The Role of GLP in Preclinical Research

The role of GLP studies in drug discovery is confusing to many scientists. The confusion has two causes.

1. Semantic
   GLP is an acronym for "Good Laboratory Practices." Hence, many scientists infer that GLP studies must therefore be "good" and non-GLP studies are of questionable quality. Actually, the "good" is more about good documentation than good science.


2. Regulatory Requirements
   The regulatory bodies require GLP for far fewer types of studies than many scientists think. GLP requirements are for safety studies, not other types of studies.

The consequences of this confusion are that many drug-discovery organizations end up wasting time and resources on unnecessary and premature GLP studies when their objectives would be better achieved without the burden of GLP.

What Is GLP?

GLP certification was established by the regulatory bodies to ensure that research submitted to them is not only properly executed, but is also documented thoroughly enough so that any scientist skilled in the art can follow the documentation and replicate the results. The level of detail required to achieve this level of documentation is substantial — so much so that the cost of generating the documentation exceeds the cost of the research itself.

When to Use GLP

GLP is unnecessary until the final stage of preclinical development, at which point GLP documentation is needed for obtaining regulatory approval for further development.

Many researchers are under the mistaken impression that at the IND (Investigational New Drug) stage all studies must have GLP documentation. Actually, the FDA requires GLP documentation for only safety studies. This includes animal toxicity, genotoxicity, supporting toxicokinetic studies,¹ and safety pharmacology.

GLP is NOT required for:

• Efficacy studies, whether in vitro or in vivo.² In fact, the IND application has no requirement at all for mechanism of action or efficacy studies.
• In vitro studies, including:
  • Pharmacokinetic analyses that support the in vivo efficacy and toxicity studies
  • Drug-drug interaction studies³
  • In vitro ADME studies

The reasons for this are easy to understand. At the IND stage the regulators' key concern is about toxicity from exposure to the New Chemical Entity (NCE). Their goal is to ensure safety for human subjects. Other risks, such as whether the NCE is efficacious or has drug-like ADME properties are essentially commercial risks that are the responsibility of the filer. In fact, safety is core to the definition of GLP:

Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals, agrochemicals, veterinary medicines, industrial chemicals, cosmetics, food and feed additives and biocides. GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments.⁴

Inappropriate Application of GLP

For the types of studies where the regulators do not require GLP, many scientists mistakenly believe that GLP is better than non-GLP. However, at the discovery stage GLP has profound disadvantages, making it unsuitable for discovery-stage work.

• Inflexibility
  In the early stages of drug discovery large uncertainties exist about how to conduct experiments. New information is constantly being generated, causing frequent changes in experimental design. Under GLP, every step taken must be decided and documented in advance, and each study must then be scheduled.


• Pace
  Because of the documentation burden, GLP studies take 4-5 times longer to execute.


• Cost
  All of that documentation makes the cost of GLP 2-10 times greater, depending on the complexity of the study.


• Scientific Challenge
  The most skilled and creative scientists do not work in GLP environments, as the work is not only repetitive, but mostly paperwork rather than conducting experiments and discussing scientific implications to move the program forward.

GLP and Discovery Research

Research approaches that are optimal at the discovery stage are different from those required for regulatory filings. To provide the needed flexibility, discovery work is best performed by highly experienced and trained scientists who know how to recognize and address the unusual and unexpected outcomes that are the norm during discovery. Because the path to success at the discovery stage is through the process of failing fast, failing cheap, and failing often, the optimal discovery research methodology focuses on the fastest and most cost-effective methods for getting correct scientific answers to direct further research.

The documentation needs of a discovery team are different from the documentation needs of regulators. Regulators need to be able to follow the research without prior background. They need protocols recorded in great detail such that someone with no prior involvement in the research can replicate the experiments if needed. Discovery teams embody substantial organization knowledge. They just need the essentials of the actual research — the key details and the implications — and the assurance that the research is scientifically valid (e.g., that controls and calibration standards were run for each assay, etc.).

Avoiding Surprises

Regulatory filings are the goal for any discovery team. Every team wishes to ensure that their filings present a strong case. Well-disciplined teams do this by replicating every study they file to ensure it is all correct. If GLP is required, GLP is utilized to replicate work originally performed non-GLP. If GLP is not required, replicating the study under GLP just adds to the cost of filing.

Conclusion

If your drug-discovery team needs help determining when to use GLP, Apredica can help, either as part our ADME Tox support for your program, or as stand-alone consulting. Contact us for details.

Footnotes

1. Guideline for Industry. Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies ICH - S3A March 1995, p.4.

2a. FDA. "Guidance for industry: S7A safety pharmacology studies for human pharmaceuticals" July 2001.
2b. 21 CFR 58: "Good Laboratory Practices for Nonclinical Laboratory Studies"

3. Strong, J. & Huang, S.-M. "U.S. regulatory perspective: Drug-drug interactions." In Drug-Durg Interactions in Pharmaceutical Development. Li, A.P., ed. Wiley: Hoboken, NJ. 2007, pp 201.

4. Medicines and Healthcare products Regulatory Agency