Early Phase, Earlier Decisions

By Sara Gambrill

A December 2010 National Institutes of Health (NIH) report states that 95% of candidate drugs prove ineffective. Drug manufacturers, CROs, and government regulators would like to decrease this percentage significantly.

To avoid costly late-stage failures, during the past decade the biopharma industry has focused on ways to facilitate earlier decision making about the potential of drug candidates. In just the past few years, the increase in discoveries of new biological targets, pathways, and biomarkers has allowed companies the opportunity to make informed decisions earlier than ever before. To fully take advantage of this opportunity, biopharma has changed the way it studies drugs.

It Starts With A Good Translation
Preclinical biologists and clinical pharmacologists are collaborating more now than ever on identifying what the target is, as well as finding out what it does, how it affects the pathways, and what markers are there. Preclinical biologists get involved early by identifying a new biological pathway that can be manipulated by a drug and then also by establishing an assay to measure the drug’s potential therapeutic effect in humans. The challenge is, after finding that the target works in a preclinical setting, seeing if it has the same effect in man.

“Essentially, you’re trying to learn from the controlled situation what your preclinical biologist can have either in an animal or in an in vitro test system and translate that into outcomes you can measure in humans and then to back-translate the results you get from humans,” said Dr. Penelope Ward, consultant pharmaceutical physician, PWG Consulting. If the molecule is not making a good enough impact on the target, it can be redesigned, and the human testing started again.

Breaking With Tradition
Biopharma has entered a new era of clinical research where the demarcations between phases have become indistinct to nonexistent. “The traditional Phase 1, 2, 3, 4 approach has disappeared, so now we talk about ‘early phase,’” said Dr. Brian Sanderson, medical director, Chiltern (Early Phase) Limited.

Ward sees drug development as having two parts, the “Learning (Early) Phase” and the “Confirm (Late) Phase.” The Learning Phase starts at the time of target selection, and the Confirm Phase begins at the end of a proof-of-concept study. As would be expected, if researchers are studying treatments for complex disorders, such as inflammatory disease, then they ask a much more complicated set of questions. Some of the targets in this area are novel, and some of the off target effects can be challenging, so researchers want to learn more about the molecule being studied before entering into large-scale clinical trials. The researchers’ aim is to prove that the target is useful as early as possible, and they want to have a much clearer idea of dose-response range for efficacy and safety reasons.

“There’s been a lot of emphasis on biomarker or some kind of pharmacodynamics measure that can be utilized either in healthy volunteers or in a patient population that measures the impact of the product on its target and the downstream effects of that impact that correlate with clinical outcomes for later-phase trials,” Ward said.

Due to a great amount of work in establishing markers to evaluate impact on the kidney — particularly on the renal tubule, the most sensitive part of the kidney — researchers can assess the potential for renal toxicity in humans much earlier than before. There is also a lot of work being done in the hepato-toxicology arena to detect a drug candidate’s propensity for causing liver trouble earlier.

“The name of the game is to try to get as much information as you can from early experience and treat everything as a matrix of information, rather than have separate parts of your company doing their bits and then passing those bits on to the next point in the chain,” Ward said. But, knowledge gained early on is useless if drug companies do not have clear decision pathways that allow them to take out of development — before they’ve invested too much money, personnel, and time — compounds that don’t meet their criteria.

More Early Phase Trials Hospital-Based
Sanderson is seeing more trial designs comprising the traditional single ascending dose study in healthy volunteers immediately followed by the study of the drug in the target patient group within the same protocol. “The reason for this is to try to get a handle on whether the drug is actually hitting the relevant target in the patient group,” he said.

Increasingly, both healthy volunteers and patient populations are being studied in the same protocol, and, as a result, early phase trials are becoming much more complex. For safety reasons as well as access to equipment, therapeutic specialists, and patient populations, the biopharma industry is now opting to have early phase trials conducted in clinical pharmacology units (CPUs) within hospitals.

First and foremost, hospitals offer immediate access to emergency medical personnel should early phase subjects need it. This was the case five years ago when TeGenero was tested for the first time in humans at a unit in Northwick Park Hospital, and six healthy volunteers became critically ill, needing intensive care.

“Following the Northwick Park incident, hospital sites have become more sought after, commercially as well. Some of the major pharmaceutical companies have that as a policy. They won’t place their first-in-man trials if the unit isn’t in a hospital site,” Sanderson said. CROs have recognized the trend and are opening CPUs within hospitals, though some CROs such as Chiltern, have had hospital-based CPUs for many years.

Hospitals provide access to specialized equipment that can be used to identify certain biomarkers, such as a PET scanner or MRI scanner, as well as therapeutic area specialists who can help interpret the results and even advise on trial design.

CPUs within hospitals offer clinicians in the hospital and clinical pharmacologists the opportunity to work more closely together. Clinicians may be able to provide patients to take part in the early phase trials, after they and the clinical pharmacologists have both worked to identify patient populations and characterize them. “In an ideal situation, the patient has access to both the clinical expert who can care for the disease but also the clinical pharmacologist who specializes in the measurement of the effects of drugs. You need much more of a partnership between the treating physician and an experimental physician,” Ward said.

Biopharma Looks Into Drug Libraries, Academia
Drug manufacturers’ increased efficiency at filtering out molecules inappropriate to take into full development coupled with ever-tightening research and development budgets have prompted them to give their drug libraries a second look. Sanderson is seeing old drugs being studied for new indications more often now. He said, “There are a lot of small and midsize companies that specialize in revisiting drug libraries because, if they can find a new indication for a drug that’s already been developed, they’ve derisked a lot of the safety issues. So, all you’re doing is putting it into a new target to see if it works. It’s a much shorter pathway to marketing for them.”

Biopharma is also taking a fresh look at academia. “A lot of these discoveries in biomarkers are coming out of academia. The challenges are to work more closely with academics who sometimes have discoveries but just don’t know how to present them to industry. I think there’s a need for that as well. Some of the well-known medical schools and universities are actually in the drug discovery business themselves. They’re finding things and want to know how to develop them,” Sanderson said.

Government Keeps Up The Pressure
The FDA’s 2006 Critical Path Opportunities Report contained a “Call to Action” directed at the biopharmaceutical industry to “create a new generation of product development tools to make good decisions about which products to move forward in testing, which doses to test, and how to design clinical trials that will provide clear information about product benefit and safety.” Five years later, this work is clearly well under way but not finished.

According to the NIH, “The increased availability of innovative technologies has generated unprecedented potential for advancing the translation of basic discoveries into therapeutics.” Yet, during the past five years, the average number of drug approvals annually has decreased in comparison with the previous 10-year period. In recognition of the challenges that drug discovery still presents as well as the opportunities, the NIH plans to open the National Center for Advancing Translational Sciences (NCATS).

NCATS will mainly comprise existing programs, including the Clinical and Translational Science Awards program that has created academic homes for clinical and translational science at 55 research institutions across the country. The final budget for the new center is unknown, though it has been estimated to be anywhere between $650 million and $1 billion. NIH hopes to open the new center in October; another center will have to be dissolved by that time, as NIH can only have 27 institutes by law. NIH is emphatic that NCATS is not intended to be a drug company, but that its central role is to facilitate translational research across NIH. According to NIH’s website, NCATS will also “seek ways to leverage science to bring new ideas and materials to the attention of industry by demonstrating their value.”

With greater government focus on translation, biopharma’s changes to how drug research is conducted, and continued discoveries of new targets, early phase trials will be an important area of drug development activity for years to come. Ward said, “It’s certainly a very exciting time to be in early clinical development right now. We’re identifying proteins, and we don’t know what they do. We’re also identifying genes, and we don’t understand what their gene products are. So, I’m sure there’s going to be an explosion of much greater understanding in the next decade.”