal detection is essential. A proper causality evaluation framework or algorithm that takes into account the intrinsic complexity of the product classes and subcategories is necessary for dietary supplements. Because of the recent spike in dietary supplement sales, there is currently a need to enhance the domestic adverse event reporting procedure. Public disclosure of analysis of reported adverse events and responses to such reports is appropriate²¹.

The FSSAI must take the lead in nutrivigilance. The approval of health supplements and nutraceuticals requires stricter standards. Healthcare practitioners who proactively identify the usage of such drugs and any adverse outcomes can have a significant impact on nutrivigilance. It is imperative that primary care providers get education regarding the appropriate use of nutraceuticals and any potential risks related to the products. Certain populations must utilize these goods with caution; athletes and sportspeople, for instance, must be mindful of the contents of any health supplements or sports drinks they consume to prevent unintentional doping. FSSAI should be the one to start using digital technologies to inform the public about the potential consequences of using nutraceuticals irrationally. It is now appropriate to list complex nutraceutical product indications in the same manner as pharmaceutical product indications. Limiting unsupported and fraudulent statements and their widespread promotion is also crucial. Nutraceutical promotional materials must be tightly regulated³.

Nutrivigilance's relevance to Indian practices today:

Food products can cause a number of unfavorable outcomes, which are ascertained by:

· Dietary supplements' inevitable side effects are caused by their active constituents.

· How medications and dietary supplements interact.

· Adverse effects are linked to adulteration in an attempt to increase activity using drugs that are pharmacologically active, like steroids and neurostimulators.

Examples include vitamin D3 and calcium phosphate, which can cause bloating, constipation, metallic taste, thirst, fatigue, weakness, appetite loss, and muscle discomfort. Tetracycline can also cause decreased absorption of antibiotics when used with quinolones. When coupled with warfarin, green tea extract (Camellia sinensis) is linked to liver damage and is used to lose weight. Aloe vera, a popular remedy in India, has been linked to negative side effects including edema, nephropathies, arrhythmias, and gastrointestinal problems. It can also cause hypoglycemia when used with anti-diabetics²¹.

CONCLUSION:

Nutraceutical clinical trials in India represent a dynamic yet challenging endeavor, shaped by regulatory frameworks, evidence gaps, and inherent complexities. Despite the growing demand for nutraceutical products, the regulatory landscape remains intricate, requiring adherence to stringent safety and efficacy standards set forth by authorities such as FSSAI and CDSCO.

The Indian industry and regulatory environment are still relatively new, but they have a lot of potential to grow and be able to compete with other international organizations. In contrast, the United States, the United Kingdom, and Europe have simplified their regulations to make them more favorable for the development of nutraceutical products. With the growing usage of nutraceuticals and the rise in product recalls, issues related to safety, quality, and efficacy have emerged and demand more stringent regulation. While phytovigilance and nutrivigilance are relatively new concepts in our country, regulatory agencies need to keep a close eye on the issues and unfavorable effects connected to subpar and counterfeit nutraceutical products. Good clinical trials evaluating the efficacy and safety of nutraceuticals across a range of therapeutic areas will support evidence-based medicine, policy development, and claim validation.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Dr. P. Shailaja, G. Snehalatha for their kind support during writing this article.

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Received on 18.06.2024 Modified on 02.07.2024

Research J. Science and Tech. 2024; 16(3):245-254.

DOI: 10.52711/2349-2988.2024.00035