Impact case study database

AMD affects more than 600,000 people in the UK and tens of millions globally and, without treatment, it quickly leads to blindness. Modern treatments, such as anti-VEGF drugs injected directly into the eye (e.g. ranibizumab and bevacizumab) typically limit the loss of vision over 5 years to 1 to 2 lines of the eye test letter chart, with many patients maintaining vision sufficient to hold a driving licence. However, the very high cost of ranibizumab imposes a huge burden on healthcare services around the world. For instance, in their longitudinal study of the use of anti-VEGF therapy for a variety of eye conditions (including AMD) in England between 2005 and 2015, Hollingworth et al concluded in 2017 that ‘The high and rising cost of anti-VEGF therapy affects the ability of the NHS to provide care for other patients’. They noted how ‘current regulations encourage the increasing use of ranibizumab and aflibercept rather than bevacizumab, which evidence suggests is more cost-effective’ and concluded that ‘NHS patients in England do not have equal access to the most cost-effective care’ .[S1]

It is against this backdrop that IVAN has had such an impact. The trial is regarded by the NIHR as one the most important trials of the last decade, and it featured as a NIHR Impact Case Study in August 2019, highlighting that ‘The IVAN trial led to significant cost savings for the NHS as well as leading to new clinical guidelines from the National Institute for Health and Care Excellence. It also had international repercussions: the trial's finding were [sic] the basis for new recommendations in a World Health Organisation report’. [S2]

IVAN had a rapid impact on policy, practice, and debate. As arguments in favour of using bevacizumab are won, the impact on policy and practice is growing, with policy makers and clinicians switching from ranibizumab to bevacizumab.

WHO Essential Medicines

In 2013, the World Health Organisation (WHO) added bevacizumab to its list of essential medicines (EML) for macular degeneration, citing the IVAN findings on safety and efficacy .[S3] When the list was revised 2 years later, Novartis (the pharmaceutical company that made both drugs) applied to have ranibizumab added but this was rejected by the WHO Expert Committee, who referred again to the IVAN findings and kept bevacizumab on the list, rejecting the option of showing ranibizumab as an alternative to bevacizumab, noting ‘given the difference in current prices of the 2 products and the legislation relating to “off-label” use of medicines in many countries, the Committee decided that indicating interchangeability could well result in considerable additional expenditure at country level, without additional clinical benefit’ and ‘The Committee considered that inclusion only of the less expensive bevacizumab on the EML might serve to facilitate its use (albeit off-label) for this indication’ .[S4]

Impact on policy in the UK

In the UK, IVAN catalysed the debate about the cost of medicines and led to a campaign for approval for use of bevacizumab. NHS Commissioners joined with doctors in calling for the right to use the drug, lobbying the National Institute for Health and Care Excellence (NICE), the Department of Health, the Secretary of State and the General Medical Council. It was reported in February 2015 that ‘clinical leaders from 120 Clinical Commissioning Groups, representing almost 60% of all CCGs, have come together to call on the doctors’ regulator the General Medical Council, the Department of Health and NHS England to remove the current barriers preventing CCGs from commissioning safe and effective eye care services using the drug Avastin ‘off- licence’ to treat the debilitating condition of Wet Age related Macular Degeneration (AMD)’ .[S5] In September 2018, in a ruling welcomed by the Royal College of Ophthalmologists ,[S6] the High Court of England and Wales supported the request from 12 NHS clinical commissioning groups (CCG) in the north of England to give bevacizumab to people with worsening sight loss, upholding the principle that commissioners of health care and doctors may offer patients this drug instead of ranibizumab or other more recently licensed treatments, [S6] and the ruling was upheld by the Court of Appeal in March 2020 .[S6] In 2019, practitioners in NHS Scotland began to use bevacizumab in preference to ranibizumab.

Impact on policy elsewhere in Europe

In November 2017, the European Union Court of Justice supported the use of bevacizumab for AMD by agreeing that it is not contrary to EU law for a national healthcare insurance system to reimburse the costs of a medicinal product for a use not covered by its marketing authorisation (off-label use). [S7] In September 2020, France fined Novartis and Roche EUR444,000,000 after its competition authority ruled that the drug companies used abusive practices to promote the use of one of their drugs Lucentis (ranibizumab) over Avantis (bevacizumab). [S8]

Impact on guidance in the UK

Current NICE guidance on AMD (published in January 2018) makes wide use of IVAN. The Guideline Committee took the view ‘that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab)’, but that ‘At the time of publication (January 2018), bevacizumab did not have a UK marketing authorisation for, and is considered by the Medicines and Healthcare products Regulatory Agency (MHRA) to be an unlicensed medication in, this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the prescribing decision. Informed consent would need to be obtained and documented’. [S9] The Royal College of Ophthalmologists noted ‘There is now the potential to make considerable cost savings whilst empowering ophthalmologists to make clinical judgements with individual patients on the most appropriate choice of treatment’ .[S10]

Impact on health expenditure in the USA

In financial terms, in 2014, Hutton et al estimated that switching to bevacizumab from other anti-VEGF agents could lead to total health savings of up to USD29,000,000,000 over 10 years in the USA .[S11] A later study, published in 2018, estimated that Medicare in the USA had saved USD17,300,000,000 billion between 2008 and 2015 from the use of bevacizumab for AMD .[S11]

Impact on the evidence base

In March 2019, the most recent update of the Cochrane Review of anti-VEGF treatments of AMD concluded that ‘ranibizumab and bevacizumab have equivalent safety and effectiveness in such eyes’ and that the stability of this evidence meant that the authors ’do not anticipate a need for future updates to this systematic review’. [S12]

Finally, IVAN’s importance was also a key factor in awards received by Professor Chakravarthy. These include her CBE (2016), the Bowman award from the Royal College of Ophthalmologists (2018), the Gass Medal from the international Macula Society (2019) and a lifetime honorary Fellowship at the Royal College of Ophthalmologists (2019).