Antibiotic Development: Limited Population Pathway In US Removes Barrier

By codifying the removal of regulatory barriers, the limited population pathway provision for certain antimicrobial drugs in the 21^st Century Cures Act will incentivize the development of infectious disease drugs that would impact small, specific populations, experts say.

There are several reasons why drugmakers have avoided antimicrobial development – antibiotic development in particular – over the past few decades. One such regulatory barrier has been the lack of available patients for clinical trials because of the small amounts of people the infections have impacted. Another factor has been the financial incentives that await sponsors once they reach the market, including public health priorities that discourage use of new products. (See sidebar for related story.)

"Basically it was because each individual infection was occurring in relatively small numbers of patients," Amanda Jezek, vice of president of public policy and government relations for the Infectious Diseases Society of America, tells the Pink Sheet. "It was very difficult to enroll a sufficient number of patients with these resistant bugs and clinical trials. So the limited population pathway will allow for smaller studies to be done, and then for the drug to just be approved for the limited number of patients who most need them."

Elizabeth Jungman, director of public health at the Pew Charitable Trusts, concurred, adding that Pew sees the provision "as an opportunity to restock the antibiotic pipeline."

"These are products that have been historically difficult to get onto the market," Jungman tells the Pink Sheet. "They are really hard trials to do, particularly trials for antibiotics that are targeting resistant infections. And so the LPAD pathway will make it more feasible for pharmaceutical companies to bring antibiotics to the market for the most urgent critical needs."

Although FDA is supportive of the provision, the agency has suggested it already had the authority to approve an antibiotic based on a limited population without legislation. (Also see "FDA Worries About Off-Label Use, Stewardship With Limited-Population Approval Pathway" - Pink Sheet, 11 Feb, 2013.)

David Nicholson, chief R&D officer at Allergan PLC, however, tells the Pink Sheet that the codification of the provision is beneficial because "it really does put Congress on the record for supporting the approach that the FDA has in fact been following for some time."

The Case Of Avycaz

One example of FDA approving an antibiotic based on a limited population is when the agency gave the thumbs up to Allergan's Avycaz (ceftazidime and avibactam) in February 2015 for the treatment of adults with complicated intra-abdominal infections in combination with metronidazole, as well as complicated urinary tract infections.

However, because only limited clinical safety and efficacy data for Avycaz – which was approved based on Phase II data – were available at the time, its use was restricted for patients who have limited or no alternative treatment options. (Also see "Actavis Avycaz Approval Shows How FDA Handles Limited-Data, Limited-Use Antibiotic" - Pink Sheet, 26 Feb, 2015.)

In the Phase II trials, only 169 patients were treated with Avycaz, and another 169 were treated with comparator treatments.

Nicholson noted that the company did still have to complete Phase III development for the drug. In June 2016, FDA approved a supplemental New Drug Application for Avycaz to include the findings from the larger Phase III trial into the label. That study involved around 2,000 patients to get the label extension.

Allergan also announced Jan. 30 an sNDA approval for Avycaz to update the labeling with clinical data from two Phase III trials for urinary tract infections. The two trials involved a combined 1,325 patients. Nicholson said the company is looking to expand the indication for the drug to pneumonia, where Phase III data would be required.

"The expedited pathway did limit the use of Avycaz," Nicholson said. "It is going to be reserved for use in patients who have limited or no alternative treatment options. So that was stipulated in the label, the original label that we got."

While the specifics are currently unclear of how FDA intends to use such a pathway, the case of Avycaz could be the textbook example.

The law provides FDA with the flexibility to approve antimicrobial drugs based on a limited population if the drug treats a life-threatening infection. In a similar fashion, Avycaz was approved following its designation as a Qualified Infectious Disease Product (QIDP), which is given to antibacterials designed for the treatment of serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) Act.

Will FDA Use The Pathway in Practice?

Experts remain confident that FDA will use the limited population pathway for antimicrobials in practice, pointing to the various safeguards the law puts in place. For instance, the labeling and advertising of the drug will have to include the phrase "Limited Population."

"So [the law] makes it very clear physicaly that this is a drug that has been studied and approved in a different way than your typical drug approval process," Jungman says. "FDA would also have the opportunity to review promotional materials for the drug to ensure they are appropriately characterizing the population for which the drug is intended. Those are the types of things that we expect to give the agency confidence that if they approve the drug for use in this limited population, that it will be used primarily in the population for which it is intended."

Jezek noted that Center for Drug Evaluation and Research Director Janet Woodcock has spoken many times about the urgent need for new antibiotics.

"I think that they will look to utilize any tool that they can in order to address that tremendous need," Jezek said.

Jezek added that with the safeguards in place, "FDA might be more willing to kind of have a different approach and kind of assessing benefit and risk, you know, recognizing that the drug wouldn’t be approved for the broad population. And so there might not be as much of a need for those larger trials."

Additionally, the legislation does not lower FDA's risk/benefit standards of drug approval.

There could be concerns, however, about just how flexible FDA will be in assessing the safety of antimicrobials. It begs the question whether a flexible agency will result in hesitant physicians. (Also see "Rx For Industry: Key Provisions Of The 21^st Century Cures Act" - Scrip, 9 Dec, 2016.)

At a November FDA advisory committee meeting, Cempra Inc.'s community acquired bacterial pneumonia (CABP) antibiotic Solithera (solithromycin) barely passed panel's vote by a 7-6 margin. Although virtually all of the panelists had concerns with the drug's hepatotoxicity risks, many were concerned about improving the toolbox to combat resistant bacteria. (Also see "Cempra’s Antibiotic Likely Needs Bigger Trial – But Might Be Able To Do It In Phase IV" - Pink Sheet, 4 Nov, 2016.)

Despite the vote of confidence from the advisory committee, however, FDA ultimately issued a complete response letter for Solithera, with concerns that Cempra had not adequately characterized the macrolide antibiotic's safety profile. (Also see "Cempra's Solithera Draws FDA Complete Response Letter On Liver Risks" - Pink Sheet, 29 Dec, 2016.)

No Set Threshold Of Patients

A Pink Sheet review of the clinical trials of all FDA-approved antimicrobials from 2014 to 2016 shows that most such products are approved based on clinical trials with between 500 and 2,000 patients taking the investigational drug.

Although that number may seem like a generally acceptable standard to establish a safety and efficacy profile of an antimicrobial, Jungman said that she does not believe FDA will use a "hard number threshold" with the provision to determine what specifically would constitute a limited population, in contrast to the Orphan Drug Act provisions.

"It is really about there being a distinct population," Jungman said. "So for example, the population of, rather than studying the drug in all patients in pneumonia, you might study the drug only in those patients with a resistant form of pneumonia. The way we anticipate this being used is really to get at the resistant form of infections."

Other Futuristic Aspects Of Development

Jezek noted that the removal of the regulatory barrier is only one piece of the pie that needs to be addressed in terms of future antimicrobial development. Economic incentives, she said, remain a concern for drugmakers.

Jezek says that "we know the economics of antibiotic R&D are so challenging. There is little to no return on investment, and there are still really high development costs. So we are going to be working on that in the coming year or years."

Economic "pull" incentives were discussed at a November forum held by the Duke University Margolis Center for Health Policy. Under one proposed incentive – a concept known as wildcard exclusivity – a company that receives FDA approval for a new antibiotic would obtain a voucher to extend the exclusivity period of another drug, likely a drug that would have more profitability than the antibiotic. A company would have the option to sell that voucher to another company, which is particularly appealing for a small company that doesn't have another drug. (Also see "Antibiotic Development: ‘Wildcard Exclusivity’ Proposal Returns" - Pink Sheet, 16 Nov, 2016.)