A poster, in a London Underground train, for Boots' “COLD & FLU DEFENCE Nasal Spray” featured text that stated “clinically proven to defend against cold and flu”.
The complainant, who understood that the nasal spray was not capable of preventing and treating colds and flu, challenged the product’s efficacy.
Boots UK Ltd stated that the product was an approved EU Class IIa medical device, which they marketed in the UK under contract from the legal proprietor who was based in Europe. They stated that the product was manufactured by an Austrian company and was supported by technical, non-clinical and clinical data, which had been reviewed and approved for sale in the EU by a notified body. They provided a copy of the certificate of approval. Boots considered that their “COLD & FLU DEFENCE Nasal Spray” was an effective treatment for the common cold, and influenza types A and B.
Boots stated that the common cold and flu were viral infections of the upper respiratory tract. The viruses that were most often responsible for those infections were rhinoviruses and influenza type A. The symptoms associated with the two infections were similar and included sneezing, sore throat, runny and blocked nose, cough, headache, feverishness and malaise. These symptoms were caused by the body’s inflammatory response to the viral infection.
Boots stated that the product contained iota-carrageenan, also called Carragelose®, and kappa-carrageenan in a saline solution and were pure sources derived from red seaweed. The product was applied to the nasal cavity and ran down the back of the throat. They referred to studies that were published in peer-reviewed journals in which the anti-viral activity of iota- and kappa-carrageenan had been investigated against rhinoviruses and influenza A. They explained that the carrageenans were large polysaccharides that were not absorbed by cells, but formed a physical barrier on the nasal mucosa. The viruses then became attached to the carrageenan preventing physical entry of the virus into the cell, thus stopping replication and the induction of the body’s inflammatory response.
Boots stated that the principal effect of the nasal spray was physical, which was why the product was classified as a medical device to prevent, treat or alleviate symptoms of disease. They stated that for the product to be most effective it had to be used just before or at the first sign of a symptom of cold or flu before the virus had the opportunity to trigger the full inflammatory response. Furthermore, their nasal spray was different to a vaccine or the neuraminidase inhibitor medicines, as the virus would become physically attached to the iota- and kappa-carrageenan preventing entry of the virus into the cell or stopping the release of the virus from infected cells. Therefore, it would effectively stop replication and the induction of the body’s inflammatory response.
Boots stated that influenza A occurred more frequently in humans and was more virulent than the other types of influenza virus. Influenza B often circulated with influenza A and caused less severe clinical illness and that influenza C, was rarely reported and caused mild or asymptomatic infections.
Boots stated that the clinical efficacy of carrageenan nasal spray had been investigated in three double-blind, placebo-controlled randomised clinical trials and the results of those studies had been published in peer-reviewed journals. The placebo in all studies was a nasal spray of 0.9% saline, which was used in some markets to relieve cold and flu symptoms. All studies were conducted to the highest standards in accordance with good clinical practice.
In one study, human subjects suffering from the early symptoms of the common cold were treated with nasal sprays three times daily for four days. Boots stated that the results showed that symptoms, as well as the presence of the virus and the body’s markers of inflammation, were reduced with the carrageenan nasal spray compared to the saline nasal spray.
In a second study, children with upper respiratory tract symptoms were treated with a nasal spray three times daily for seven days, and had their symptoms recorded throughout the study (21 days). Boots stated that the study found that the amount of time it took for the carrageenan nasal spray to clear the illness was shorter (7.6 vs. 9.4 days saline) and that there was also a significant reduction in the presence of the cold viruses.
Boots stated that the results from the above trials were validated in a further study conducted on adults in 2013. The results showed that common cold virus symptoms were alleviated 2.1 days faster with carrageenan nasal spray compared with saline, and that there was a significant reduction in the presence of the viruses.
Boots stated that the latter two studies reported the results for the common cold viruses only, which were responsible for 60% of the illnesses. However, those studies also collected clinical data associated with influenza virus types A and B and were used in a further study conducted in 2014. Boots stated that that study showed that the main viruses responsible for the illnesses in the previous clinical trials were human rhinovirus (46%), human coronavirus (25%) and influenza A (14%). The data demonstrated that carrageenan nasal spray was significantly more effective at reducing the illness duration (range: 1.9 days, 3.9 days and 3.3 days respectively), and that those patients had fewer symptom relapses after treatment had stopped. Furthermore, the viruses were cleared from the nasal passages more effectively with the carrageenan nasal spray and fewer viruses were detected.
Boots stated that the 2014 study showed that of the 254 subjects who had participated in the previous two studies, only 1% had influenza B and were children. The prevalence of the viruses exhibited from participants had reflected their natural occurrence in humans and consequently, conducting a randomised controlled clinical study with influenza B was very difficult, unless coincidentally there was a naturally high prevalence. Boots stated that an alternative clinical study methodology would be to intentionally infect participants with influenza B, but would be inappropriate considering the infection was predominantly seen in children. Therefore, greater reliance was placed on in vitro data.
Boots referred to a study which looked at the efficacy of their nasal spray. The study investigated the spray’s effect against influenza types A and B using a standard in vitro plaque reduction evaluation to assess prophylaxis and a replication reduction assay to assess treatment of influenza B. The nasal spray contained iota-carrageenan at 1.2 mg/ml and kappa-carrageenan at 0.4 mg/ml and the study was conducted using a serial dilution of that product. The results showed, at much lower concentrations than were contained in the marketed product, that there was a 50% reduction of plaque formation of influenza types A and B (infectivity), and a 50% reduction in the viral load of influenza B in the replication reduction assay compared to untreated cells. Boots believed that the study demonstrated that their nasal spray was effective at preventing and stopping the replication of influenza B, and the efficacy against influenza types A and B was comparable, as they believed that both viruses were commonly referred to as ‘flu’.
Boots believed that the use of the words “defend” and “defence” were not synonymous with prophylaxis. The Oxford Dictionary defined “defend” as “to resist an attack on; protect from harm”, and “defence” as “the action of defending from or resisting attack”. Boots considered that these definitions were consistent with how their nasal spray worked - by physically attaching to the virus and preventing entry into an uninfected cell or stopping the release of the virus from infected cells.
The ASA acknowledged that the nasal spray had been assessed by a notified body based in Austria which had approved the product as an EU Class IIa medical device.
We considered that the claim “COLD & FLU DEFENCE Nasal Spray” along with “clinically proven to defend against cold and flu” suggested that the product had been tested in clinical studies and shown to be capable of preventing and treating the symptoms of a common cold and flu. We noted Boots’ view that the phrase “defend against” was not a claim that the product would prevent cold and flu infections, but we considered that consumers would interpret the claim as a whole as meaning that the product had been shown to have a prophylactic effect.
We understood that colds and flu shared some of the same symptoms, but were caused by different viruses. We noted that the NHS website stated that there were three types of influenza virus, known as A, B and C and that there were many strains of these flu viruses, hence why the vaccine has to change each year to protect individuals against the most common types. However, we acknowledged that influenza C was rarely reported in the UK and caused mild or asymptomatic infections. We also understood from the NHS website that more than 200 types of virus could cause a cold and those most responsible for causing colds belonged to one of two groups, either rhinoviruses or coronaviruses. Furthermore, we noted that the NHS advised that there were several ways of preventing flu, one of which included antiviral medicines, specifically Relenza and Tamiflu.
We acknowledged that the claim “clinically proven to defend against cold and flu” was based on the product’s ingredient carrageenan. We noted that Boots had referred to studies where the anti-viral activity of iota- and kappa-carrageenan had been investigated against influenza and rhinovirus infection, stating that the substance was not absorbed by the body’s cells, but formed a physical barrier on the nasal mucosa preventing physical entry of a virus into the body’s cells. We acknowledged however, that both studies agreed that clinical trials were needed to determine whether iota-carrageenan based products were effective in preventing and treating influenza A and rhinovirus infection.
We acknowledged that Boots stated that the clinical efficacy of carrageenan nasal spray had been investigated in three double-blind, placebo-controlled randomised clinical trials on patients suffering from the early symptoms of the common cold, and that the results of those studies had been published in peer-reviewed journals. Furthermore, Boots referred to a subsequent study that used the results of two clinical trials for retrospective analysis of carrageenan nasal spray. We therefore, sought expert advice on the studies supplied by Boots.
The first study investigated the efficacy of an iota-carrageenan nasal spray in patients with common cold symptoms. A small group of 35 patients were recruited at the onset of symptoms of a common cold and a significant difference was detected between the control and placebo groups of the study. Symptoms displayed by patients in the placebo group had worsened before any improvement was noted, while the symptoms displayed by patients in the treatment group remained steady before improving. However, we noted that the statistical difference was marginal and the results were not conclusive proof that carrageenans were an effective treatment for colds and flu. We also understood that the study was designed to be a preliminary investigation into the efficacy of iota-carrageenan nasal spray and while the data suggested that carrageenans might be effective in the treatment of acute respiratory viral infections, further study into the matter was required. Therefore, we considered that the study did not provide robust evidence showing that the nasal spray was clinically proven to prevent and treat colds and flu.
The second study initially involved 213 children, in a randomised study, who had developed cold symptoms; the number remaining to the end was 153. Examination of viral infection and viral load in nasal secretions demonstrated a significant reduction in the treated group compared to the control group. However, iota-carrageenan was not observed to have any significant effect to alleviate acute cold symptoms in those children and we therefore, considered that the study was not sufficiently robust to show that the nasal spray was clinically proven to prevent and treat colds and flu.
Regarding the third study, it investigated carrageenan nasal spray in the treatment of acute viral upper respiratory tract infections, where patients were recruited within the first 48 hours of displaying mild to moderate cold symptoms. The study reported that direct local administration of carrageenan with nasal spray reduced the duration of cold symptoms. Furthermore, a significant reduction of the viral load in the nasal wash fluids of patients confirmed similar findings from earlier trials in children and adults.
However, during the study a proportion of patients were excluded from analysis due to protocol violations such as non-compliance with the treatment or taking prohibited concomitant therapy. Of the 211 patients recruited, 118 were confirmed as being virus positive. We understood that this did not necessarily represent the entire patient population, as those patients experiencing more severe symptoms were likely to have taken additional medications and therefore, would have been excluded from the analysis, leaving a higher proportion of patients with milder symptoms, on whom the spray worked more effectively. As this patient selection may have been biased, it reduced the strength of the study, but did not invalidate the findings. Furthermore, of the 211 patients recruited, only 118 were confirmed as being virus positive.
We understood that the study was to examine the effectiveness of the treatment by measuring the number of patients (from both groups) who had recovered from their reported symptoms and were symptom-free for a period of 48 hours thereafter. However, this was changed during the course of the study to all other study days with patients being symptom-free being measured after they were no longer displaying any of their reported symptoms. Contrary to the new measurement, when the data was analysed following the original method, no significant difference was observed. We understood that the change was made following the publication of another clinical trial on treatment of the common cold, and it appeared that the change resulted in a more stringent criteria for recovery. However, we understood that such a change during a study was not considered to be best practice and was likely to influence the results of the study.
In the study, we noted that 90% of patients suffered from colds, 10% from influenza A and no patients were reported with influenza B. However, no sub-division was made as to those suffering from colds vs flu and the implication of that was that the treatment was effective against both illnesses, but with a low number of patients suffering from flu (seven in the treatment group; six in placebo), we considered that the sample size was too small to show efficacy.
We considered that the third study provided some evidence that the carrageenan nasal spray could reduce symptoms and duration of those viral infections detected in the patients, when taken alone and appropriately. However, the evidence from the study was not sufficiently robust to show that the nasal spray was clinically proven to treat and prevent colds and flu.
We understood that the 2014 study was conducted to gain a deeper insight into the results of the clinical trials reported in the above studies (specifically the latter two), so that further evidence for the antiviral effectiveness of carrageenan could be obtained. The study examined the effect on the treatment group versus placebo for all virus-positive patients with respect to duration of illness, number and frequency of relapses and viral load in nasal secretions.
Data was obtained from 254 patients, who were identified in the laboratory to be infected with rhinovirus, coronavirus, influenza A, influenza B, metapneumovirus, parainfluenza and respiratory syncytial virus. The first three of these accounted for 85% of all infections in both treatment and placebo groups. A significant reduction in duration of disease was demonstrated between the treatment and placebo groups. Additionally, the number of relapses experienced by patients in the treatment versus the placebo group was significantly lowered. This was further analysed by dividing the patients into subgroups of those suffering from either rhinovirus, coronavirus or influenza A virus. All three of these subgroups showed a reduction in the number of both relapses and illness duration, some of which reached the level of statistical significance and some did not. The most benefit was demonstrated for patients suffering from coronavirus infection, followed by rhinovirus and then influenza A.
Although the study demonstrated a reduction in illness duration and number of relapses in the patient population as a whole, we acknowledged that it was a retrospective analysis and in general, would be considered to generate weaker evidence than a prospective clinical trial. Furthermore, the effect of carrageenan was different in the three subgroups analysed, being least effective against influenza A compared to rhinovirus and coronavirus. Therefore, we considered it was difficult to use this analysis as evidence that the treatment was specifically effective against influenza A infection.
Regarding the study of paediatric patients referenced in the 2014 study, we noted that it included 136 patients whereby 15 children were suffering from influenza B. As the proportion of patients suffering from influenza B was relatively low and were not identified or analysed separately, we considered it would be difficult to determine whether any efficacy was demonstrated specifically against influenza B (or indeed A) in that study. Therefore, we understood that the main findings of the study demonstrated no benefit of carrageenan nasal spray treatment on symptoms of colds and flu in children, although it indicated that the treatment resulted in a shorter duration of illness.
We also noted that the authors speculated that the reduction in relapses seen in the treated group in the study suggested that carrageenan treatment may have a prophylactic effect in preventing viral infection. However, there was no evidence in the study to support that claim.
We considered, therefore, that the 2014 study in its entirety was not robust enough to show that the nasal spray had been clinically proven to prevent and treat colds and flu.
Boots had stated that influenza B infections were rarer than influenza A, and were more commonly observed in children than adults and consequently, conducting clinical trials in that context was more difficult and justified why they had submitted the 2014 study, which had pooled data from clinical trials that included patients with either influenza A or B. We noted that Boots had stated that “of the 254 patients who participated in those studies, only 1% had influenza B”. However, we noted that the 2014 study stated that 5% of the treatment group and 7% of the placebo group were identified as influenza B positive. Although influenza B was rarer across the general population, the study of paediatric patients referenced in the 2014 study demonstrated that influenza A was identified in 19% of subjects and influenza B in 11%. This we considered showed that in a targeted population it would be possible to obtain a group of influenza B-positive patients.
We acknowledged the in vitro data Boots had provided for their nasal spray which they believed suggested efficacy against influenza types A and B, inferring that there would be a similar in vivo effect against the two types. However, we considered that this did not negate the need for clinical trials proving that the nasal spray was effective in patients. It was not sufficient for Boots to rely on in vitro data to substantiate their product’s efficacy against influenza types A and B without subsequently conducting robust clinical studies.
Therefore, although the product could possibly reduce the duration and symptoms of acute upper respiratory tract infections in some patients under certain circumstances, we considered that the clinical studies were not sufficiently robust to show that Boots' “COLD & FLU DEFENCE Nasal Spray” had been “clinically proven” to treat and prevent the symptoms of a common cold and influenza types A & B, and concluded that the ad was misleading.
The ad breached CAP Code (Edition 12) rules
Marketing communications must not materially mislead or be likely to do so.
Before distributing or submitting a marketing communication for publication, marketers must hold documentary evidence to prove claims that consumers are likely to regard as objective and that are capable of objective substantiation. The ASA may regard claims as misleading in the absence of adequate substantiation.
Marketing communications must not mislead consumers by exaggerating the capability or performance of a product.
Objective claims must be backed by evidence, if relevant consisting of trials conducted on people. Substantiation will be assessed on the basis of the available scientific knowledge.
Medicinal or medical claims and indications may be made for a medicinal product that is licensed by the MHRA, VMD or under the auspices of the EMA, or for a CE-marked medical device. A medicinal claim is a claim that a product or its constituent(s) can be used with a view to making a medical diagnosis or can treat or prevent disease, including an injury, ailment or adverse condition, whether of body or mind, in human beings.
Secondary medicinal claims made for cosmetic products as defined in the appropriate European legislation must be backed by evidence. These are limited to any preventative action of the product and may not include claims to treat disease. and 12.11 12.11 Medicines must have a licence from the MHRA, VMD or under the auspices of the EMA before they are marketed. Marketing communications for medicines must conform with the licence and the product's summary of product characteristics. For the avoidance of doubt, by conforming with the product's indicated use, a marketing communication would not breach rule 12.2.
Marketing communications must not suggest that a product is "special" or "different" because it has been granted a licence by the MHRA, VMD or under the auspices of the EMA. (Medicines, Medical Devices, Health-Related Products and Beauty Products).
The ad must not appear again in its current form. We told Boots UK Ltd that their future advertising for their “COLD & FLU DEFENCE Nasal Spray” must not state or suggest that it could be used to treat and prevent infection with the common cold and influenza types A and B.