Responses to criticisms of the IVAN trial

Despite peer review of the funding application, industry representatives have claimed that the trial has been badly designed and is of poor quality. One possible reason for this allegation is that industry and the NHS may have different priorities when designing studies, for example because industry and the NHS often have subtly different research objectives. The fact that the IVAN trial shares many design features with a similar trial funded in America by the National Institutes for Health should reassure the research community that the design of the IVAN trial is robust and stands up to scientific scrutiny.

Responses to specific criticisms are described below.

Criticism 1. “The study is not big enough to test whether one drug is better than the other”

Response: The IVAN trial is not designed to test whether the less expensive drug, or reduced treatment frequency, is better than the other. Instead, it is designed to test whether the less expensive drug and the reduced treatment frequency are as good as the more expensive drug and continuous treatment, within a defined margin of error. Another way of stating this is that the IVAN trial is designed to rule out a difference in outcome greater than specified amount.

The primary outcome is logMAR visual acuity and the IVAN trial aims to rule out an average difference of greater than or equal to 4 letters (0.08 logMAR, less than one line on the logMAR letter chart) between groups of patients allocated to different drugs, and groups allocated to different treatment frequencies.

As a general principle, a trial designed like IVAN will have a larger target sample size than a trial designed to test whether one drug is better than another. Consistent with this principle, the IVAN trial aims to recruit about 30% more patients than an industry-sponsored trial of Lucentis® compared with the best alternative. Furthermore, the proposed sample size for IVAN was approved by independent peer review and the HTA Board.

It is important to note that deciding the target sample size for a randomised trial involves judgements and estimating unknown quantities. Therefore, it is not an exact process. It is an example of how the differing priorities of the main stakeholders can influence trial design

Criticism 2. “The outcomes measured are not relevant to determining relative cost effectiveness”

Response: The IVAN trial is measuring a range of health outcomes, as well as visual acuity, so that the effects of different drugs and treatment frequencies can be assessed from different perspectives. For example, data will be collected about adverse effects, the quality of life of patients and their satisfaction with treatment, ability to read and other aspects of vision, in addition to data about visual acuity and costs.

Standard questionnaires will be used which will allow health economists to estimate cost-effectiveness in ways recommended by the UK National Institute of Health and Clinical Excellence.

Criticism 3. “The IVAN trial is using a surprising HIGH dose of Avastin®”

Response: Avastin is commonly used in a dose of 1.25 mg. The rationale for its use at this dose is that the molar concentration achieved after intravitreal injection is very similar to that achieved by the 0.5 mg dose of Lucentis®. A recent review reported that 1.25mg was the most commonly used dose amongst about 2700 patients who had been treated with Avastin®. A dose escalation study found no systemic or ocular SAE following a single injection of 1.0, 1.5 or 2.0 mg of Avastin®.

Criticism 4. “There is a lack of appropriate dose ranging studies for Avastin”

Response: This is well recognised by all experts in this field. Such studies are needed and are underway. IVAN will contribute to informing this gap in knowledge by comparing different treatment frequency regimens (in effect, different cumulative drug doses) for both drugs.

Criticism 5. “The recruitment criteria for the study are flawed or inappropriate”

Response: Recruitment criteria are another aspect of study design which may be affected by the differing priorities of the main stakeholders. A contrast can be drawn between “explanatory” (industry) and “pragmatic” (NHS) trials. The IVAN trial has been designed to have eligibility criteria that are as inclusive as possible, to ensure the results are applicable to the kinds of patients likely to be treated by the NHS.

Criticism 6. “The length of the study is inappropriate”

Response: The IVAN trial requires participants to be followed monthly over two years, with the primary trial endpoint being two years after the start of treatment. An interim analysis will be carried out at one year. Other analyses may be requested by the Data and Safety Monitoring Committee, to protect the interests of patients. This duration of follow-up is very similar to the durations in other trials of intravitreal drug injections for nAMD, including trials sponsored by the pharmaceutical industry.

It is important to bear in mind that the likely average age of participants will be about 75 years and that the monthly follow-up schedule may be demanding for elderly people.