Stability studies
Clinical-trial materials are by their nature experimental items that undergo evolution as the potential drug candidate progress
through clinical development. Because they are experimental, there is a certain amount of risk originating from the relative
lack of information regarding functional performance and how critical dosage form attributes might be changing over time.
From the standpoint of the formulation scientist, two principal risk-management goals need to be achieved during a clinical
trial. First, the safety of participating study volunteers must be ensured by minimizing controllable safety threats. Second,
if an investigational compound fails to meet clinical-study objectives, whether for efficacy or toxicological reasons, it
should be from a intrinsic outcome of the compound itself and not because of a failure in performance of the dosage form.
Table I. Comparison of various features: clinical investigation at different stages and extent of control over distributed
trial supplies.
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The risk-management exercise is driven by the general interest in moving to human trials as soon as possible to validate a
proof of concept for pharmacological activity and determine if a particular compound is worthy of further consideration. As
a consequence, early-development timelines typically are short, meaning that only a limited amount of information is available
on dosage-form performance as a function of time and storage conditions. The uncertainty from the lack of stability data is
partially balanced by the fact that early clinical trials are short in duration, involve a small numbers of subjects, and
have a high level of control over the storage and handling of the clinical-trial materials. As illustrated in Table I, when
a compound moves to the next stages of clinical development, the amount of data collected on performance increases, thereby
resulting in reduced uncertainty in some respects. In parallel, the length of trial, the numbers of subjects involved, and
the diminished control over the test articles also are increasing, thereby somewhat offsetting the increased data set.
The statistical tools and evaluation criteria for stability data collected at the end stages of development, especially in
support of marketing authorizations, are well developed. They primarily consist of linear least-squares techniques with hypothesis
testing on slopes to determine whether a significant change over time is occurring for critical parameters. Poolability of
slopes and intercepts is used to determine if product characteristics are reproducible between batches.
These tools are less useful at the earlier stages in development because of the limited duration of available stability data.
Formulations typically are undergoing rapid evolution and are produced in very limited quantities, so homogeneity across batches
cannot be ensured. Opportunities to use neural networks in cases such as these have been explored but have not been widely
implemented (18). Other multivariate techniques, such as cluster analysis or pattern-recognition methods, which capitalize
on previous work with related compounds or formulations would be worthy of further exploration.
Conclusion
There is considerable opportunity to improve drug development without compromising the strong safeguards that mitigate risk
to subjects in clinical trials, including, areas that would benefit from additional consideration and harmonization. Although
broad regulatory requirements exist for materials going into clinical trials, more defined best practices that reflect the
stage of development and risk-management practices would be a benefit to industry, regulators, and patients. The vetting of
such best practices should be through an open process that involves these same stakeholders. To be most effective, best practices
should be sufficiently detailed yet flexible and subject to continuous improvement. The current philosophy of regulatory
agencies has been to set a general framework for regulatory expectations through formal guidance documents but not to supply
the level of detailed implied herein. As a result, there is the belief that drug developers either individually or collectively
justify approaches that satisfy these general expectations. Further clarification for industrywide best practices, however,
would be tremendously beneficial. The vehicle for establishing these best practices needs to be carefully considered and can
include pharmacopeial standards, publications by industry consortia, or other standard-setting bodies.
Dennis Sandell* is director of S5 Consulting, Järnåkravägen 3, SE-222 25, Lund Sweden, tel. + 46 46 150703, dennis@s5consulting.com
. Terrence Tougas is a highly distinguished research fellow, Dennis O'Connor is clinical supplies officer, and Steve Horhota is a highly distinguished research fellow, all with Boehringer Ingehelheim.
*To whom correspondence should be directed.
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