As calls to develop novel antibiotics to treat drug-resistant bacteria grow louder, financial incentives remain a focus in the search for options to stimulate drug discovery.

Improving the economics of antibiotic development is paramount since generics are available to treat run-of-the-mill infections and public health officials seek to restrict use of innovative products to the most recalcitrant infections in order to preserve their effectiveness.

"The market would not necessarily be there, as it [a new antibiotic] would only be used in relatively few circumstances," AstraZeneca CEO David Brennan pointed out during an April 14 seminar on securing effective antibiotics.

AstraZeneca sponsored the gathering as part of a spring series of health seminars being conducted at the Swedish Embassy in Washington. The discussion on the lack of an antibiotics pipeline and possible solutions came as the Infectious Diseases Society of America published a white paper urging development of 10 new antibiotics by 2020 and a congressional panel scheduled a hearing on antibacterial resistance (see chart: " ¹ An Antibiotic A Year To Keep Resistance At Bay ").

A key question confronting stakeholders is how to make new antibiotics financially viable when they are used for a limited course of treatment, have generic competition and doctors are discouraged from using them lest bacteria become resistant.

Incentives have repeatedly come up as a possible solution. At the AstraZeneca-sponsored seminar, Chantal Morel, a research fellow at the London School of Economics, took on that topic. Morel collaborated on a study of "Policies and Incentives for Promoting Innovation in Antibiotic Research" that was commissioned by the Swedish government. The final report is in preparation for publication.

Financial inducements to drug companies consist of push incentives, those that support research and remove barriers to developer entry, and pull incentives, which are "large rewards that are offered after the fact," she explained.

A combination of the two types helps mitigate early risk but "maintains an entrepreneurial framework of relative high risk to the developer, compensated by appropriate rewards."

Examples of push incentives are grants and fellowships for translational research. Their advantages, Morel said, are they involve smaller outlays and would enable smaller companies to participate in the antibiotic space.

Pull mechanisms include higher prices for the drug, longer patent protection or stronger intellectual property protection.

FDA discussed incentives at a 2008 workshop, where the incentives in the Orphan Drug Act - seven years of marketing exclusivity, research grants, a tax credit for clinical research and a waiver of user fees - were assessed as a model for antibiotics (² Also see "Antimicrobial Resistance Rallies Calls For Active FDA, R&D Incentives" - Pink Sheet, 19 May, 2008.). A program similar to orphan designation is appropriate for antibiotics because it combines both the early incentives to research as well as greater opportunity for profit after development, Morel noted.

Price Should Reflect Value

She also cited the benefit of "further exploration into reforming the pricing and reimbursement framework such that the price is more reflective of therapy value." Drug-resistant infections cost $35 billion each year in the U.S. alone, she pointed out.

More public awareness about the cost of infections and drug-resistant bacteria would allow better valuation of antibiotics, Brennan suggested. "I truly believe that if the true cost of resistance was really appreciated by society, there would be a corresponding willingness to support pricing and reimbursement for antibiotics in line with their actual value in terms of lives as well as years of productive life that is saved by their use."

Morel's other recommendations included:

Application of tax incentives to research, not sales and marketing, "because we do not want to be encouraging further consumption of these products";

Targeting incentives to drugs for priority pathogens, i.e., gram negative bacteria;

Setting up long-term incentives so they cannot be undone by future political or budgetary processes; and

Requiring the results of publicly funded research to be publicly available.

National Security Risk

Brad Spellberg, an assistant professor at UCLA's David Geffen School of Medicine and a member of the task force that wrote the IDSA white paper, suggests a different avenue for bolstering funds for antibiotic development: national security. He contends that drug-resistant bacteria pose a safety risk for the country. As such, antibiotic research should be part of the agenda for the Biomedical Advance Research and Development Authority, he said in an interview.

"Antibacterial-resistant organisms are an equal, if not greater, national security problem, so why not allow BARDA to provide funding and bridge academic translation of technologies that are related to treatment of antibiotic-resistant bacteria even if they aren't a bioterrorism pathogen?"

BARDA provides funding for research into countermeasures for biological attacks, and HHS just unveiled a pilot program in which top scientists from HHS agencies, would work closely with drug companies in the early development stage on drugs to counteract pathogens (³ Also see "Rx Countermeasures: HHS Launching "Pivotal Studies" To Engage Industry" - Pink Sheet, 12 April, 2010.).

Spellberg also suggested the creation of a system similar to as the Vaccine Injury Compensation Trust Fund to respond to liability claims for antibiotics.

Antibiotics are a critical public health instrument, much like vaccination, he pointed out, and there needs to be a means of dealing with rare adverse events that are not found in clinical trials.

It would be reasonable to set up a system similar to that for vaccines, "where you have an excise tax on the sale of antibiotics and that money goes into a publicly operated insurance fund. So if people think they have adverse effects from antibiotics, they actually get paid. They file claims and get paid out of that fund." Liability is an issue for some, although not all companies, he noted.

One Study, Multiple Diseases

To attract companies to the antibiotic field, even more important than money is an improved clinical trial process, Spellberg said.

His prescription for change is to tailor trial design for organism-specific studies - as opposed to infection-location based trials, like pharyngitis or sinusitis, as currently used. Currently, antibiotic trials often will include analyses for pathogen-type, to build some evidence of effectiveness against MRSA, for example.

Evaluating a drug to treat highly resistant bacteria in one or more diseases in a single study would improve the economics because more patients would be available for enrollment and the trial could be completed faster and less expensively, Spellberg maintained.

He noted that FDA and industry appear to be waiting for the other to make a move on the topic.

"FDA's waiting for sponsors to bring them protocols. Sponsors are waiting for FDA to say 'yes, you can do that kind of a study.' What they need to do is start talking to each other."

The topic is open for discussion, FDA's Office of Antimicrobial Products Director Ed Cox indicated during the seminar.

The move to tissue-specific indications came two decades ago for scientific reasons, when there was recognition that treatment time might vary depending on the particular bacterial problem, he explained.

It could be feasible to study a drug for a particular organism that can affect several sites where the course of disease is similar, he suggested.

"There may be a way to come up with an informative study design [that] targeted, particularly a problem pathogen, for instance, in a serious disease condition. It's an idea worth talking about further."

Spellberg expressed hope that those conversations will begin over the next few years. There are some sponsors with drugs that are active against resistant gram negative bacteria, for which organism-specific studies are attractive, he said. These compounds are not yet in Phase III, but as "companies map out their development program over the next four to five years," those conversations could come up, he predicted.

On the question of clinical trials, Brennan stressed that "the regulatory environment has to be changed to make the journey from bench to bedside faster, relevant to the current challenges and appropriate to the urgency of the situation. The changes have to be coherent and done in a dialogue that takes place between public authorities and the industry."

Uncertainty has been a problem for industry as FDA decides how to define non-inferiority success for antibiotics and updates guidance for specific indications.

Cox reported the agency expects to put out new guidance on skin structure infections and hospital-acquired ventilator bacterial pneumonia within the next few months. The last guidances that touched on those topics were released as drafts in 1998. Sponsors of treatments for skin infections have been forging ahead with trials despite the lack of an official guidance, though there was an Anti-Infectives Advisory Committee recommendation for tighter non-inferiority margins that provides some instruction (⁴ Also see "Antibiotic Firms Push Ahead With cSSSI Trials, Despite Lack Of FDA Guidance" - Pink Sheet, 23 November, 2009.).

Cox noted that the agency is going back to work on draft guidance for community-acquired pneumonia, following an advisory committee meeting where the Anti-Infectives panel split on whether endpoints for clinical trials should be mortality or symptom reduction (⁵ Also see "Advisory Committee Splits The Difference On CABP Trials" - Pink Sheet, 21 December, 2009.).

Otto Cars, of Uppsala University, suggested that finding efficacy could be accomplished more swiftly by relying on pre-clinical data so that big trials are not necessary.

- Cathy Dombrowski ( ⁶ c.dombrowski@elsevier.com )

Financial Incentives Seen As A Path To Resurgence Of Antibiotics

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