Collaborating On the Drug Development Process

Eisai and Janssen Pharmaceutica formed a strategic partnership to seek Food and Drug Administration (FDA) approval to market rabeprazole, a new "proton pump inhibitor," that reduces gastric acid secretion.

Knowledge about the pathophysiology of the diseases being treated, as well as the clinical pharmacology of rabeprazole, had increased substantially since the beginning of the clinical development program. Thus, new analyses and interpretations of the clinical trial results were needed before submitting a New Drug Application (NDA) to FDA.

Working in collaboration with the Eisai and Janssen team, we produced an NDA within six months that was subsequently approved by FDA.

Science for Organizations carried out analyses that demonstrated:

	which dose of rabeprazole should be approved
	results that initially raised safety concerns actually reflected the drug's long term effectiveness
	rabeprazole had a faster first-day effect than competing products

Garvey Associates provided:

	important overall regulatory and scientific perspective
	evaluations of various clinical results regarding the drug's safety

Arishel analyzed results from the drug's pharmacokinetic studies, showing that:

	the formulation used for clinical trials was bioequivalent to the final marketed product
	potential drug interactions related to metabolism of rabeprazole through the cytochrome P450 system lacked important clinical significance

Our affiliates each do what they do best, in much the same way that a seasoned team of movie makers: director, actors, camera operators, sound crews, and so forth--come together to make a movie. We have collaborated on all kinds of projects, in many different organizations, sometimes over many years together.

As a result, we are efficient, focused and effective, with a solid record of accomplishments. We can quickly assemble a team that can step right into a clinical development program and usher it through FDA approval.

Developing a better measure of gastric and esophageal acid exposure

Eisai, Inc. wanted to provide clinical evidence of the efficacy of its new proton pump inhibitor, rabeprazole, as part of its New Drug Application (NDA) to the FDA. The company asked SFO to analyze data from 24-hour recordings of gastric and esophageal pH from 30 GERD patients. However, commonly used analyses permitted only a semi-quantitative assessment of the acidity. SFO's solution was to develop Integrated Acidity - a method of analyzing pH data that fully quantified gastric and esophageal acid exposure over time. Using this method, we could quantify acid exposure in the 30 GERD patients and determine precisely how much this acid exposure decreased during treatment with rabeprazole. This method has also been accepted by the FDA; and companies now routinely provide data using this method to the FDA.

[View SFO's technique for determining integrated acidity from pH recordings in References 330 and 331.]

Providing support for drug claims

Eisai used SFO's Integrated Acidity analysis to support its proposed dosage for the new drug and its claim that the drug achieved 80% of its maximum effect on gastric acidity on the first day of dosing. FDA agreed with the analysis and approved the drug.

Characterizing a way to prevent drug-induced gastric pathology

Pozen, Inc., wanted to determine how much gastric acidity had to be reduced by famotidine in order to prevent the gastroduodenal pathology caused by a particular nonsteroidal anti-inflammatory drug (NSAID).

SFO answered this question for Pozen by calculating integrated acidity from gastric pH recordings from human subjects taking the NSAID.

Defining the onset of action of a drug

SFO also worked with Warner-Lambert Company (now Pfizer), to analyze gastric pH data from subjects being treated with a placebo, with famotidine (marketed by J&J-Merck) and with ranitidine (marketed by Warner-Lambert). The goal was to develop a method to determine the onset of action of the two drugs. Our analyses showed that the onset of action of the drug could be defined by the earliest time after dosing that the gastric pH was significantly different from that with placebo

[View the details of the technique used and resultant findings in Reference 334.]

Developing a new method to measure gastric acid secretion after a meal

While working with the Warner-Lambert data, SFO realized that our analytic method could also be used to measure the amount of gastric acid that is secreted after eating a meal. In GERD patients, this meal-stimulated secretion is a common cause of esophageal acid reflux and heartburn. This was an important discovery because the only existing analytic method was not only complicated to use, but could not be used at all during the normal living conditions of patients who were taking a gastric antisecretory drug.

[View details of the new method in Reference 333.]

Identifying a novel action of cisapride

We also used our method to measure meal-stimulated gastric secretion for Janssen Pharmaceutica. Our work showed that cisapride, a drug Janssen manufactured, reduced esophageal acid exposure in GERD patients by inhibiting meal-stimulated gastric acid secretion, and not by increasing the emptying of gastric acid as had been assumed earlier. This finding identified a novel target for drugs that might inhibit meal-stimulated secretion.

[View details in Reference 335.]

Creating new analytical methods to predict elevated esophageal acidity

Probing further into the Janssen data, SFO's analysis showed that integrated gastric acidity after a meal was a particularly robust measure of meal-stimulated secretion. Furthermore, GERD patients had significantly greater meal-stimulated gastric acid secretion than did control subjects. Finally, the analysis showed that it is possible to predict the probability of pathological esophageal acid exposure from the value of gastric acidity after eating. As a result of these findings, clients of SFO, such as Santarus Inc., could estimate the effect of their drugs that inhibited gastric acid secretion on esophageal acid exposure by measuring gastric pH alone.

[View the details in References 336 and 337.]

Showing how symptom severity can be used to predict elevated esophageal acidity

Determining integrated acidity from recordings of esophageal pH made it possible to show that the severity of heartburn in GERD patients could be used to predict the probability of esophageal acid exposure with high reliability.

[View the detailed results in Reference 338.]

This finding was important because some investigators and regulatory authorities had maintained that no apparent relationship existed between esophageal acid and heartburn, and would not accept measures of esophageal pH as a surrogate for symptom relief in GERD patients.

Explaining why a drug's effect was much less than expected

Janssen also was interested in exploring why rabeprazole is more effective in relieving heartburn in GERD patients with erosive esophagitis than in those without erosive esophagitis. (This result was unexpected because GERD patients with erosive esophagitis have higher esophageal acid exposure and were expected to be less responsive to drugs like rabeprazole.) SFO's analysis of a large database of 24-hour pH recordings provided by Janssen, showed that GERD patients without erosive esophagitis had integrated gastric acidity after eating that was resistant to inhibition by rabeprazole and similar drugs. The results provide a clear rationale for using higher doses of rabeprazole in such cases and point to a phenomenon for which a pharmaceutical company might try to develop a better treatment.

[View the details of the study in Reference 339.]

Developing a Reliable Measure of Abnormal Esophageal Acid Exposure in GERD Patients Treated with a Proton Pump Inhibitor

In patients with gastroesophageal reflux disease (GERD), esophageal acid exposure is typically measured as the percentage of time esophageal pH is below 4. Using this measure, two different studies found that approximately half of GERD patients treated with a proton pump inhibitor, had abnormal esophageal acid exposure. This surprisingly high prevalence of abnormal esophageal acidity turned out to be an artifact of the way that esophageal acidity was measured. Measuring esophageal acid exposure as integrated esophageal acidity, a technique developed by Science for Organizations, found that in these same two studies, nearly all subjects had normal esophageal acid exposure.

[View the details in Reference 344.]

PHYSIOLOGY OF GASTROESOPHAGEAL REFLUX IN HEALTH AND DISEASE

Our research identified a fractal pattern for both human gastric pH and esophageal pH. We proposed that the fractal pattern of gastric pH encodes information regarding gastric acidity that is decoded by the esophagus during gastroesophageal reflux, and depending on the value of gastric acidity, the esophagus can signal the stomach to alter gastric acidity by changing gastric secretion of acid or bicarbonate. This hypothesis also predicted that gastric pH values should provide important information regarding subsequent values of esophageal pH and vice versa. In later analyses we showed that in normal subjects, gastric pH and esophageal pH provide important information regarding subsequent values of each other and that this ability is reduced substantially in subjects with gastroesophageal reflux disease. Reflux disease may result from ineffective communication between the esophagus and the stomach.

[View the details of these analyses in References 342, 346 and 348.]