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1.  Consumers of natural health products: natural-born pharmacovigilantes? 
Background
Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.
Methods
Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques.
Results
Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible.
Conclusion
Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.
doi:10.1186/1472-6882-10-8
PMCID: PMC2847952  PMID: 20184759
2.  Pharmacists’ attitude, perceptions and knowledge towards the use of herbal products in Abu Dhabi, United Arab Emirates 
Pharmacy Practice  2010;8(2):109-115.
Objective
The purpose of the study was to assess pharmacists’ current practice, perception and knowledge towards the use of herbal products in Abu Dhabi, United Arab Emirates (UAE). The study assessed the need for incorporating herbal medicine as a separate topic in under- graduate pharmacy student curricula.
Methods
The study was done on 600 pharmacists employed in Abu Dhabi, who were contacted electronically, out of which 271 had completed the survey. The data was collected using a structured questionnaire.
Results
Pharmacists’ use of herbal products is high in the UAE, as they have a high belief on the effectiveness of herbal products, and only age was found to be the most predominant variable that was influencing pharmacists’ personal use of herbal products (p-value=0.0171). Pharmacists were more knowledgeable on the uses/indications of herbal products (47%) rather than on other areas. Knowledge of the dispensing mode (prescription only or over the counter medicines) mandated by the Ministry of Health was quite good, however, it is to be noted that the source of information on the dispensing mode was provided by medical representatives (48%). Knowledge of dispensing mode of herbal products was found to be significantly influenced by the place of work with more knowledge of the dispensing mode by pharmacists working in the private sector (p-value 0.0007). The results from the study also underscores the need for including herbal medicine as a separate topic in pharmacy college curriculum and to provide for more seminars and continuing pharmacy education programs targeting pharmacists in the Emirate of Abu Dhabi.
Conclusions
Pharmacists need to be informed on indications, drug interactions, adverse events and precautions of herbal products. Concerned bodies must also provide them with regular continuing education programs apart from putting their efforts to incorporate relevant topics on herbal medicine in the pharmacy students’ curriculum.
PMCID: PMC4133064  PMID: 25132878
Herbal Medicine; Education; Pharmacy; United Arab Emirates
3.  Buyer beware? Does the information provided with herbal products available over the counter enable safe use? 
BMC Medicine  2011;9:94.
Background
Herbal products obtained over the counter are commonly used in Europe, North America and Australia. Although there is concern about a lack of information provided to consumers to allow the safe use of these products, there has been no published research to confirm these fears. In this study, we evaluated written information provided with commonly used herbal products in the UK in advance of a European Union Directive issued in April 2011 that tightened regulations for some herbal products, including requirements to provide safety information.
Methods
Five commonly used herbal products were purchased from pharmacies, health food shops and supermarkets: St John's wort, Asian ginseng, echinacea, garlic and ginkgo. Written information provided with the products (on the package or on a leaflet contained in the package) was evaluated for inclusion of each of the key safety messages included in the monographs of the US National Center for Complementary and Alternative Medicine. Specifically, we looked for information on precautions (such as Asian ginseng not being suitable for people with diabetes), interactions with conventional medicines (such as St John's wort with the contraceptive pill and warfarin) and side effects (such as ginkgo and allergic reactions).
Results
Our analysis showed that, overall, 51 (75%) of 68 products contained none of the key safety messages. This included 4 of 12 St John's wort products, 12 of 12 ginkgo products, 6 of 7 Asian ginseng products, 20 of 21 garlic products and 9 of 13 echinacea products. The two products purchased that are registered under the new European Union regulations (for St John's wort) contained at least 85% of the safety messages.
Conclusions
Most of the herbal medicine products studied did not provide key safety information which consumers need for their safe use. The new European Union legislation should ensure that St John's wort and echinacea products will include the previously missing information in due course. The legislation does not apply to existing stock. Depending on therapeutic claims made by manufacturers, garlic, ginkgo and Asian ginseng products may not be covered by the legislation and can continue to be bought without the safety information. Also, consumers will still be able to buy products over the internet from locations outside European Union jurisdiction. Potential purchasers need to know, in both the short term and the long term, how to purchase herbal products which provide the information they need for the safe use of these products.
doi:10.1186/1741-7015-9-94
PMCID: PMC3180693  PMID: 21827684
4.  Self-medication with nutritional supplements and herbal over-thecounter products 
In recent years, the popularity increased for nutritional supplements and herbal products. Prescription drugs, but not herbal therapies are paid by health insurances. They are sold over-the-counter (OTC) on the patients’ own expense. However, there are potential risks of self-medication, e.g. incorrect self-diagnosis, severe adverse reactions, dangerous drug interactions, risk of addiction etc. They are often used by patients at their own discretion without knowledge of and control by their physicians. Certain users are at risk of intoxication. Multiple medications taken by older patients increase the risk for adverse drug reactions, drug-drug interactions, and compliance problems for this age group (polypharmacy). Herbals should be discontinued prior to operations to avoid interactions with anesthetics or anticoagulants. Herbal preparations may also be carcinogenic or interfere with cancer treatments. Pregnant women use various OTC preparations. However, in many cases, it is unclear whether their use is safe for mother or baby. Self-medication with herbals is also largely distributed among anxious and depressive patients, and patients with other conditions and symptoms. The popularity of herbal products has also brought concerns on quality, efficacy and safety. Cases of botanical misidentification, contaminations with heavy metals, pesticides, radioactivity, organic solvents, microbials as well as adulteration with chemical drugs necessitate the establishment of international quality control standards. Hepatotoxic effects have been reported for more than 300 plant species, and some commonly used herbs have been demonstrated to interact with Western medication. Health care professionals have a critical responsibility assessing the self-care ability of their patients. Databases are available for pharmacists with information on action, side effects and toxicities as well as herb-drug interactions. There is a need for established guidelines regarding the correct use of nutritional supplements and herbal OTC preparations (phytovigilance). Physicians, pharmacists, and other health care professionals have to counsel patients and the general public on the benefits and risks associated with herbal drugs. Information centers for consumers and general practitioners are needed, and convincing evidence on safety and efficacy of herbal products has to be demonstrated in placebo-controlled, double blind and randomized clinical trials.
doi:10.1007/s13659-011-0029-1
PMCID: PMC4131654
botanicals; contamination; complementary and alternative medicine; drug interactions; geriatric; gynecology; insomnia; hepatotoxicity; menopause; nephrotoxicity; over-the-counter; pain; phase I/II enzymes; pharmacognosy; pharmacovigilance; phytochemicals; phytotherapy; phytovigilance; quality control
5.  Availability and needs of herbal medicinal information resources at community pharmacy, Riyadh region, Saudi Arabia 
A cross-sectional survey of community pharmacists in Riyadh region, Saudi Arabia was conducted over a period of 6 months from July through December 2011. Data collection was carried out using a structured self-administered questionnaire. The survey questionnaire consisted of a brief introduction to the study and eleven questions. The questions consisted of close ended, multiple-choice, and fill-in short answers. A stratified random sample of one thousand and seven hundred registered pharmacy practitioners all over Saudi Arabia were randomly chosen to respond to the survey. The data from each of the returned questionnaire were coded and entered into Statistical Package for the Social Sciences (SPSS) version 19 software (SPSS Inc., Chicago, IL, USA) which was used for statistical analysis. Only one thousand four hundred one pharmacists responded to the survey (response rate is 82.4%) with a completely answered questionnaire. The study results show that 59.7% of the participants sometimes discuss herbal medicine use with their patients, while only 4.25% never discuss it. The study shows 48.5% of participated pharmacists record herbal medicine use sometimes where only 9.4% of them never did so. However, with regard to initiation of the discussion, the study shows that 44.3% of the respondents reported that patients initiate herbal issue discussion while 20.8% reported that pharmacists initiate the discussion. This discussion was reported to be a one time discussion or an ongoing discussion by 14.3% or 9.9% of the respondents respectively. According to the study results, respondents reported that the most common barriers that limit discussing herbal medicines’ use with their patients were lack of time due to other obligations assigned to the community pharmacist (46%), lack of reliable resources (30.3%), lack of scientific evidence that support herbal medicine use (15.2%), or lack of knowledge of herbal medicines (13.4%). Yet, a small number of respondents was concerned about interest in herbal medicines (9.1%) and other reasons (2.4%). So it is urgent to ensure that pharmacists are appropriately educated and trained. Extra efforts are needed to increase the awareness of pharmacists to adverse drug reactions reporting system at Saudi Food and Drug Authority. Finally, more consideration to herbal issues should be addressed in both pharmacy colleges’ curricula and continuous education program..
doi:10.1016/j.jsps.2012.11.004
PMCID: PMC3824944  PMID: 24227954
Recourse; Medicinal; Herbal; Availability
6.  Pharmacovigilance of herbal medicines: Current state and future directions 
Pharmacognosy Magazine  2011;7(25):69-73.
Currently, a majority of the adverse events related to the use of herbal products and herbal medicines that are reported are attributable either to poor product quality or to improper use. Inadequate regulatory measures, weak quality control systems, and largely uncontrolled distribution channels (including mail order and Internet sales) may have been contributing to the occurrence of such events. In order to expand the knowledge about genuine adverse reactions to herbal medicines, and to avoid wasting scarce resources for identifying and analyzing adverse events, events resulting from such situations will need to be reduced or eliminated. Member States of the World Health Organization (WHO) are therefore encouraged to strengthen national regulation, registration and quality assurance and control of herbal medicines. In addition, the national health authorities should give greater attention to consumer education and to qualified practice in the provision of herbal medicines.
doi:10.4103/0973-1296.75905
PMCID: PMC3065161  PMID: 21472083
Guidelines; herbal medicines; pharmacovigilance; regulatory
7.  Herbal products in Canada. How safe are they? 
Canadian Family Physician  1997;43:697-702.
OBJECTIVE: To examine existing evidence and inform family physicians about issues concerning herbal product use in Canada. QUALITY OF EVIDENCE: The Canadian Food and Drug Act and findings of an Expert Advisory Committee on Herbs and Botanical Preparations were consulted to provide an overview of the issues regarding herbal product regulation in Canada. Case reports of herbal toxicity were identified to illustrate some of the hazards of herbal products, and references provided to guide health professional in searching the literature for clinical trials that evaluate these drugs' efficacy. MAIN FINDINGS: Herbal products not registered as drugs in Canada are sold as foods and are exempt from the drug review process that evaluates product efficacy and safety. This places the public at risk of unwanted effects from the use of herbal products that are adulterated with other substances and of forgoing effective conventional therapy. Moreover, consumers are exposed to a plethora of information portraying herbal products as harmless. Some progress has been made to address these concerns by facilitating the registration of herbal products as drugs. CONCLUSIONS: Most herbal products that were evaluated were unsafe or ineffective, or no information was available to evaluate their efficacy. Despite the perception that herbal products are innocuous, family physicians need to be aware that herbal therapy can be harmful in order to help their patients make informed choices.
Images
PMCID: PMC2255469  PMID: 9111986
8.  Topical herbal therapies for treating osteoarthritis 
Background
Before extraction and synthetic chemistry were invented, musculoskeletal complaints were treated with preparations from medicinal plants. They were either administered orally or topically. In contrast to the oral medicinal plant products, topicals act in part as counterirritants or are toxic when given orally.
Objectives
To update the previous Cochrane review of herbal therapy for osteoarthritis from 2000 by evaluating the evidence on effectiveness for topical medicinal plant products.
Search methods
Databases for mainstream and complementary medicine were searched using terms to include all forms of arthritis combined with medicinal plant products. We searched electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE, AMED, CINAHL, ISI Web of Science, World Health Organization Clinical Trials Registry Platform) to February 2013, unrestricted by language. We also searched the reference lists from retrieved trials.
Selection criteria
Randomised controlled trials of herbal interventions used topically, compared with inert (placebo) or active controls, in people with osteoarthritis were included.
Data collection and analysis
Two review authors independently selected trials for inclusion, assessed the risk of bias of included studies and extracted data.
Main results
Seven studies (seven different medicinal plant interventions; 785 participants) were included. Single studies (five studies, six interventions) and non-comparable studies (two studies, one intervention) precluded pooling of results.
Moderate evidence from a single study of 174 people with hand osteoarthritis indicated that treatment with Arnica extract gel probably results in similar benefits as treatment with ibuprofen (non-steroidal anti-inflammatory drug) with a similar number of adverse events. Mean pain in the ibuprofen group was 44.2 points on a 100 point scale; treatment with Arnica gel reduced the pain by 4 points after three weeks: mean difference (MD) −3.8 points (95% confidence intervals (CI) −10.1 to 2.5), absolute reduction 4% (10% reduction to 3% increase). Hand function was 7.5 points on a 30 point scale in the ibuprofen-treated group; treatment with Arnica gel reduced function by 0.4 points (MD −0.4, 95% CI −1.75 to 0.95), absolute improvement 1% (6% improvement to 3% decline)). Total adverse events were higher in the Arnica gel group (13% compared to 8% in the ibuprofen group): relative risk (RR) 1.65 (95% CI 0.72 to 3.76).
Moderate quality evidence from a single trial of 99 people with knee osteoarthritis indicated that compared with placebo, Capsicum extract gel probably does not improve pain or knee function, and is commonly associated with treatment-related adverse events including skin irritation and a burning sensation. At four weeks follow-up, mean pain in the placebo group was 46 points on a 100 point scale; treatment with Capsicum extract reduced pain by 1 point (MD −1, 95%CI −6.8 to 4.8), absolute reduction of 1%(7%reduction to 5% increase). Mean knee function in the placebo group was 34.8 points on a 96 point scale at four weeks; treatment with Capsicum extract improved function by a mean of 2.6 points (MD −2.6, 95% CI −9.5 to 4.2), an absolute improvement of 3% (10% improvement to 4% decline). Adverse event rates were greater in the Capsicum extract group (80% compared with 20% in the placebo group, rate ratio 4.12, 95% CI 3.30 to 5.17). The number needed to treat to result in adverse events was 2 (95% CI 1 to 2).
Moderate evidence from a single trial of 220 people with knee osteoarthritis suggested that comfrey extract gel probably improves pain without increasing adverse events. At three weeks, the mean pain in the placebo group was 83.5 points on a 100 point scale. Treatment with comfrey reduced pain by a mean of 41.5 points (MD −41.5, 95% CI −48 to −34), an absolute reduction of 42% (34% to 48% reduction). Function was not reported. Adverse events were similar: 6%(7/110) reported adverse events in the comfrey group compared with 14% (15/110) in the placebo group (RR 0.47, 95% CI 0.20 to 1.10).
Although evidence from a single trial indicated that adhesive patches containing Chinese herbal mixtures FNZG and SJG may improve pain and function, the clinical applicability of these findings are uncertain because participants were only treated and followed up for seven days. We are also uncertain if other topical herbal products (Marhame-Mafasel compress, stinging nettle leaf) improve osteoarthritis symptoms due to the very low quality evidence from single trials.
No serious side effects were reported.
Authors’ conclusions
Although the mechanism of action of the topical medicinal plant products provides a rationale basis for their use in the treatment of osteoarthritis, the quality and quantity of current research studies of effectiveness are insufficient. Arnica gel probably improves symptoms as effectively as a gel containing non-steroidal anti-inflammatory drug, but with no better (and possibly worse) adverse event profile. Comfrey extract gel probably improves pain, and Capsicum extract gel probably will not improve pain or function at the doses examined in this review. Further high quality, fully powered studies are required to confirm the trends of effectiveness identifed in studies so far.
doi:10.1002/14651858.CD010538
PMCID: PMC4105203  PMID: 23728701
Arnica; Capsaicin [therapeutic use]; Comfrey [chemistry]; Drugs, Chinese Herbal [administration & dosage]; Hand Joints; Osteoarthritis [*drug therapy]; Osteoarthritis, Knee [drug therapy]; Phytotherapy [*methods]; Plant Extracts [*administration & dosage]; Humans
9.  Case Report: Potential Arsenic Toxicosis Secondary to Herbal Kelp Supplement 
Environmental Health Perspectives  2007;115(4):606-608.
Context
Medicinal use of dietary herbal supplements can cause inadvertent arsenic toxicosis.
Case Presentation
A 54-year-old woman was referred to the University of California, Davis, Occupational Medicine Clinic with a 2-year history of worsening alopecia and memory loss. She also reported having a rash, increasing fatigue, nausea, and vomiting, disabling her to the point where she could no longer work full-time. A thorough exposure history revealed that she took daily kelp supplements. A urine sample showed an arsenic level of 83.6 μg/g creatinine (normal < 50 μg/g creatinine). A sample from her kelp supplements contained 8.5 mg/kg (ppm) arsenic. Within weeks of discontinuing the supplements, her symptoms resolved and arsenic blood and urine levels were undetectable.
Discussion
To evaluate the extent of arsenic contamination in commercially available kelp, we analyzed nine samples randomly obtained from local health food stores. Eight of the nine samples showed detectable levels of arsenic higher than the Food and Drug Administration tolerance level of 0.5 to 2 ppm for certain food products. None of the supplements contained information regarding the possibility of contamination with arsenic or other heavy metals. The 1994 Dietary Supplement Health and Education Act (DSHEA) has changed the way dietary herbal therapies are marketed and regulated in the United States. Less regulation of dietary herbal therapies will make inadvertent toxicities a more frequent occurrence.
Relevance to Clinical Practice
Clinicians should be aware of the potential for heavy metal toxicity due to chronic use of dietary herbal supplements. Inquiring about use of dietary supplements is an important element of the medical history.
doi:10.1289/ehp.9495
PMCID: PMC1852683  PMID: 17450231
arsenic; DSHEA; heavy metal; herbal supplement; kelp; toxicity
10.  Herbal medicine: women's views, knowledge and interaction with doctors: a qualitative study 
Background
There is growing concern that serious interactions are occurring between prescribed/over the counter and herbal medicines and that there is a lack of disclosure of herbal use by patients to doctors. This study explores women's perspectives about the safety of herbal remedies, herb-drug interactions and communication with doctors about herbal medicines.
Methods
Qualitative, cross-sectional study, with purposive sampling which took place in Cheshire, UK. Eighteen in depth semi-structured interviews were conducted with female herbal medicine users aged 18 years and above.
Results
The large majority did not inform their GPs of their use of herbal medicines. This was due to lack of physician enquiry, perception of importance and fear of a negative response. Several women were not aware that herbal remedies could interact with prescribed or over the counter medicines. Of the women who had experienced adverse effects none had reported them, believing them of low importance.
Conclusion
The women had little knowledge about herb-drug interactions and rarely disclosed use of herbal medicines to their doctor. Doctors' communication and openness regarding herbal medicines needs to improve and there should be increased access to accurate information on herbal medicines in the public and health care domain.
doi:10.1186/1472-6882-6-40
PMCID: PMC1702550  PMID: 17156416
11.  Knowledge, attitudes, and practice of doctors to adverse drug reaction reporting in a teaching hospital in India: An observational study 
Background:
Underreporting of spontaneous adverse drug reaction (ADR) is a threat to pharmacovigilance. Various factors related with the knowledge and attitudes are responsible for underreporting of ADRs.
Aims:
The study was aimed at investigating the knowledge and attitudes of doctors to ADR reporting.
Materials and Methods:
It was a questionnaire-based cross-sectional study. One hundred and eight questionnaires were administered to doctors working in a teaching hospital with an ADR monitoring center.
Statistical Analysis Used:
The descriptive statistics were used for responses to evaluate the knowledge and attitudes toward ADR reporting. Pearson's Chi-square test was used to observe the association of knowledge and attitude with experience and position.
Results:
The response rate was 62.9%. Spontaneous reporting rate was found to be 19.1%. The major factors found to be responsible for underreporting of ADR include inadequate risk perception about newly marketed drugs (77.9%), fear factor (73.5%), diffidence (67.7%), lack of clarity of information on ADR form about reporting (52.9%), lethargy (42.7%), insufficient training to identify ADRs (41.2%), lack of awareness about existence of pharmacovigilance program (30.9%) and ADR monitoring center in the institute (19.1%), and inadequate risk perception of over-the-counter (OTC) product (20.6%) and herbal medicines (13.2%). Experience and position did not influence the knowledge and attitudes of doctors.
Conclusion:
The deficiencies in knowledge and attitudes require urgent attention not only to improve the rate of spontaneous reporting, but also for enhanced safety of the patients and society at large.
doi:10.4103/0976-9668.107289
PMCID: PMC3633276  PMID: 23633861
Attitude; doctors; knowledge; pharmacovigilance; spontaneous reporting
12.  Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals 
PLoS Medicine  2013;10(12):e1001566.
Agnes Dechartres and colleagues searched ClinicalTrials.gov for completed drug RCTs with results reported and then searched for corresponding studies in PubMed to evaluate timeliness and completeness of reporting.
Please see later in the article for the Editors' Summary
Background
The US Food and Drug Administration Amendments Act requires results from clinical trials of Food and Drug Administration–approved drugs to be posted at ClinicalTrials.gov within 1 y after trial completion. We compared the timing and completeness of results of drug trials posted at ClinicalTrials.gov and published in journals.
Methods and Findings
We searched ClinicalTrials.gov on March 27, 2012, for randomized controlled trials of drugs with posted results. For a random sample of these trials, we searched PubMed for corresponding publications. Data were extracted independently from ClinicalTrials.gov and from the published articles for trials with results both posted and published. We assessed the time to first public posting or publishing of results and compared the completeness of results posted at ClinicalTrials.gov versus published in journal articles. Completeness was defined as the reporting of all key elements, according to three experts, for the flow of participants, efficacy results, adverse events, and serious adverse events (e.g., for adverse events, reporting of the number of adverse events per arm, without restriction to statistically significant differences between arms for all randomized patients or for those who received at least one treatment dose).
From the 600 trials with results posted at ClinicalTrials.gov, we randomly sampled 50% (n = 297) had no corresponding published article. For trials with both posted and published results (n = 202), the median time between primary completion date and first results publicly posted was 19 mo (first quartile = 14, third quartile = 30 mo), and the median time between primary completion date and journal publication was 21 mo (first quartile = 14, third quartile = 28 mo). Reporting was significantly more complete at ClinicalTrials.gov than in the published article for the flow of participants (64% versus 48% of trials, p<0.001), efficacy results (79% versus 69%, p = 0.02), adverse events (73% versus 45%, p<0.001), and serious adverse events (99% versus 63%, p<0.001).
The main study limitation was that we considered only the publication describing the results for the primary outcomes.
Conclusions
Our results highlight the need to search ClinicalTrials.gov for both unpublished and published trials. Trial results, especially serious adverse events, are more completely reported at ClinicalTrials.gov than in the published article.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When patients consult a doctor, they expect to be recommended what their doctor believes is the most effective treatment with the fewest adverse effects. To determine which treatment to recommend, clinicians rely on sources that include research studies. Among studies, the best evidence is generally agreed to come from systematic reviews and randomized controlled clinical trials (RCTs), studies that test the efficacy and safety of medical interventions by comparing clinical outcomes in groups of patients randomly chosen to receive different interventions. Decision-making based on the best available evidence is called evidence-based medicine. However, evidence-based medicine can only guide clinicians if trial results are published in a timely and complete manner. Unfortunately, underreporting of trials is common. For example, an RCT in which a new drug performs better than existing drugs is more likely to be published than one in which the new drug performs badly or has unwanted adverse effects (publication bias). There can also be a delay in publishing the results of negative trials (time-lag bias) or a failure to publish complete results for all the prespecified outcomes of a trial (reporting bias). All three types of bias threaten informed medical decision-making and the health of patients.
Why Was This Study Done?
One initiative that aims to prevent these biases was included in the 2007 US Food and Drug Administration Amendments Act (FDAAA). The Food and Drug Administration (FDA) is responsible for approving drugs and devices that are marketed in the US. The FDAAA requires that results from clinical trials of FDA-approved drugs and devices conducted in the United States be made publicly available at ClinicalTrials.gov within one year of trial completion. ClinicalTrials.gov—a web-based registry that includes US and international clinical trials—was established in 2000 in response to the 1997 FDA Modernization Act, which required mandatory registration of trial titles and designs and of the conditions and interventions under study. The FDAAA expanded these mandatory requirements by requiring researchers studying FDA-approved drugs and devices to report additional information such as the baseline characteristics of the participants in each arm of the trial and the results of primary and secondary outcome measures (the effects of the intervention on predefined clinical measurements) and their statistical significance (an indication of whether differences in outcomes might have happened by chance). Researchers of other trials registered in ClinicalTrials.gov are welcome to post trial results as well. Here, the researchers compare the timing and completeness (i.e., whether all relevant information was fully reported) of results of drug trials posted at ClinicalTrials.gov with those published in medical journals.
What Did the Researchers Do and Find?
The researchers searched ClinicalTrials.gov for reports of completed phase III and IV (late-stage) RCTs of drugs with posted results. For a random sample of 600 eligible trials, they searched PubMed (a database of biomedical publications) for corresponding publications. Only 50% of trials with results posted at ClinicalTrials.gov had a matching published article. For 202 trials with both posted and published results, the researchers compared the timing and completeness of the results posted at ClinicalTrials.gov and of results reported in the corresponding journal publication. The median time between the study completion date and the first results being publicly posted at ClinicalTrials.gov was 19 months, whereas the time between completion and publication in a journal was 21 months. The flow of participants through trials was completely reported in 64% of the ClinicalTrials.gov postings but in only 48% of the corresponding publications. Results for the primary outcome measure were completely reported in 79% and 69% of the ClinicalTrials.gov postings and corresponding publications, respectively. Finally, adverse events were completely reported in 73% of the ClinicalTrials.gov postings but in only 45% of the corresponding publications, and serious adverse events were reported in 99% and 63% of the ClinicalTrials.gov postings and corresponding publications, respectively.
What Do These Findings Mean?
These findings suggest that the reporting of trial results is significantly more complete at ClinicalTrials.gov than in published journal articles reporting the main trial results. Certain aspects of this study may affect the accuracy of this conclusion. For example, the researchers compared the results posted at ClinicalTrials.gov only with the results in the publication that described the primary outcome of each trial, even though some trials had multiple publications. Importantly, these findings suggest that, to enable patients and physicians to make informed treatment decisions, experts undertaking assessments of drugs should consider seeking efficacy and safety data posted at ClinicalTrials.gov, both for trials whose results are not published yet and for trials whose results are published. Moreover, they suggest that the use of templates to guide standardized reporting of trial results in journals and broader mandatory posting of results may help to improve the reporting and transparency of clinical trials and, consequently, the evidence available to inform treatment of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001566.
Wikipedia has pages on evidence-based medicine and on publication bias (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Food and Drug Administration provides information about drug approval in the US for consumers and health-care professionals, plus detailed information on the 2007 Food and Drug Administration Amendments Act
ClinicalTrials.gov provides information about the US National Institutes of Health clinical trial registry, including background information about clinical trials, and a fact sheet detailing the requirements of the 2007 Food and Drug Administration Amendments Act
PLOS Medicine recently launched a Reporting Guidelines Collection, an open access collection of reporting guidelines, commentary, and related research on guidelines from across PLOS journals that aims to help advance the efficiency, effectiveness, and equitability of the dissemination of biomedical information; a 2008 PLOS Medicine editorial discusses the 2007 Food and Drug Administration Amendments Act
doi:10.1371/journal.pmed.1001566
PMCID: PMC3849189  PMID: 24311990
13.  Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints 
PLoS Medicine  2011;8(4):e1000431.
Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices.
Background
Despite regulatory restrictions, off-label marketing of pharmaceutical products has been common in the US. However, the scope of off-label marketing remains poorly characterized. We developed a typology for the strategies and practices that constitute off-label marketing.
Methods and Findings
We obtained unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing (January 1996–October 2010) and conducted structured reviews of them. We coded and analyzed the strategic goals of each off-label marketing scheme and the practices used to achieve those goals, as reported by the whistleblowers. We identified 41 complaints arising from 18 unique cases for our analytic sample (leading to US$7.9 billion in recoveries). The off-label marketing schemes described in the complaints had three non–mutually exclusive goals: expansions to unapproved diseases (35/41, 85%), unapproved disease subtypes (22/41, 54%), and unapproved drug doses (14/41, 34%). Manufacturers were alleged to have pursued these goals using four non–mutually exclusive types of marketing practices: prescriber-related (41/41, 100%), business-related (37/41, 90%), payer-related (23/41, 56%), and consumer-related (18/41, 44%). Prescriber-related practices, the centerpiece of company strategies, included self-serving presentations of the literature (31/41, 76%), free samples (8/41, 20%), direct financial incentives to physicians (35/41, 85%), and teaching (22/41, 54%) and research activities (8/41, 20%).
Conclusions
Off-label marketing practices appear to extend to many areas of the health care system. Unfortunately, the most common alleged off-label marketing practices also appear to be the most difficult to control through external regulatory approaches.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before a pharmaceutical company can market a new prescription drug in the US, the drug has to go through a long approval process. After extensive studies in the laboratory and in animals, the pharmaceutical company must test the drug's safety and efficacy in a series of clinical trials in which groups of patients with specific diseases are given the drug according to strict protocols. The results of these trials are reviewed by Federal Drug Administration (FDA, the body that regulates drugs in the US) and, when the FDA is satisfied that the drug is safe and effective for the conditions in which it is tested, it approves the drug for sale. An important part of the approval process is the creation of the “drug label,” a detailed report that specifies the exact diseases and patient groups in which the drug can be used and the approved doses of the drug.
Why Was This Study Done?
Physicians can, however, legally use FDA-approved drugs “off-label.” That is, they can prescribe drugs for a different disease, in a different group of patients, or at a different dose to that specified in the drug's label. However, because drugs' manufacturers stand to benefit financially from off-label use through increased drugs sales, the FDA prohibits them from directly promoting unapproved uses. The fear is that such marketing would encourage the widespread use of drugs in settings where their efficacy and safety has not been rigorously tested, exposing patients to uncertain benefits and possible adverse effects. Despite the regulatory restrictions, off-label marketing seems to be common. In 2010, for example, at least six pharmaceutical companies settled US government investigations into alleged off-label marketing programs. Unfortunately, the tactics used by pharmaceutical companies for off-label marketing have been poorly understood in the medical community, in part because pharmaceutical industry insiders (“whistleblowers”) are the only ones who can present in-depth knowledge of these tactics. In recent years, as more whistleblowers have come forward to allege off-label marketing, developing a more complete picture of the practice is now possible. In this study, the researchers attempt to systematically classify the strategies and practices used in off-labeling marketing by examining complaints filed by whistleblowers in federal enforcement actions where off-label marketing by pharmaceutical companies has been alleged.
What Did the Researchers Do and Find?
In their analysis of 41 whistleblower complaints relating to 18 alleged cases of off-label marketing in federal fraud cases unsealed between January 1996 and October 2010, the researchers identified three non–mutually exclusive goals of off-label marketing schemes. The commonest goal (85% of cases) was expansion of drug use to unapproved diseases (for example, gabapentin, which is approved for the treatment of specific types of epilepsy, was allegedly promoted as a therapy for patients with psychiatric diseases such as depression). The other goals were expansion to unapproved disease subtypes (for example, some antidepressant drugs approved for adults were allegedly promoted to pediatricians for use in children) and expansion to unapproved drug dosing strategies, typically higher doses. The researchers also identified four non–mutually exclusive types of marketing practices designed to achieve these goals. All of the whistleblowers alleged prescriber-related practices (including providing financial incentives and free samples to physicians), and most alleged internal practices intended to bolster off-label marketing, such as sales quotas that could only be met if the manufacturer's sales representatives promoted off-label drug use. Payer-related practices (for example, discussions with prescribers about ways to ensure insurance reimbursement for off-label prescriptions) and consumer-related practices (most commonly, the review of confidential patient charts to identify consumers who could be off-label users) were also alleged.
What Do These Findings Mean?
These findings suggest that off-labeling marketing practices extend to many parts of the health care delivery system. Because these practices were alleged by whistleblowers and were not the subject of testimony in a full trial, some of the practices identified by the researchers were not confirmed. Conversely, because most of the whistleblowers were US-based sales representatives, there may be other goals and strategies that this study has not identified. Nevertheless, these findings provide a useful snapshot of off-label marketing strategies and practices allegedly employed in the US over the past 15 years, which can now be used to develop new regulatory strategies aimed at effective oversight of off-label marketing. Importantly, however, these findings suggest that no regulatory strategy will be complete and effective unless physicians themselves fully understand the range of off-label marketing practices and their consequences for public health and act as a bulwark against continued efforts to engage in off-label promotion.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000431.
The US Food and Drug Administration provides detailed information about drug approval in the US for consumers and for health professionals; its Bad Ad Program aims to educate health care providers about the role they can play in ensuring that prescription drug advertising and promotion is truthful and not misleading.
The American Cancer Society has a page about off-label drug use
Wikipedia has pages on prescription drugs, on pharmaceutical marketing, and on off-label drug use (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Taxpayers Against Fraud is a nonprofit organization dedicated to helping whistleblowers, and it presents up-to-date information about False Claims Act cases
The Government Accountability Project is a nonprofit organization that seeks to promote corporate and government accountability by protecting whistleblowers, advancing occupational free speech, and empowering citizen activists
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
doi:10.1371/journal.pmed.1000431
PMCID: PMC3071370  PMID: 21483716
14.  Underestimating the Toxicological Challenges Associated with the Use of Herbal Medicinal Products in Developing Countries 
BioMed Research International  2013;2013:804086.
Various reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. The World Health Organisation indicates that 80% of the Asian and African populations rely on traditional medicine as the primary method for their health care needs. Since time immemorial and despite the beneficial and traditional roles of herbs in different communities, the toxicity and herb-drug interactions that emanate from this practice have led to severe adverse effects and fatalities. As a result of the perception that herbal medicinal products have low risk, consumers usually disregard any association between their use and any adverse reactions hence leading to underreporting of adverse reactions. This is particularly common in developing countries and has led to a paucity of scientific data regarding the toxicity and interactions of locally used traditional herbal medicine. Other factors like general lack of compositional and toxicological information of herbs and poor quality of adverse reaction case reports present hurdles which are highly underestimated by the population in the developing world. This review paper addresses these toxicological challenges and calls for natural health product regulations as well as for protocols and guidance documents on safety and toxicity testing of herbal medicinal products.
doi:10.1155/2013/804086
PMCID: PMC3791562  PMID: 24163821
15.  Roles of Chemical Complexity and Evolutionary Theory in Some Hepatic and Intestinal Enzymatic Systems in Chemical Reproducibility and Clinical Efficiency of Herbal Derivatives 
The Scientific World Journal  2014;2014:732045.
Despite the great marketing success, most physicians attribute poor efficacy to herbals. This perception is due to two situations that are an integral part of the herbal topic. The first is the poor phytochemical reproducibility obtained during the production process of herbal extracts, as herbal extracts are not always standardized in the whole manufacturing process, but only in their titer. The second problem is linked to the evolution of important enzymatic systems: cytochromes and ABC proteins. They are both enzyme classes with detoxifying properties and seem to have evolved from the molecular mould provided by active plant substances. During the evolution, as still happens today, polyphenols, saponins, terpenes, and alkaloids were ingested together with food. They do not possess any nutritional value but seem to be provided with a potential pharmacological activity. Cytochromes and ABC proteins, which evolved over time to detoxify food from vegetable chemical “actives,” now seem to limit the action of herbal derivatives. The comprehension of these 2 events may explain the origin of the widespread scepticism of physicians about herbal medicine and suggests that, after correct herbal standardization, use of antagonists of cytochromes and ABC systems will make it possible to recover their pharmacological potential.
doi:10.1155/2014/732045
PMCID: PMC3997956  PMID: 24977222
16.  A Systematic Review of the Reporting of Adverse Events Associated With Medical Herb Use Among Children 
Purpose:
Information about the safety of herbal medicine often comes from case reports published in the medical literature, thus necessitating good quality reporting of these adverse events. The purpose of this study was to perform a systematic review of the comprehensiveness of reporting of published case reports of adverse events associated with herb use in the pediatric population.
Methods:
Electronic literature search included 7 databases and a manual search of retrieved articles from inception through 2010. We included published case reports and case series that reported an adverse event associated with exposure to an herbal product by children under the age of 18 years old. We used descriptive statistics. Based on the International Society of Epidemiology's “Guidelines for Submitting Adverse Events Reports for Publication,” we developed and assigned a guideline adherence score (0-17) to each case report.
Results:
Ninety-six unique journal papers were identified and represented 128 cases. Of the 128 cases, 37% occurred in children under 2 years old, 38% between the ages of 2 and 8 years old, and 23% between the ages of 9 and 18 years old. Twenty-nine percent of cases were the result of an intentional ingestion while 36% were from an unintentional ingestion. Fifty-two percent of cases documented the Latin binomial of the herb ingredients; 41% documented plant part. Thirty-two percent of the cases reported laboratory testing of the herb, 20% documented the manufacturer of the product, and 22% percent included an assessment of the potential concomitant therapies that could have been influential in the adverse events. Mean guideline adherence score was 12.5 (range 6-17).
Conclusions:
There is considerable need for improvement in reporting adverse events in children following herb use. Without better quality reporting, adverse event reports cannot be interpreted reliably and do not contribute in a meaningful way to guiding recommendations for medicinal herb use.
doi:10.7453/gahmj.2012.071
PMCID: PMC3833530  PMID: 24416663
Herbs; adverse events; pediatric; systematic review
17.  DNA barcoding detects contamination and substitution in North American herbal products 
BMC Medicine  2013;11:222.
Background
Herbal products available to consumers in the marketplace may be contaminated or substituted with alternative plant species and fillers that are not listed on the labels. According to the World Health Organization, the adulteration of herbal products is a threat to consumer safety. Our research aimed to investigate herbal product integrity and authenticity with the goal of protecting consumers from health risks associated with product substitution and contamination.
Methods
We used DNA barcoding to conduct a blind test of the authenticity for (i) 44 herbal products representing 12 companies and 30 different species of herbs, and (ii) 50 leaf samples collected from 42 herbal species. Our laboratory also assembled the first standard reference material (SRM) herbal barcode library from 100 herbal species of known provenance that were used to identify the unknown herbal products and leaf samples.
Results
We recovered DNA barcodes from most herbal products (91%) and all leaf samples (100%), with 95% species resolution using a tiered approach (rbcL + ITS2). Most (59%) of the products tested contained DNA barcodes from plant species not listed on the labels. Although we were able to authenticate almost half (48%) of the products, one-third of these also contained contaminants and or fillers not listed on the label. Product substitution occurred in 30/44 of the products tested and only 2/12 companies had products without any substitution, contamination or fillers. Some of the contaminants we found pose serious health risks to consumers.
Conclusions
Most of the herbal products tested were of poor quality, including considerable product substitution, contamination and use of fillers. These activities dilute the effectiveness of otherwise useful remedies, lowering the perceived value of all related products because of a lack of consumer confidence in them. We suggest that the herbal industry should embrace DNA barcoding for authenticating herbal products through testing of raw materials used in manufacturing products. The use of an SRM DNA herbal barcode library for testing bulk materials could provide a method for 'best practices? in the manufacturing of herbal products. This would provide consumers with safe, high quality herbal products.
doi:10.1186/1741-7015-11-222
PMCID: PMC3851815  PMID: 24120035
18.  Tobacco Company Efforts to Influence the Food and Drug Administration-Commissioned Institute of Medicine Report Clearing the Smoke: An Analysis of Documents Released through Litigation 
PLoS Medicine  2013;10(5):e1001450.
Stanton Glantz and colleagues investigate efforts by tobacco companies to influence Clearing the Smoke, a 2001 Institute of Medicine report on harm reduction tobacco products.
Please see later in the article for the Editors' Summary
Background
Spurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco “harm reduction,” leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine how the tobacco industry organized to try to influence the IOM committee that prepared the report.
Methods and Findings
We analyzed previously secret tobacco industry documents in the University of California, San Francisco Legacy Tobacco Documents Library, and IOM public access files. (A limitation of this method includes the fact that the tobacco companies have withheld some possibly relevant documents.) Tobacco companies considered the IOM report to have high-stakes regulatory implications. They developed and implemented strategies with consulting and legal firms to access the IOM proceedings. When the IOM study staff invited the companies to provide information on exposure and disease markers, clinical trial design for safety and efficacy, and implications for initiation and cessation, tobacco company lawyers, consultants, and in-house regulatory staff shaped presentations from company scientists. Although the available evidence does not permit drawing cause-and-effect conclusions, and the IOM may have come to the same conclusions without the influence of the tobacco industry, the companies were pleased with the final report, particularly the recommendations for a tiered claims system (with separate tiers for exposure and risk, which they believed would ease the process of qualifying for a claim) and license to sell products comparable to existing conventional cigarettes (“substantial equivalence”) without prior regulatory approval. Some principles from the IOM report, including elements of the substantial equivalence recommendation, appear in the 2009 Family Smoking Prevention and Tobacco Control Act.
Conclusions
Tobacco companies strategically interacted with the IOM to win several favored scientific and regulatory recommendations.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Up to half of tobacco users will die of cancer, lung disease, heart disease, stroke, or another tobacco-related disease. Cigarettes and other tobacco products cause disease because they expose their users to nicotine and numerous other toxic chemicals. Tobacco companies have been working to develop a “safe” cigarette for more than half a century. Initially, their attention focused on cigarettes that produced lower tar and nicotine yields in machine-smoking tests. These products were perceived as “safer” products by the public and scientists for many years, but it is now known that the use of low-yield cigarettes can actually expose smokers to higher levels of toxins than standard cigarettes. More recently, the tobacco companies have developed other products (for example, products that heat aerosols of nicotine, rather than burning the tobacco) that claim to reduce harm and the risk of tobacco-related disease, but they can only market these modified risk tobacco products in the US after obtaining Food and Drug Administration (FDA) approval. In 1999, the FDA commissioned the US Institute of Medicine (IOM, an influential source of independent expert advice on medical issues) to assess the science base for tobacco “harm reduction.” In 2001, the IOM published its report Clearing the Smoke: Assessing the Science Base for Tobacco Harm and Reduction, which, although controversial, set the tone for the development and regulation of tobacco products in the US, particularly those claiming to be less dangerous, in subsequent years.
Why Was This Study Done?
Tobacco companies have a long history of working to shape scientific discussions and agendas. For example, they have produced research results designed to “create controversy” about the dangers of smoking and secondhand smoke. In this study, the researchers investigate how tobacco companies organized to try to influence the IOM committee that prepared the Clearing the Smoke report on modified risk tobacco products by analyzing tobacco industry and IOM documents.
What Did the Researchers Do and Find?
The researchers searched the Legacy Tobacco Documents Library (a collection of internal tobacco industry documents released as a result of US litigation cases) for documents outlining how tobacco companies tried to influence the IOM Committee to Assess the Science Base for Tobacco Harm Reduction and created a timeline of events from the 1,000 or so documents they retrieved. They confirmed and supplemented this timeline using information in 80 files that detailed written interactions between the tobacco companies and the IOM committee, which they obtained through a public records access request. Analysis of these documents indicates that the tobacco companies considered the IOM report to have important regulatory implications, that they developed and implemented strategies with consulting and legal firms to access the IOM proceedings, and that tobacco company lawyers, consultants, and regulatory staff shaped presentations to the IOM committee by company scientists on various aspects of tobacco harm reduction products. The analysis also shows that tobacco companies were pleased with the final report, particularly its recommendation that tobacco products can be marketed with exposure or risk reduction claims provided the products substantially reduce exposure and provided the behavioral and health consequences of these products are determined in post-marketing surveillance and epidemiological studies (“tiered testing”) and its recommendation that, provided no claim of reduced exposure or risk is made, new products comparable to existing conventional cigarettes (“substantial equivalence”) can be marketed without prior regulatory approval.
What Do These Findings Mean?
These findings suggest that tobacco companies used their legal and regulatory staff to access the IOM committee that advised the FDA on modified risk tobacco products and that they used this access to deliver specific, carefully formulated messages designed to serve their business interests. Although these findings provide no evidence that the efforts of tobacco companies influenced the IOM committee in any way, they show that the companies were satisfied with the final IOM report and its recommendations, some of which have policy implications that continue to reverberate today. The researchers therefore call for the FDA and other regulatory bodies to remember that they are dealing with companies with a long history of intentionally misleading the public when assessing the information presented by tobacco companies as part of the regulatory process and to actively protect their public-health policies from the commercial interests of the tobacco industry.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001450.
This study is further discussed in a PLOS Medicine Perspective by Thomas Novotny
The World Health Organization provides information about the dangers of tobacco (in several languages); for information about the tobacco industry's influence on policy, see the 2009 World Health Organization report Tobacco interference with tobacco control
A PLOS Medicine Research Article by Heide Weishaar and colleagues describes tobacco company efforts to undermine the Framework Convention on Tobacco Control, an international instrument for tobacco control
Wikipedia has a page on tobacco harm reduction (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The IOM report Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction is available to read online
The Legacy Tobacco Documents Library is a public, searchable database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The University of California, San Francisco Center for Tobacco Control Research and Education is the focal point for University of California, San Francisco (UCSF) scientists in disciplines ranging from the molecular biology of nicotine addiction through political science who combine their efforts to eradicate the use of tobacco and tobacco-induced cancer and other diseases worldwide
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001450
PMCID: PMC3665841  PMID: 23723740
19.  Attitude and use of herbal medicines among pregnant women in Nigeria 
Background
The use of herbal medicines among pregnant women in Nigeria has not been widely studied.
Methods
Opinion of 595 pregnant women in three geopolitical zones in Nigeria on the use of herbal medicines, safety on usage, knowledge of potential effects of herbal remedies on the fetus and potential benefits or harms that may be derived from combining herbal remedies with conventional therapies were obtained using a structured questionnaire between September 2007 and March 2008. Descriptive statistics and Fisher's exact tests were used at 95% confidence level to evaluate the data obtained. Level of significance was set at p < 0.05.
Results
More than two-third of respondents [67.5%] had used herbal medicines in crude forms or as pharmaceutical prepackaged dosage forms, with 74.3% preferring self-prepared formulations. Almost 30% who were using herbal medicine at the time of the study believed that the use of herbal medicines during pregnancy is safe. Respondents' reasons for taking herbal medications were varied and included reasons such as herbs having better efficacy than conventional medicines [22.4%], herbs being natural, are safer to use during pregnancy than conventional medicines [21.1%], low efficacy of conventional medicines [19.7%], easier access to herbal medicines [11.2%], traditional and cultural belief in herbal medicines to cure many illnesses [12.5%], and comparatively low cost of herbal medicines [5.9%].
Over half the respondents, 56.6% did not support combining herbal medicines with conventional drugs to forestall drug-herb interaction. About 33.4% respondents believed herbal medicines possess no adverse effects while 181 [30.4%] were of the opinion that adverse/side effects of some herbal medicines could be dangerous. Marital status, geopolitical zones, and educational qualification of respondents had statistically significant effects on respondents views on side effects of herbal medicines [p < 0.05)] while only geopolitical zones and educational qualifications seemed to have influence on respondents' opinion on the harmful effects of herbal medicines to the fetus [p < 0.05].
Conclusion
The study emphasized the wide spread use of herbal medicines by pregnant women in Nigeria highlighting an urgent need for health care practitioners and other health care givers to be aware of this practice and make efforts in obtaining information about herb use during ante-natal care. This will help forestall possible interaction between herbal and conventional medicines.
doi:10.1186/1472-6882-9-53
PMCID: PMC2808296  PMID: 20043858
20.  Factors associated with herbal use among urban multiethnic primary care patients: a cross-sectional survey 
Background
The use of herbal supplements in the United States has become increasingly popular. The prevalence of herbal use among primary care patients varies in previous studies; the pattern of herbal use among urban racially/ethnically diverse primary care patients has not been widely studied. The primary objectives of this study were to describe the use of herbs by ethnically diverse primary care patients in a large metropolitan area and to examine factors associated with such use. The secondary objective was to investigate perceptions about and patterns of herbal use.
Methods
Data for a cross-sectional survey were collected at primary care practices affiliated with the Southern Primary-care Urban Research Network (SPUR-Net) in Houston, Texas, from September 2002 to March 2003. To participate in the study, patients had to be at least 18 years of age and visiting one of the SPUR-Net clinics for routine, nonacute care. Survey questions were available in both English and Spanish.
Results
A total of 322 patients who had complete information on race/ethnicity were included in the analysis. Overall, 36% of the surveyed patients (n = 322) indicated use of herbs, with wide variability among ethnic groups: 50% of Hispanics, 50% of Asians, 41% of Whites, and 22% of African-Americans. Significant factors associated with an individual's herbal use were ethnicity other than African-American, having an immigrant family history, and reporting herbal use by other family members. About 40% of survey respondents believed that taking prescription medications and herbal medicines together was more effective than taking either alone. One-third of herbal users reported using herbs on a daily basis. More Whites (67%) disclosed their herbal use to their health-care providers than did African-Americans (45%), Hispanics (31%), or Asians (31%).
Conclusions
Racial/ethnic differences in herbal use were apparent among this sample of urban multiethnic adult primary care patients. Associated factors of herbal use were non-African-American ethnicity, immigrant family history, and herbal use among family members. Whereas Hispanics and Asians reported the highest rates of herbal use, they were the least likely to disclose their use to health-care professionals. These findings are important for ensuring medication safety in primary care practices.
doi:10.1186/1472-6882-4-18
PMCID: PMC539258  PMID: 15575960
21.  Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis 
BMC Medicine  2015;13:26.
Background
Post-marketing withdrawal of medicinal products because of deaths can be occasioned by evidence obtained from case reports, observational studies, randomized trials, or systematic reviews. There have been no studies of the pattern of withdrawals of medicinal products to which deaths have been specifically attributed and the evidence that affects such decisions. Our objectives were to identify medicinal products that were withdrawn after marketing in association with deaths, to search for the evidence on which withdrawal decisions were based, and to analyse the delays involved and the worldwide patterns of withdrawal.
Methods
We searched the World Health Organization’s Consolidated List of [Medicinal] Products, drug regulatory authorities’ websites, PubMed, Google Scholar, and textbooks on adverse drug reactions. We included medicinal products for which death was specifically mentioned as a reason for withdrawal from the market. Non-human medicines, herbal products, and non-prescription medicines were excluded. One reviewer extracted the data and a second reviewer verified them independently.
Results
We found 95 drugs for which death was documented as a reason for withdrawal between 1950 and 2013. All were withdrawn in at least one country, but at least 16 remained on the market in some countries. Withdrawals were more common in European countries; few were recorded in Africa (5.3%). The more recent the launch date, the sooner deaths were reported. However, in 47% of cases more than 2 years elapsed between the first report of a death and withdrawal of the drug, and the interval between the first report of a death attributed to a medicinal product and eventual withdrawal of the product has not improved over the last 60 years.
Conclusions
These results suggest that some deaths associated with these products could have been avoided. Manufacturers and regulatory authorities should expedite investigations when deaths are reported as suspected adverse drug reactions and consider early suspensions. Increased transparency in the publication of clinical trials data and improved international co-ordination could shorten the delays in withdrawing dangerous medicinal products after reports of deaths and obviate discrepancies in drug withdrawals in different countries.
Please see related article: http://dx.doi.org/10.1186/s12916-015-0270-2.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0262-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0262-7
PMCID: PMC4318389  PMID: 25651859
Death; Drug withdrawal; Review; Voluntary recall
22.  Effects and treatment methods of acupuncture and herbal medicine for premenstrual syndrome/premenstrual dysphoric disorder: systematic review 
Background
During their reproductive years about 10% of women experience some kind of symptoms before menstruation (PMS) in a degree that affects their quality of life (QOL). Acupuncture and herbal medicine has been a recent favorable therapeutic approach. Thus we aimed to review the effects of acupuncture and herbal medicine in the past decade as a preceding research in order to further investigate the most effective Korean Medicine treatment for PMS/PMDD.
Methods
A systematic literature search was conducted using electronic databases on studies published between 2002 and 2012. Our review included randomized controlled clinical trials (RCTs) of acupuncture and herbal medicine for PMS/PMDD. Interventions include acupuncture or herbal medicine. Clinical information including statistical tests was extracted from the articles and summarized in tabular form or in the text. Study outcomes were presented as the rate of improvement (%) and/or end-of-treatment scores.
Results
The search yielded 19 studies. In screening the RCTs, 8 studies in acupuncture and 11 studies in herbal medicine that matched the criteria were identified. Different acupuncture techniques including traditional acupuncture, hand acupuncture and moxibustion, and traditional acupuncture technique with auricular points, have been selected for analysis. In herbal medicine, studies on Vitex Agnus castus, Hypericum perforatum, Xiao yao san, Elsholtzia splendens, Cirsium japonicum, and Gingko biloba L. were identified. Experimental groups with Acupuncture and herbal medicine treatment (all herbal medicine except Cirsium japonicum) had significantly improved results regarding PMS/PMDD.
Conclusions
Limited evidence supports the efficacy of alternative medicinal interventions such as acupuncture and herbal medicine in controlling premenstrual syndrome and premenstrual dysphoric disorder. Acupuncture and herbal medicine treatments for premenstrual syndrome and premenstrual dysphoric disorder showed a 50% or better reduction of symptoms compared to the initial state. In both acupuncture and herbal medical interventions, there have been no serious adverse events reported, proving the safety of the interventions while most of the interventions provided over 50% relief of symptoms associated with PMS/PMDD. Stricter diagnostic criteria may have excluded many participants from some studies. Also, depending on the severity of symptoms, the rate of improvement in the outcomes of the studies may have greatly differed.
doi:10.1186/1472-6882-14-11
PMCID: PMC3898234  PMID: 24410911
Premenstrual syndrome; Premenstrual dysphoric disorder; Acupuncture; Herbal medicine; TCM; CAM; PMS; PMDD
23.  Herbal medicine use among urban residents in Lagos, Nigeria 
Background
Over three-quarter of the world's population is using herbal medicines with an increasing trend globally. Herbal medicines may be beneficial but are not completely harmless.
This study aimed to assess the extent of use and the general knowledge of the benefits and safety of herbal medicines among urban residents in Lagos, Nigeria.
Methods
The study involved 388 participants recruited by cluster and random sampling techniques. Participants were interviewed with a structured open- and close-ended questionnaire.
The information obtained comprises the demography and types of herbal medicines used by the respondents; indications for their use; the sources, benefits and adverse effects of the herbal medicines they used.
Results
A total of 12 herbal medicines (crude or refined) were used by the respondents, either alone or in combination with other herbal medicines. Herbal medicines were reportedly used by 259 (66.8%) respondents. 'Agbo jedi-jedi' (35%) was the most frequently used herbal medicine preparation, followed by 'agbo-iba' (27.5%) and Oroki herbal mixture® (9%). Family and friends had a marked influence on 78.4% of the respondents who used herbal medicine preparations. Herbal medicines were considered safe by half of the respondents despite 20.8% of those who experienced mild to moderate adverse effects.
Conclusions
Herbal medicine is popular among the respondents but they appear to be ignorant of its potential toxicities. It may be necessary to evaluate the safety, efficacy and quality of herbal medicines and their products through randomised clinical trial studies. Public enlightenment programme about safe use of herbal medicines may be necessary as a means of minimizing the potential adverse effects.
doi:10.1186/1472-6882-11-117
PMCID: PMC3252251  PMID: 22117933
24.  Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis 
PLoS Medicine  2013;10(3):e1001407.
In an evaluation of medicines approved by the European Medicines Agency 2000 to 2010, Ruben Duijnhoven and colleagues find that the number of patients evaluated for medicines approved for chronic use are inadequate for evaluation of safety or long-term efficacy.
Background
At the time of approval of a new medicine, there are few long-term data on the medicine's benefit–risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations.
Methods and Findings
All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968–3,195) for standard medicines and 438 (IQR 132–915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462–4,135) than medication for intermediate (878, IQR 513–1,559) or short-term use (1,315, IQR 609–2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo).
Conclusions
For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any new medicine is marketed for the treatment of a human disease, it has to go through extensive laboratory and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments, and test these interventions in disease models, some of which involve animals. The safety and efficacy of potential new interventions is then investigated in a series of clinical trials—studies in which the new treatment is tested in selected groups of patients under strictly controlled conditions, first to determine whether the drug is tolerated by humans and then to assess its efficacy. Finally, the results of these trials are reviewed by the government body responsible for drug approval; in the US, this body is the Food and Drug Administration, and in the European Union, the European Medicines Agency (EMA) is responsible for the scientific evaluation and approval of new medicines.
Why Was This Study Done?
Clinical trials are primarily designed to test the efficacy—the ability to produce the desired therapeutic effect—of new medicines. The number of patients needed to establish efficacy determines the size of a clinical trial, and the indications for which efficacy must be shown determine the trial's duration. However, identifying adverse effects of drugs generally requires the drug to be taken by more patients than are required to show efficacy, so the information about adverse effects is often relatively limited at the end of clinical testing. Consequently, when new medicines are approved, their benefit–risk ratios are often poorly defined, even though physicians need this information to decide which treatment to recommend to their patients. For the evaluation of risk or adverse effects of medicines being developed for chronic (long-term) treatment of non-life-threatening diseases, current guidelines recommend that at least 1,000–1,500 patients are exposed to the new drug and that 300 and 100 patients use the drug for six and twelve months, respectively, before approval. But are these guidelines being followed? In this database analysis, the researchers use data collected by the EMA to determine how many patients are exposed to new medicines before approval in the European Union and how many are exposed for extended periods of time to medicines intended for chronic use.
What Did the Researchers Do and Find?
Using the European Commission's Community Register of Medicinal Products, the researchers identified 161 standard medicines and 39 orphan medicines (medicines to treat or prevent rare life-threatening diseases) that contained new active substances and that were approved in the European Union between 2000 and 2010. They extracted information on the total number of patients studied and on the number exposed to the medicines for six months and twelve months before approval of each medicine from EMA's European public assessment reports. The average number of patients studied before approval was 1,708 for standard medicines and 438 for orphan medicines (marketing approval is easier to obtain for orphan medicines than for standard medicines to encourage drug companies to develop medicines that might otherwise be unprofitable). On average, medicines for chronic use (for example, asthma medications) were studied in more patients (2,338) than those for intermediate use such as anticancer drugs (878), or short-term use such as antibiotics (1,315). The safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and twelve months in 46.4% and 58.4% of new medicines, respectively. Finally, among the 84 medicines intended for chronic use, 72 were studied in at least 300 patients for six months, and 70 were studied in at least 100 patients for twelve months.
What Do These Findings Mean?
These findings suggest that although the number of patients studied before approval is sufficient to determine the short-term efficacy of new medicines, it is insufficient to determine safety or long-term efficacy. Any move by drug approval bodies to require pharmaceutical companies to increase the total number of patients exposed to a drug, or the number exposed for extended periods of time to drugs intended for chronic use, would inevitably delay the entry of new products into the market, which likely would be unacceptable to patients and healthcare providers. Nevertheless, the researchers suggest that a reevaluation of the study size and long-term data requirements that need to be met for the approval of new medicines, particularly those designed for long-term use, is merited. They also stress the need for continued study of both the safety and efficacy of new medicines after approval and the importance of post-marketing studies that actively examine safety issues.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001407.
The European Medicines Agency (EMA) provides information about all aspects of the scientific evaluation and approval of new medicines in the European Union; its European public assessment reports are publicly available
The European Commission's Community Register of Medicinal Products is a publicly searchable database of medicinal products approved for human use in the European Union
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals
The US National Institutes of Health provides information (including personal stories) about clinical trials
doi:10.1371/journal.pmed.1001407
PMCID: PMC3601954  PMID: 23526887
25.  A Systematic Review of the Reporting of Adverse Events Associated with Medical Herb Use among Children 
Purpose
To perform a systematic review of adverse events associated with herb use in the pediatric population. Since many health care providers get their information about the safety of herbal medicine from case reports published in the medical literature, it is important to assess the quality of these case reports.
Methods
Electronic literature search included 7 databases and a manual search of retrieved articles from inception through 2010. We included case reports and case series that reported an adverse event associated with exposure to an herbal product by children under the age of 18 years old. Based on the International Society of Epidemiology's “Guidelines for Submitting Adverse Events Reports for Publication”, we assigned a guideline adherence score (0-17) to each case report.
Results
Ninety-six unique journal papers were identified and represented 128 cases. Of the 128 cases, 37% occurred in children under 2 years old, 38% between the ages of 2 – 8 years old, and 23 % between the ages 9-18 years old. In a few cases, the child used a product that was contaminated (5%) or adulterated (2%). Twenty-nine percent of cases were the result of an intentional ingestion while 36% were from an unintentional ingestion. Mean guideline adherence score was 12.5 (range 6 – 17).
Conclusions
There is considerable need for improvement in reporting adverse events in children following herb use. Without better quality reporting, adverse event reports cannot be interpreted reliably, and do not contribute in a meaningful way to guiding clinical recommendations.
doi:10.1016/j.jaci.2009.01.001
PMCID: PMC3891367  PMID: 19203654
herbs; adverse events; pediatric; systematic review

Results 1-25 (1001021)