Overregulation May Delay Access to Life-Prolonging Medications, Increase Costs

David J. Stewart, MD

Overregulation of new drug development has driven up the cost of care and resulted in significant loss of human life by delaying the approval of effective medications, according to a presentation by David J. Stewart, MD, at the 2015 World Conference on Lung Cancer.

"The huge cost of driving clinical research is rising much faster than the rate of inflation, and it is all about complying with regulation," Stewart, head, Division of Medical Oncology, University of Ottawa/The Ottawa Hospital, said during a press briefing. "For people with a 100% lethal disease, we need to completely change the way that we apply the rules to get these drugs to patients much faster and much cheaper. The costs are going through the roof, and that is driven largely by the costs of doing the research. We're going to bankrupt ourselves."

At the conference, Stewart presented an analysis of 21 drugs that were shown to significantly prolong overall survival (OS) in phase III clinical trials between 2000 and 2015 across 10 incurable malignancies. The analysis excluded adjuvant trials and those for uncommon diseases. The number of life-years potentially lost was assessed by multiplying the improvement in OS in years seen with each treatment by the estimated number of patients who died annually from the relevant indication.

For each therapy, the median time from drug discovery to approval was 12 years. Across all indications worldwide, the median number of life-years lost per year was 2.54 million. From discovery until approval, there was a total loss of 31.54 million years of life. By reducing the average time of development to 5 years, the authors predicted that 19.4 million life-years could be saved.

In North America, 29 life-years were lost for every hour that approval was delayed. Taking this into account, each year of development equated to 251,626 life-years or slightly over 3 million life-years over the full 12-year course of development.

Added safety measures that were a byproduct of regulation were not without their merit. These measures were found to save <700 life-years for each drug. However, when looking at the two figures in contrast, there were approximately 50,000 life-years lost due to delays for every 1 life-year saved through greater clinical research safety.

While the exact costs associated with the development of each agent were not explored, some reports have placed the cost of development for a drug from discovery to approval at over $1 billion.

"We need to take the speed of approval and the expense of approval and make that our top priority for lethal diseases," Stewart said. "Regulation is absolutely essential but we need something that is equivalent to the autobahn in Germany—unlimited speed limits but yet one of the lowest traffic fatality rates in Europe&mdash;it's because they have smart regulations: not too much, not too little. Right now, our regulation is not smart."

While accelerated approvals and breakthrough designations have made strides toward improving the speed of new drug approvals, additional changes are still needed. Many of the speed bumps toward rapid drug development involve documentation, preclinical studies, and delays associated with setting up clinical trial locations. Not only can these processes slow down development but they can also add considerable costs, Stewart said.

"A massive driver of costs is the documentation of things that are of minimal value, like all of the massive documentation of grade 1 and 2 toxicity for drugs that are never approved," Stewart said. "This is a huge expense. It is a huge amount of time. The documentation has to be looked at carefully."

In many situations, an effective medication may spend large amounts of time in preclinical studies. While these studies can provide valuable information for future clinical trials, large amounts of the data collected during this phase of research are of little importance, according to Stewart.

"Preclinical toxicology is useless. It can take 1, 2, or 3 years to get a drug to the first patient once the preclinical toxicology is done," he explained. "It shows you the obvious—the drug is going to cause myelosuppression&mdash;or it misses important toxicity by telling you toxicity that isn't important."

The only relevant findings from preclinical toxicology are those that guide an effective starting dose for human trials, Stewart suggested. Similar can be said about preclinical pharmacology, with very few of the main findings aiding actual human use. "All of the rest of the findings are added timing and adding expense for getting the drug to the patient," he suggested.

Once a drug reaches clinical trials, there are further obstacles that prevent rapid development. In the area of precision medicine, distinct demographic challenges face patient enrollment, specifically in regard to patient access to clinical trials.

"It might be just 1% of the patients who may have the right mutation to get a patient on the study, but you have months of work and thousands lost trying to get the study up and running at your place," Stewart said. "We need a completely new system to take this into consideration, for just in time trial activations."

In this system, molecularly based clinical trials could be opened in a matter of hours as opposed to months, if next-generation sequencing identifies a distinct mutation, Stewart suggested. Under this proposed system, online training could be utilized to accomplish training goals in a matter of hours.

Outside of preclinical work, documentation, and clinical trial locations, other examples of delays were far more trivial. In one example, Stewart explained that something as simple as wording could delay a trial for several months as a protocol attempted to pass institutional review boards. "Patients are dying while the wording is perfected, the priorities are all wrong," he concluded.

Stewart DJ, Stewart AA, Wheatley-Price P, et al. Impact of Time to Drug Approval on Potential Years of Life Lost: The Compelling Need for Improved Trial and Regulatory Efficiency. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1547.

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