Innovation in Oncology Drug Development

Figure 1

Typical Clinical Development Pathway for a Cytotoxic Cancer Chemotherapy Drug. Commonly used preclinical and clinical development pathway for cytotoxic chemotherapy drugs. A typical pathway for the development of cytotoxic cancer drugs started with demonstration of differential cytotoxicity in human cancer cell lines compared to nontransformed human umbilical cord endothelial cells (HUVECs). This was routinely followed by tumor xenograft studies in nude mice with nontoxic doses of the test drug (doses that did not produce weight loss) that are growing subcutaneous or orthotopic human tumor tumors. Efficacy was based upon slowing down of human tumor growth rate or even tumor regressions. This was followed by compliance with the regulatory requirements needed for approval of an IND to be able to treat patients in phase 1. Phase 1: the purposes of phase I studies for cytotoxic drugs are to assess the initial safety/tolerability and identify the maximal tolerated dose (MTD) and the recommended dose for phase 2 studies (RDP2). Phase I studies for cytotoxic cancer drugs are typically conducted in cancer patients since the drug is predicted to have safety concerns. Phase 2: with the identification of an acceptable dose/schedule from phase 1, supported by PK and even potentially PD data, it is possible to proceed to phase II exploratory therapeutic/efficacy trials in selected patient populations to get an initial estimate on antitumor efficacy in one or more tumor types while concomitantly expanding the safety data base on the investigational oncology compound. Phase 3: typically for registration and marketing approval. Commonly compares the overall safety and efficacy of the new treatment to the standard of care in a randomized, statistically rigorous, and blinded trial. However, it must be recognized, that by definition, these trials generate data from a highly controlled setting, which may not be reflective of “real-world” settings. Phase 4: phase 4 trials are also known as postmarketing surveillance trials. Phase 4 trials involve the safety surveillance or pharmacovigilance and ongoing technical support of a drug. Phase 4 trials generate additional important data that require longer periods of time or large patient populations to emerge, such as rare side effect profiles. These postapproval safety signals may result in the drug being withdrawn from the market or the label being more restrictive. Phase 4 studies may be required by regulatory authorities or may be initiated by the sponsoring company. MTD, maximal tolerated dose; PDP2, recommended dose for phase 2; HUVEC, human umbilical cord vascular endothelial cells; SOC, standard of care; NDA, new drug application.