Such coordination can also inform the choice of models. This is an iterative process, going from preclinical models through clinical studies and then back to the models to assess their predictability and their future utility, Dr. Huber suggests. “Animal and human models have a good correlation for some diseases like blood pressure,” Dr. Lavrovsky adds, “but others, like depression, are less straightforward and are difficult to model in animals.” Therefore, research in such areas constitutes proof of concept and safety’ studies and then moves quickly to human trials.
To learn which models are likely to be predictive for a given compound, Dr. Huber recommends testing a class of drugs on a variety of models to develop confidence in specific models and build a knowledge base that can be referenced over time. “Draw conclusions about the model, as well as about the compound,” he advises.
“Companies are seizing on sequential design as a solution to clinical failures,” Dr. Huber continues. “That’s a great way to narrow the field of possibilities, but results in making fundamental decisions based on less and less data.”
Additionally, Dr. Meinert says, despite ever-increasing knowledge of receptors as specific targets of interest, mechanisms of action are less well-known and researchers tend to approach receptors one at a time. Instead, he says, “we need to hit a series of receptors.”
“Statistical problems should never make or break a drug,” Dr. Huber says, yet they do remain an issue. The problem, he notes, is that researchers prospectively design a study based on their assumptions regarding efficacy, safety, and the like, and the trial is also designed based upon those assumptions. Then, if the actual data doesn’t match some of those assumptions, the expectations weren’t met.
It’s important, Dr. Lavrovsky notes, to design trials that closely mimic real-world situations. Patients, he says, unlike lab animals, aren’t pretreated, and often have undergone all the traditional therapies before enrolling in trials. Therefore, CROs often recommend a polypharmaceutical approach throughout trials, “but preclinical work that’s focused on shortening the time to begin human testing doesn’t include that,” Dr. Meinert says, “even though more preclinical testing could shed light on what may happen in late-phase trials.”
Traditionally, in the early phases, patients in trials have advanced stages of the disease and have undergone several conventional therapies. “That’s not the best setting,” Dr. Huber says, suggesting that companies conduct less single agent, salvage-type therapy and treat patients earlier in the disease process, and add their drug to a traditional therapeutic regimen.
Know your drug, the CROs overwhelmingly say, to further chances of success. Oftentimes, Dr. Cato elaborates, people look at endpoints, expecting to see effects within about two weeks. “For some compounds, though, they have to treat for three weeks” to determine whether the drug is working. Consequently, good compounds are discarded because the trials aren’t long enough.
Similar situations arise with doses. Nowadays, companies treat to the maximum tolerated dose, but “dose-response curves often are bell-shaped,” Dr. Cato says. Consequently, doses are only effective at the curve’s mid-levels.