Why some promising phase II drugs fail in phase III
Anyone who has been involved in pharmaceutical product development for any length of time, has probably experienced the profound disappointment of seeing a promising new medicine achieve its objectives in phase II trials, only to fail in phase III. It’s a costly experience for any company and has resulted in the failure of many smaller pharmaceutical companies.
There are a limited number of reasons why a drug might fail to achieve its phase III objectives and one particularly stands out, not only because it occurs repeatedly, but also because it is predictable and preventable. Oral drug products can’t provide a therapeutic benefit if patients don’t absorb enough drug. Many readers may believe this issue is adequately addressed in phase I, but very often, it is not. Phase I studies provide a snapshot in time of a drug product’s in vivo performance and frequently do not highlight how in vivo performance may change with long term use. Based on the experience of this author, approximately 20% of oral drugs have the capacity to alter the gastrointestinal transit rate with repeated dosing. The change in GI transit rate may not produce any important change in systemic drug exposure during the first several days of continuous use but the effect is progressive. With long-term use, the drug can pass through the body so rapidly that there simply isn’t time for adequate drug absorption.
Some oral drugs are potent gastrointestinal irritants which induce rapid acceleration of gastrointestinal transit. These drugs typically exhibit a significant loss in systemic exposure during phase I multi-dose trials. Unfortunately, exposure data obtained at the end of a phase I multi-dose trial may not represent the drug’s actual performance during long-term use. In many cases, the decrease in gastrointestinal residence time and resulting decrease in systemic exposure would continue long after the time interval used for phase I multi-dose testing.
To further complicate this issue, many oral drugs accelerate gastrointestinal transit more gradually. Factors that influence accelerated GI transit rate include dose size, dose frequency, excipients present and the chemical and physical properties of the drug substance. When these factors combine to induce gradual acceleration of the GI transit rate, systemic exposure may appear to be reasonably constant during phase I multi-dose testing and the drug product may be found to be efficacious in short-term, phase II studies. The first hint of a problem comes when the drug product fails to meet primary endpoints, during phase III trials.
So how can this phenomenon be predicted and prevented? In the first place, intestinal residence time is directly measurable in absorption rate profiles, which are obtained from individual pharmacokinetic data. Any change in intestinal residence time observed during phase I testing signals the probability of a sharp drop in systemic exposure during long term use. Once a drug’s potential for accelerating GI transit is identified, the risk can be managed by adopting a more appropriate formulation strategy. The specific formulation strategy needs to be tailored to the specific properties of the drug but in general, a good formulation is one that takes full advantage of a drug’s regional absorption characteristics, while minimizing the drug’s ability to cause irritation in the GI tract. Through early identification and appropriate management of a drug’s capacity to accelerate gastrointestinal transit rate, it is conceivable that many, if not most failures in phase III could be eliminated.