Rare cancers through the looking glass

espite the rarity of each of the so far 198 types of rare cancers, they account for approximately 22% of all cancer cases diagnosed in EU each year. This estimate is higher than any single common cancer and represents a significant public health issue. In addition, survival rates for rare cancers are lower than those for common cancers.

The definition of rare cancer has been debated for many years. Since prevalence is affected by mortality the Surveillance of Rare Cancers in Europe (RARECARE) project has proposed a definition for rare cancers as those that have an incidence of less than 6 per 100,000 in the population. The prevalence number of a rare disease/disorder used by the European Medicines Agency (EMA) to grant orphan drug designation is that it should affect fewer than 5 in 10,000 citizens is the EU. Using incidence rather than prevalence as a criteria for rarity, would minimise the risk of misjudging a rare cancer which is frequently cured or managed in the sense of constantly increasing overall survival (OS) (and hence has a high prevalence) for a common cancer with high mortality rates (and thus a low prevalence) for a rare cancer.

Rare cancers are primarily identified by anatomical location; however, all cancers, including rare and common ones, are now being broken down into subgroups based on molecular characteristics. Consequently, cancers like breast and lung cancer will have subgroups that are rare even though, as a whole entity, they are common cancers. It is expected that an increasing number of cancers will be categorised as rare cancers due to advancements in genomics and precision medicine.

It is appreciated that rare cancers are challenging to study and require knowledge in both oncology and rare disease. In some instances rare oncology research has greater similarities to non-oncology rare disease research than it does to oncology studies of more common types of cancers. With a small patient population the trial design benefits from adaptive design techniques, in-depth oversight of patient eligibility and alternative statistical principles.

The selection of endpoints differs significantly between solid tumours and haematological conditions and this can add complexity to the design and conduct of the trial. The Response Evaluation Criteria in Solid Tumours is used by most solid tumour cancer trials, whereas haematological cancers rely on different measurements for capturing treatment related changes and disease progression. The gold standard for evaluating efficacy of cancer treatment is OS, however the most commonly used surrogate endpoint for trials for advanced cancers is progression-free survival. The study design for rare cancer trials should put special attention to the use of biomarkers and surrogate endpoints of efficacy, such as response duration and PFS as they may play an important part of the strategy for the regulatory review and approval process. Other progression related surrogate endpoints include disease-free or event-free survival; response rate or objective response rate; and time to progression. Drug developers should take into account that validation of surrogate endpoints is problematic in rare cancers and that guidance from regulatory health authorities should be sought early.

In the case of rare cancers, what is the EMA doing to pave the path for drug developers and speed up evaluation so these medicines can reach patients faster? The EMA may recommend the accelerated assessment pathway or the more recent PRIority MEdicines (PRIME) scheme. PRIME enable enhanced interaction and early dialogue with drug developers aiming to optimise development plans. These pathways can reduce review time from 210 days to 150 days excluding clock-stops. Approval will likely be granted on promising surrogate or intermediate clinical endpoints and a conditional marketing approval (CMA) may be obtained before completion of long-term survival or outcome studies. As a result, specific obligations in terms of post authorisation follow up studies will be imposed on the marketing authorisation holder. The EMA has recently published a report with data from CMAs between 2006 and June 2016 showing that the majority of CMAs is for oncology medicines.

Overall survival improvement is the preferred criteria by HTA bodies in EU for the demonstration of the benefit and the collection of information beyond survival is becoming more important, with the payer’s increasingly requiring quality survival to be demonstrated. However, for rare cancers, a higher degree of uncertainty could be justified with the given prerequisites in mind.

In conclusion, drug development plans should strive to bridge the gap between clinical trial designs, regulatory approval and meeting the expectations from the payer.