FDA mulls change to anti-infectives trials

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New FDA guidance could move the goal posts for drug makers in the anti-infectives space, including those targeting the so-called superbug MRSA.

The regulatory agency is eyeing a change to clinical trial endpoints that experts told Pharmawire has created major uncertainty in the industry and may impact investor funding and partnerships.

At present, drugs in the anti-infective and antibiotics space only need to show that they are non-inferior to the current standard of care. However, the FDA is mulling a change to the margin of non-inferiority (NI) that an investigational drug needs to meet, experts said.

An ex-FDA anti-infective medical officer said the push by the FDA is for companies to design clinical trials that truly demonstrate the efficacy of the drug. However, the situation has created a state of limbo for companies whose trials are already underway -- and that are now seeking reassurance that their protocols are good enough for approval.

Forest Laboratories (NYSE:FRX)/AstraZeneca, Paratek Pharmaceuticals/Novartis, Basilea Pharmaceutica (SIX:BSLN), Trius Therapeutics and Rib-X Pharmaceutical are all in various stages of developing anti-infective drugs and are at risk of being affected by the changes, the sources noted.

David Shlaes, an independent infectious diseases consultant at Anti-Infectives Consulting, LLC, said pharma’s uncertainty about the changes will likely impact the small and mid-size companies developing antibiotics in terms of investor funding and big pharma partnerships. Big pharma firms could reconsider further investment in the space, he said.

Anti-infectives consultants said big pharma -- including Roche and Sanofi Aventis (EPA:SAN) -- has already pulled back interest from the anti-infectives space. They added that, in their opinion, Novartis (NYSE:NVS) and Johnson & Johnson (NYSE:JNJ) are at risk of doing so.

Pfizer (NYSE:PFE), GlaxoSmithKline (NYSE:GSK), AstraZeneca (NYSE:AZ) and Merck (NYSE:MRK) are on the “very short list” of large pharma firms that have not totally abandoned the anti-bacterials space, they said.

Shlaes said he did not anticipate the FDA implementing a requirement for superiority trials but noted that, at present, the FDA is undecided on how to set the NI margin in some antibiotic indications. The FDA has previously rethought the NI criteria for community-acquired pneumonia and now wants to do the same for complicated skin and soft tissue infections (cSSSI), he said.

The FDA is currently drawing up draft guidance on Phase III trial design for antibiotics that treat SSSIs, sources familiar with the agency said. One source claimed that the FDA plans to publish its guidance documents around July, after which point there is likely to be a public workshop to debate the proposed changes. An FDA spokesperson said the agency intends to publish the guidance as soon as possible.

Shlaes said he has discussed the issue with the agency at length and “the implication is that the FDA is willing to put decisions regarding SSSIs on hold while they examine the science.”

Dr Daniel Sahm, principal investigator of the Network on Antimicrobial Resistance in the Staphylococcus aureus project, supported by the National Institute for Allergy and Infectious Diseases, agreed that the FDA’s reluctance to fully embrace NI trial design has made developing antibiotic drugs a “risky business.”

Sahm said there is uncertainty as to the FDA’s thought process and how it evaluates clinical trial data. As such, many in the industry view the FDA as a “moving target,” and do not know how the FDA views the application until the sponsors file a New Drug Application at the end of Phase III.

Dr George Retsch-Bogart from the division of pediatric pulmonology at the University of North Carolina, Chapel Hill, and an investigator for many trials including the inhaled antibiotic aztreonam, added that in the design of NI trials, the communication can be murky between the sponsor and the FDA.

A second ex-FDA medical officer said Optimer Pharmaceuticals’ (NASDAQ: OPTR) Phase III trials for fidaxomicin for Clostridium difficle (CDI) may be impacted as no NI margins for CDI have been established by the FDA. The problem is that there is a huge range of patients and they will get better anyway with the effect not necessarily attributable to drug, said the same source.

A third ex-FDA medical officer cited the example of Gilead’s (NASDAQ:GILD) Cayston (inhaled aztreonam), claiming that even though the trials were designed well, and the data was clear and easy to interpret, the FDA still gave the company a hard time and requested another trial. The agency approved the drug on 23 February for cystic fibrosis-associated respiratory tract infections.

An FDA spokesperson commented via e-mail that the agency provides advice to companies on recommended clinical trial designs. In the area of non-inferiority trials for antibacterial drugs, there have been considerable scientific advances over the last several years and this has led to uncertainty because trial design and endpoints may be different compared to the past, the spokesperson added.

The FDA is working to address these issues through scientific discussions at workshops, advisory committees and by publishing guidance documents. The goal is to be able to provide advice on scientifically sound and feasible trial designs, the spokesperson noted.

Uncertainty on NI trial design contributed to the downfall of Arpida’s (SWX: ARPN) iclaprim. The FDA rejected the cSSSI indication in early 2009 after determining that that the NI margin for iclaprim to linezolid has not been established, as well as other trial design concerns.

One anti-infectives consultant said the FDA had signaled prior to the complete response letter to Arpida its intention for a 10 percent NI margin for cSSSI antibiotics, but the pivotal iclaprim trials were designed to show 12.5 percent non-inferiority. At the time, Arpida said the 12.5 percent margin was pre-arranged with the FDA before it commenced the trials. But the consultant pointed out that the FDA has the freedom to reject studies that no longer conform to its revised standards, even if a prior agreement had been made with a company.

More recently in the nosocomial pneumonia/hospital acquired pneumonia indication, Theravance (NASDAQ:THRX) hit a stumbling block in late 2009 after the FDA “switched the goal posts” in terms of the design and analysis of the Phase III program, according to a second anti-infectives consultant. The FDA indicated that an additional clinical trial was required, but there was no guidance provided regarding the primary clinical efficacy endpoint suitable for approval, the size or number of additional studies required, or statistical methods for evaluation of clinical results, according to a Theravance press release at the time.

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