A Scoping Review of Published Literature on the Contributions of the Natural Health Products (NHPs) Industry to Pharmacovigilance for NHPs

Abstract

Background

The natural health products (NHPs) industry is a key stakeholder in pharmacovigilance for NHPs. However, the specific contributions that the NHPs industry makes to pharmacovigilance for NHPs are not well-understood.

Objective

This scoping review aimed to identify and map published literature describing the contributions of the NHPs industry to pharmacovigilance activities for NHPs. Assessment of benefit–harm balance for individual NHPs/natural ingredients is outside the scope of this review.

Methods

Using predetermined keywords and Medical Subject Headings, seven international electronic biomedical journal databases were searched to identify articles describing the contributions of the NHPs industry to pharmacovigilance for NHPs in relation to product surveillance and stakeholders’ views on the NHPs industry and its pharmacovigilance activities.

Results

Of the 2285 records identified, 40 articles (representing 40 studies) met the inclusion criteria for this review. Among these, 33 described post-marketing surveillance activities and seven explored stakeholders’ views. Of the articles describing post-marketing surveillance studies, 22 were authored and/or sponsored by the industry; the remaining 11 involved contributions from the NHPs industry in the form of safety data submitted as spontaneous reports to a national or state pharmacovigilance database. Contributions of the NHPs industry were primarily through passive surveillance via spontaneous reporting. In total, 13 active surveillance studies were undertaken by the NHPs industry, mainly in clinical care settings such as medical centres, hospitals, and private practices, and were focused on single products. There were limited findings relating to stakeholders’ views on pharmacovigilance and the NHPs industry’s involvement.

Conclusions

The NHPs industry contributes to pharmacovigilance for NHPs primarily through passive surveillance measures. Active surveillance involving the NHPs industry was typically undertaken in non-community settings. Additional research exploring stakeholders’ views on and preparedness for participating in active surveillance involving the industry, focusing particularly on models based on the consumer–industry reporting pathway, could identify new strategies for strengthening post-marketing safety monitoring for NHPs.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40264-025-01587-w.

Plain Language Summary

Natural health products (NHPs) are products made from natural ingredients such as plants, vitamins, minerals, or non-human animal products, and used for human health and wellbeing. Internationally, NHPs are known by many names, such as traditional medicines, herbal medicines, dietary supplements, health supplements, alternative medicines, complementary medicines, and so forth. While NHPs are regulated in several jurisdictions as ‘low-risk’ products, they can cause side effects (harms). The activity of continuously monitoring the safety of medicinal products, including NHPs, in humans is known as pharmacovigilance. Effective pharmacovigilance for NHPs involves many stakeholders, including NHPs users, health professionals, medicines regulators, NHPs practitioners, and the NHPs industry. This review identified and summarised the worldwide published literature on the contribution of the NHPs industry to pharmacovigilance for NHPs. The review found that the NHPs industry contributed to pharmacovigilance mainly via passive surveillance, i.e. collecting reports of side effects associated with NHPs from consumers and others, likely driven by regulatory requirements. In addition, some industry parties carried out active surveillance activities via observational studies or post-marketing safety trials; these were usually done in clinical care settings, such as medical centres, hospitals and private practices. However, these studies are unlikely to engage community-based NHPs consumers. There is limited information on stakeholders’ views on the contributions of the NHPs industry towards pharmacovigilance for NHPs. Future research exploring the feasibility of studies collecting information on side effects directly from consumers could identify potential strategies for strengthening safety monitoring for NHPs.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40264-025-01587-w.

Key Points

The natural health products (NHPs) industry contributes to pharmacovigilance primarily through passive surveillance; there was limited published literature on how the NHPs industry contributes to safety signal detection, assessment and management.

Active surveillance, when undertaken by the NHPs industry, is undertaken for specific products, and mostly in specific clinical care settings such as medical centres, hospitals and private practices.

There is currently limited information on stakeholders’ views on the roles and contributions of the NHPs industry in undertaking pharmacovigilance, which warrants further investigation.

Background

The term natural health products (NHPs) generally refers to products used to improve or maintain health and wellbeing and that contain natural ingredients, such as herbal substances, dietary supplements (including vitamins and minerals) and animal-based products. NHPs are also commonly known as complementary/alternative medicines/remedies, dietary supplements, nutraceuticals and/or traditional medicines [1]. There is no standard definition for NHPs globally. NHPs may be regulated as different subcategories, such as herbal medicines, homoeopathic medicines, traditional medicines, nutraceuticals, functional foods, dietary supplements, food supplements, etc., across various jurisdictions [2, 3]. For this review, the term ‘NHPs’ is used when referring to this group of products with ingredients of natural origins.

The prevalence of use of NHPs is high internationally. A recent systematic review reported the 12-month prevalence of traditional and complementary medicine use (including NHPs and therapies such as acupuncture/massage) to be 24–71.3% across 14 countries [1]. Specifically for NHPs, a cross-sectional study among over 2000 Australian adults, undertaken in 2017, reported that almost half of the respondents had used complementary medicine products (the collective term for NHPs in Australia) in the past 12 months [4]. More recently, a cross-sectional survey of adults in New Zealand estimated the current, the last 12 months and the lifetime prevalence of use of NHPs to be 38.4%, 57.6% and 69.6%, respectively [5]. In the USA, the National Health and Nutrition Examination Survey found that 58.5% of adults used at least one dietary supplement within the past 30 days during the survey period from 2017 to March 2020 [6]. The trend in increasing use of NHPs worldwide is also reflected in the estimates and forecasted growth of the global herbal market, which includes health-related herbal products, dietary supplements, cosmetics and food, valued at approximately 152 billion USD in 2021 and projected to reach 347.5 billion USD in 2029. Of these, herbal products in pharmaceutical and nutraceutical forms, which reflect finished herbal products likely intended to be used for health-related purposes, make up more than two-thirds of the global herbal market [7]. In the USA, sales of dietary supplements in 2023 were estimated to be US$12.551 billion, representing a 4.4% growth from 2022 [8].

Some consumers associate ‘natural’ with ‘safe’ [9] and perceive NHPs as being safer than conventional medicines [10, 11]. Studies involving consumers in the USA found that food and multivitamin products labelled with ‘natural’ images or wordings evoked positive feelings and associations with safety, which can affect purchase decisions [9]. While NHPs are regulated in several jurisdictions as ‘low-risk’ products, they can cause harm. Harms from NHPs can be due to intrinsic toxicities resulting from specific bioactive constituents and their pharmacological activities, and/or extrinsic toxicities related to adulteration or other ingredient or product quality issues (e.g. microbial contamination, heavy metal contamination, and the use of ‘incorrect’ plant species or plant parts) [12]. Many NHPs are generally considered to have low intrinsic toxicity when taken within recommended doses for limited periods. However, if excessive doses are used, and/or for prolonged time periods, or, in some cases, if used by vulnerable populations (e.g. children, older patients, pregnant women and patients with liver or kidney impairment), low-risk products can cause harm [13–16]. For example, prolonged use of vitamin B6 can lead to peripheral neuropathy [14]. Other NHPs, such as Hypericum perforatum (St. John’s wort), can interact with certain conventional medicines, leading to reduced therapeutic efficacy of those conventional medicines [17]. Certain NHPs, such as those containing plant extracts with aristolochic acid constituents, are associated with serious harms, including nephropathy and cancer. Consequently, products containing aristolochic acids are prohibited from sale in several jurisdictions [14, 18, 19]. A more recent high-profile example of harm associated with NHPs concerns over 300 cases of serious renal injuries—resulting in hospitalisations and, in some instances, deaths—associated with exposure to a specific brand of red yeast rice product in Japan [20, 21]. In addition to ingredient- and product-specific toxicity concerns, NHPs marketed for certain indications, especially weight loss and sexual health, are frequently found to be adulterated with prescription medicines and/or synthetic substances not approved for human use [22, 23]. Given these known risks associated with NHPs use, safety monitoring, i.e. pharmacovigilance activities for these products, is essential.

At present, the identification of safety concerns associated with NHPs relies on passive pharmacovigilance systems, namely the collection and analysis of spontaneous adverse drug reaction (ADR) reports. ADR reports can be submitted by healthcare professionals and, in some countries, users of NHPs and NHP manufacturers/sponsors/market authorisation holders (MAHs), to health authorities or national/regional pharmacovigilance centres [24]. Being a potential point of contact, manufacturers/sponsors/MAHs of NHPs may receive reports of ADRs from consumers, healthcare professionals or others (e.g. retailers). Whether these industry stakeholders then subsequently submit spontaneous reports to health authorities/medicines regulators or national/regional pharmacovigilance centres, or engage in other pharmacovigilance activities, is likely to be driven mainly by the regulatory status of NHPs and whether there are mandated pharmacovigilance requirements [25]. For example, in the USA, manufacturers of dietary supplements (the collective term for NHPs in the USA) are currently required to submit reports of serious adverse events (AE) within 15 days of becoming aware of such reports [26]. In the European Union (EU), MAHs of herbal medicinal products are required to comply with the same pharmacovigilance requirements as for pharmaceutical (conventional medicine) products, including maintaining a pharmacovigilance system, submitting reports of ADRs, monitoring for safety issues, and appointing a qualified person for pharmacovigilance (QPPV), with the exception of submitting periodic safety update reports (PSURs) unless requested to do so by the competent authority [27]. In some countries (e.g. New Zealand), there are limited specific regulatory requirements for NHPs and manufacturers are not obligated to undertake pharmacovigilance activities for unapproved 'dietary supplement' products [28]. In such instances, it remains unclear whether manufacturers of these unregulated products voluntarily engage in pharmacovigilance activities, such as submitting spontaneous reports or undertaking other related activities. To effectively monitor and address potential adverse effects associated with their products, it is essential for the NHPs industry, i.e. manufacturers/sponsors/MAHs, to be informed of such events by users and/or their healthcare professionals.

The NHPs industry is clearly a key stakeholder in considering pharmacovigilance for NHPs, but the industry’s current roles and contributions are not well understood. This scoping review was conducted to collate and map the worldwide literature on the contributions of the NHPs industry concerning pharmacovigilance for NHPs, specifically:

• Involvement with passive and/or active safety surveillance activities and risk communication;

• Key stakeholder views on the contributions of the NHPs industry to pharmacovigilance.

Methodology

A scoping review design was considered most suitable for this literature review due to its systematic approach to searching, screening and selecting articles, and to data acquisition while allowing the flexibility to cover a broad topic [29].

Methods

This scoping review followed the framework as recommended by Arksey and O’Malley [30], advanced by Levac et al. [31], and the Joanna Briggs Institute (JBI) manual for evidence synthesis [32]. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) checklist [33] was used to guide the reporting of this work and is appended in Supplementary Table S1.

Search Strategy

A comprehensive, structured search strategy was developed to identify published articles relevant to the research questions from seven biomedical electronic databases: MEDLINE, EMBASE, CINAHL, AMED, International Pharmaceutical Abstracts (IPA), PsycINFO, and Scopus. Databases were searched from their inception to 24 February 2025 (when updated searches were last undertaken). The full MEDLINE search strategy using a combination of predetermined keywords and Medical Subject Headings (MeSH) terms, where applicable, is appended in Supplementary Table S2. This search strategy was adapted for use with each different database.

Study Selection

Published articles identified through the literature search were imported into a bibliographic manager, EndNote X8.0 (Clarivate Analytics, PA, USA), and then into Rayyan (a web application for conducting systematic and scoping reviews) [34] for deduplication. Title and abstract screening, followed by full-text screening, was then undertaken against the inclusion criteria of population, concept and context domains, and types of sources (see next subsections). Only English-language articles were included.

For title and abstract screening, a pilot screening process that achieved high agreement rates (at least 80% based on Fleiss’ kappa [35]) was undertaken by two independent reviewers (X.Y.L. and A.M.) against the inclusion criteria (see below) for 30 randomly selected articles identified through the literature search. A single investigator (X.Y.L.) performed the remaining screening process. Similarly, two independent reviewers (X.Y.L. and A.M.) performed full-text screening on 30 articles to achieve high consensus rates (at least 80%), and the rest was undertaken by a single investigator (X.Y.L.). A third and senior investigator (J.B.) addressed disparities. Reasons for the exclusion of any articles during full-text screening were recorded. Reference lists of included articles (from full-text screening) were additionally screened against the inclusion criteria (see next subsections).

Population

This review focused on NHPs and the NHPs industry. The following operational definitions of NHPs and NHPs industry (see Table 1) were used throughout this review.

Table 1.

Operational definitions of population

Term	Operational definition
NHPs	• Focus: For this review, ‘natural health products’ (NHPs) referred to, but was not limited to, herbal medicines, traditional medicines (e.g. traditional Chinese medicines, Ayurvedic medicines, traditional Māori medicines), plants or plant-based medicinal-type preparations, vitamins, minerals, pre- and probiotics, amino acids, non-human animal products, medicinal fungi preparations, medicinal algae preparations and dietary supplements taken via any routes of administration (e.g. oral, topical). A list of examples of types of NHPs is presented in Supplementary Table S3 • Form: Any form ranging from crude extracts (e.g. fresh or dried leaves, stalks, roots) to finished products in pharmaceutical forms (e.g. capsules, oils, tablets), which are processed or manufactured on an industry-scale basis by NHPs manufacturers or companies • Exclusions: Raw natural materials, extemporaneous preparations and individualised remedies/preparations by traditional, complementary and alternative medicine practitioners for their patients on an individual basis that did not involve industrial-scale processing and manufacturing
NHPs industry	• Focus:   ○ Individual companies that process, manufacture, market, and/or distribute NHPs, including license/patent holders, manufacturers, MAHs, sponsors, companies and distributors   ○ Umbrella organisations representing the NHPs industry, e.g. Natural Health Products New Zealand (NHPNZ), European Scientific Cooperative on Phytotherapy (ESCOP), British Herbal Medicine Association (BHMA), Complementary Medicines Australia (CMA), etc.   ○ Pharmaceutical industries of conventional medicines to the extent where there is a clear linkage of, or impact from, safety issues resulting from herb–drug interactions

Concept

This review explored two pre-planned concepts related to the NHPs industry’s contributions towards pharmacovigilance for NHPs, as defined in Table 2.

Table 2.

Definitions and scopes of concepts

Concepts	Definition and scope
Contributions	Pharmacovigilance activities undertaken by the NHPs industry, including e.g. passive and active surveillance, risk communication [N.B. This review does not seek to assess the benefit–harm balance of specific NHPs or NHP ingredients, nor identify preclinical toxicology studies or clinical trials reporting safety information]
Views	Information on experience on, awareness with, and other views (e.g. challenges, enablers) by main stakeholders of the NHPs pharmacovigilance system, including the NHPs industry, retailers, healthcare professionals, regulators, traditional, complementary, and alternative practitioners, and consumers pertaining to the roles and contributions of the NHPs industry on pharmacovigilance for NHPs

Context

This review focused on the worldwide literature on the contributions of the NHPs industry on pharmacovigilance for NHPs.

Types of Sources

Table 3 presents the inclusion and exclusion criteria for evidence sources.

Table 3.

Inclusion and exclusion criteria for evidence sources

Include

Exclude

Original research articles describing NHPs industry involvement with any of the following study designs and where the research purpose was primarily for exploring pharmacovigilance/safety outcomes relating to NHPs: ● Observational, non-interventional clinical studies, both retrospective and prospective, such as cohort, case-control, cross-sectional surveys and other observational studies ● Analysis of spontaneous reports of ADRs/AEs and serious ADRs/AEs from:     ◯ National, international, industry-based pharmacovigilance databases     ◯ Product complaint databases of the NHPs industry     ◯ Poison control centre databases ● Phase IV industry-sponsored studies (interventional and non-interventional) that document the safety of NHPs as the primary objective ● Original qualitative research articles ● Post-marketing quality analysis of NHPs that specifically addresses pharmacovigilance for NHPs and roles/responsibilities of the NHPs industry

Non-phase IV interventional studies (i.e. clinical trials) conducted by the industry which assessed efficacy as the primary objective Individual case studies/series Opinion, expert commentary, short communication and letter articles Review articles Book chapters Conference abstracts/proceedings/posters Preclinical studies

Data Extraction and Charting

Data extraction was performed by a single investigator (X.Y.L.) using a specifically designed data extraction table in Microsoft Excel^™. This data extraction table was tested on three purposively selected articles of different study designs to optimise the data extraction tool before the commencement of full data extraction. No clarification was sought from the authors of the included articles.

In the first data extraction table for published literature, general data item categories included:

• Article characteristics (authors, year, title, study design, study objective, theme of study, study duration/data collection period).

• Population (author’s affiliation, author’s relationship with industry, NHPs of interest, study population, study country/region).

• Key findings relating to: (i) contributions of industry (e.g. surveillance activities undertaken); and (ii) stakeholders’ views on the contributions of industry (e.g. challenges, enablers etc.).

Data Analysis and Presentation

This review presents an overview of the worldwide literature on the contributions of the NHPs industry on pharmacovigilance for NHPs, including contributions towards pharmacovigilance activities and qualitative views by stakeholders regarding this topic. Key findings were summarised and described in two major categories: ‘industry contributions’ and ‘stakeholders’ views’.

Results

From published literature, 2285 records were identified from the keyword search. After screening against the a priori inclusion and exclusion criteria, 40 articles describing a total of 40 studies were included in this review. Of these, 33 described the NHPs industry’s contributions through surveillance activities and seven explored stakeholders’ views. The article screening process and study inclusion are presented in Fig. 1.

Fig. 1.

PRISMA flow diagram. NHP, natural health product; PV, pharmacovigilance

NHPs Industry Contributions to Pharmacovigilance for NHPs

Characteristics of Included Studies

A total of 33 studies containing information relating to the contributions of the NHPs industry to pharmacovigilance for NHPs was included. Characteristics of the included studies are presented in Supplementary Table S4. Over two-thirds (n = 22) [36–57] involved authorship and/or sponsorship from the industry, while the remainder (n = 11) [12, 25, 58–66] involved contributions from the NHPs industry in the form of spontaneous reports of suspected ADRs associated with NHPs submitted to a pharmacovigilance database.

Of the 22 industry-authored/co-authored/sponsored studies, 19 [36–43, 45–48, 50–52, 54–57] described safety surveillance activities. Of these, 18 [36–43, 45, 46, 48, 50–52, 54–57] involved NHP manufacturers undertaking post-marketing surveillance for their own products, mainly through prospective observational cohort studies and/or retrospective analyses of spontaneous reports obtained from the manufacturer’s own pharmacovigilance database. All the prospective studies (i.e. active surveillance) [37–41, 45, 46, 47, 48, 51, 52, 56, 57] were performed in clinical care settings, such as medical centres, hospitals and private practices. In- and outpatients were recruited into active surveillance studies based on exposure to a specific product, with or without a specific indication, and usually monitored or reviewed by doctors. The remaining three studies with NHP-industry authors reported on: (1) an NHPs’ label compliance study towards regulatory requirements [44], (2) selected findings from an industry-developed pharmacoepidemiology study on users of herbal medicinal products via retrospective surveys [49], and (3) a survey among anthroposophic medicine practitioners, which estimated the occurrences of adverse effects associated with anthroposophic medicinal products [53].

Industry-initiated safety surveillance studies mostly involved a single product (n = 13) [37, 39–41, 45–48, 50–52, 56, 57], while other studies focused on small product ranges involving different formulations/extracts of the same plant/mixture of plants (n = 3) [36, 38, 42], a full range of marketed anthroposophic medicinal products (n = 2) [54, 55] and dietary supplements in general (n = 1) [43]. The duration of data collection was typically 1–2 years, except for three studies that analysed spontaneous reports collected over 10–20 years [36, 54, 55].

All eleven studies that did not involve members of the NHPs industry as authors/sponsors (but involved data/reports originating from the NHPs industry) presented findings from analyses of spontaneous reports [12, 25, 58–66] involving NHPs in general, or specific categories of NHPs, such as traditional Chinese medicines (TCMs), herbal medicinal products and food supplements. These analyses were conducted mainly by non-industry researchers and personnel from pharmacovigilance centres and regulators [12, 25, 58–66].

Contributions of the NHPs Industry to Pharmacovigilance for NHPs

The industry contributed to pharmacovigilance for NHPs by collecting and providing safety-related information (safety data) via passive and active surveillance, and other pharmacovigilance-related studies (e.g. surveys), funding studies, and sponsoring investigational products (Table 4). Tables 5, 6, 7 and 8 summarise the main pharmacovigilance findings from included studies that analysed state/province/national pharmacovigilance databases containing spontaneous reports submitted by industry (n = 11), industry-owned databases (n = 7), industry-initiated/sponsored active surveillance studies (n = 13), and other pharmacovigilance activities (n = 3).

Table 4.

Contributing role of the NHPs industry towards pharmacovigilance for NHPs (n = 33)

Author, year [Ref]	Surveillance type			Contributing role
	Passive surveillance	Active surveillance	Others	Authorship	Product manufacturer/distributor/MAH/sponsor	Research funding	Safety data
Choi, 2024 [66]	•						•
Malek, 2024 [50]	•			•	•
Li, 2022 [64]	•						•
Silva 2022 [44]			•	•
van Hunsel, 2022 [65]	•						•
Banach, 2021 [58]	•					•	•
Cui, 2021 [51]		•				•
Ippoliti, 2021 [61]	•						•
He, 2020 [39]		•		•	•		•
Jong, 2020 [54]	•					•	•
Nieber, 2020 [49]			•	•		•	•
Schmitz, 2020a [43]	•			•			•
Schmitz, 2020b [42]	•			•			•
Li, 2019 [63]	•						•
Suzuki, 2019 [46]		•		•	•
Li, 2018 [41]		•		•	•
Timbo, 2018 [25]	•						•
Xu, 2018 [12]	•						•
Chang, 2016 [36]	•			•	•		•
Guo, 2015 [60]	•						•
Klontz, 2015 [62]	•						•
Yang, 2014 [47]	•			•	•		•
Jong, 2012 [55]	•					•	•
Stauss-Grabo, 2011 [45]		•		•	•
Frankos, 2010 [59]	•						•
Ebrahimi, 2009 [52]		•			•
Fazio, 2009 [38]		•		•	•
Kamin, 2007 [40]	•	•		•	•
Baars, 2005 [53]			•			•	•
Horoszkiewicz-Hassan, 2005 [48]		•		•	•
Hübner, 2001 [57]		•		•	•
Ernst, 1995 [37]		•		•	•
Woelk, 1994 [56]		•		•	•
Total, n (%)	19 (57.6)	12 (36.4)	3 (9.1)	17 (51.2)	14 (42.4)	6 (18.2)	20 (60.6)

MAH, market authorisation holder

Table 5.

Studies that analysed state/national pharmacovigilance databases (n = 11)

Author, year [Ref]	Country	NHP(s) under studya	Database name	No. of reports associated with NHPs	No. of reactions associated with NHPs	Proportion of industry-submitted reportsb	Serious ADR findingsb
Li, 2022 [64]	China	TCM	Pan-pearl Delta ADR Monitoring Platform, China	Unclearc	Not reported	Overall, 16% of ICSRs with death as an outcome were reported by manufacturers/distributorsd	This study focused entirely on serious ADRs (death as an outcome)
Guo, 2015 [60]	China	TCM	China FDA national ADR monitoring annual report	2009: 13.3% of 638,996 2010: 13.8% of 692,904 2011: 15.2% of 852,799 2012: 17.1% of 1,200,000 2013: 17.3% of > 1,317,000	Not reported	Percentage of reports submitted by pharmaceutical companies (for all TCMs): 2009, 12.3%; 2010, 12.7%; 2011, 13.7%; 2012, 24.4 %; 2013, 21.0%d	Percentage of serious ADRs (for TCM injections only): 2010, 6.2%; 2011, 6.0%; 2012, 5.3%; 2013; 5.6%
Li, 2019 [63]	China	TCM injections	Guangdong Provincial Centre for ADR Monitoring	50,243	93,666	Drug distributors (n = 95) and manufacturers (n = 72) contributed 0.33% of the reports	3026 serious reports (6.02%)
Yang, 2014 [47]	China	Xingxue® SXN injectione	State ADR Monitoring Centre SRS	Not reported	Not reported	Industry contribution to reports were not reported	3.93% of ADRs were serious
Timbo, 2018 [25]	USA	DS	CAERS	15,430	Not reported	10,327 (66.9%) mandatory reports, 4972 (32.2%) voluntary reports and 132 (0.9%) mandatory and voluntary reportsf	6304 serious outcomes (% unclear)
Frankos, 2010 [59]	USA	DS	CAERS	1080	Not reported	408 (37.8%) mandatory reports, 662 (61.3%) voluntary reports and 10 (0.9%) mandatory and voluntary reportsf	Not reported
Klontz, 2015 [62]	USA	OxyELITE ProTM e	MedWatchg	114	Not reported	Two (1.8%) reports were submitted by industry	58 hospitalisations (33 likely linked to OxyELITE Pro) and three deaths (none likely linked to OxyELITE Pro)
Choi, 2024 [66]	Republic of Korea	HMPs	KAERS	1054	1629	377 (35.8%) reports submitted by pharmaceutical companiesh	48 ICSRs (4.6%) included one or more serious AEs 99 AEs (6.1%) were identified as serious
van Hunsel, 2022 [65]	Netherlands	HMPs and HS	Pharmacovigilance Centre Lareb	789	1727	Uncleari	115 serious cases (14.6%)
Ippoliti, 2021 [61]	Italy	FS used as cognitive and physical performance enhancers	Italian Phytovigilance System	110	Not reported	Unclearj	37 serious reports (33.6%)
Xu, 2018 [12]	Singapore	CHPs	Singapore HSA Vigilance & Compliance Branch	893	1111	Manufacturers reported ten (1.1%) AE reports suspected to be related to CHPs	449 serious cases (50%)

ADR, adverse drug reaction; AE, adverse event; CAERS, Centre for Food Safety and Applied Nutrition Adverse Event Reporting System; CHP, complementary health products; DS, dietary supplements; FS, food supplements; HMP, herbal medicinal product; HS, health supplements; HSA, Health Sciences Authority; ICSRs, individual case safety reports; NHP, natural health products; SRS, spontaneous reporting system; SXN, Shuxuening; TCM, traditional Chinese medicine

^aRefer to Supplementary Table S4 for additional details

^bTerms and figures presented exactly as used in respective studies

^cA total of 1731 reports: among the 3861 drugs implicated in death ICSRs, there were 3357 conventional medicines and 504 TCMs. TCMs accounted for 13.05% of the total number of drugs implicated

^dFigures are collective of conventional medicine and TCM industry

^eIngredients: SXN: Yinxingye (Folium Ginkgo) extract; OxyELITE Pro^TM: aegeline, higenamine, caffeine and yohimbine, or, in some products, a trio of 1,3-dimethylethylamine (DMAA), caffeine and yohimbine

^fMandatory reports are submitted by dietary supplement firms, voluntary reports are typically submitted by consumers, healthcare professionals, governmental agencies and others

^gDatabase investigated not clearly reported. [N.B: MedWatch reports can be collected by FAERs or CAERs]

^hThis study presented findings on the proportion of reporters, including those from the industry, collectively named as pharmaceutical companies, without further clarifying if they were specifically NHP companies

ⁱStudy stated that some reports had been received indirectly via MAHs but did not explicitly report the quantity

^jStudy stated that some reports were filled in by the same companies that marketed the products based on the information received by consumer complaints but did not explicitly report the quantity

Table 6.

Studies that analysed industry-held pharmacovigilance databases (n = 7)

Author, year [Ref]	Country(ies)	NHP(s) under studya	Database name	No. of reports associated with NHPs	No. of reactions associated with NHPs	Main PV findings (e.g. ADR incidence, rate, frequency, serious ADRs)b
Jong, 2020 [54]	Germany	Anthroposophic medicinal products	Helixor Heilmittel GmbH (Rosenfeld, Germany), Iscador (Arlesheim, Switzerland), WALA Heilmittel GmbH (Bad Boll/Eckwälden, Germany) and Weleda AG (Arlesheim, Switzerland) PV databases	Not reported	5506	104 serious ADRs reported (1.9%) Relative frequency of ADRs: 1.5 per million MDAD sold Relative frequency of serious ADRs: 0.03 per million per million MDAD sold
Jong, 2012 [55]	Germany	Anthroposophic and homeopathic solutions for injection	Eight German manufacturer PV databasesc	486	1180	46 (9.5%) were classified as serious; 48% of serious cases were assessed as unlikely related to product The overall reporting rate of ADRs: < 4 per 1 million sold ampoules
Schmitz, 2020a [43]	USA and others (not specified)	Dietary supplements	Supplement Safety Solutions AE database (two manufacturers)	41,121	Not reported	203 (0.48%) serious AE reports with 532 reactions
Schmitz, 2020b [42]	USA	Full spectrum hemp extract PlusCBDTM products	CV Science’s product complaint database	1151	1429	Two serious AEs reported From a total of approximately 5 million product units sold, 1429 (0.03%) AEs were reported
Malek, 2024 [50]	Germany, Mexico, Italy	Pelargonium sidoides root extract (EPs 7630)	Dr. Willmar Schwabe GmbH and Co. KG, Karlsruhe, Germany (Schwabe) Global Pharmacovigilance Safety Database	44d	Not reported	14 patients (31.8%) reported AEse
Banach, 2021 [58]	16 countries (Italy, Spain, Ireland, Germany, Greece, Belgium, Luxemburg, Malta, Hungary, Poland, Russia, Belarus, Ukraine, Thailand, Singapore, and Taiwan)	Red yeast rice	Meda Pharma SpA, a Viatris Company, Monza, Italy Nutrivigilance system	542	855	Consumers who reported ≥ 1 AEs: 0.0237% of the 1-year exposed consumers Consumers with serious AEs (n = 26); prevalence: 0.0011% of exposed consumers Consumers with serious suspected ARs (n = 6); prevalence: 0.0003% of exposed consumers
Chang, 2016 [36]	Germany, North America (USA, Canada), South Africa	ERr 731f	Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co. KG (Göppingen, Germany), and Dr. Loges + Co. GmbH (Winsen [Luhe], Germany) PSUR, SRS, and product complaint databases	Germany: 124 North America and South Africa: 79	Germany: 215 North America and South Africa: Not reported	Germany: 5.9 AEs for every 6.7 million doses sold/year. One serious case report (serious toxic parenchymal damage to liver) North America and South Africa: 14.6 complaints for every 2.4 million doses sold/year. One serious case report (endometrial cancer)

ADR, adverse drug reaction; AE, adverse event; AMP, anthroposophic medicinal product; DS, dietary supplements; MDAD, maximum daily administration doses; NHP, natural health products; PSUR, periodic safety update report; PV, pharmacovigilance; SRS, spontaneous reporting system; TCM, traditional Chinese medicine

^aRefer to Supplementary Table S4 for additional details

^bTerms and figures presented exactly as used in respective studies

^cManufacturer name not specified

^dCase reports for off-label use in the context of the treatment or prophylaxis of a COVID-19 infection

^eNo information reported by authors for serious ADRs

^fIngredients: Err 731: extract of Rheum rhaponticum

Table 7.

Active surveillance studies undertaken by the industry (n = 13)

Author, year [Ref]	Country/ region	NHP(s) under studya	Study sample; sample sizea	Data collection period; duration	Setting	Main PV findings (e.g. ADR incidence, rate, frequency, serious ADRs) as reported in the publication
Stauss-Grabo, 2011 [45]	Germany	Prospan® Cough film-coated tabletsb	Adults with URTI; n = 330	2008; duration not reported	‘Under practice conditions’; nature of practice not specified	‘During the treatment period no serious or unexpected ADR was reported’
Kamin, 2007c [40]	Germany	Pinimenthol ointmentb	Adult URTI patients; n = 3060: prospective = 1986 patients, retrospective = 1074	Not reported	Private practices	AE reported in 1.3% (total of 39 patients with 43 AEs) with 1 case of severe AE (acute intermittent porphyria, considered as not treatment related) ‘26 AEs were assumed to be ADRs’
Hübner, 2001 [57]	Germany	Hypericum perforatum extract	Children with depression; n = 101 started the study, n = 75 completed the study	March to November 1998; 9 months	Outpatient centres	No AE reported
Ernst, 1995 [37]	Germany	Sinupret® tabletb	Patients with uncomplicated, acute bronchitis; n = 3187	Not reported	Private practices	ADRs are more frequent when a second medication (e.g. antibiotics) has been prescribed concomitantly versus monotherapy (0.8% versus 3.4%)d
Woelk, 1994 [56]	Germany	H. perforatum extract	Patients with depression; n = 3250	Period not reported; 1.5 years	General physician practices	Total number of undesired drug effects reported in 79 (2.43%) patients
Cui, 2021 [51]	China	Qishe Pillb	Adults with cervical radiculopathy; n = 2023	May 2012 to April 2015; 3 years	Hospitals	AEs: 174 reported in 156/2023 patients (7.70% incidence rate) ADRs: 87 (4.1%) reported in 82/2023 patients Serious AEs: two in two patients; considered unrelated to Qishe Pill (pneumonia and asthma)
He, 2020 [39]	China	XST injectionb	Patients who received XST; n = 30,008	May 2005 to November 2017; 2.5 years	Hospitals	ADEs associated with XST injection were reported in 0.5% (n = 150) of patients, and ADRs were reported in 0.33% (n = 98) No severe ADR reported
Li, 2018 [41]	China	XST injectionb	In-patients who received XST; n = 30,884	January 2015 to December 2016; 2 years	Hospitals	Incidence of ADRs: 4.14% Severity of ADRs: severe (4.69%), moderate (86.72%) and mild (8.59%)
Yang, 2014 [47]	China	Xingxue® SXN injectionb	Patient case notes from 20 HIS; n = 48,445	Not reported	Hospitals	No significant effect on renal and hepatic function; further analysis needed to validate findings on allergic reactions Overall, manufacturer has put in place a series of Risk Minimisation Action Plans for Xingxue® SXN, ‘established a study panel for safety re-evaluation of TCM injection and a medicine safety panel responsible for the identification, evaluation, and management of drug risks’
Suzuki, 2019 [46]	Japan	NYTb	Elderly patients with clinical indications for NYT; n = 808	February 2016 to March 2017; 1 year	Hospitals or clinics	‘31 incidents of ADRs occurred in 25 patients’; (incidence 3.1%) ‘In terms of severity, there was one case of cholecystitis leading to hospitalization (with an unknown causal relationship with NYT) and one case of non-mild constipation (with a causal relationship with NYT); the remaining 29 cases were classified as mild’
Fazio, 2009 [38]	Latin America	Hedera helix extract	Patients with bronchitis; n = 9657, children = 5181	January 2003 to November 2004; 23 months	Physician practices	AEs: Reported in 2.1% of the patients, while 112 of these events (1.2%) involved children. ‘All AEs were of mild and transient nature’
Ebrahimi, 2009 [52]	Iran	ANGIPARSTM capsule and gelb	Adult patients with diabetic foot ulcers; n = 75	Study period not reported; 6 months	Hospital clinic	‘No clinically significant “side effects” were observed’ ‘45 days after drug administration, no significant laboratory changes were observed with exception of falling of ESR. Six months after follow up, a statistically significant increase in serum creatinine, serum calcium and PT was observed. Red blood cell count, total billirubin, amylase and ESR levels also decreased significantly. Other clinically meaningful alterations in the other haematology and chemistry parameters were not observed’
Horoszkiewicz-Hassan, 2005 [48]	Poland	Bioaron C® syrupb	Children with URTI; n = 313	Study period not reported; 14 weeks	Paediatric centres	‘No AEs or serious AEs were reported throughout the study’

ADE, adverse drug event; ADR, adverse drug reaction; AE, adverse event; HIS, hospital information system; NYT, Ninjin’yoeito; SXN, Shuxuening; URTI, upper respiratory tract infection

^aRefer to Supplementary Table S4 for additional details

^bIngredients: Prospan®: Hedera helix extract; Pinimenthol: eucalyptus oil, pine-needle oil, menthol; Sinupret®: Gentianae radix, Primulae flos (c. Calicybus) (cowslip flowers with calyx), Rumicis herba (sour dock herbs), Sambuci flos (elder flowers), Verbenae herba (shop vervain wort herbs); Qishe Pill: Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, Calculus Bovis Artifactus; XST: extract of Panax notoginseng; SXN: Yinxingye (Folium Ginkgo) extract; NYT: dried extract of Rehmannia root, Japanese Angelica root, Atractylodes rhizome, poria sclerotium, ginseng, cinnamon bark, Peony root, Citrus Unshiu peel, Polygala root, Astragalus root, Schisandra fruit, Glycyrrhiza; ANGIPARS^TM: extract of Melilotus officinalis; Bioaron C^®: aqueous extract of Aloe arborescens leaves, juice of Aronia melanocarpa fruit, ascorbic acid

^cThis study collectively analysed retrospective tolerability data and prospective observational data at 108 centres (general practitioners and medical specialists in private practice) in Germany

^dDescribed as both prevalence and incidence

Table 8.

Other post-marketing surveillance studies undertaken by the NHPs industry (n = 3)

Author, year [Ref]	Country(ies)	NHP(s) under study	Study designa	Main study findings
Silva, 2022 [44]	USA	Bovine liver supplements	Labelling compliance and assessment	Lack of a domestic mailing address or phone number was observed in 19 samples of 49 (38.7%)
Nieber, 2020 [49]	Germany	Herbal medicinal products	Survey	93.7% of 2063 paediatric survey participants who have used herbal medicinal products in the past 8 weeks experienced no AEs 0.8% reported a marked impairment due to side effects
Baars, 2005 [53]	European countries: Austria, Belgium, Finland, France, Germany, Ireland, Italy, the Netherlands, Spain, Sweden, Switzerland, and the UK	Homeopathic injectables	Survey	Practitioners estimated that 91 subcutaneous preparations caused a total of 212 adverse effects On average, 4.5 patients per practice throughout the whole career are estimated to have adverse effects caused by the preparation used (average 1.4 patients per year)

AE, adverse event

^aRefer to Supplementary Table S4 for additional details

Proportion of AE/ADR Reports Contributed by the Industry to State/Province and National Pharmacovigilance Databases

Of the 11 studies [12, 25, 41, 47, 59–62, 64–66] that analysed state/national pharmacovigilance databases (Table 5), 10 [12, 25, 41, 59–62, 64–66] reported information or provided indications on the extent to which the NHPs industry contributes to spontaneous reporting of AEs/ADRs of NHPs (or a specific category of NHPs) to these databases [N.B. These reports are collected by the NHPs industry, e.g. manufacturers/sponsors/MAHs from primary reporters such as healthcare professionals or consumers, and are subsequently submitted to health authorities/medicines regulators or national/regional pharmacovigilance databases]. Of these, four [12, 41, 60, 62] clearly specified the number, or proportion, of reports contributed by the NHPs industry. In addition, two studies [25, 59] from the USA analysed the CFSAN Adverse Event Reporting System (CAERS) database, which collects AE reports and product complaints associated with foods, dietary supplements and cosmetics submitted to the United States Food and Drug Administration (US FDA); these studies reported the proportions of mandatory and voluntary reports submitted. In the USA, dietary supplement sponsors must submit reports of serious AEs only (i.e. mandatory reporting). It is unclear if any of the voluntary reports in these two analyses were submitted by the industry [25, 59]. Two studies presented findings from analysis of China’s pharmacovigilance database [60, 64]. Both reported the combined percentage contributions of the conventional medicines and TCM industries, so the distinct contribution of the TCM industry is unclear. Similarly, one study analysed reports involving 84 registered herbal medicinal products within the Korea Adverse Event Reporting System (KAERS) [66]. This study presented findings on the proportion of reporters, including those from the industry, collectively labelled or named as pharmaceutical companies, without further clarifying if they were specifically NHP companies.

Post-marketing Surveillance Activities Undertaken by the NHPs Industry

The NHPs industry undertook both passive (n = 7) and active surveillance (n = 13) (Tables 6, 7). Industry-initiated or -sponsored active surveillance studies were primarily undertaken by manufacturers/MAHs based in Germany from the mid-1990s to the early 2010s. In contrast, the TCM industry in China has increasingly contributed to such studies since the mid-2010s.

Different statistical approaches were used to estimate the incidence of AEs and ADRs. Five articles describing retrospective analyses of spontaneous reports, periodic safety update reports (PSURs), and product complaints [36, 42, 54, 55, 58] attempted to estimate ADR/AE reporting rates, relative frequencies or prevalence using the number of doses or units of NHPs sold or manufactured as the denominator. In contrast, six active surveillance studies calculated the incidence of suspected ADRs and/or AEs on the basis of the number of participants included in the study. Reported incidence rates from active surveillance studies ranged from 0.8% to approximately 4% for ADRs and from 1.3 to 7.7% for AEs [37, 38, 40, 41, 46, 51].

Reporting of Serious ADRs and AEs, Signals and Risk Communication

Approximately two-thirds of the studies (n = 19) reported information on serious ADRs. Proportions of serious ADRs and/or AEs of the total number of analysed ADRs/AEs in the included studies are presented in Tables 5, 6 and 7. From analysis of provincial/state/national pharmacovigilance databases, the proportion of serious reports for TCM injections (out of all ADR reports for TCM injections under study/monitored/analysed in individual studies) in China ranged from 3.9 to 6.0% (information was unclear as to the proportion of these that were contributed by the industry) [47, 60, 63], to up to 50% of AE reports suspected to be related to complementary health products in Singapore (whereby industry contributed to 1.1% of the total number of reports) [12]. In addition, two studies provided information on the contribution of the NHPs industry towards the detection and/or management of safety signals [47, 62]. No studies described risk communication (e.g. product labelling changes) initiated by the industry. Overall, TCM injections were the most frequently studied NHPs in pharmacovigilance studies where there was industry contribution and/or involvement (n = 6), of which four examined, to some extent, serious ADRs/AEs [39, 41, 47, 60, 63, 64].

Stakeholders’ Views on the NHPs Industry’s Contribution to Pharmacovigilance

Table 9 summarises the findings of seven studies [67–73], conducted primarily using qualitative study designs or cross-sectional surveys, reported on stakeholders’ views on the roles and contributions of the NHPs industry to pharmacovigilance for NHPs. All seven studies were conducted by non-industry researchers, and predominantly involved non-industry participants, such as pharmacists and consumers. A study in Thailand included some herbal medicine manufacturers in a focus group discussion, but did not explicitly report the manufacturers’ views [72] (Table 9).

Table 9.

Characteristics of included studies on stakeholders’ views (n = 7)

Author, year [Ref]	Country(ies)	Study design	Study population; sample size	Study period; duration	Views on industry’s contribution
Worakunphanich, 2023 [72]	Thailand	Interview and FGD	Interview: Chronic disease patients, village health volunteers, consumers, community pharmacists; n = 50 FGD: Academics, herbal medicine manufacturers, a medical doctor, pharmacists, a Thai traditional medicine doctor, a policy maker, PV officers, a patient, a representative from patient organisation; n = 12	Interview: February to June 2020; 4 months FGD: August 2020; 1 session	Consumers prefer to be able to access multiple routes for reporting ADRs, including through manufacturers
Memişoğlu, 2022 [68]	Turkey	Survey	Community pharmacists; n = 879	April to June 2019; 3 months	1.4% of community pharmacists were made aware of phytovigilance through manufacturers, though details on their awareness and experiences were not elaborated
Barnes, 2020 [73]	New Zealand	Interview	Community pharmacists; n = 27	November 2007 to March 2008; 5 months	Among the two participants who had reported suspected ADRs associated with complementary medicine use, one had contacted the manufacturer Some participants suggested that consumers might prefer to contact manufacturers directly rather than inform pharmacists about ADRs
Harnett, 2019 [67]	Australia, China (Macau), USA	Interview	Practising pharmacists and representatives of stakeholder organisations; n = 22a	July to October 2018; 4 months	A single participant stated that dietary supplement companies in the USA are generally not interested in conducting research on adverse effects and drug interactions, as they are not legally required to do so
Pascale, 2016 [69]	USA	Survey	Physician members of the American Medical Society for Sports Medicine; n = 311	April 2013; duration not reported	Among the 10% who reported AEs associated with dietary supplements, none had reported to any company
Walji, 2010 [70]	Canada	Interview	NHP consumers who had experienced a self-identified suspected ADR associated with use of an NHP within the past 5 years; n = 12	September to December 2007; 3 months	Three felt comfortable reporting to manufacturers
Walji, 2009 [71]	Canada	Interview	Health food store personnel; n = 12	Not reported	Despite unfamiliarity with the concept of PV, health food store personnel relayed potential ADR information to manufacturers when submitting reports of consumer product complaints and product return requests

ADR, adverse drug reaction; AE, adverse event; FGD, focus group discussion; PV, pharmacovigilance

^aPractising pharmacists, pharmacy owners, pharmacist professional organisations, consumer advocacy groups, physician professional organisations, pharmacy schools, and regulatory authorities

Three studies indicated that health professionals, including community pharmacists and sports medicine physicians, have low awareness of and limited experience with reporting ADRs/AEs to NHP companies [68, 69, 73]. Three other studies suggested that consumers are willing to report ADRs to manufacturers [70–72], with one study providing evidence that such reports are sometimes conveyed to manufacturers indirectly through product complaints submitted at health food stores [71]. One interview participant commented on the lack of interest by dietary supplement companies in the USA to undertake safety-related research [67].

Discussion

This scoping review aimed to summarise the published scientific literature on the NHPs industry’s contribution towards pharmacovigilance for NHPs, and on stakeholders’ views on and experiences with the contributions of the NHPs industry in this area. This is the first review to explore the literature on this topic using a systematic scoping review approach. The review found that the NHPs industry contributes towards pharmacovigilance primarily through passive surveillance via the collection of spontaneous reports received from consumers and health professionals. Active surveillance, when undertaken, was focused mostly on specific marketed products and conducted in clinical care settings, such as medical centres, hospitals or private practices, which does not account for most NHP use in the community. TCM injections was the category of NHPs most frequently monitored through active surveillance undertaken by the industry. In recent years, there has also been an increase in the number of studies authored by researchers affiliated with Chinese TCM manufacturers. There was limited published literature that explored in-depth the views and experiences of stakeholders with respect to the NHPs industry’s contributions to pharmacovigilance for NHPs.

Gaps: Passive Surveillance for NHPs

There is little published literature documenting exactly the proportion of spontaneous reports of suspected ADRs involving NHPs submitted by the NHPs industry to national pharmacovigilance systems. This is not surprising given the relatively short history of mandatory spontaneous reporting for the NHPs industry for NHPs; where there is mandatory reporting, this is typically limited to reporting of serious AEs/suspected ADRs only. Moreover, these regulatory obligations do not apply uniformly across countries. [N.B.: In some countries, such as the USA, while dietary supplement manufacturers and/or distributors are mandated to report serious AEs, they are nevertheless required to maintain appropriate records of all other AEs reported to them, which must be available for regulatory inspection upon request] [26].

Regulatory requirements are likely to be a key driver for engaging in pharmacovigilance for the NHPs industry [74]. Since 2007, manufacturers of dietary supplements in the USA have been mandated to report serious AEs (reported to them by, for example, consumers or healthcare professionals) within 15 business days [26]. Further, all dietary supplement product labels must include local contact information for the company (domestic mailing address or phone number) to facilitate reporting of AEs by consumers [44]. Following the introduction of regulations, the number of mandatory AE reports associated with dietary supplement use received by CAERS (CAERS collects AE reports and product complaints associated with foods, dietary supplements and cosmetics submitted to the US FDA) annually has increased significantly from 0 to approximately 600 in 2008, and more than 3000 in 2013 [N.B. these numbers were estimated from a graph published in the original article] [25]. Similar trends have been observed in Germany for reports collected by manufacturers and relating to suspected ADRs involving anthroposophic and homoeopathic solutions for injection following the introduction of pharmacovigilance guidelines for manufacturers [55]. While increases in the number of AE/ADR reports are commonly observed following the introduction of mandatory reporting requirements, these increases could also be attributed to other factors, such as an increase in the number of products sold [47, 58], availability of clear guidelines for pharmacovigilance [54] and/or growing consumer awareness of ADR reporting to industry, a factor that has not yet been well explored in the literature.

Currently available published literature does not provide clear insights into whether there are other important enablers in addition to regulatory mandates that drive the undertaking of pharmacovigilance by the NHPs industry. A study exploring the reporting of non-serious ADRs by all MAHs to the EudraVigilance system found that the number of such reports substantially increased following the implementation of mandatory reporting of all ADRs (both serious and non-serious), compared with numbers pre-implementation. The study showed that spontaneous reports of non-serious ADRs were being submitted to the EudraVigilance system prior to the implementation of mandatory reporting requirements [75]. The study did not differentiate between MAHs of conventional medicines and those of herbal medicinal products, but indicated that the top ten most frequently reported substances consisted solely of conventional medicines and vaccines. It is, therefore, unclear whether any of the non-serious reports submitted before the mandate originated from MAHs of herbal medicinal products (In the EU, MAHs of herbal medicinal products are subject to the same regulatory reporting obligations for non-serious ADRs as those for conventional medicines, with the exception of requirements relating to PSURs [76]). Specifically for dietary supplements, data from CAERS showed that voluntary reports of AEs were submitted to the US FDA before mandatory serious AE reporting was introduced. However, it is also unclear whether and to what extent these voluntary reports originated from dietary supplement manufacturers [25]. In Germany, it was reported that manufacturers of anthroposophic injection solutions were collecting a limited number of ADR reports (about 20/year from a total of eight manufacturers) before the introduction of mandatory ADR reporting requirements in the EU in 2001 [55].

The drivers for the NHPs industry undertaking pharmacovigilance and their approach to handling ADR reports by consumers or patients in the absence of regulatory mandates are currently unclear. Potential company-specific factors warranting further investigation include external drivers, such as the need to align with international standards (particularly when products are also marketed in external jurisdictions that mandate ADR reporting in addition to local requirements), as well as internal drivers, such as the presence of established pharmacovigilance systems within companies that manufacture both pharmaceuticals and NHPs. In addition, the perception or belief that establishing a pharmacovigilance system offers a competitive advantage by providing enhanced safety assurance to consumers may further motivate companies to engage in these activities voluntarily [77].

Passive surveillance through the collection and analysis of spontaneous reports of suspected ADRs involving medicinal-type products, remains the cornerstone of pharmacovigilance and is the primary mechanism towards safety signal detection, particularly for NHPs. According to the EMA, a safety signal is ‘information on a new or known AE that is potentially caused by a medicine and that warrants further investigation’ [78]. Several studies included in this review analysed spontaneous reporting databases (national, state and industry-owned/managed), but few (n = 2) described the NHPs industry’s contribution to signal detection, assessment and/or management, including risk communication [47, 62]. Of these two, one discussed management strategies (such as establishing a medicine safety panel to identify, evaluate and manage risks) initiated by the industry [47]. Beyond the included literature, an analysis of 29 spontaneous reports of hepatobiliary-type ADRs involving the use of a supercritical carbon dioxide extract of Artemisia annua L. submitted to the New Zealand Pharmacovigilance Centre from its inception to 2019 concluded that the reports raised a safety signal that warranted further investigation [79]. Following this, and submission of further reports, all A. annua L. products were reclassified as prescription-only medicines in New Zealand [80]. The national industry body of New Zealand (Natural Health Products New Zealand) contested that the liver injuries were specific to quality/extract issues [81]. In this incident, none of the spontaneous reports were submitted by the industry, and safety signal assessment was undertaken by regulators and pharmacovigilance professionals working outside the NHPs industry [79, 80]. In certain jurisdictions, for example, countries within the EU, in addition to submitting reports of serious ADRs to competent authorities as individual case safety reports (ICSRs), MAHs for specific categories of NHPs (i.e. herbal medicinal products) are also required to monitor emerging safety issues relating to their products, which may include identifying potential safety signals. To facilitate this, MAHs for such products should have a signal management system in place to collect reports, analyse data, identify signals and notify the relevant competent authorities as appropriate [78, 82]. This type of information relating to the NHPs industry’s contributions to pharmacovigilance was not identified through our search strategy, but may have been published as grey literature on the respective company’s or authority’s website or elsewhere. A future targeted grey literature search and review could provide a better understanding of the NHPs industry’s activity in this area.

A known limitation of passive surveillance is difficulty in ascertaining causal relationships. The completeness of information provided in spontaneous reports is essential to facilitate formal causality assessment processes. In the absence of mandated pharmacovigilance requirements, it is currently not known what resources the NHPs industry commits to receiving and following-up reports of suspected ADRs that it receives from consumers, healthcare professionals and other stakeholders. Another well-known limitation of passive surveillance data—and evident from the studies included in this review—is the inability to directly or accurately determine the frequency of an ADR/AE through the analysis of spontaneous reports. Some industry-initiated or industry-involved studies included in this review estimated the incidence of ADRs/AEs and reporting rates on the basis of using recorded or estimated sales volume data to produce a denominator [36, 54, 55, 58]. Such estimates are considered imprecise and do not reliably reflect the true incidences of ADRs/AEs. Sales data, which serve as the denominator for this estimation method, fail to accurately account for variations in frequency and duration of use, the number of purchasers of an NHP, and the number of purchasers who consumed the NHP [74]. In addition, the numerator, i.e. the number of ADR/AE reports received through spontaneous reporting for NHPs by manufacturers, is often inaccurate owing to significant underreporting. As with conventional medicines, follow-up observational studies and large, prospective active surveillance studies will provide more accurate quantitative estimates of the true incidence [74, 83], especially where a safety signal has been identified.

Opportunities: Active Surveillance for NHPs

Most active surveillance studies involving the NHPs industry included in this review focused on specific marketed products and were undertaken in clinical settings such as medical centres, hospitals or private practices. No studies of prospective cohort-event monitoring involving the NHPs industry conducted in community settings were identified, even though this setting accounts for a significant proportion of, if not most, access to NHPs [10, 84, 85]. To monitor this substantive population of users of NHPs, two studies from the UK and New Zealand attempted to employ the ‘cohort-event monitoring’ or ‘intensive-monitoring’ method in pharmacies. However, both were unsuccessful in achieving meaningful user recruitment [86, 87]. These studies did not involve the NHPs industry (e.g. manufacturers, MAHs, etc.).

Despite its potential as a more comprehensive safety monitoring mechanism for specific situations (e.g. when a safety signal has been detected through passive surveillance), undertaking active surveillance for NHPs in community settings is inherently challenging. Active surveillance for NHPs requires the committed engagement of healthcare professionals, retailers, NHP users and significant resources. There are fundamental challenges in identifying and tracking the ‘cohort’, i.e. purchasers/users of the NHP(s) of interest. Almost anyone can easily purchase NHPs from many sources, including pharmacies, supermarkets, health food stores, online, etc. Therefore, a robust active surveillance study would require identifying, recruiting, and retaining product purchasers/users from all these sources, and following them over time. Unlike new prescription-only (conventional) medicines or vaccines, in which traceability can be relatively direct (e.g. use of smartphone applications to trace recipients of COVID-19 vaccines [88]), the identity of an NHPs user is not usually recorded at the point of sale; potential exceptions to this could include where natural-health or traditional-medicine practitioners supply or administer NHPs [24], where NHPs are purchased online and customer details are recorded on a supplier or company database, or where NHPs are purchased at outlets with customer loyalty programmes, which, in some cases, are linked with patients’ pharmacy electronic health records. The authors of a ‘purchase event’ monitoring study undertaken in New Zealand (mentioned above) argued that the feasibility of other approaches to recruiting users of NHPs in the community setting, such as through the NHPs industry (e.g. through inserts in product packaging) or directly recruiting NHP consumers, needs to be tested [86]. As a potential point of contact for consumers, the NHPs industry could be well-positioned to support or undertake active surveillance studies, and this possibility should be further explored.

A potential motivator for the NHPs industry to undertake active surveillance studies is the opportunity such studies present to include assessment of ‘perceived efficacy’ or, rather, effectiveness, alongside harms. Studies using this approach typically report few ADRs/AEs associated with product use, either serious or non-serious [37, 38, 40, 45, 46, 48, 51, 52]. From a practical standpoint, it is reasonable to anticipate that industry sponsors of studies would be driven to collect effectiveness-related data in ‘safety studies’ owing to revenue considerations: the ability to substantiate effectiveness can provide competitive advantages in the market. Large-scale, observational, post-marketing surveillance studies have been criticised for promoting product use rather than focusing on pharmacovigilance [89]. However, the present review identified three recent active surveillance studies conducted in China and involving TCM injections that focused solely on safety evaluation [39, 41, 47]. Given that these three studies assessed TCM injections and were conducted in the same country, it could be hypothesised that certain TCM injections are considered high-risk ‘medicines’ [N.B. TCMs are regulated as medicines in China] in China; indeed, some TCM injections have been implicated in spontaneous reports of death [64]. Consequently, risk-mitigation could be a significant driver for the industry to ensure continuous safety monitoring to minimise harm and maintain an NHP company’s reputation or trust among patients. Nevertheless, owing to the limited literature available on this topic, the motivators for industry stakeholders to undertake post-marketing active surveillance studies with safety monitoring as the sole objective, apart from fulfilling regulatory requirements, remain to be explored.

The Unknown: Stakeholders’ Views

To understand the potential for enhanced industrial involvement in pharmacovigilance, especially active safety surveillance for NHPs within a community setting, it is crucial to further explore the views of the NHPs industry and other stakeholders on this topic. However, information from scientific studies in this area is limited. Effective pharmacovigilance via industry requires consumers and their healthcare professionals to be vigilant about the potential for users to experience ADRs associated with use of NHPs and to be willing to submit ADR reports to NHP companies, but awareness of contacting manufacturers of NHPs as a route for reporting ADRs remains low among healthcare professionals [68, 69] and has not been explored comprehensively among consumers [70, 72, 86]. Direct reporting of experiences of suspected ADRs by patients was introduced only about two decades ago in many countries (and has not yet been implemented in others), with the initial emphasis placed on reporting to health authorities/national pharmacovigilance centres [74]. Beyond the general lack of awareness regarding ADR reporting, consumers may also be unaware of the importance of reporting known or previously documented ADRs. Given the critical role of consumer reporting through all potential channels in strengthening pharmacovigilance for NHPs, the ADR reporting pathway where consumers directly communicate with NHP companies warrants further exploration. This area of research is particularly relevant, given the growing emphasis on consumer self-empowerment and holistic health management approaches worldwide [90].

Strengths and Limitations

A strength of this review is its use of comprehensive literature search strategies across seven biomedical electronic databases. Nevertheless, it is possible that some relevant articles were not identified by the searches, particularly articles focusing on a specific product or herbal drug substance, e.g. in cases where a specific product or natural ingredient name is used throughout an article, as the keyword search did not include individual products, plants or other natural ingredient names. This study did not specifically search for studies on medicinal cannabis; however, one study which analysed spontaneous AE reports of a specific hemp product was identified and included. As medicinal cannabis is often regulated distinctively from other NHPs in many jurisdictions [91, 92], a separate review is warranted to explore this topic comprehensively.

This review focused on primary published literature sources reflecting industry contributions to pharmacovigilance for NHPs through surveillance activities. The research team did not contact individual NHP manufacturers/sponsors/MAHs for unpublished pharmacovigilance studies. This review also excluded NHPs industry contributions to case reports and case series describing suspected ADRs associated with NHPs. Consequently, potential industry contributions to pharmacovigilance documented in unpublished records or through publication of case reports/series were not assessed. Also, this review only included articles published in English due to language constraints, so relevant studies published in other languages may have been missed. Another limitation is the exclusion of opinion or commentary-type articles, which may have led to missing some information on stakeholders’ views. As such, this review found a lack of published primary literature on stakeholders’ views on the roles and contributions of the NHPs industry for pharmacovigilance of NHPs. This presents a significant research gap and warrants further in-depth exploration.

Product quality is an important consideration in regard to safety (and efficacy) and has some unique elements with respect to NHPs. The NHPs industry contributes to broader safety-related initiatives for specific NHP ingredients, including through information sharing, supporting quality standards (ingredient authentication and assessments of microbial and heavy metal contamination) for raw materials, conducting and reviewing preclinical toxicity studies and clinical trials, and contributing to the development of monographs [93–96]. A comprehensive evaluation of these types of contributions is beyond the scope of this review. As outlined in the a priori protocol, this scoping review aimed to capture published literature analysing the quality of marketed NHPs involving industry participation and that had a primary focus on pharmacovigilance documenting or reporting ADRs/AEs among end users. However, no published studies meeting these inclusion criteria were identified. Although numerous studies that reported on quality analysis of marketed products were initially identified through keyword searches, none declared NHPs industry involvement [97–103]. These studies [97–103] collectively highlighted substantial issues for marketed NHPs regarding authentication of starting materials, adulteration and contamination in the supply chain, and finished products. A few studies included in this review assumed that the quality of the NHPs of interest was not in question as they were produced by reputable manufacturers who comply with Good Manufacturing Practice (GMP) standards, as required by the law in their respective country of sale [42, 43]. Nevertheless, the quality of products was not (or most likely could not be) assessed in most of the included studies within this review.

This review also encountered challenges in interpreting pharmacovigilance terminologies, including the distinction between ‘severe’ and ‘serious’ ADRs/AEs. ‘Serious’ and ‘severe’ are not synonymous [104], yet some studies may have used these terms interchangeably without adequate clarification. The distinction between other terminologies, including ‘ADR’, ‘AE’, ‘side effects’, ‘adverse effects’, and ‘adverse drug events’, was also unclear in some studies. To avoid misrepresenting the original studies, pharmacovigilance findings are reported using the terminologies presented in the individual articles.

Lastly, although a cross-checking and quality assurance process among two independent investigators was adopted for title, abstract, and full-text screening for this review, data extraction was performed by a single investigator. There may be some risk of investigator bias and potential human error.

Future Studies

Considering the current gaps in the NHPs industry’s contributions to pharmacovigilance, future efforts could focus on several key areas. These include updated and real-time assessments of the extent to which the industry collects, monitors, and evaluates safety reports, including product ‘complaints’, and the actions taken in response to these (e.g. risk communication/labelling changes), on a country-by-country basis. These analyses could also be supplemented with in-depth examination of the legislative differences and nuances that shape pharmacovigilance practices for NHPs across different jurisdictions. Such efforts are ideally done in collaboration with local health authorities/medicines regulators and other key pharmacovigilance stakeholders to identify and explore enablers and barriers to the industry undertaking pharmacovigilance, both in the presence and absence of regulatory mandates. Lastly, as previously discussed, there is a need to explore alternative methods of safety monitoring for NHPs beyond passive surveillance among community users, including ways in which the industry can contribute to active surveillance. Potential findings on these key areas could inform the development of public health policies and regulatory frameworks that set clearer expectations of the NHPs industry’s responsibilities towards consumer safety, while balancing access to products.

Conclusions

The NHPs industry contributes towards pharmacovigilance activities primarily through passive surveillance via submitting spontaneous reports of suspected ADRs associated with their products to a competent authority, particularly, but not exclusively, where this is mandated in regulations. However, there is a paucity of published literature describing safety signal detection, assessment, and management by the industry. Active surveillance activities conducted by the industry are typically limited to specific products (as is appropriate) in clinical settings, such as medical centres, hospitals or private practices, but overlook community-dwelling NHP users. There is limited information on stakeholders’ perspectives regarding the NHPs industry’s roles and contributions to pharmacovigilance. Additional research exploring stakeholders’ interest in and preparedness for active surveillance, and focusing on the consumer-industry reporting pathway, is warranted and could identify potential strategies for enhancing and improving post-marketing safety monitoring of NHPs.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions.

Declarations

Conflict of interest

X.Y.L. is a doctoral candidate studying the contributions of the natural health products (NHPs) industry to pharmacovigilance for NHPs. S.R. and S.S. have no conflict of interest to declare. In the last 3 years, J.B. has received: royalties from Elsevier and SpringerNature in respect of authorship of reference texts on herbal medicines; travel expenses and/or conference expenses from United States Pharmacopeia, UK Drug Safety Research Unit, University of Mississippi, Southern Cross University, International Society of Pharmacovigilance and the South African Botanical Products Association in respect of invited meetings/conference presentations; non-financial support (clinical trial supplies) from Achieve Life Sciences and NZVAPOR (both 2022–2024) as a co-investigator. J.B. is an Editorial Board member of Drug Safety. J.B. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Funding

Open Access funding enabled and organised by the Council of Australian University Librarians (CAUL) and its Member Institutions. This manuscript forms part of the doctoral research of X.Y.L. X.Y.L. is a recipient of the Auckland Medical Research Foundation Maclaurin & Barham Doctoral Scholarship (1224004). No other funding was received for this review.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Code availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Ethics approval

This is a scoping review. No ethical approval is required.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Author contributions

All authors contributed to the idea for the article and developed the literature search strategy. X.Y.L. performed the literature search, study screening, selection, and data extraction. X.Y.L. drafted the article and J.B., S.R. and S.S. critically revised the work. All authors read and approved the final manuscript.