|When drugs did show survival gains over existing treatments the benefits were marginal, the report says. Treatments that improved life expectancy gave patients a median of an extra 2.7 months of life often at significant cost. Notwithstanding, researchers stressed that when someone is dying of cancer even a few extra months of life with loved ones are priceless, and they also understood that it takes time to prove a drug will improve life expectancy. Notwithstanding, researchers suggested that drug firms could be needlessly raising the hopes of cancer patients and exposing them to unnecessary side effects. “At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications,” researchers said. Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up, 35 had shown a significant improvement in survival or quality of life, while 33 remained uncertain.
“It is remarkable that cancer drugs enter the European market without any clear data on outcomes that matter to patients and their doctors: longer survival and better quality of life,” said Huseyin Naci, a co-author. “There is a clear need to raise the bar for approving new cancer drugs. When expensive drugs that lack robust evidence of clinical benefit are approved and reimbursed within publicly funded healthcare systems, individual patients may be harmed, and public funds wasted,” say the researchers. “There is growing concern that the benefits offered by many new treatments for cancer, which are often discussed and promoted as ‘breakthroughs’, are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs,” says Courtney Davis of Kings College London (KCL) and the lead author of the study.
Editors’ note of caution
Editors of the BMJ noted that the study was limited by the EMA’s“incomplete and variable” reporting of clinical studies, which contributed to the “possible overestimation of the proportion of drugs that offer survival or quality of life benefits”. They further suggested that the researchers did not consider the “appropriateness of clinical trial design”, which affects patient outcomes, and they also failed to take into account the “negative studies” for the indications they were studying.
Randomized controlled trials
Paradigm shifts in science, rapidly changing technologies, the increasing influence of patient advocacy groups and economic pressures on pharmaceutical companies are conspiring to drive change in randomized controlled trials (RCT), which were introduced 70 years ago to reduce bias when testing for a new treatment. RCTs have reshaped medical knowledge and practice and have become the “gold standard” means to assess the clinical efficacy of new or improved cancer therapies. In such procedures participants are randomly assigned to receive either the treatment under investigation or, as a control, a placebo or the current standard treatment. The randomization process helps ensure that the various groups in the study are identical across a number of relevant variables such as age, gender and socioeconomic status. This minimizes the potential for bias. Despite their strengths, only a modest percentage of therapies successfully navigate the regulatory minefield of RCTs from early stage to final approval. It takes between 10 to 15 years for a drug to pass through all the development stages and become approved for prescription. Only 5 in 5,000 drugs that enter preclinical testing progress to human testing, and only 1 in 5 of these is approved for prescription in clinics. The cost of developing a drug that gains market approval is estimated to be about US$2.6bn.
Enhanced understanding of cancer biology
One of the main limitations of cancer care has been our understanding of the biology of the disease, but this is beginning to change. Over the past 2 decades, oncologists have witnessed significant advances in our understanding of cancer biology and major breakthroughs in a number of therapeutic areas, which impact on drug targets and drug development. For example, next generation genome sequencing has increased the application of more robust models for different types of cancers. Cancer immunotherapy has captured the attention of scientists and has become a significant focus for drug delivery, and the development of genome editing technologies such as CRISPR Cas-9 have significantly impacted the direction and progress of nonclinical anticancer drug development.
Personalized medicine approaches have led to significant changes in the way oncology is practiced. Clinical and translational research is adapting to a rapidly changing environment with the intention to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients, but not without significant challenges. Some of which are described by Axel Walther a medical oncologist and Director for Research in Oncology at University Hospitals Bristol, see video below. “If we combine patients in clinical trials with the concept of personalized medicine we start to add a lot of variables. This is because we want to target a novel treatment to the individual cancer of a specific patient. The challenge is to find that patient for whom the specific treatment is appropriate. If you have a treatment that addresses a specific abnormality you need to find all the patients with that abnormality. This is relatively easy if it’s a common abnormality but significantly more difficult if the abnormality isn’t common,” says Walther.
Pressures to change RCTs
Such scientific advances have shifted the emphasis of cancer treatment from histopathologically based methods (the microscopic examination of tissue in order to study the manifestations of disease) to molecular and genetically based treatments, which has significantly improved our understanding of disease processes and advanced drug development. Technologies, which use high-throughput screening of a number of potential target molecules are significant additions to our investigational medicinal product portfolio. Further, enhanced big data assets benefit from enhanced high volume, high velocity, high variety processing and interpretation and increasingly provide new and significant opportunities to conduct large-scale studies with many of the benefits of RCTs but without the expense. Big data techniques also allow for the study of rare cancers effecting small populations, which are often excluded from RCTs because of cost and other constraints. Such scientific and technological advances, together with the rapid expansion of the portfolio of therapeutic modalities, which can be used in various combinations to improve clinical outcomes, challenge traditional RCTs. Further, the costs and increasing complexity of RCTs means that promising drug candidates are sometimes abandoned for economic or logistical reasons rather than for their efficacy. For these reasons regulatory bodies, including the EMA, support changes in RCTs and are encouraging ‘adaptive clinical trials”.
Adaptive clinical trials
Adaptive clinical trials can be used in every phase of drug development. Rather than wait until the end of the trial to analyse data, adaptive trials accumulate and analyse data during the trial period and use results to change the actual direction of the trial. Adapting trials in this way is expected to reduce risks for both patients and pharmaceutical companies, particularly at challenging decision-points, such as dose selection. Significantly, adaptive trials can reduce the total number of patients required to obtain results. This, cuts cost and alleviates time constraints on sponsors, researchers, monitors, and trial sites and increases the capacity of the entire clinical development system. Notwithstanding, a concern is that data from such studies tend to be challenging to provide definitive answers.
Researchers drew attention to the fact that a significant number of cancer drugs become available in the UK without evidence that they significantly extend life. The slow pace and the eye-watering costs of traditional RCTs are increasingly being challenged by pharmaceutical companies, governments, scientists, patient advocacy groups and regulators. Fuelling such challenges is the unprecedented pace of change in our understanding of cancer biology, which has significantly influenced drug development and the modalities of treatments. New science is positioned to transform medicine beyond our recognition. But the science itself and the process by which it is transformed into useful medicine collide with RCTs.