Drug Development (Chapter 3)
In drug development, a series of preclinical safety, toxicity and efficacy studies are performed in vitro and in animals prior to administering these drugs to humans. Clinical trials are designed to first addressing safety, then dosing, then efficacy, and finally larger Phase III trials to look at efficacy and other endpoints (e.g. overall survival).
Personalized Medicine Implications
New animal models may need to be developed in order to effectively evaluate safety and efficacy of personalized medicines. Since mammalian pathways are quite similar across species, good animal models exist for many diseases. However, with the advent of personalized medicines targeted to certain kinds of genomic profiles, it may be necessary to create new xenograft models or genetically engineered mouse (GEM) models with specific genomic profiles necessary for assessing safety and efficacy. Creating such models could involve significant time and money.
Personalized medicine poses even bigger implications for human trials. Genomic information will not likely be needed for Phase I trials which are typically in healthy volunteers. However, Phase I/II trials often require measurement of a biomarker to show both safety and a “signal of efficacy” in order to receive funding for additional studies. Therefore, it is likely that all trials after the 1st Phase I trial will require monitoring by biomarker, despite known challenges to identify response biomarkers a priori, before there’s any clinical data. Phase II trials should collect patient genomic information as it is often unknown which patients will respond to the medicine (e.g. those who over-express/under-express a particular receptor, those with a particular genomic profile, etc.). In addition, early on, both responders and non-responders will be needed to develop companion diagnostics and better understand the safety and efficacy profile of the medicine.
Recruiting the number of patients for large-scale Phase III trials becomes significantly more challenging. If a genomic test doesn’t exist, it will need to be developed, and all patients will need to be tested. Testing all patients to find those with the specific genomic profile will cost additional money and may significantly slow enrollment, particularly if only a minority of patients tested meet the target genetic profile. To keep costs down and speed enrollment, drug companies will either need to increase the number of investigator sites or focus on investigator sites with large numbers of patients who have already been sequenced. Lastly, the genomic profile may only be part of the story as genes can be switched on and off; some diseases and personalized medicines may not be related to genomics, but rather RNA or protein expression.
Here are a few more suggestions for drug developers.
- Genetic material (blood/tissue) should be gathered and preserved for all human trials. As our knowledge of genomics expands, companies will want to apply this knowledge retrospectively to see how it might impact safety, efficacy, and other endpoints. NOTE: Proper patient consent must be obtained; consult with Legal.
- Although retrospective analysis of subpopulations could provide significant value, it could also have unintended regulatory, legal, and commercial consequences. Proceed with caution.
- If pathway and genetic implications are known, then companion diagnostic tests need to be simultaneously developed with the drug (best practice is to have the diagnostic leader participate as a full-fledged member of the drug development team).
- Recent FDA approvals (e.g. Xalkori® and Zelboraf®) have included the need for an FDA-approved diagnostic test in the product label. Personalized medicines lacking a companion diagnostic may place themselves at risk for FDA approval (e.g. Omapro® by ChemGenex).
- Pharmaceutical companies need to establish tight partnerships with diagnostic firms. Developing a diagnostic requires a different set of skills (scientific, clinical, and commercial) and has a very different regulatory path than for a therapeutic.
- In very competitive markets with little differentiation between products (e.g. kidney cancer), a companion diagnostic that allows for more targeted patient selection might help a late-to-market product gain patient share.
Lastly, drug development and portfolio management teams will need to constantly evaluate competitors and their relative progress through clinical trials. Whereas in the past, markets were big enough so that 4 or 5 products could compete for market share, markets for some personalized medicines may not allow for more than 1 or 2 products. Therefore, if a product is going to be second or third to market, it had better be a big enough market or a clear winner.
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