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FDA's 'Phase 0' Microdosing Studies Not Useful Preclinical Tool, Pharma Exec Says

PHILADELPHIA — Pre-clinical microdosing studies aimed at gauging the activity of investigational drugs in humans on a metabolic and pharmacokinetic level, commonly referred to as “Phase 0” studies, won’t predict whether a drug candidate will succeed or fail at higher doses and in broader populations, a Novartis exec said last week.
However, a different type of service, called Phase Zero and provided by Asterand, relies on human tissues rather than human beings, and may be right up pharma’s alley as companies increasingly try to employ predictive technologies to make go/no-go decisions in preclinical studies.
Microdosing studies – often called “Phase 0” studies since they are done prior to large scale clinical trials – are “not as useful as maybe we thought they were,” Robert Schmouder, executive director of translational medicine at Novartis, said at a Cambridge Healthtech Institute conference translational medicine held here last week.
These studies rely on “a much smaller dose than you are going to give actually, so you are really restricted in the amount of drug you can give. … We see a lot of examples where [microdose studies] don’t give you the data that you want to have” before going into clinical development, he said.
According to a high-level US Food and Drug Administration official, Phase 0 trials are meant to encourage industry to move away from the traditional three-phase drug-development model toward more predictive strategies. 
As described in a January 2006 FDA guidance on “Exploratory Investigational New Drug Studies,” Phase 0 studies allow companies and academic researchers to test how sub-therapeutic doses of a drug will affect humans.
These exploratory INDs, or eINDs, are part of the agency’s Critical Path initiative to streamline drug development and improve the understanding of drugs early in the clinical process.
However, Asterand, a company that provides human tissue-based research for the pharmaceutical and biotechnology industry, offers its Phase Zero study as an alternative.
Using human tissue samples rather than human beings, Asterand’s Phase Zero Drug Discovery Service investigates a drug candidate’s efficacy, pharmacology, safety profiling, and metabolism by using a variety of techniques, including gene-expression profiling and protein expression profiling.
While some in industry may question the utility of FDA’s Phase 0 studies, Asterand’s version may be more attractive to big pharma, particularly at a time when the industry is embracing R&D strategies that provide greater clarity about the likelihood of a drug candidate’s success prior to entering full-fledged clinical development [see related story, in this issue].
Phase Out
The FDA’s guidance defines an exploratory IND trial as a study that “is conducted early in Phase I, involves very limited human exposure, and has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies).”
A microdose exploratory IND study would expose a small number of patients to “1/100th of the dose of a test substance [needed] to yield a pharmacologic effect of the test substance with a maximum dose of <100 micrograms.”
Through a microdose study, investigators would be able to test whether the drug is distributed and metabolized in the body on a molecular level and whether it is actually reaching the intended target.
Janet Woodcock, deputy commissioner and chief medical officer of the FDA, previously told Pharmacogenomics Reporter that through Phase 0 studies the agency is encouraging industry’s move away from the traditional three-phase drug-development model toward more predictive strategies. 
“Everyone wants to move from what has basically been, after the discovery phase, almost a trial-and-error approach, to a more mechanistic approach, where we have much more predictive information that we can generate at each step of the way,” Woodcock had said when the agency first introduced the draft version of its eIND guidance in 2005 [see PGx Reporter 05-12-05].
However, as a company that has performed between five or 10 of the eINDs, Novartis is “still assessing what the utility of the eINDs are,” according to Schmouder.
An FDA spokesperson told Pharmacogenomics Reporter this week that the agency does not have data regarding how many exploratory INDs have been submitted as part of new drug applications.
The agency also maintains that it does “not recognize the term ‘Phase 0’” even though several high-ranking FDA officials, Woodcock among them, have referred to eINDs as Phase 0 studies.
At the time the FDA had released its final eIND guidance, agency officials had touted the eIND studies as a way for companies to limit exposing patients to highly toxic therapies. 
Although the permissible dosing levels in such studies may be too small to yield such information, Schmouder did highlight a few instances when FDA’s Phase 0 studies could come in handy.
“Some drugs you can’t really scale a lot … so eINDs would give you the information you need,” he said, adding that the company has also done microdosing studies to compare two drug candidates with imaging technology.
Ultimately, “eINDs are just one of the tools in the tool chest, [but] they don’t represent the be all and end all of the future of translational medicine,” Schmouder said. “They are just another way of providing information and insight.”
However, a study by R.A. Boyd and R.L Lalonde of Pfizer, published in January in Clinical Pharmacology & Therapeutics, concluded that although microdose studies “under the right circumstances … may help early drug-development decisions to be made more efficiently … they will allow only assessment of pharmacokinetic properties.”

“Exploratory INDs are just one of the tools in the tool chest, [but] they don’t represent the be all and end all of the future of translational medicine. They are just another way of providing information and insight.”

According to the authors, “microdose studies will have a very limited impact on the overall efficiency of drug development.”
Embracing Asterand’s Phase Zero
According to Amanda Woodrooffe of Asterand’s department of biochemical pharmacology, 18 out of the top 20 pharma companies, as well as key biotech companies, are using the company’s Phase Zero services.
“I think the pharmaceutical industry is really buying into managing risk and helping build confidence that they are making the right decision early on,” Woodrooffe said.
Asterand’s Phase Zero services could be attractive to industry because they allow companies to use human tissue approaches in their early discovery phase to weed out the compounds that have lower chances for success. In this way “the companies can actually focus their budgets on investing in the compounds that are more likely to have success once they do get into the clinic,” Woodrooffe said.
Still, attrition rates continue to hamper drug development, contributing to the $800 million price tag for bringing a single compound to market.
A 2004 study published in Nature Review Drug Discovery shows that while pharmacokinetics has historically been the main reason for attrition in drug development, currently the prevailing cause of drug candidate failures is lack of efficacy, accounting for 30 percent of all attritions.
According to the FDA, nine out of 10 compounds fail in the clinic because they were advanced to human subjects based on how they metabolized in animal studies. 
Woodrooffe would not comment on why some drug companies did not find value in the FDA’s version of Phase 0 but noted that at Asterand “we have a very different business.
“Yes, it’s human, yes, it comes before Phase I, but we’re not dealing with human volunteers here,” she said. “We’re dealing with human tissues. It’s fundamentally different.”
“The reason that Asterand was founded was based on the belief that using human tissue in vitro approaches can help build confidence in making the right decisions as companies go forward with their drug discovery and development,” Woodrooffe said.
Asterand, traditionally a US-based supplier of human tissue samples to academic and industry researchers, gained its Phase Zero business after its merger last year with UK-based Pharmagene.
The company offers the services using a variety of techniques including gene- and protein-expression profiling. For gene expression, Asterand provides three services dedicated to identifying and validating new drug targets, including its XpressWay genetic data repository, in situ hybridization services, and Custom Mapping services for site-specific qualitative RT-PCR gene-expression analysis.
In June, Asterand penned an agreement with Rubicon Genomics to discover novel biomarkers for cancer diagnosis. Under the partnership, Asterand will supply tissue and biofluid samples from its biorepository and its worldwide network of clinical collaborators, and Rubicon will study the samples using its MethylPlex technology to discover methylated DNA markers for cancer diagnosis and prognosis [see PGx Reporter 06-28-06].

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