Introduction Medical devices (MedDevs) and medicines are assessed (and monitored) differently before and after launch. There are products for repeated oral ingestion that are marketed in the European Union as MedDevs.
Objectives and methods To illustrate the consequences of these differences in assessment, we compared the leaflet information of three MedDevs with the standards for medicines and with published evidence at launch. As examples, gelatin tannate (GT), its combination with tyndalised probiotics (TP) (GTTP) for diarrhoea and a gel containing hyaluronic acid (HA)/chondroitin sulfate (CS)/poloxamer (Pol407) (HACSPol) for gastro-oesophageal reflux disease were examined.
Results Applying standards for medicines, product composition is insufficiently defined in the MedDev leaflet (eg, plant origin, polymerisation grade, dose and ratio of the relevant constituents). As no age limit is mentioned in the leaflets, all 3 products allow use in children from birth onwards, although published clinical documentation in children was poor (GT) or lacking (GTTP and HACSPol). MedDev leaflets do not mention adverse events (AEs), while literature search suggests safety concerns such as tannic acid (TA) cytotoxicity, potentially more diarrhoea/AEs with TP, use of doses higher than established safe (TA and HA) and lack of chronic toxicity studies for oral Pol407. None refers to interactions with medicines, although some ingredients may affect medicine absorption.
Conclusion Although these MedDevs require repeated oral intake as do medicines, their assessment and monitoring differ significantly from the standards for medicines. Compared with medicines, MedDevs for repeated oral use are poorly labelled and rely on very limited clinical information at market release.
- Medical Devices legislation
- clinical pharmacology
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What is already known on this topic?
Marketing of medical devices (MedDevs) is regulated differently from marketing of medicines.
Current legislation resulted in the marketing of MedDev perceived as if it were medicines, without review by the European Medicines Agency or competent national medicinal authorities.
What this study adds?
Using an illustrative approach, leaflet content of orally ingested MedDevs is shown not to attain the quality of leaflets for medicines.
Efficacy and safety in children are not granted at launch of these MedDevs: randomised placebo-controlled trials to document efficacy and safety in children were limited(initiated after launch in the case of gelatin tannate (GT)), or even still lacking (combination of GT with tyndalised probiotics, and hyaluronic acid/chondroitin sulfate/poloxamer).
Based on this illustrative approach, we highly recommend that MedDev regulation needs further revision, reconsidering MedDevs for repeated oral intake and including the needs of children.
The term ‘Medical device (MedDev)’ covers a wide array of products for medicinal use, from wound dressings, surgical instruments to implants. European regulation defines a MedDev as ‘any instrument… material or article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following medical purposes: … prevention… treatment or alleviation of disease… modification of anatomy or of a physiological or pathological process… AND does not achieve its principal intended action by pharmacological, immunological, or metabolic means in or on the human body, but which may be assisted in its function by such means’.1 MedDevs are classified according to their intended purpose and inherent risks (classes I, IIa, IIb and III).1
MedDevs are regulated in the European Union (EU) by the Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs (GROW), requiring local notification of ‘CE-certified’ products.2 3 The digits following a CE mark identify the notifying body, an EU-accredited private company contracted and paid by the manufacturer or marketing company to supply certification to enter the market. A CE mark without digits indicates the company has self-marked/self-certified the product.4 While the US Food and Drug Administration (FDA) requires evidence of safety and efficacy of MedDevs, premarket evaluation of MedDevs in the EU only requires safety justification, and eventually ‘performance’ demonstration.5 6 Pharmacokinetic, pharmacodynamic and efficacy studies are not required for MedDevs.5 6 Following certification, MedDevs enter the EU as over-the-counter (OTC) products in (drug)stores and pharmacies through free movement of goods by CE marking. There is no claim control, and direct-to-consumer promotion is permitted. In contrast, medicine ‘evaluation’ requires pharmacokinetic, pharmacodynamic and clinical efficacy studies to enter the EU by the European Medicines Agency (EMA)7. Medicines are subjected to strict claim control and are prescription-only at launch. Direct-to-consumer promotion is only permitted for OTC products and is controlled by the authorities. Table 1 summarises the main differences in definition, regulatory approach and (post)marketing. Particularly for children, this differs significantly from paediatric medicine development.8–11
The last part of the MedDev definition (‘does not achieve its principal intended action by pharmacological, immunological, or metabolic means in or on the human body, but which may be assisted in its function by such means’) leaves room for different interpretations. By claiming a barrier mechanism as principal mode of action (a prerequisite for borderline products to follow the MedDev approach)12 products for repeated oral intake with medicinal indication are marketed in the EU as MedDevs. When challenging doctors, pharmacists and patients with such MedDevs, or read press articles,13 we believe that these products could be perceived as medicines, likely because of their indication, formulation and repeated mode of administration similar as for a medicinal drug. Van Norman et al, comparing European and US approval processes of medicines and MedDevs pointed to the fact that: ‘Although the CE mark is often mistakenly equated to being a seal of quality… CE marking does not represent quality, even though consumers often assume that products bearing CE marking are of better quality’.5 As there is a clear difference between MedDevs and medicines in assessment before and after launch in the EU (table 1), we sought to demonstrate how the information presented for MedDevs intented for repeated ingestion differs from that expected for a medicine, using three MedDevs promoted for gastrointestinal problems as examples.
We compared the leaflet information of three MedDevs with the standards required for medicines.7 Examples were chosen because as clinical gastroenterologists, we were confronted with promotion for these products, and were surprised to find they were marketed as medical devices and not as medicines. Leaflets were screened for information on product composition and ingredients, usage/indications, clinical efficacy, interactions, toxicity and (long-term) safety. In addition, this was compared with published evidence on efficacy and safety of the specific MedDev in children at time of launch (appendix for search strategy). We analysed information on gelatin tannate (GT), marketed as Tasectan/Gelenterum in the EU,14 and its combination with tyndalised (heat-killed) probiotics (TP) (GTTP), internet available as Tasectan Duo für Kinder (Austria) and Gelenterum Duo (Italy),15 16 both promoted to treat diarrhoea, also in children. Furthermore, the hyaluronic acid (HA), chondroitin sulfate (CS) and poloxamer (Pol 407) (HACSPol) combination, launched as Ziverel/Esoxx in Italy, Spain, France, Austria and the Benelux17 to treat gastro-oesophageal reflux disease (GORD) was evaluated. SH prepared the initial analysis, which was cross-checked by MVW on the basis of the original leaflets.
Table 2 lists the ingredients with their characteristics, together with the information not provided, applying quality requirements for medicines. When using this approach, composition and dose are not sufficiently accurately defined for all three products. Tasectan sachets contain 250 mg GT powder, but the exact tannate (type, origin, ratio tannic acid (TA)/gelatin (G)) is not specified. Publications referring to this MedDev intermix the substance TA (usually per pharmacopoeia from oak galls) with gallic acid, elagitannins, wine/fruit (non-hydrolysable), vegetable and carob tannins18–20 and even with propyl gallate (Chemical Abstract Service (CAS) number provided by manufacturer).21 Tannin chemistry is complex: TA/G ratios and dissociation of GT also depends on the polymerisation grade of G (Bloom strength).22–24 This information is lacking in the leaflet, so the exact TA dose and exposure are unknown. Moreover, pharmacological activities and toxicities of tannins and by-products differ according to their origin (eg, differing between Chinese and Turkish galls).25 26 Tannins also show structure-related specificity,22 27 depending on their source. For GTTP, the powder additionally contains TPs (see table 2), but units or mg doses remain undisclosed.
The HACSPol gel leaflet does not disclose HA, CS or Pol407 doses; only a per cent composition was provided by the manufacturer on our request so that daily exposure has been calculated (table 2).28 Although the molecular weight (MW) and HA polymerisation grade affect absorption and its pharmacological actions29 30, these characteristics are not addressed in the leaflet. Pol407 is a surfactant-enhancing viscosity, affecting delivery of drugs, peptides/proteins and particles and is not developed for recurrent oral consumption.31 32
Efficacy in children
Table 3 lists the major claims and findings in children, as stated in the MedDev leaflet, including age limit and treatment duration. As no age limit is mentioned in the leaflet, all 3 products allow use in children from birth onwards. No well-performed randomised clinical trials to demonstrate efficacy and safety in children could be identified at time of MedDev launch. GT and GTTP claim effective relief of diarrhoea of various origin within 12 hours.14–16 33 Based on literature search, the only support identified for the 12-hour claim at time of launch were open label observations in two cohorts. First, a cohort of 97 children with acute diarrhoea receiving oral rehydration solution (ORS)+GT.34 Their characteristics and outcomes were published 3 years earlier than the findings in the control cohort of 114 children on ORS only.35 From a medicine evaluation perspective, these studies had—besides the open cohort design—other limitations (concomitant antibiotics allowed but not documented; diagnostic criteria for diarrhoea and stool rating scales not described; the ORS group having a significantly worse stool frequency at baseline; efficacy based on this parameter at 12 hours only; and no further observations confirming efficacy beyond 12 hours).35 A placebo-controlled study in adults at product launch (20 patients/group) did not confirm this 12-hour claim.36 Postlaunch studies are of low quality, except for one recent well-randomised, placebo-controlled study showing lack of efficacy of GT in acute gastroenteritis in children.37 A prior small open Italian study (country of notification), labelled ‘prospective’ in 2013,38 was republished in 2017 as ‘single-blind study’ with discrepant results.19 Moreover, the study protocol was posted in december 2015 more than 2 years after the study was started and published as an abstract (2013)rendering it non ICMJE (International Committee of Medical Journal Editors) compliant (clinicaltrials.gov).39 Baseline patient and stool features were poorly characterised. A more recent Turkish placebo-controlled study on GT, claiming efficacy, mixed antibiotic-associated and infectious diarrhoea.40 Placebo composition, baseline characteristics per treatment group and primary efficacy parameters were not disclosed. Unusual in acute gastroenteritis, 80% of the children still vomited 36 hours after starting ORS+placebo, while the proportion with fever was different between text (65%) and figure (12%).40
For GTTP (also notified in Italy), no proof was found in the literature for the claimed ‘normalisation of dysbacteriosis’, associated with relief of diarrhoea in inflammatory bowel conditions according to the leaflet. Killed TP strains may have immunomodulatory effects by the release bacteriocins and anti-inflammatory agents41–43 and hence do not necessarily act as a barrier. Some TPs have been associated with increased diarrhoea and gastrointestinal symptoms in critically ill patients and in healthy newborns; an international panel assessing the safety of probiotics for human use concludes that ‘Products comprising heat-killed microbes should not be made available to infants until any adverse effects (AEs) from such products are better understood’.44 References to clinical trials with GTTP were not found. Two references recommending GTTP for chronic diarrhoea did not disclose studies with GTTP and at best referred to a review with Saccharomyces boulardii, not present in GTTP.45–47
HACSPol is promoted for mucosal repair and relief of GORD symptoms.17 Clinical documentation is poor and limited to adults treated for 2 weeks add-on to proton pump inhibitors (PPIs), mixing naïve and PPI-resistant patients, with Vaseline oil in water as placebo.48 49 There are no data comparing HACSPol with PPIs or the single ingredients (justifying the combination), nor data on use beyond 2 weeks. The company was contacted but has not provided data in children, except for the information that ‘one child’ was included in the clinical trial mentioned earlier.48
Safety, with focus on children
Table 4 summarises the safety information with regard to AEs, toxicity, overdose and interactions, as retrieved from published evidence. The assessed MedDev leaflets do not mention AEs nor overdose instructions.14–17 Experience in clinical trials was limited, both with regard to length of treatment and absolute number of subjects treated or even lacking in children at time of launch.
No active monitoring surveillance studies were retrieved, although safety concerns regarding several ingredients can be raised (table 4). Hydrolysable tannates have a complex metabolic fate, as they are hydrolysed, bacterially fermented and absorbed.22 23 Tannates (ng/mL–µM range) inhibit the sodium-glucose transporter, digestive and other enzymes50–53 depress the immune response54 55 have been associated with hepatoxicity56 and display cytotoxicity57 also in human enterocytes.58 They are not classifiable as safe with regard to carcinogenicity in humans.56 59–61 The TA dose in GT and in GTTP (1/20 of LD50 in the dog)62 surpasses doses considered safe for use as food additive in humans and animals by the European Food Safety Authority (EFSA), its FEEDAP panels or FDA.63–66 The adult mg dose of GT (500 mg, 4–6 times/day) corresponds to the dose of Tannalbin, a medicinal tannate–(chicken) protein-complex that is only allowed for use in children from 5 years onwards in Germany.67 As herbal tannates have not been studied in children, EMA does not recommend their use below 12 years.68 In the USA, oral tannate is on the list of OTC products for which efficacy and safety is unproven69: ‘albumin tannate/tannin albuminate’, a TA complex with albumin, is no longer available, while Factmed.com (an online platform analysing FDA data) still reveals its particular AE profile: this includes anaemia and low numbers of various blood cells.70 This is in line with the potential of tannates to bind iron and other minerals, proteins and many organic compounds.71–74
The concept that TPs are safer than their living strains cannot be taken for granted. As mentioned, TPs may result in more diarrhoea and AEs, calling for well-controlled studies on GTTP.41 44 Concerns during heating include enhanced bacteriocin production (potentially >7 fold),75 and rapid lysis of dead bacteria on exposure to digestive fluids,76 potentially inducing effects beyond those established for viable strains.41 44 In the USA, TPs are only FDA approved if supported by extensive toxicity and tolerability studies.77 78
The HA origin (animal or bacterial) is undisclosed in the leaflet, while the dose is 5–20 fold the food supplement dose approved by EFSA (rooster high-MW HA).79 On request, the marketing company disclosed that the HA corresponds to low-MW HA originating from microbial fermentation by Streptococcus equi. This bacterial low-MW HA was not considered safe for oral consumption by EFSA in 2009, because of lack of information on toxicity and bioavailability.80 Current concerns with long-term HA and CS exposure relate to stimulation of cell growth of hepatic, pancreatic or residual cancer cells.81–85 HA antiadhesion barrier films for gastrointestinal surgery have raised concerns, since causing more (serious) AEs versus controls.86 Seprafilm sheets (containing HA 700 mg) are contraindicated for gastrointestinal anastomotic sutures because of increased incidence of abscesses, fistulae and sepsis.87 Oral experience with Pol407 (surfactant) is limited to ~5–6 mg/day as excipient for delayed release formulations, yet the daily Pol407 exposure, according to the leaflet of HACSPol, surpasses 1 g/day. Chronic oral toxicity for Pol407 is unavailable according to recent chemical review31 and was neither provided following our request. Pol407 has been abandoned in injectables due to nephrotoxicity and AEs on lipid balance.88
Finally, none of the leaflets refers to MedDev–drug interactions although plausible: TA is known to adsorb iron, many compounds and drugs71–73 89 and is an inhibitor of cytochrome P450, other enzymes and P-glycoprotein (P-gp).90–92 HA/Pol407 complexes enhance or delay drug absorption88 93 while Pol407 itself inhibits P-gp, multidrug resistance-associated proteins and (blood–brain barrier) efflux transporters and interferes with delivery of proteins and peptides.94–96
EU marketing of barrier-claiming MedDevs for repeated oral use only requires national notification, bypassing the in-depth critical expert review by medicinal authorities. Our analysis of three examples indicates that compared with the standard requirements for medicines in children, this results in marketing of oral MedDevs providing extremely limited information to patients and healthcare professionals, as there is considerably less (or no) investigational clinical data available (table 1). For GT, the lack of adequate clinical documentation at launch has already been reported.97–99 Recently, a well-controlled clinical trial did not find efficacy in childhood gastroenteritis,37 in contrast to the outcomes of prior low-quality studies.34–36 40 For HACPol for GORD, no comparative studies comparing directly to PPIs in children or beyond 2 weeks, could be provided by the marketeer on our request.
When compared with the standard information that should be included in leaflets for medicines according to EMA guidance,7 all three leaflets studied are deficient. Regulations permit efficacy claims to be made, unsubstantiated by good quality clinical trials. As no age limits are mentioned, they allow unlimited use in children from birth onwards, without any well-controlled clinical data in children. Finally, data on interactions are lacking and safety issues remain unmentioned and unexplored.
Yet, these products are directly available OTC in the EU by CE marking and are actively promoted to health professionals and the public. Although in the small letter section of the advertisements, reference is made to the products as MedDevs, the promotional messages regarding their indication suggest that they are similar to medicines. Their medicinal image is reinforced by publications referring to them as ‘Paediatric Drugs’19 or among ‘drug treatments’.100
The three MedDev leaflets neither mention AEs nor information on interactions. As MedDevs generate safety data postlaunch instead of prelaunch, there is a clear difference in risk assessment when compared with medicines, for which AEs are identified prior to entering the market through controlled clinical trials in sufficient numbers of patients exposed over relevant periods of treatment. Although no AEs have been published, attributable to one of the MedDevs evaluated, this is no proof of safety. As stated by the FDA: ‘Once a product leaves the controlled study environment and enters general clinical use, the ability to detect the actual incidence of an AE can essentially be lost’.101 There are important limitations when using spontaneously reported AE information, including difficulties with AE recognition, under-reporting, biases, estimation of population exposure and report quality.101–103 Although a more stringent European vigilance programme is under development,104 the vigilance requirements itself are less stringent for MedDevs than for medicines, resulting in improper ‘pharmaco’vigilance for a regularly taken oral product. According to the Belgian ‘materiovigilance’ instructions, reporting of AEs associated to MedDev is ‘obligatory’ only if there are ‘serious consequences’, while reporting of other AEs remains ‘facultative’.105
With the new EU regulations for MedDevs (regulation EU 2017/745),1 authorities seek more stringent clinical assessment of performance (not equal to efficacy) for some MedDev classes. So far, trials were not registered at the European level (European Union Drug Regulating Authorities Clinical Trial database (EUDRACT) being only for medicines). An information platform (European Database on Medical Devices (EUDAMED)), including a database on ‘Clinical Studies and Performance Studies’ and a vigilance module will be launched in 2020 to exchange legal information between the Department responsible for MedDevs and the Competent Authorities in the EU Member States.104 Yet, as EMA consultation is non-binding in this legislation, no approval of the MedDevs by an independent regulatory body is required in the EU (in contrast to approval by the FDA in the USA),106–109 and class III even expands gastrointestinal use of MedDevs,1 these adaptations unlikely will prevent the registration of substances for oral intake as MedDevs based on a claimed barrier effect. There is neither any requirement for efficacy and safety clinical trials specific for children.
In conclusion, this analysis indicates relevant differences in the leaflets and standards used to certify MedDevs for oral use in children in the EU, when compared with medicines. We found that oral MedDevs requiring repeated ingestion to treat a medical condition (similarly as required for medicines) are hardly or not evaluated in children. This is likely because the regulatory requirements of MedDevs differ significantly from the registration standards for medicines. In our opinion, MedDev regulations need revision, excluding all substances for repeated oral intake.
Contributors SH conceived the idea of the work and presented a first draft; all
authors contributed to the acquisition, analysis or interpretation of data for the work.
All authors contributed to drafting the work or revising it critically for important
intellectual content, approved the final version to be published and they agree to be
accountable for all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.