Approximately 80-90% of oncology drugs that enter into clinical development (Phase I) never make it to approval (Phase III). Most oncology drugs fail either in Phase I (drug safety) or Phase II (efficacy). The probability of success (POS)/likelihood of approval (LOA) of therapies in Phase I has been reported to be between 3.4% and 5% but between 2014 and 2015 the POS was reported to be between 2.5 and 8.3% respectively. In a recent report from Massachusetts Institute of Technology (MIT), the authors evaluated 21,000 compounds in clinical development, from 2000-2015, and found the POS was 13.8% for all drugs but oncology drugs only had a POS of 3%.
According to clinicaltrials.gov, approximately 6,000 Phase I clinical trials are ongoing where a variety of therapies are being evaluated, including small molecule inhibitors, biologics (antibodies, antibody drug conjugates, bispecific antibodies, oncolytic viruses) and cell therapies (CAR-T cells, NK cells). Each therapeutic has its own set of risks, benefits and costs associated with it.
The vast majority of FDA approved oncology drugs are classified as small molecule inhibitors. When we evaluated the number and types of FDA approved therapies from 1996 - 2020, approximately 195 therapies have been approved with 65% (127) being small molecule inhibitors, 19% (36) antibodies and 5% (10) antibody drug conjugates (ADCs). https://www.jackson-consulting-group.com/fda-approved-drugs-for-oncology
The overwhelming question is why the majority of oncology therapies fail in clinical development despite promising preclinical data.
Some of the reasons for the poor success rate for oncology drugs :
1. The intended target is not critical for tumor growth.
2. Mouse tumor models don't accurately reflect the complexities of human tumors.
3. The therapeutic does not inhibit the intended target.
4. Lack of biomarkers.
5. Poor clinical trial design.
6. Pressure to quickly push therapeutics into clinical development.
Things companies should consider to improve clinical success for oncology drugs
1. Stringent evaluation of the target in human tumors.
Confirmation that the target is critical for tumor growth, survival and/or metastasis.
Address heterogeneous expression of the target in a large number of human patient tumor samples.
2. Confirmation the therapeutic inhibits the intended target.
a. Show the therapeutic only works when the target is present.
b. Address how much target expression is required for the therapeutic to work effectively.
3. Development of better preclinical tumor models tumors.
Incorporate the use of several patient derived tumors (PDX) early.
Use tumor bearing mice that have human immune cells.
Consider using orthotopic tumor implantation.
4. Develop biomarkers for target inhibition and tumor efficacy that can be used in clinical trials.
5. Improve Pharmacokinetic/Pharmacodynamic (PK/PD) relationship.
6. Develop better toxicology models that mirror human drug levels and safety.
7. Improve methods to identify the appropriate patients for the clinical trial.
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