Site-Agnostic Cancer Drugs: HTAs Will Need Post-Approval Data
Early Scientific Advice From HTA Bodies Also Recommended
Executive Summary
With histology-independent cancer drugs such as Vitrakvi coming to market, a new paper explores how to address the challenges in assessing the clinical and cost effectiveness of these new types of treatments.
Post-authorization data collection will be needed when it comes to assessing whether histology-independent cancer drugs are clinically effective and offer good value for money.
This is one of the conclusions of a paper authored by staff at England’s health technology assessment body, NICE, who explore the challenges these new types of cancer treatments pose for the HTA process because of the way in which they are usually tested during development.
It is likely that additional data collection, for example through England’s Cancer Drugs Fund, will be necessary, according to the paper, published this week in the BMJ.
In addition, companies developing such medicines – also known as tissue/site-agnostic cancer drugs – should seek scientific advice from HTA bodies to ensure they consider evidence requirements to assure timely patient access, the paper’s authors advise.
US and EU Approvals
Histology-independent cancer drugs are relatively new. Other types of cancer medicines are tested, and then appraised by NICE, for one type of cancer, such as advanced lung cancer. A histology-independent drug, on the other hand, can be indicated for a multitude of tumor types, as long as it expresses a given genomic mutation.
Since 2017 the US Food and Drug Administration has approved three drugs for histology-independent indications – Merck & Co's Keytruda (pembrolizumab), Bayer's Vitrakvi (larotrectinib) and Roche's Rozlytrek (entrectinib). In September 2019, Vitrakvi became the first histology-independent product to be approved in the EU. It was granted a conditional marketing authorization by the European Commission for treating solid tumors that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion. This means that it can be used to treat non-hematological tumors with this specific mutation, regardless of where in the body the tumor originated. NICE guidance is currently being developed to appraise the clinical and cost effectiveness of larotrectinib within its marketing authorization for treating NTRK fusion-positive advanced solid tumors.
The Problem For HTA Bodies
According to the authors of the new paper, histology-independent cancer drugs “might offer substantial health benefits to patients and could provide treatment options for patients with rare tumour types, for whom none currently exists.”
The difficulty for HTA bodies and payers concerns the way in which these products are tested during their development.
As explained in the paper, the prevalence of the biomarkers that are targeted by histology-independent drugs can be low, which means that conducting randomized controlled trials is not always feasible.
Histology-independent drugs are developed in basket trials instead, which can test a drug in multiple rare indications simultaneously. However, these trials do not include a comparator arm or randomization procedure and include only a handful of patients per tumor type, with the primary endpoint of objective response rate, the authors say.
The clinical evidence on the effectiveness of these drugs in treating the tumors is based on immature data and on studies with extremely small sample sizes. “This will make it very challenging to assess whether the drug provides value for money to the NHS” [National Health Service], the paper says.
The authors observe that when a drug is approved by regulators based on a single arm trial, its clinical effectiveness can only be estimated by indirect comparisons with external controls (data from an unrelated, previously conducted study). “This can result in biased effectiveness estimates, so HTA bodies are usually cautious about drawing conclusions from such evidence.”
They also note that histology-independent drugs that have received marketing authorizations in the US and EU “thus far did not have a standardised diagnostic test available at the time.” They say that this will make it difficult to assess how well basket trial populations reflect eligible patients in clinical practice, as the testing strategy in England’s NHS will probably differ from the patient selection strategy used in the basket.
They note that although NHS England has announced the introduction of a new Genomic Medicine Service that will provide routine genomic testing, the service is still in the process of being rolled out. “Unless all patients with cancer receive routine genomic testing, it will be difficult to predict which patients will be treated with a histology independent cancer drug in the NHS. Treating NHS patients earlier or later in the treatment pathway than patients in the basket trial will change the relevant comparator treatment, which differs by treatment line and tumour type. This will complicate estimating the drug’s clinical and cost effectiveness before the drug is introduced in clinical practice.”
The authors conclude that health care systems wanting to facilitate patient access to histology-independent cancer drugs will need to rely on post-authorization evidence generation, as the marketing authorization is likely to be granted without mature evidence on the drug’s efficacy on progression-free survival and overall survival.
They also observe, however, that “European payers and HTA bodies remain hesitant to use data collection arrangements on a wide scale. Many payers prefer to manage decision uncertainty by negotiating price discounts rather than using more complex arrangements that require data collection.”
The authors advise drug companies, regulatory agencies and HTA bodies to work together to discuss the evidence generation strategy for histology-independent drugs before they enter the market. “The use of basket trials for these types of drugs can make the job of HTA bodies much more difficult."
They add that "early interactions with companies can help HTA bodies make relatively informed recommendations, especially around facilitating timely discussion about what additional data collection might be required. This will enable reimbursement decisions to be made without causing unnecessary delays to patient access.”
They observe that some of the challenges that HTA bodies face now that the first histology independent cancer drugs are coming to market could have been prevented or mitigated through earlier and better consideration of HTA evidence requirements, using mechanisms such as the European Medicines Agency’s adaptive pathways initiative.
“For the histology independent cancer drugs that are already being appraised by HTA bodies, we don’t know whether decision makers will deem the substantial uncertainty about the drugs’ clinical and cost effectiveness acceptable against the drugs’ potential health benefits," the authors say.
They note that the Canadian HTA body, CADTH, published a “do not reimburse” recommendation for larotrectinib in November 2019. “Whether patients will gain access to these new drugs will vary in different countries, depending on the opportunities for conditional reimbursement arrangements, infrastructure for postauthorisation evidence generation, and the willingness and appetite for risk sharing between healthcare systems and companies.”
NICE, meanwhile, is doing more work to identify the best way to appraise histology-independent cancer drugs. A research project, funded by the National Institute for Health Research, will provide recommendations on the methods for the appraisal of these types of drugs. The results of this project will be considered as part of NICE’s methods review.