From Laboratory to Licensure: Preclinical Phase Critical in Creating New Targeted Therapies

One billion dollars.

That can be the list price for bringing a new cancer-fighting agent from preclinical design through approval by the US Food and Drug Administration, according to Michael R. Grever, MD, of the Ohio State University.

When Dr Grever announced that amount during the education session, “A Fresh Look at Drug Approval: Moving Away from Tradition,” it’s hard to say which was more startling — the size of Grever’s estimate, or the fact that none of the scientists in the room flinched.

At the 55^th American Society of Hematology Annual Meeting and Exposition in New Orleans, there has been plenty of news about targeted therapies: advancements to treat chronic lymphocytic leukemia (CLL) and multiple myeloma filled meeting halls and attracted worldwide press coverage.

But as exciting as the marriage of genetics and pharmacy has been for the treatment of blood cancers, the high cost of therapy has been an undercurrent at several sessions. Dr Grever’s talk outlined why that happens, and what steps can be taken to prevent the approval process from being any longer or expensive than necessary.

For all the complaints directed at FDA, Dr Grever said, drug developers can hurt their own cause with poor coordination or lack of accountability among members of the team. “There are many points along the regulatory process, and there are plenty of opportunities along the way for getting effective therapy to our patients, but it all starts with optimizing a lead compound and going after a lead target,” he said.

In other words, he said, “We are testing hypotheses, not just drugs.” The focus among researchers must be a robust scientific process that develops a good hypothesis and tests it rigorously, not a race to get compounds out of the lab. End points must be clearly defined. This is where “teamwork is critical, and accountability for task completion is essential,” Grever said.

In a companion paper for his talk,¹ Dr Grever noted that half the patent time on a new therapy can be lost in the approval process. The results are not only diminished returns for a pharmaceutical company, but also astronomically high prices for cancer patients, their insurance companies, or taxpayers who pay for Medicare and Medicaid.

To avoid this outcome, Grever wrote in his paper, “The time investment in the preclinical pharmacology is important to insure that the targeted levels of the agent achievable in vivo and whether an effective schedule of administration can be designed.” Failure at this stage can make an initial trial unsafe for patients.¹

One of the challenges of targeted therapy — and one of the reasons a well-ordered preclinical process is needed – is that a key element in the approval process is the development of assay that measures the phamarcodynamics in the tumor or cells. The relationship between pharmacodynamics – what the drug does to the body – and pharmacokinetics – what the body does to the drug – comes into play. “Pharmacokinetics have been part of drug development for decades,” Grever said. “They offer the only way to get real-time data, and the only way to improve design and implementation of the study.”

“When we are using targeted therapy, it is important to look at kinetics in the enzyme and in the normal cells,” he explained.

Even while the safety phases are being completed, identification of patients with the proper genetic markers to test the agent should be underway. Engaging a physician scientist on the team is an important way to identify trial participants, and for a doctor’s real-world knowledge to find its way into the research process.

The very nature of these new drugs demands that patient eligibility criteria be defined at the molecular level; in some cases, patients who would not have made the cut in trials years ago will be part of studies.

Most of all, today’s well-run development process requires many moving parts, not phases done in sequence. “If these steps are done in series, it will take too long to get to the FDA for approval,” Grever explained.

As risky as drug development seems today, however, opportunities abound. “We need to keep in mind the strategic combinations for long-lasting control of the disease,” he said.

Reference

1. Grever MR. Accelerating safe drug development: an ideal approach to approval. Hematology Am Soc Hematol Edu Program, 2013; 2013:24-29.