US Food and Drug Administration (FDA) has now issued a guidance to the clinical research organisations (CROs) titled M3(R2) Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. The guidelines are seen to come in as a big relief to Indian CROs which are now looking to ensure that all human studies and the related protocols for approvals are transparent and documented with adequate data.

The guidance focuses on juvenile animal studies and phase I for humans. It is an evaluation for a new formulation containing a previously approved drug substance and of a product proposed for use by an alternate route of administration which was not previously approved, according to the regulatory authority.

It has classified sections covering: limit dose of toxicity, metabolites, reversibility of toxicity, exploratory clinical trials, reproductive toxicity and juvenile animal studies.

Although the ICH M3 (R2) guidance is still in its early phases of implementation, the complexity of the norms, its broader scope, and numerous changes in recommendations from the M3 (R1) guidance have generated questions that have an impact on its successful implementation.

According to Indian CROs, the new norms of M3 (R2) Non-clinical Safety Studies bring in the required clarity and the much-needed clarifications to carry out the juvenile animal and phase I studies.

Under toxicity, the guidelines have dealt on 50-fold approach for small molecules administering high dose to maximize exposure to the drug.

In a similar manner, US FDA has provided information in a simple manner on metabolites. Here the regulator has stated that clinical studies assessing safety pharmacology endpoints are generally conducted during phase I,  before a full characterisation of the metabolites are conducted to understand the drug mechanism.

The guidance is a revision of the ICH guidance dated February 2012 (M3(R2) Q&As. In fact the February 2012 guidance addressed the first set of Q&As on Limit Dose for Toxicity Studies, Metabolites, and Reversibility of Toxicity that was finalized in June 2011.

In December 2011, a second set of Q&As addressing combination drug toxicity testing was approved for integration in the M3(R2) Q&As. In March 2012, an additional question on limit dose for toxicity studies and four additional sections addressing safety pharmacology, exploratory clinical trials, reproductive toxicity, and juvenile animal studies were approved for integration in the (M3(R2) Q&As.

The objective  of the non-clinical safety evaluation includes a characterization of toxic effects with regard to target organs, dose dependence, relationship to exposure, besides the potential reversibility factor, said the regulatory authority.

On the scientific assessment of reversibility, the guidelines stated that it could be included to the extent and severity of the pathologic lesion, regenerative capacity of the organ system showing the effect of other drugs.

It is accepted that combination toxicity studies on advanced cancer, tuberculosis, and HIV products are generally not warranted unless there is a specific cause for concern under clinically relevant conditions. Further the combination toxicity studies are also not generally warranted for antiviral agents to treat hepatitis C. There are other situations where combinations of drugs are standard clinical practice for serious or life-threatening conditions without current effective therapies where a  similar approach might also apply, stated the guideline.