Drug Interaction Studies - Recommendations for Sponsors of New Drug Applications (NDAs) and Biologics License Applications (BLAs)

Last month, long-awaited draft guidance from the Food and Drug Administration was published titled Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations.

In it the paper provides recommendations for sponsors of new drug applications (NDAs) and the process of biologics license applications (BLAs) for those who are regulated by the Center for Drug Evaluation and Research (CDER).

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It comes after the availability of the original draft guidance was announced back in September 2006, with comments from industry experts taken on board and used to revise the notes.

The guidance has been produced in order to highlight the agency's viewpoint that "the pharmacokinetic interactions between an investigational new drug and other drugs should be defined during drug development". This should help to assess the effectiveness, and just as importantly, the safety of the new drug.

Included in the guidance are a number of important points to sponsors when they are considering evaluating drug-drug interactions. One of these is the need to consider whether such interactions will show that an adjustment in dosage is required, or whether additional therapeutic monitoring is needed, thus reducing the level of risk.

Sponsors were told that those who believe a complete evaluation of drug-drug interactions is not needed to be carried out for an investigational medication because of its target population need to contact the Office of Clinical Pharmacology and the Office of New Drugs for further guidance.

The draft guidance also carries a number of decision trees for sponsors to look at. These should help when it comes to trying to decide what type of drug-drug interaction studies are needed for different products.

For instance, pharma experts can run through a chart which explains when in vivo metabolism-based interaction studies are highlighted, based on a number of factors.

Users of the tree are asked to decide whether the investigational drug is an interacting drug of an enzyme, with yes or no choices to make. They are then asked to go along the chart, with the conclusion being that no further studies are needed or a dosage adjustment is required.

Another chart for sponsors to look at helps to determine whether an investigational drug is an inhibitor of OATP1B1 or OATP1B3, with the conclusion being whether the result requires an in vivo clinical study.

Following the guidance the FDA announced that it was notifying health care professionals that statins could cause drug-drug interactions which might potentially affect patients with HIV or hepatitis C.

It noted that atorvastatin, Rosuvastatin and simvastatin will carry new warnings, as the protease inhibitors which are taken with these medications increase the concentration of statins in the blood.

This in turn increases the risk of muscle injury, including rhabdomyolysis.

"The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed," said the FDA.

"Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin," it went on to say.

Labeling was an area covered in the draft guidance from the FDA, with sponsors being encouraged to recommend specific 'no effect' boundaries if it wants to include a statement that no known drug-drug interaction of clinical significance was found to be present.

When the draft guidance is finished it will form the backbone of the FDA's thinking on the topic of conducting studies into drug interactions during the development of medication.

Sponsors are also told that alternative approaches to their work may be used if they comply with current statutes and regulations.

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