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editorial
. 2018 Nov 29;33(4):521–528. doi: 10.1038/s41433-018-0280-3

Table 2.

Six issues analysed by the Court

Issue Bayer and Novartis’ position Court’s analysis
1) Does the EMA have exclusive competence to determine whether Avastin is effective and/or clinically effective for ophthalmic use? There is no lawful basis for the supply of Avastin for ophthalmic use because the EMA (and the MHRA in relation to the UK market only) have exclusive competence to determine the safety, clinical efficacy and quality of medicines available to the public. Protection of human health would be jeopardised if a mass supply of unlicensed medicine were permitted. This means that only the EMA has competence to determine whether a medicine is safe and clinically effective for ophthalmic use. Avastin has not been deemed safe and clinically effective because the EMA has not assessed it for ophthalmic use [28] The EMA’s role is limited to determining the safety and efficacy of a medicine for the particular therapeutic purpose for which the marketing authorisation is sought. It does not have exclusive competence beyond that point, namely to determine whether the same medicine is effective and safe for other uses. Such a conclusion would prohibit national healthcare authorities from considering the safety and efficacy of medicines and would be “seriously detrimental to the wider public interest in maintaining a cost-effective public health system”. NICE and the CCGs also have competence in assessing any medicine which is proposed for use outside its marketing authorisation and this role is recognised in EU case law and domestic statutes, and is “fundamental to the operation of a rational and effective public health system”. Indeed, NICE has conducted a comparison of the three drugs and the claimants did not assert that this was in excess of NICE’s powers [29]
2) Can treating clinicians lawfully choose Avastin on grounds of cost? Clinicians are not permitted to take account of cost at the point of prescribing. This is largely based on the GMC’s guidance to the effect that a doctor could only prescribe an unlicensed medicine where there were “medical reasons” for so doing, and on the basis that it was “necessary to do so to meet the specific needs of the patient”, which, it was argued, precluded a doctor from selecting a drug on the basis of cost alone [30]. However, the claimants accepted during the hearing that if faced with several licensed drugs of similar efficacy, it was permissible for the clinician to consider cost as a “tie-breaker” [31]

Treating clinicians can lawfully choose Avastin for ophthalmic use on grounds of cost:

a) The GMC guidance permits exceptions. The express exception that a doctor considers the prescription of an unlicensed drug to be necessary on medical grounds cannot be the only possible exception to the general rule: “There may be other exceptions too, not spelt out in the guidance”. Further, the present situation is “very unusual” because Avastin as the unlicensed alternative is equally safe and effective as the licensed alternatives. This is “far outside the category of ‘usual’ cases” at which the guidance is directed [32]. In this situation a clinician would, “as a matter of professional conduct, be free to choose whichever medicine he or she considers to be most suitable, taking account of his obligations to the patient, and to patients more generally” [33].

b) The Directive does not preclude this practice because such a reading would stray over the line which separates EU and Member State competence.

c) Professional misconduct is not the same as unlawfulness. Even if such conduct contravened the GMC guidance, that conduct would not be unlawful simply by virtue of breaching professional guidance [34]
3) Is Avastin safe for ophthalmic use?

Avastin is not safe, or not as safe as Lucentis or Eylea, for ophthalmic use due to:

a) different molecular size and structure from the two licensed medicines, not being designed for use in the eye;

b) compounding process (which involves opening a vial and dividing it into aliquots) which raises issues of shelf life, stability and contamination which have not been assessed;

c) more injections of Avastin are required to achieve the same result as either of the licensed alternatives;

d) greater patient monitoring requirements which some NHS departments do not have the capacity to provide;

e) manufacturing to a different standard with a lower concentration of particulate matter than is permitted for solutions intended for intravenous use; and

f) not being subject to pharmacovigilance for ophthalmic use.

Treating patients with Avastin would therefore expose them to risk and thereby undermine the harmonised system (created to avoid recurrence of the thalidomide tragedy) which is aimed at protecting patients [46]

 The safety of Avastin for ophthalmic purposes did not arise for the purposes of the judicial review because the claimants did not challenge the rationality of the CCGs’ conclusion that Avastin was equally safe and effective. However, even if it were not irrelevant, NICE has concluded that Avastin so used is safe and that settled the issue [47]
4) Is there a mature and established market in compounded bevacizumab prepared for ophthalmic use? There is no mature and established market for Avastin for ophthalmic use [35] Avastin is widely available in the UK, the EU and further afield for ophthalmic use as acknowledged by the European Court of Justice [36]. The market is established although there is no direct evidence of its size or maturity [37]. The Court did not appear to analyse the difference between the terms “mature” and “established”.
5) Is compounded bevacizumab an unlicensed medicine or an off-label use of a licensed medicine? Avastin for ophthalmic use is an unlicensed medicine rather than off-label medicine, meaning that the compounding process for ophthalmic use created a new product which required its own marketing authorisation. A large-scale commercial supply of an unlicensed drug would be unlawful, making the Policy unlawful [38] Based on the MHRA guidance, Avastin is an unlicensed medicine for ophthalmic conditions, and not an off-label use. The Court considered that “the position is highly unsatisfactory” partly as the European Court of Justice has accepted the ophthalmic use of Avastin as off-label, and “it is time the MHRA reviewed its position” [39]
6) What is the relevant test by which the lawfulness of the Policy is to be judged, in domestic law?

Lawfulness of the Policy stood or fell with the lawfulness (or not) of the actions envisaged by the Policy. The claimants cited case law which concerned legal aid for representation at an inquest into death and asked whether the Policy would “(i) lead to unlawful acts (ii) permit unlawful acts or (iii) encourage such unlawful acts” [40, 41].

The CCGs contend that the Policy is lawful not by virtue of what it envisages, but if it is capable of lawful implementation, and that there are a variety of means by which the Policy might lead to Avastin being purchased by NHS Trusts. The question is therefore whether individual decisions of NHS Trusts following the Policy are lawful.

Bayer and Novartis argued that the defendants cannot rely on this argument because in reality the Policy is aimed at promoting the widespread ophthalmic use of Avastin, which is itself unlawful. The CCGs should not rely on the possibility that NHS Trusts adopt a lawful means of implementation of the Policy given that they are on notice, by the Court proceedings, that the underlying supplies and purpose of the Policy would be unlawful [42]

Even though Avastin is unlicensed for ophthalmic use, the Court did not consider the Policy unlawful because the four modes of supply of Avastin for ophthalmic use were capable of being carried out lawfully. This was so because:

a) the Policy is merely advisory (rather than mandatory like in other cases [43], leaving up to the NHS Trusts to decide whether and how to implement the Policy;

b) the Policy was not inherently flawed but rather individual decisions made by NHS Trusts pursuant to it might be open to challenge; [44, 45] and

c) the Policy could be fulfilled by four different modes rather than a single mode (bulk procurement ahead of prescription). The four modes were (i) original vial use; (ii) compounded “in house” by the hospital’s own pharmacy; (iii) compounded by another NHS hospital pharmacy; and (iv) compounded by a commercial entity outside the NHS. The Court included that each of of the four modes might be lawful.