Science for Organizations can quickly assemble a team that can step right into a clinical development program and usher it through FDA approval.
Science for Organizations also brings novel perspectives to data analysis in ways that provide clients with new understanding of, their products.
SFO's work on gastroesophageal reflux disease (GERD) illustrates our innovative thinking regarding one particular clinical condition, and shows how our analyses highlighted previously unrecognized aspects of GERD, as well as potential new uses of particular products.
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
||important overall regulatory and scientific perspective
||evaluations of various clinical results regarding the drug's safety
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
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.
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
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.]
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.
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.]