Table 2.

Possible regulatory challenges encountered during clinical trials involving cancer immunotherapeutic products [41, 45, 47]

Therapy/problem	Challenge	Possible solution
Dose identification	Lack of animal models for some targeted mAbs	A small rapid human trial with a minimum number of patients to identify the dose
Relevant patient population	Regular trials recruit patients with advanced/metastatic cancer: the immune response may be hindered in them	Selection of heterogeneous patient population (patients with minimum disease burden and patients with advanced/metastatic disease) may resolve it to some extent
Personalized therapy	Each patient recruited for the trial may be unique in terms of subtype of molecular targets. This may pose difficulty for the sufficient sample size required for licensure	A flexible approach of “limited approval,” i.e., high efficacy in a particular subset of patients may be provided
Study design	All the new products cannot be designed for superiority trials. Non-inferiority trials have their own complexities	The study design may be adapted from a case-to-case basis, and discussion with the regulators for the adoption of relevant study design may help
Relevant endpoint selection	Regular cancer trials require OS as the endpoint, which may require long follow-up and a large sample size	Adopting other endpoints like PFS and ORR for conditional approval by EMEA or accelerated approval by FDA
Choice of comparator/control or placebo group	The regulators ask for a comparator group that has a proven efficacy or registered for the said indication. This may not be possible for all novel products. The definition of proven efficacy varies among regulators from clinical practice Placebo may not always be ethical in oncology trials	A discussion with the regulators before the start of the trial for the selection of the control/comparator or placebo group in the study design can resolve the issue on a case-to-case basis
Bias	Blinding may not always be possible with all the immunotherapeutic products	The assessment for bias to be discussed with the regulators, preferably at the end of phase 2 trials, may prevent future hindrances in getting licensure
Statistical analysis plan	Presence of disparities among different regulatory agencies about the efficacy cut-offs	An international harmonized approach is needed to address this challenge
Global harmonization	Differences between the regulatory agencies across the globe affect the time to market timelines for international trials	Development of a harmonized regulatory framework across the globe may help the investigators to make the trials less burdensome

mAbs monoclonal antibodies, OS overall survival, PFS progression-free survival, ORR overall response rate, EMEA European Medicines Agency, FDA Food and Drug Administration