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Clinical development case study

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Nonclinical and Regulatory Expertise Accelerates Development Into Phase II-III Clinical Studies

Situation

The client needed assistance with the development of nonclinical program and regulatory documentation to support Phase II-III clinical trials in Europe (daily dosing for one year). The off-patent drug had not been marketed in Europe, but was approved and used for more than 15 years in other regions (and for other indications) at a dosage level five times lower than that in the planned trials.

Insight

The client had not conducted any nonclinical pharmacology and toxicology studies. The key challenge was to minimize the number of costly and time-consuming, nonclinical studies to be conducted by the client, while still having a high-quality nonclinical file to obtain regulatory acceptance by the “top five” European regulatory agencies.

PharmaNet reviewed the publicly available nonclinical studies (conducted by another pharmaceutical company) and also reviewed the public assessment reports from regulatory agencies and scientific articles in the open literature. A number of issues were identified:

  • It was not possible to evaluate if the doses used in the conducted toxicology studies (supporting safety for a clinical dose that was five times lower) had been high enough to establish safety in the planned trial.
  • There were deficiencies in the nonclinical program in relation to current regulatory expectations (e.g., safety pharmacology and kinetics).
  • There were adverse findings in the toxicology studies and inconsistencies in the documentation, which needed to be addressed.
Solution

PharmaNet addressed these issues with the design of two small studies (one in vivo and one in vitro). The studies generated safety pharmacology and toxicokinetic information that showed the exposures in publicly available toxicological studies (conducted by another company) had been high enough to establish adequate safety margins for the selected dosages in the planned trial. PharmaNet presented evidence that key toxicological findings were not relevant in the human therapeutic situation and also assisted the client with writing the nonclinical part of the regulatory submission.

Results

PharmaNet was able to rapidly get regulatory approval for the client to start Phase II-III trials in the desired European countries. By identifying gaps and supporting the client with solutions, including the conduct of specially designed toxicology "bridging" study and efficient use of public data, it was possible to develop an adequate nonclinical file in six months. Using more conventional approaches (e.g., conducting new chronic toxicology studies) would have taken much longer (at least two years) and increased the client's development costs materially.

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