ClinicSpeak & OffLabel: unlicensed vs. off-label prescribing

Unlicensed vs. Off-label prescribing. Do you know the difference? #ClinicSpeak #MSBlog #MSResearch #OffLabel

"I attended an interesting meeting yesterday when off-label, and unlicensed, prescribing in MS was discussed in detail. This is particularly pertinent to the ongoing debate about the use of the cheaper, but off-label, bevacizumab (Avastin) rather than the licensed, but more expensive, ranibizumab (Lucentis),  to treat age-related macular degeneration."


"Unlicensed prescribing refers to the prescribing of a drug that has never been licensed for an indication and hence is not manufactured by a pharmaceutical company. An example of this would have been the prescribing of 4-aminopyridine for MS-related walking problems in the past. You could not write a prescription and expect your local pharmacy to dispense an unlicensed drug . In the case of 4-aminopyridine, you would have had to get a compounding pharmacist to make-up the drug and formulate it for you. This was not without problems; for example there were several case reports of accidental over-dosage with compounded 4-aminopyridine. Some of the latter overdose were life-threatening. Compounding pharmacists simply do not  have the resources and time for adequate quality control. However, once 4-aminopyridine was formulated into a slow- or delayed-release formulation (Famridine or Dalfampridine) and was licensed for walking-impairment in MS things changed. 4-aminopyridine was now being produced, marketed and sold by a Pharmaceutical company as a specific licensed product. With a license, or more correctly marketing-authorisation, comes  the responsibility of ensuring a supply of the drug, quality control and a whole raft of post-marketing responsibilities, including safety updates. With the licensing of the 4-aminopyridine the prescribing of an unlicensed formulation became illegal under EU law. This is why legal action was taken against several European compounding pharmacies to stop them formulating 4-aminopyridine."

"In comparison, off-label prescribing is when you prescribe a drug that is available on the market for an indication that is not covered by its license. For example, prescribing bevacizumab (Avastin), which is licensed as a cancer treatment, for age-related macular degeneration. Off-label prescribing is not illegal if there are no other licensed drugs for that indication. It only becomes illegal when there is a licensed drug; in the case of age-related macular degeneration bevacizumab (Avastin) should not be prescribed because ranibizumab (Lucentis) is the licensed drug. The legislation protecting licensed drugs from off-label, and unlicensed competition, was clearly put in place to protect the pharmaceutical industry and to make sure incentives exist for the pharmaceutical industry to innovate. I am aware that some of you disagree with this legislation, but I would urge you to take a wider view of drug development and pharmaceutical innovation in particular. At present it is very difficult to develop drugs outside of Pharma; with very exceptions academics don't have the resources or skills to do this. We only know this too well; our experience with VSN16 our putative anti-spastic drug  is a typical example. We have had to wait for Big Pharma investment to get the drug into phase 2. We currently have an active drug discovery programme for progressive MS that have stalled simply because we need investment of an order of magnitude higher than we can get from typical academic funding sources. We have two very exciting classes of compound that are neuroprotective in our animal model of progressive MS, but can't take them forward without Pharma-level investment. As someone who is faced with the unmet needs of progressive MSers on a daily basis this is very frustrating."

"You have to realise that the short-term costs to the NHS, and other healthcare systems, for prescribing expensive innovator drugs is the result of the deal our politicians have struck with the Pharma industry. In return we get the promise of cheaper drugs in the future when the innovator drugs come off-patent and we get the promise of continued innovation by the pharmaceutical industry as they use the profits from the sale of their current drugs to reinvest in R&D and new product development. Do you want this system to change? If you do then we need to get our politicians engaged. I personally think we need new legislation to re-purpose off-patent generic drugs. We need some form of incentive to encourage Pharma to invest in off-patent drugs or a new system to allow non-profit organisations to license off-patent drugs cheaply without the expensive post-marketing commitments. This is what we refer to as the BPA (Big Pharma Alternative) in our recent commentary (Giovannoni et al. The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015 Jan;4(1):3-5)."



"The following piece in last week's BMJ summarizes, very succinctly, the legal issues I refer to above in relation to unlicensed and off-label prescribing."

David Lock (Queen’s Counsel, London, UK). Briefing: Avastin and Lucentis: a guide through the legal maze. BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1377 (Published 01 April 2015) Cite this as: BMJ 2015;350:h1377

Excerpts:

....... Many doctors believe that bevacizumab (Avastin) is a clinically acceptable alternative to ranibizumab (Lucentis) for patients with wet age related macular degeneration (AMD) and presents a more cost effective alternative for the NHS. However is a doctor acting lawfully when prescribing bevacizumab for patients with wet AMD? ......

...... Every drug for clinical use needs a marketing authorisation, commonly called a licence, before it can be lawfully marketed by a drug company in the UK. The marketing authorisation defines the patient group for which the drug can be advertised. A drug that does not have a marketing authorisation is unlicensed and (broadly) can be sold in the EU only if there are no licensed alternatives. But the licensing regime does not impose legal obligations on doctors to use drugs only for the conditions set out in the licence. Using a licensed drug for conditions that are outside those described in the licence is commonly called “off-label” prescribing.......

.... Could a doctor who prescribes bevacizumab for wet AMD be prosecuted for a breach of the criminal law? .....

..... There is nothing to suggest that a doctor who appropriately prescribes bevacizumab for someone with wet AMD acts in breach of the criminal law. ......

...... Could a doctor who prescribes bevacizumab for wet AMD be sued in negligence? .....

...... It is highly unlikely that a doctor would breach a duty of care by appropriately prescribing bevacizumab provided the patient made an informed choice to select the drug. NHS patients who come within the clinical guidelines set by the National Institute for Health and Care Excellence for ranibizumab have a legal right to be prescribed it on the NHS..... 

..... Could a doctor who prescribes bevacizumab for wet AMD be reported to the GMC? ......

..... There is a theoretical possibility that a doctor could be reported to the General Medical Council for prescribing bevacizumab rather than ranibizumab for wet AMD. GMC guidance requires doctors to make resource allocation decisions that take account of their responsibilities towards patients and the wider population. However, the GMC guidance about prescribing off-label suggests that doctors should not make prescribing decisions for resource allocation reasons......

..... Can a CCG  (clinical commissioning groups or payers) make arrangements to provide bevacizumab for NHS patients?...

..... Because NICE has conducted a technology assessment of ranibizumab clinical commissioning groups (CCGs) must fund the drug for patients who meet NICE criteria. However, this does not prevent CCGs offering alternative treatments to NHS patients.... 

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