Available data are unlikely to support the use of non-inferiority studies as a means of demonstrating the effectiveness of antibacterial drugs in indications such as acute bacterial sinusitis (ABS), acute bacterial otitis media (ABOM) and acute bacterial exacerbation of chronic bronchitis (ABECB), the US Food and Drug Administration has confirmed.

Sponsors should “consider other study designs (e.g., superiority studies) to provide evidence of effectiveness in these three indications”, the agency recommends in newly issued draft guidance for industry on Antibacterial Drug Products: Use of Noninferiority Studies to Support Approval. “In some cases,” the FDA adds, “it may be useful to compare time for clinical improvement in addition to overall cure rates.”

While the agency has been moving away from recognising non-inferiority studies as standard clinical evidence for antibiotics in less serious infections such as sinusitis, it has been under pressure to publish guidelines in the face of complaints that the policy change was not properly communicated to industry. In particular, the FDA was accused of exercising a U-turn in two cases where sponsors said they had filed approval applications on the understanding that non-inferiority trials would be acceptable.

In the first case, the agency’s Anti-infective Drugs Advisory Committee (AIDAC) turned down an application to expand the indications for Oscient Pharmaceuticals’ Factive (gemifloxacin mesylate) to acute bacterial sinusitis in September 2006. In the second, the FDA issued a non-approvable letter in October 2006 for a new drug application filed by Replidyne for faropenem medoxomil in acute bacterial sinusitis, community-acquired pneumonia, acute exacerbation of chronic bronchitis and uncomplicated skin and skin structure infections.

Writing in Nature Biotechnology in December 2006, Ralph Christoffersen, general partner at Morgenthaler Ventures and a board member of Replidyne, said these “arbitrary retrospective changes without even draft guidance from the FDA, which have cost companies millions, are totally unacceptable, especially when political influences and lack of FDA leadership seem to have played a non-trivial role in the process. Such actions will surely have a chilling effect on the willingness of the investment community to make additional investments in new antibiotics.”

The political context referred to here was increasing scrutiny of non-inferiority studies as a basis for antibiotic approvals in the wake of allegations that the FDA had glossed over evidence of fraud and misconduct in a key clinical trial for Sanofi-Aventis’ Ketek (telithromycin), which had been linked to several cases of serious liver injury and liver failure. In September 2006 a cross-party alliance of US Congressmen asked the Government Accountability Office (GAO) to investigate the FDA’s reliance on non-inferiority studies when approving antibiotics and other drugs.

NI margins

The agency says its draft guidance was issued “in response to a number of public discussions in recent years regarding the use of active-controlled studies designed to show non-inferiority (NI) as a basis for approval of antimicrobial drug products”. While these discussions had focused primarily on ABS, ABOM and ABECB, the “broader question of the role of active-controlled studies designed to show NI to support approval of antimicrobial drugs and the selection of appropriate NI margins...have been issues of recent concern”, the FDA notes.

For example, following the September 2006 advisory committee meeting on Factive and earlier discussions about clinical trials for acute bacterial sinusitis by the AIDAC in October 2003, the FDA “has not found it possible to define an NI margin for active-controlled NI studies in ABS because a consistent and reliable estimate of the efficacy of active treatment relative to placebo has not been established”.

Non-inferiority study designs “may be appropriate when there is adequate evidence of a defined effect size for the control treatment so that the proposed NI margin can be supported”, the draft guidance states. In these cases, “having an adequately justified NI margin is essential to having an informative study”, it adds.

If NI studies are being considered, “a comprehensive synthesis of the evidence that supports the effect size of the active control and the proposed NI margin should be assembled during the period of protocol development and provided to the FDA along with the protocol”, the FDA advises.

In addition, it calls on sponsors to re-evaluate “all ongoing or completed NI studies that will be submitted to a new drug application for antibacterial indications to ensure there is adequate scientific rationale for the effect size of the active control and the proposed NI margin that is used”. This includes trials that “may have been previously reviewed by the Office of Antimicrobial Products under a special protocol assessment (SPA). Because the state of the science has changed, prior commitments from the FDA under an SPA may no longer be valid for some products.”