A licence to cure
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1723 (Published 01 April 2015) Cite this as: BMJ 2015;350:h1723
- 1Nuffield Department of Primary Care Health Sciences, Oxford OX2 6GG, UK
- 2West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham, UK
- Correspondence to: J K Aronson jeffrey.aronson{at}phc.ox.ac.uk
Almost 800 years ago the Ordinances of the Guild of Pepperers of Soper Lane (1316) prohibited mixing products of different quality and price, adulteration, and wetting to falsify.1 UK medicines regulation has seen the establishment of the Committee on Safety of Drugs,2 the Medicines and Healthcare Products Regulatory Agency (MHRA), and the Commission on Human Medicines.
Under the 1968 Medicines Act, an important landmark, applicants are granted licences (properly called marketing authorisations) permitting them to market medicinal products, a process now covered by the 2012 Human Medicines Regulations.3 The terms of a product’s licence, known as the label, are described in the Summary of the Product Characteristics (also known as the product information), the format of which is regulated.4 The summary specifies, for example, indications, dose regimens, routes of administration, contraindications, and cautions. If a licensed product is used in any other way than described—for example, for an unspecified indication or in an unspecified dose or patient population—it is said to be used off-label. The term “unlicensed” refers to a product that does not have a licence at all. These terms can be confusing and are often confused.
Licensing and pricing
In 2014 the European Medicines Agency (EMA) recommended 82 products for human use.5 They included a new oral solution for treating proliferating haemangiomas in infants, Hemangeol, whose brand name obscures the identity of the active ingredient—the β blocker propranolol.
Propranolol was fortuitously discovered to reduce the size of infantile haemangiomas when it was given to a child with hypertrophic cardiomyopathy.6 Oral solutions of propranolol hydrochloride containing up to 10 mg/mL are licensed in the UK, but not for treating haemangiomas. Hemangeol contains propranolol hydrochloride in a different strength, 4.28 mg/mL, costing $402.69 (£265; €370) for 120 mL in the United States.7 When it becomes available in the UK, prescribers may feel that they should prescribe it rather than any other liquid formulation. However, it costs 40 times more than the cheapest oral solution available. A small premium would be acceptable, but this differential is unreasonable.
Licensing has affected prices in other cases. In 2010 the estimated cost of treating a patient with sickle cell disease using hydroxycarbamide (hydroxyurea) capsules 500 mg licensed for chronic myeloid leukaemia was £160 a year; using hydroxycarbamide tablets 1 g licensed for sickle cell disease cost £14 900 a year.8 Bevacizumab (Avastin) is as effective as ranibizumab (Lucentis) in wet age related macular degeneration (AMD),9 10 and differences in adverse reactions are small.11 Ranibizumab is licensed, and in equieffective doses costs about 35 times as much as bevacizumab (licensed, but not for AMD).12 Deborah Cohen discusses this in detail in related articles in The BMJ.13 14
Need for clarity
An ophthalmologist who drew up a solution of bevacizumab for intravitreal injection from a vial marketed for treating cancer would be using it off-label. If a pharmacist diluted the solution before use, the secondary formulation would be unlicensed. How much manipulation results in an unlicensed product is debatable. Unlicensed medicines can be supplied by so-called “special order” manufacturers, paradoxically under licence from the MHRA, obviating the need for a marketing authorisation, although MHRA guidance states that “an unlicensed product should not be used where a product available and licensed within the UK could be used to meet the patient’s special need.” (emphasis added) 15 The General Medical Council provides similar, albeit less strict, guidance (emphasis added): “You should usually prescribe licensed medicines in accordance with the terms of their licence. However, you may prescribe unlicensed medicines where, on the basis of an assessment of the individual patient, you conclude, for medical reasons, that it is necessary to do so to meet the specific needs of the patient. Prescribing unlicensed medicines may be necessary where . . . there is no suitably licensed medicine that will meet the patient’s need . . . or where a suitably licensed medicine that would meet the patient’s need is not available.”16 The use of the word “unlicensed” in these statements suggests that they do not cover off-label use. The MHRA, following a judgment of the European Court relating to importation, not off-label use or secondary formulations,17 specifically excludes “cost, convenience [and] operational needs” as criteria of special need.
The licensing system is intended to protect patients from the use of medicines with a poor benefit to harm balance, based on quality, efficacy, and safety, not cost. However, expenditure on any technology introduces an opportunity cost that reduces the quality of care that can be delivered elsewhere in the NHS.18 The National Institute for Health and Care Excellence (NICE) estimates that there is an 81-97% likelihood that ranibizumab is cost effective at a willingness to pay threshold of £30 000 per quality adjusted life year.19 NICE has not issued guidance (that is, a technology appraisal) on the cost effectiveness of bevacizumab in AMD, although that would not preclude its assessment in the forthcoming NICE guideline on therapeutic management of AMD, due in 2017,20 when ranibizumab biosimilars will be emerging.21 22
It is time for a robust solution to this problem. When choosing between different formulations of the same medicine, especially one as well established as propranolol, there should be no difficulty in using the cheapest licensed formulation available, off-label if necessary. Secondary formulations of licensed products, produced by licensed specials manufacturers, should be considered to be licensed. Suspected adverse reactions to all medicinal products should be reported, independent of licensed status. When there is sufficient evidence of quality, efficacy, and safety, the cheapest product should be prescribable.
Notes
Cite this as: BMJ 2015;350:h1723
Footnotes
Competing interests: We have read and understood BMJ policy on declaration of interests and declare: JKA is a member of a NICE technology appraisal committee, a member of the Advisory Board of the British National Formularies, and a president emeritus of the British Pharmacological Society. REF is NHS member of the NICE Appeal Panel, and his unit receives funding from the MHRA. Both JKA and REF have from time to time prepared medicolegal reports relating to licensed and unlicensed products.
Provenance and peer review: Commissioned; not externally peer reviewed.