FDA issues draft guidance on development of combinations of investigational drugs

While challenges exist for the pharma and biotech industry to reach through corporate walls to collaboration, the FDA helps to remove a couple hurdles on the regulatory side

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In early December, the U.S. Food and Drug Administration (FDA) issued a draft guidance for industry titled, "Co-development of Two or More Unmarketed Investigational Drugs for Use in Combination." The goal of the guidance, according to FDA commissioner Margaret Hamburg and CDER director Janet Woodcock, is to make it more feasible, from a regulatory perspective, for two different companies to collaborate on the development of multi-component therapeutics when none of the components has previously been approved (or even tested in humans) individually.  

Recognizing that there are major unmet therapeutic needs in the treatment of a number of serious diseases, the agency published this new guidance to promote effective collaboration among various parties in the development of novel drug combinations. Hamburg and Woodcock spoke about this initiative at the Partnering for Cures conference, sponsored by Michael Milken's FasterCures group, Dec. 14 in New York.  Most of the specific diseases on the agenda were various cancers or infectious diseases such as malaria, tuberculosis and AIDS.

Using cancer as an example, Woodcock gave specific examples of the more rational and mechanistic, less empirical approach to drug development the FDA foresees going forward. There will be more reliance on biomarkers, which in combination with drug combinations, molecular diagnostics and adaptive clinical trial designs, is expected to accelerate drug development. Several conditions must be satisfied for co-development of investigational drug combinations: a serious disease (e.g., cancer); a compelling biological rationale for the combination; preclinical data showing synergistic activity or a more prolonged response with the combination; likelihood of a significantly greater response with the combination; and a reason that the components cannot be developed individually (e.g., development of resistance or low activity of each drug separately).

Of course, there are numerous barriers in the path of collaboration among drug companies, and the FDA can only address one of them: The regulatory hurdle. I daresay this is probably the least daunting one, but it is a promising sign nonetheless.  

Translational medicine, the process of turning a benchtop discovery into a bedside cure, is widely viewed as the key to solving the current trend of fewer new medicines and higher cost per new medicine. As Hamburg said, something has to be done differently, and for its part, the FDA can most directly influence regulatory science.  

Now, don't be cynical and say, "Hey, there's an oxymoron!" The new guidance is part of the agency's effort to accelerate the use of new testing paradigms and other novel approaches.

Among the many different stakeholders, the most directly impacted and most passionate might be patients and various patient advocacy groups. They may not appreciate all the nuances of drugs and drug development, but they are acutely aware that there has got to be a better way.

From where I sit—at a preclinical contract research organization specializing in the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of drugs—one issue to consider is whether there are any drug-drug interactions among the components of the combination. This question must always be addressed during the development of a new drug, but generally, the question is only whether there is a risk of interactions with other drugs that might be co-administered with the new drug. In this case, there is that question, as well as the additional question of whether there is a risk of interaction with other drug(s) that will always be co-administered.

In fact, with drug combinations, sometimes the idea is to take advantage of a drug-drug interaction. The reason for developing a combination product may be that one of the components is, therapeutically, relatively or completely inert but boosts the bioavailability or efficacy of the other component, for example by inhibiting an efflux transporter or a drug-metabolizing enzyme.

That's not a new approach. Pharmacokinetic (PK) boosters such as ritonavir are used in HIV cocktails. Clavulanate potassium is added to amoxicillin in the product Augmentin.  Inhibitors of multidrug resistance transporters such as P-glycoprotein, often upregulated in tumors, have been tried in cancer cocktails, but abandoned for the most part because of their undesirable systemic effects. What is new here is that the individual components have never been tested individually in humans before, so we know little or nothing about their clinical safety, efficacy and PK.

This draft guidance brings back memories of my early years in the drug industry more than 20 years ago with Sterling Winthrop in Rensselaer, N.Y. At that time, the cardiovascular pharmacology department where I worked was on the cutting edge of research on cyclic nucleotide phosphodiesterase (PDE) inhibitors. We had discovered numerous potent and selective inhibitors for most of the PDE isozymes that were then known. We knew that other drug companies, including Warner Lambert (since swallowed up by Pfizer) and SmithKline Beecham (now GlaxoSmithKline) were working in the same area, for some of the same indications.

Two things in particular bothered me about drug development in general, at least the way it was practiced at Sterling.

First, our goal was to discover the most potent and selective inhibitors (usually) of a selected molecular target (generally an enzyme or a receptor). The theory was that with a very potent drug, you could give a lower dose, which should be safer, and a highly selective drug would be less likely to have off-target effects. The problem, as I saw it, was that we were developing excellent pharmacologic tools, but not necessarily useful drugs. A compound that is very potent at one molecular target might well be just as potent, or even more so, at another.  

Or, for example, it could cross the blood-brain barrier and cause central nervous system (CNS) side effects, whereas another, less potent compound, might not get into the brain at all. Furthermore, even at that time, we knew that many useful drugs were "dirty" in the sense that they hit multiple targets. In many cases, the built-in polypharmacology was necessary for the drug's efficacy, although we didn't understand why (and still don't) and couldn't model it (and still can't).

Second—and this point is more relevant to the new FDA draft guidance in question—we would undoubtedly have made faster progress if we had been able to collaborate with scientists at other companies who were working on the same molecular mechanisms (e.g., PDE inhibition) and/or therapeutic targets (e.g., heart failure). There were too many hurdles, and they were too daunting for someone at my level (managing a group of lab technicians) to consider surmounting: Commercial (greed), marketing (e.g., is there or isn't there a market), legal (liability, co-development responsibilities, etc.), intellectual property (ownership of ideas, composition of matter, etc.), and regulatory.

The FDA's draft guidance on co-development of combinations of investigational drugs addresses and lowers only the last of these hurdles. I suspect the infamous patent cliff, multiple late-stage drug failures, dry pipelines and scarcity of innovation may finally provide the impetus to drive drug developers to overcome the other barriers, as well.

I think it's encouraging that the FDA has at least illuminated the regulatory pathway for combination drug products. The agency is accepting comments for 60 days from the date the guidance was announced in the Federal Register, so let them know what you think.

Dr. Chris Bode is vice president of corporate development at Absorption Systems in Exton, Pa., where he is responsible for the identification and development of new business opportunities, marketing and sales support, development of research protocols, project management and consulting with customers, particularly in the area of in-vitro drug metabolism. Bode previously served as vice president of operations for Tissue Transformation Technologies, a leading provider of tissue-based reagents used in ADME studies. He has also worked in high-throughput screening at Rhone-Poulenc Rorer and in cardiovascular pharmacology at Sterling Winthrop, where his area of expertise was cyclic nucleotide phosphodiesterases. Bode received his Ph.D. in pharmacology from the University of Colorado, where his research focused on the effects of ethanol on the physical and functional properties of mammalian cell membranes. His postdoctoral research at the University of California, San Diego, was in the area of integration of cell signaling pathways.

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