The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) will continue to study for two more years whether guidance can be revised on certain situations when sponsors will not have to conduct and submit a two-year rat carcinogenicity study for a developing drug.
In order to test the feasibility of eliminating such studies in some cases, which would be part of revisions to ICH’s S1 Guideline, ICH began collecting voluntarily submitted Carcinogenicity Assessment Documents (CADs), which address the carcinogenic potential of an investigational pharmaceutical and help predict the outcome and value of the planned two-year rat carcinogenicity study, or whether such a study can be waived.
Most recently, the ICH S1 Expert Working Group (EWG) met in Jacksonville, Florida, in December 2015 to discuss the status of the evaluation study, which began in August 2013 with the publication of a Regulatory Notice Document (RND). The EWG’s report on that meeting was released this week.
From August 2013 to September 2015, participating regulators (US Food and Drug Administration [FDA], Health Canada, Japan’s Ministry of Health, Labour and Welfare, and the European Medicines Agency) received and reviewed 25 CADs, which ICH says is approximately one-third the number of two-year rat study protocols received by the FDA’s Executive Carcinogenicity Assessment Committee over the same period.
The 25 CADs comprised diverse chemical classes and clinical indications, ICH noted, including several first-in-class compounds. The RND directs sponsors to classify their investigational compound into one of the following categories:
- Category 1: Highly likely to be carcinogenic in humans (rodent carcinogenicity studies would not add value).
- Category 2: Uncertain carcinogenic potential (rodent carcinogenicity studies are likely to add value).
- Category 3a: Highly likely to be carcinogenic in rats through prior established and well-recognized mechanisms known to be human irrelevant (rat carcinogenicity study would not add value).
- Category 3b: Highly unlikely to be carcinogenic in both rats and humans (a rat carcinogenicity study would not add value).
A majority of sponsors (64%) proposed Category 3, split evenly between categories 3a and 3b, meaning that existing data would be sufficient to characterize the carcinogenic risk of a compound without a two-year rat carcinogenicity study.
But the participating regulators did not necessarily agree with the sponsors’ determinations in each case.
After review and discussion, the regulators concurred with the sponsor’s proposal of a Category 3a or 3b for six of the 16 cases (37% concurrence). But the regulators did not concur with the sponsor’s proposed Category 3a/b in seven cases, concluding instead that the compound should fall under Category 2, meaning a two year rat study would add value. For the other remaining three Category 3a/b cases, the regulators could not reach consensus.
“Differences in categorization between sponsors and DRAs [drug regulatory agencies] arose from differences in scientific opinion of the data presented and from various deficiencies in the CAD write-ups,” ICH said. “Differences in scientific opinion arose on various aspects, including the relevance of toxicological or hormonal findings seen in the chronic studies, the implications of the pharmacological complexity or off-target activity of the compound, and the importance of prior experience with other compounds in the same or similar pharmacological class. The DRAs generally agreed that because prior class experience is absent for first-in-class compounds, a higher evidentiary standard would be needed to support a category 3a/b designation.”
Based on the rate of sponsor participation and submissions, which was lower than expected, the EWG has agreed to extend the period for CAD submissions by two years, to the end of December 2017.
“The EWG recognizes that alignment around category 3 CADs that are substantiated by results from 2 year rat studies are most important, as such cases may dictate the conditions under which a 2 year rat study waiver is feasible,” ICH said. “Therefore, the EWG agreed that a decisional analysis would be appropriate when the dataset includes 20 category 3 cases (i.e., CAD + study report), irrespective of the total number of CAD cases received.”
For the purposes of reaching a decision in a timely manner, ICH says that Category 3 cases are defined as those CADs where at least one regulator concurs with the sponsor that a two-year rat study waiver is appropriate. The EWG also agreed that an interim analysis should be conducted when the dataset includes six or more Category 3 cases and 10 or more Category 2 cases. The final analysis is intended to define the scope of any potential changes to the S1 Guideline.
This two year extension to the study is expected to allow for the interim analysis to occur sometime around November 2016 and a decisional analysis of 20 or more CADs is expected to occur by the end of 2019.
The ICH S1 Regulatory Testing Paradigm of Carcinogenicity in rats - Status Report