Billions Wasted on Futile Onco Drug Development Indicates a Disturbing Trend
(Thursday, August 3, 2023)
Developing new drugs is an expensive and time-consuming venture. One would expect developers to conduct extensive due diligence before investing resources into developing a new drug. What if their due diligence is influenced by non-scientific factors such as herd instinct and fear of missing an opportunity? Can multiple independent developers make a common mistake? What is the cost of such mistake to the patients? A case study of the futile development of a new class of oncology drugs in multiple trials over 2 decades at tremendous expense by multiple companies shows a disturbing trend in clinical research which should be lesson for future.
A retrospective research article published in the Journal of American Medical Association (JAMA) presents such a case. For about two decades, between the years 2000 and 2021, 16 independent companies conducted 183 clinical trials recruiting a total of over 12,000 participants at an estimated total cost of about $2 Billion to evaluate 16 different IGF-1R inhibitors. Overall, 9 monoclonal antibodies, 6 small molecules and one cell therapy were evaluated against the same target across 8 different cancer indications. The retrospective analysis of the data shows that companies invested money in these development projects despite having scant non-clinical evidence of benefit or multiple trials failing to yield reasonable results. All the clinical trials failed in showing any benefits of any of the 16 drugs and biologics tested and none of these inhibitors was approved by any regulatory agency.
The authors of the JAMA report discussed that while several factors could have contributed to this disastrous outcome, the primary contributors were lax target validation and deficient preclinical models which led to less effective and lenient decisions. But a more prominent reason pointed out by the authors of this study is the rampant me-too programs, particularly in anti-cancer drug discovery, owing to high expectations due to strong competition and need to fill drug pipelines, which led to management decisions dominated by herd instinct. The herd instinct is defined as a decision influenced not only by rational risk-return considerations, but also by expectations and perceptions of other’s behavior. It seems managements in these companies put less weight on internal doubts, if any about their programs, and more emphasis on their competition pursuing similar programs. Competition superseded internal conflicts. This led to 16 companies dashing competitively towards clinical trials of IGF-1R inhibitors, all of which failed.
This is unfortunately not uncommon. According to the JAMA report, “in the drug industry, cancer R&D that is failing or destined to fail will currently incur an annual expense that is in the order of $50 billion to $60 billion.” And this is not limited to oncology drugs; similar trends can be seen in other indications such as Alzheimer’s disease, diabetes, Duchenne muscular dystrophy (DMD), and ALS, where despite limited success, multiple me-too programs are being pursued. It would seem that the industry shies from “thinking outside the box”, which is very unfortunate. Companies box themselves into considering what their competitors are doing as the norm and the best approach; it could be far from it as evident from the JAMA report.
More than 12,000 patients who participated in the oncology trials for IGF-1R studies were potentially subjected to futile clinical trials and may have deferred other clinical trials or treatments that could have helped them better. Since, per the projections made in this study, the IGF-1R programs represent a very small fraction of all the ongoing me-too programs, the negative impact of this practice is enormous. In the last two decades, 83% of cancer programs have failed to yield clinical benefits, and of drugs that offered an overall survival benefit, it was for a mean of only 6 months of life extension with diminished quality of life. It cannot be said that this is only because of programs like those for IGF-1R but seems worth looking at as one of the factors.
This practice can be checked by stricter due diligence based on objective preclinical justification before moving a product to clinical trials, technical diversification to avoid overinvestment in me-too programs, and rigorous analyses of major translational failures. Most importantly, “thinking outside the box” should not just be an adage, but a practice.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC