In the July/August issue of Hospital Pharmacist (2008;15:266), Ron Pate described the difficulties in introducing a new licensed medicine to replace the established use of an unlicensed equivalent, and posed the question of whether there was vested interest from technical services pharmacists that was impeding the uptake of these new medicines. I would like to suggest an alternative cause.
As we are aware, clinical practice in UK hospitals varies considerably. In many cases this variation is at individual practitioner level but, increasingly often, many local practices have been formalised locally in protocols and procedures. Clinicians may have invested considerable intellectual capital in these locally developed practices, which may sometimes have evolved in response to adverse incidents. It is often the case that, within specialist or developmental areas of medicine, unlicensed formulations have to be used initially because no suitable licensed products exist (eg, methotrexate syringes for rheumatoid arthritis). Partly as a result of the current legal ban on advertising unlicensed medicines, the product choices made by different people at different trusts are varied.
When questioned, most clinicians will recognise the advantages of standardised practice — in terms of safety, efficacy and practicality. However, normally, they prefer that the standard reflects their own practice. If, consequently, a new and similar, but not necessarily identical, option (in the form of a licensed medicine) is introduced with no consultation or rationale, then there may be a considerable resistance to change from the local practice which has been developed in a logical and sensible, albeit isolated, way.
What is required is a facilitated change process involving as much consultation and explanation as possible. This can only be accomplished from within the NHS. There are a number of groups that have begun this process and are trying to deliver consensus in defined areas of clinical practice to engender demand for standard presentations of medicines — to allow many more to be delivered as licensed products.
I suggest the way forward for industry is not to license a medicine aimed at replacing an established unlicensed equivalent and expect clinical practice to automatically migrate towards it. Rather, it should engage with and support an NHS-facilitated change process. I am confident that this approach will show that real win-win scenarios are possible.
Kevan Wind
Medicines procurement specialist pharmacist, London, Eastern & South East Specialist Pharmacy Services
Ron Pate replies
Mr Wind is also helpfully making my point. He seems to indicate that technical service pharmacists are hiding behind the cloak of clinicians who are resistant to standardised practice and like to do what they want. Surely hospital pharmacists should be leading the way in arguing for standardised practice for commonly used medicines to improve safety?
Methotrexate syringes are offered as an example by Mr Wind, who states that unlicensed formulations have to be used initially because no suitable licensed products exist. However, the licensed methotrexate product is the dominant product used in mainland Europe, so why not here?
That all being said, Mr Wind makes an important point regarding consultation between manufacturers of licensed medicines and NHS users and my article did not cover this. However, the evidence does not stack up.
Ask any manufacturer about consultations they have with the NHS about products they may need and they tell you the answers are wide and variable, thereby making investment risky and difficult to justify. Again, using methotrexate injection as an example, if the licensed product is not meeting clinicians’ needs, why has a competitor not stepped in with a licensed alternative? Is it because they know from experience that technical pharmacists will continue to make their own version, hiding behind section 10 exemption? (EDITOR — hospital manufacturing units that produce unlicensed products do so by operating under the exemption contained in Section 10 of the Medicines Act 1968.)
Continuing with the theme of consultation, the National Board for Modernising Manufacturing has worked extremely hard in its consultation process with the NHS in an attempt to standardise a number of injectable preparations. What limited standardisation that has been archived has taken an age and getting agreement or support from the royal colleges has been like getting blood from a stone. Is that because clinicians have a vested interest and are resistant to standardised practice?
Do not get me wrong, I accept there is a need for specials for some patients but, by definition, these cannot be the norm.
My view is we need to free up capacity in NHS units to make those products that cannot be purchased (eg, products identified in audits arising from National Patient Safety Agency alerts 20 and 21) and so improve patient safety.
Key stakeholders in any consultation on product development include the Medicines and Healthcare products Regulatory Agency and pharmacists specialising in quality control or quality assurance — both of whom should be exerting pressure on section 10 units where these are making products for in-house use when a licensed product could be purchased.
Procurement pharmacists should also be included in the consultation process, so that they do not contract for unlicensed products when they could easily contract for a licensed version. But will we ever get agreement on what we want? Leadership and collaboration is needed, not self-interest.
Ron Pate
Secondary care pharmaceutical adviser to the department of medicines management at Keele UniversityHospital pharmacists do not ignore industry initiatives
With reference to the Comment article “Licensed vs unlicensed — to make medicines, or to buy them?” we wish to respond to the suggestion that hospital pharmacists ignore initiatives from the industry with reference to the specific example given, by the author, of Metoject (methotrexate) injection.
First, the author makes the same error the company did in November 20071 when it advertised the product as “the only officially licensed MTX product” and was told by the Medicines and Healthcare products Regulatory Agency to amend this to include the wording “the only MTX licensed for active rheumatoid arthritis” as this was and is misleading as there are other licensed methotrexate injections available for other indications.
Secondly, given the clinical indication of this product is rheumatoid arthritis, where it is preferable for patients to self-treat at home where possible, we would suggest that the reason Metoject is not universally used is that it is absolutely clear within the summary of product characteristics2 for this product that “it is to be administered by healthcare professionals” only and therefore does not actually meet the needs of the intended patient groups. In an article where NHS manufacturing pharmacists are being challenged on their ethics, it is surprising that it is suggested by the author to use a product outside the terms of its product licence.
There are a number of other inconsistencies in the author’s argument, most notably that the undertaking to check whether there is an equivalent licensed product already on the market before preparation, although an ethical question, is more importantly a requirement issued by the regulator, the MHRA, within Guidance Note 14,3 and is therefore considered by all hospital pharmacists to be mandatory.
In fact, I would further invite the author to read MHRA Guidance Note 14. He would then understand that the document specifically relates to products being placed “on the market” and therefore should an NHS trust make a local risk-based decision to source an unlicensed special product in-house for the benefit and treatment of its own patients that this would not be outside the guidance.
The author asks the question whether investment in NHS manufacturing is the best way forward. In response to this we direct the author to the key roles for the NHS manufacturing service, which were clearly identified by the Department of Health further to its risk assessment and supported by a £42m capital investment over the past four years.4
We, as hospital manufacturing pharmacists, are only too keen to embrace the use of new licensed products as they emerge. Certainly we have more than enough to cope with manufacturing those unstable, short dated, commercially unviable products that will never get licensed. Only by further dialogue with the industry, which we are happy to engage in, can we ensure that in the future that any further initiatives and effort more closely match both the clinical needs of patients and the needs of the service.
Tony WestChief pharmacist and clinical director (pharmacy and medicines management)
Paul Forsey
Associate chief pharmacist
Sarah Ryan
Principal pharmacist manufacturing
Guy’s and St Thomas’ NHS Foundation Trust
London
References
1. MHRA. Advertising Complaint — Metoject (methotrexate) — Journal Advertisement — November 2007 (accessed 14 October 2008).
2. Summary of product characteristics for Metoject injection. Available at http://emc.medicines.org.uk (accessed 14 October 2008).
3. MHRA. Guidance Note 14: The supply of unlicensed relevant medicinal products for individual patients (PDF 155K) (accessed 14 October 2008).
4. Department of Health. Modernising the NHS hospital medicines manufacturing service; Implementation plan: Allocation of capital funding for financial years 2004–05 & 2005–06 (accessed 14 October 2008).
Some helpful points
The authors of this letter make some helpful points, many of which I agree with. However they also have inaccuracies in their letter since I did not suggest that Metoject is used outside its product licence (and incidentally use of vials of methotrexate for rheumatoid disease is outside its product licence). I stated that “hospital pharmacists need to ensure that the product they make or buy from a specials manufacturer is in fact a different concentration to the licensed product or their actions would be deemed illegal by the MHRA”.
Incidentally, where patients are not self-treating at home I would hope that a product such as methotrexate injection when administered in a clinical environment is indeed administered by (or supervised by) a healthcare professional. I fully support the authors’ assertion that a trust should make a risk-based decision on whether to source an unlicensed product in-house though since such a product will be used in-house it is not being “placed on the market” and is therefore allowable under MAL 14. However, when such a product is sold on by such a trust is that not placing it on the market?
It is disappointing that the thrust of this letter focuses on Metoject (I did raise two product examples to illustrate my points) and not the overall issue which I was raising and the authors identify only in the final paragraph of their letter.
The authors should also know of my support for the national investment in modernising NHS manufacturing which I led for the Midlands and East of England. However it may help to make it clear I was not referring to NHS lead and support units identified in that strategy but other hospital aseptic manufacturing units.
I remain of the view that we, in hospital pharmacy, are too quick to make medicines when we could buy them, we are not exactly proactive in pushing industry to take on and license medicines we make and, with overstretched units, we are not making those products that are needed. This issue needs unlocking and having this debate is helpful to that process and one which the MHRA needs to be part of.
Ron PateSecondary care pharmaceutical adviser to the department of medicines mangement at Keele University
From Robert Lowe, MRPharmS
I have read with interest the original article by Ron Pate (Hospital Pharmacist 2008;15:266) and the subsequent letter from Kevan Wind and Mr Pate’s reply in last month’s issue (Hospital Pharmacist 2008;15:346) and I believe both authors have raised some very valid points. However, there is one issue I feel does require some further clarification.
In the original article and in his reply Mr Pate makes mention of Metoject syringes, which are a licensed pre-filled syringe containing methotrexate at a concentration of 10mg/ml. To my mind, at least, the implication given in the article and correspondence was that if a pharmacist failed to use the licensed Metoject preparation they were doing something wrong (if not illegal). I do not happen to share this view.
When a hospital pharmacist receives a prescription for methotrexate this will be written generically. In this situation the pharmacist can supply licensed Metoject syringes or, equally, he or she can prepare a methotrexate syringe using licensed methotrexate vials. In either case a licensed product is used and the person administering the product receives the drug in a ready-to-use format. The methotrexate in the vials may well be licensed only for use in neoplastic conditions, so an “off label” use of this product will occur.
However, given the large amount of “off label” use of medicines that occurs due to differences between generic licences or lack of licensed indications for particular age groups (especially children) this situation is not at all uncommon. I believe that either method of supply is equally valid and the choice of which method of supply is used will probably hinge around issues such as the capacity of the cytotoxic unit to prepare these products in a timely manner.
Where the matter becomes slightly more complicated is when a NHS pharmacy manufacturing unit holding a manufacturing licence from the MHRA chooses to sell methotrexate syringes it has prepared from vials of methotrexate, or when a hospital pharmacy chooses to procure these syringes from a specials manufacturer (be that a commercial supplier or a licensed NHS unit) rather than use the licensed pre-filled syringe.
The Medicines for Human Use (Marketing Authorisations etc.) Regulations 1994 SI no.3144 (Schedule 1 Exemptions) upon which the MHRA’s Guidance Note 14 is based, state that it is unlawful for a specials manufacturer to place an unlicensed medicine on the market which is pharmaceutically equivalent to a licensed product. Pharmaceutical equivalence in this case is defined as products which contain the same amount of the same active substance (or the same concentration if a liquid) and are of the same dosage form. It should also be noted that to justify a pharmacist procuring an unlicensed medicine for use the product must be supplied to meet the special needs of an individual patient.
It can therefore be argued by specials manufacturers that the product they supply made from methotrexate vials is not pharmaceutically equivalent because it will contain methotrexate at a concentration of 25mg/ml, not the 10mg/ml found in the licensed Metoject product.
Given that methotrexate when administered for the treatment of rheumatoid arthritis will be given by IM or SC injection, the volume of the dose does become important and favours the more concentrated unlicensed product. As a general rule I would encourage the use of licensed products whenever possible (including for unlicensed indications or so-called “off-label” use).
Given that the licensed pre-filled syringe at the lower concentration is widely used in Europe, one might well suggest that the argument for a smaller injection volume as a “special need” of the patient is somewhat tenuous, assuming that the product is administered by the same route in Europe.
I would suggest that whenever you are dealing with unlicensed medicines the question you should always ask yourself is “what is the special need of this patient that justifies the use of an unlicensed medicine as opposed to a licensed one?” If you can answer this question to your own satisfaction then you should proceed with the use of the unlicensed medicine, provided that you are equally happy with the quality, safety and efficacy of the unlicensed preparation you are using.
Director of Quality Assurance Specialist Services, East of England and NorthamptonshireRobert Lowe