Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognized. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico‐legal responsibilities of the prescriber and dispenser.

Vitamin D: quality and safety There has been a considerable increase in interest surrounding vitamin D over the last decade with the number of publications relating to vitamin D having risen by more than 250% over the last decade (Figure 1). This research may have been stimulated by the re‐emergence of diseases such as rickets and osteomalacia, a high prevalence of deficiency together with a greater appreciation of the ubiquitous presence of the vitamin D receptor and potential role beyond regulation of calcium and bone. As such, vitamin D deficiency is implicated in increased risk of fractures, falls and mortality 1, 2. Treatment with vitamin D appears to reduce risk of falls 3, fractures 4 and, potentially, mortality 5. In consequence, the Chief Medical Officers of the United Kingdom have recommended treatment with vitamin D for at risk groups, particularly the young, pregnant and the elderly 6. Figure 1 Open in figure viewer PowerPoint Comparison of number of published scientific articles retrieved by Web of Knowledge for some commonly prescribed medicines (Web of Knowledge search term: Topic=[‘Vitamin{letter}']/‘opioid’ OR ‘opiate'/‘aspirin'/‘NSAID*’]; Timespan = 2012; Search language = Auto). , vitamin A; , vitamin B; , vitamin C; , vitamin D; , vitamin E; , opiates; , aspirin; , NSAID Accompanying this increased research interest, there has also been a considerable rise in the number of prescriptions of vitamin D in the UK over the last decade. Since 2008, vitamin D monotherapy in primary care in England has increased more 8000% in prescription numbers and 5000% in cost (Figure 2) 7. These data reveal that currently, 190 000 prescriptions for vitamin D are issued each month at a net ingredient cost of £2.22 million, with cholecalciferol accounting for 98% and 93% of volume and cost, respectively. However, of these prescriptions, the majority (59%) relate to the use of unlicensed treatments. One might speculate that in the current times of austerity that price might be driver for the use of unlicensed products in preference to licensed drugs, expecting the unlicensed alternatives to be cheaper. Yet analysis of this prescription cost analysis (PCA) data comparing similarly formulated preparations reveals, in general, that comparable licensed preparations are almost 50% cheaper per 1000 units supplied (Table 1). Figure 2 Open in figure viewer PowerPoint Growth in vitamin D monotherapy dispensed in England between 2008 and 2014 (Source: NHSBSA Prescription Cost Analysis 7). , ergocalciferol (n); , cholecalciferol (n); , cholecalciferol (£); , ergocalciferol (£). Solid bars refer to the number of prescriptions dispensed. Dotted lines refer to Net Ingredient Cost of dispensed prescriptions Table 1. Current monthly prescription of oral cholecalciferol in NHS England primary care by unit dose (NHS Business Services Authority Prescription Cost Analysis January 2014) Unlicensed Licensed prescriptions NIC NIC/1000IU prescriptions NIC NIC/1000IU Low dose (400 to 1000 IU) 44 605 £ 576 673 £ 0.27 77 067 £ 503 245 £ 0.15 Mid dose (2000 to 10000 IU) 8 478 £ 166 909 £ 0.29 – – £ 0.14* High dose (>10000 IU) 50 344 £ 525 542 £ 0.05 – – – It may seem unimportant that prescriptions for vitamin D are being fulfilled by unlicensed therapies. However, the use of unlicensed vitamin D preparations can pose safety concerns for the patient, which may have legal implications for the prescriber and dispenser. Indeed, the Medicines and Healthcare Products Regulatory Authority (MHRA), the body that oversees the licensing of medicines within the UK, stipulate that unlicensed products should not be used where licensed products exist as licensed formulations meet the acceptable standards of safety, efficacy and quality 8. This is particularly important in the case of a sterol hormone, as is vitamin D, yet it may be an issue with which prescribers are unfamiliar. The manufacture of appropriate prescription quality vitamin D is not straightforward. Indeed, studies reveal that unlicensed vitamin D supplements are beset with quality issues leading to uncertain dosing. Of 14 analyzed formulations of vitamin D3, only eight were within 10% of the stated dose 9. Compared with variations in stated dose ranging from 8% to 201% of the claimed dose the two licensed formulations had vitamin D concentrations of 90 ± 4% and 97 ± 2% of stated dose. Similarly, Leblanc et al. 10 revealed that of 15 vitamin D3 preparations analyzed, there was substantial variation compared with stated dose both in pills from the same bottle (52–136% of expected dose) and between separate preparations (9–140% of stated dose). Only one third of the pills analyzed were within 10% of stated dose. Of these, the licensed products revealed the greatest accuracy and least variation with stated dose. Similar findings of inaccurate doses with unlicensed products are noted by others 11 with accurate dosing noted only with licensed formulations of vitamin D. Over estimation of the stated dose may pose problems for the treating physician. The current guidelines which clarify the appropriate testing and management of vitamin D deficiency argue that repeated measurement of serum 25‐hydroxy‐vitamin D concentration (25OHD) is unnecessary with the use of appropriate replacement regimes 12 as adequate vitamin D treatment should produce predictable increases in plasma 25‐hydroxy‐vitamin D concentrations and hence adequate replacement. Indeed the MHRA stipulate that prescribers must ‘take responsibility for prescribing the medicine and for overseeing the patient's care, including monitoring and follow‐up’ 8, implying a higher degree of monitoring than might otherwise be the case with a licensed alternative. Similarly, the use of an unappreciated lower than stated dose, could result in ineffective treatment, exposing the patient to the risk of persisting symptoms or indeed subjecting them to unnecessary investigation for suspected malabsorption.

Safety and toxicity of vitamin D Whilst vitamin D therapy is considered a safe medication with studies revealing that long term doses of up to 10 000 IU daily are not associated with toxicity 13, the use of errantly manufactured and wrongly labelled vitamin D preparations exposes patients to the risk of toxicity. Benemei et al. 14 reported three cases of vitamin D intoxication with severe hypercalcaemia where the patients had been treated with a vitamin D formulation with a stated dose of 600 IU where in fact, the actual content was 52 800 IU. Similarly, Kara et al. 15 reported seven paediatric cases admitted with hypercalcaemia and vitamin D intoxication associated with an approximate 4000 times higher vitamin D content than stated within a fish oil supplement. Examples of toxicity associated with inaccurately manufactured and labelled vitamin D supplements is an international problem which is increasingly reported 16-22. These reports of vitamin D toxicity due to mislabelling and errant manufacture are found in adults and children and have resulted in severe hypercalcaemia warranting hospitalization and emergency treatment. To our knowledge, such errant labelling has not been reported in conjunction with licensed formulations.

The medico‐legal position relating to the prescription of unlicensed vitamin D These data demonstrating potential toxicity of unlicensed, unqualified preparations of vitamin D highlight the key problems with the use of unlicensed medicines and explain why the law demands medicinal products are granted marketing authorization licences before they can be supplied to the public. This regulatory framework ensures that the benefit risk profile of a product is appropriate for use in the licensed indication(s) and that the pharmaceutical quality of the product is guaranteed as fit for purpose. This quality assurance ensures in particular that dosing with the formulation is consistent and accurate. Licensing medicines ensures they have an acceptable balance of risk vs. benefit based on the toxicological, clinical safety and efficacy data together with pharmaceutical quality data of the product. Under European law all medicinal products have to have marketing authorization before being supplied and distributed 23. In the UK, supervision of marketing authorization is the responsibility of the MHRA. If an application dossier for marketing authorization has not been submitted to the Regulatory Authority it cannot be granted marketing authorization and the product, or the unapproved indication and/or pharmaceutical formulation, is unlicensed. The product cannot be placed on the market, and it cannot be supplied for therapeutic use. As illustrated in Figure 2, this is in contrast with the current position of the majority of prescribed vitamin D in the UK being met by unlicensed product. The classification of ‘unlicensed medicinal product’ infers that either the data and general information on the product does not confer an appropriate risk : benefit profile because the regulator is not confident that the product can safely be placed on the market and/or that the producer has failed to investigate the quality safety and efficacy of the product 24. Either way, the prescriber and producer of an unlicensed product must comply with the specific provisions for the production and use of medicinal products under the exemption provisions for marketing authorization. The statutory exemptions from marketing authorization apply if the product fulfils a special need in response to a bona fide unsolicited order, formulated in accordance with the specification of a clinician. These are the so‐called ‘specials’. A number of special formulations are legitimately required, for instance in the reformulation of a licensed product to meet a patient's need, such as liquid formulation in patients with swallowing problems. However, in the case of vitamin D where suitable licensed formulations exist for the treatment of deficiency and maintenance therapy, it is difficult to see the rationale for using unlicensed formulations against prescriptions. Again, the use of an unlicensed product under these statutory exemptions from licensing brings into play specific liabilities and obligations of all those involved in the supply, prescribing and dispensing of the unlicensed product. For example there will be liabilities both in common law (negligence and possibly contract), statutory obligations and liabilities under the Consumer Protection legislation and obligations under the appropriate professional codes of conduct (General Medical Council [GMC] and the General Pharmaceutical Council [GPhC]). The appropriate professional guidance for medical staff is outlined in the supplementary guidance issued by the GMC's, Good Practice in Prescribing Medicines 24. Doctors may prescribe medicines for unlicensed indications provided that it would better serve the patient's need than an appropriately licensed alternative, there is sufficient evidence or experience on its safe and effective use and they take sole clinical responsibility for prescribing and they must explain to the patient the reasons for prescribing a medicine where there may be little research or other evidence to support its use 8. It is also important to note there are situations where regulatory infractions regarding the manufacture, supply and use of unlicensed medicinal products can give rise to criminal liability. Specific offences in part II of the Medicines Act 1968 include sale or supply of a medicinal product without a product licence (other than by a doctor), manufacturing or assembling of a medicinal product without a product licence or wholesale dealing without a wholesale dealers licence and failure to inform employees and/or subcontractors of licence provisions relevant to their role in production of medicine 25. Also selling, supplying, or possessing a medicinal product in the course of a business which does not comply with those regulations or which does not include the information required by the European regulations is an offence, as is supplying or possessing a leaflet to go with a medicinal product that is false or misleading. The maximum penalty is a fine not exceeding £5000 in the Magistrates Court or 2 years imprisonment and/or an unlimited fine in the Crown Court.

Supply of unlicensed preparations by pharmacists As the vast majority of vitamin D prescriptions in the UK are dispensed by community pharmacies, so ethical supply of vitamin D also becomes the pharmacist's concern. As the prescriber may issue a generic prescription for vitamin D/cholecalciferol, it is the dispenser's responsibility to ensure the safe fulfilment of that prescription. Pharmacists supplying an unlicensed medicinal product against such a generic prescription must ensure that the prescriber is aware of the unlicensed status of the medicine and the possible consequences of unlicensed use 26. Similarly, the pharmacist is responsible for the quality of the unlicensed medicine they supply to the patient 27. This is always more difficult to discharge where unlicensed medicines are supplied. The GPhC Standards of Conduct, Ethics and Performance 28 stipulate that within their first duty (‘Make patients your first concern’), pharmacists must ensure that services provided are ‘of safe and acceptable quality’. In the case of GPhC vs. Patel 29, supply of an unlicensed preparation where a licensed alternative existed, was a contributory factor in the death of a patient arising from accidental overdose of warfarin. Unlicensed medicines use carries a greater risk of adverse drug reactions than the use of licensed medicines 30, 31. The NHS has stipulated that whilst the prescriber (provided that he/she is aware that the product is unlicensed) is primarily responsible for any harm arising to the patient from the medicine in terms of side effects or adverse reactions 32, 33, pharmacists are primarily responsible in terms of liability to the patient, for the suitability and quality of the medicine. With particular reference to vitamin D, the use of imported ‘specials’ has been a particular concern to the MHRA with the issue of a safety alert relating to high dose imported, unlicensed vitamin D. In these cases, important safety data on packaging regarding avoidance in known allergic individuals was written in German, hence presenting risk to both dispensing pharmacist and patient 34. Similar concerns were expressed regarding Canadian and US imported vitamin D where such safety data, required by the MHRA for licensed products, may not necessarily be included. To discharge this responsibility, pharmacists will need to have knowledge of the formulation of each unlicensed medicine and be satisfied that it has been appropriately manufactured and that there is adequate evidence of testing against an agreed specification (e.g. by scrutiny of a certificate of analysis). Clearly this is beyond the scope of daily practice in community pharmacy and serves to underline why the licensing laws exist for the benefits of patients and practitioners.

Conclusion Vitamin D is an important regulatory hormone and evidence is emerging of its role beyond bone. The last decade has witnessed a revival in interest and an expansion in the prescription of vitamin D. However, this expansion has been mostly met by unlicensed formulations within the UK which may lack efficacy and more worryingly may pose significant clinical risk to the patient. Thus, greater awareness through education as well as potential specific legislation may be required to reduce the potential for public harm from unlicensed vitamin D supplementation. Prescribers and dispensers need to appreciate the potential dangers to their patient and also the risk to their professional status associated with the use of unlicensed vitamin D products.

Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare JSD has undertaken consultancy work with Internis Pharmaceutical, Prostrakan and Sandoz in the previous 3 years, PF has undertaken client work for Internis Pharmaceuticals in the previous 3 years and CDP has undertaken consultancy work for Internis Pharmaceuticals, Norgine and Sandoz.