A limited use approval pathway is one of the more intriguing components of the “21^st Century Cures” FDA reform provisions. As the legislation moves to the Senate, FDA is joining other stakeholders to outline its vision for how the new authority would work.

Part of the message is explaining why a pathway that limits an approved indication is actually an incentive for drug development.

The answer, Center for Drug Evaluation & Research Director Janet Woodcock suggested during a July 28 Capitol Hill briefing, is clear, if you consider the model of orphan drugs.

LPAD, she suggested, would allow FDA to apply the regulatory flexibility it routinely uses in the context of rare diseases with the assurance that the resulting product would in fact be used sparingly.

“We approve many, many drugs on a streamlined development program all the time,” she said, referring to drugs for rare diseases that are serious or life threatening. “What isn’t common, what’s different, and why this is useful” is the concern for historic overuse with antibiotics. That is less of an issue for drugs for very rare conditions.

So Woodcock stressed, the issue is not whether FDA can meaningfully reduce the pre-market regulatory demands for drugs to treat resistant organisms; the question is whether Congress (and FDA) can create a workable formula to assure that the resulting products will, in practice, be limited to that population after approval.

“That’s why we’re interested in some kind of mechanism that identifies for the clinical community that these drugs are different and targeted toward a limited population,” Woodcock said. “We believe with the rising recognition of antimicrobial resistance and stewardship programs, these can work together really well.”

Ironically, FDA has for years resisted giving orphan drug status to antibiotics for resistant organisms, on the grounds that the underlying infection is not a “rare” disease. Now the agency is hoping to see a regulatory pathway that allows the agency to apply orphan drug style reviews to those same products. Also see "The Popularity of “Special Pop”: Antibiotics Incentives and PDUFA V" - Pink Sheet, 9 April, 2012.

Limited Focus on Limited Use

The July 28 briefing was hosted by The Pew Charitable Trusts, the Infectious Diseases Society of America and the Trust for America’s Health. Pew and IDSA have been the prime moving forces behind special treatment for antibacterial drug development for more than three years.

The briefing was explicitly geared towards raising the visibility of LPAD to Senate offices. The Senate is moving into the next gear on the development of its “parallel” version of “21^st Century Cures.”

LPAD has a good starting position in the Senate. There was a bill introduced In January that would create an LPAD pathway, S. 185, the Promise for Antibiotics and Therapeutics for Health (PATH) Act, sponsored by a strong bipartisan pairing: Senators Orrin Hatch (R-UT) and Michael Bennet (D-CO).

Hatch staffer Matthew Richardson said at the briefing that the Senate Health Committee is currently working on discussion of the “nuts and bolts” of provisions and that antibiotic resistance “is a large part of this.” He said the PATH Act specifically would be a “significant portion of what the Senate does to address antibiotic resistance.”

One subtext of the meeting may be to make sure that the Senate does not drop the LPAD concept even if it decides not to move forward on the second major part of the antibacterial incentive in the House – enhanced Medicare reimbursement for new products (known as DISARM). That provision faces a more challenging landscape in the Senate; there are concerns both about the need for an incentive in that space and about the risk that enhanced payment might encourage overuse of products that should be reserved for only resistant infections. ([A#2014500091])

DISARM had good staying power through the House drafting process – one of the few proposed economic incentives to make it through in the final bill. However, the pool of money to be devoted to increased payments was reduced throughout the drafting process, and an amendment was added to study the effects of the provision on the development of antimicrobial resistance right at the end before passage.

The proponents of DISARM got a timely boost for their cause with the rejection from the Centers for Medicare & Medicaid Services on July 31 of a New Technology Add-on Payment for Astellas Pharma Inc.’s antifungal, Cresemba. That rejection reiterates the need for a special antibiotic program.

In the interim final rule, CMS determined that the Cresemba technology is “substantially similar” to other antifungal drugs used to treat similar conditions currently available to Medicare beneficiaries, and so does not meet the “newness criterion.” CMS also does not believe Cresemba represents a “substantial clinical improvement over existing technologies.” ([A#14150812001])

To encourage support for the LPAD pathway, speakers at the briefing emphasized that it is not a new idea and has been thoroughly debated and discussed in public forums: “well vetted.”

The implied message: don’t let any controversy over reimbursement interfere with enactment of the regulatory reforms. FDA’s endorsement of LPAD should certainly help, by deflecting any criticism the program faces as one step towards lowering the standards for FDA approval.

Key is How to Limit Use

The LPAD proponents at the Hill briefing emphasized that the provision would have a broad public health impact. Tufts’ Helen Boucher speaking on behalf of IDSA said that PATH would address antibiotics for otherwise healthy people who get resistant infections; Woodcock mentioned it would help more than just the “super elderly.” IDSA handouts at the briefing to educate potential cosponsors for the bill focused on the aging population and the military and veterans.

Woodcock said that FDA believes a “clear branding mechanism” would convey to the clinical community that the development program on which the product was approved was for a limited population. The PATH Act as introduced would require the labeling of the drugs “through a logo or other means” to indicate that the drug has been approved for use only in a limited population.

The House bill does not include a logo per se, but does require that “Limited Population” accompany the brand in labeling. The extent and visibility of the special population alert on the new products has been a nuance dividing FDA and sponsors throughout the development of the proposal.

Woodcock also noted that drugs qualifying for LPAD are likely to be “very expensive specialty drugs” and the cost will also act to limit use. That is an argument that may come back to make DISARM harder to sell in the Senate as a companion incentive. Woodcock noted the cost of the products is “not an FDA issue, but a realistic issue.”

Boucher explained how antibiotic stewardship programs will also work to keep LPAD drug use limited. She mentioned the recent Centers for Medicare and Medicaid Services proposal for stewardship programs in long-term care hospitals. A July 16 proposed rule from CMS would update requirements for long-term care facilities and require certain antibiotic stewardship provisions as a Condition of Participation in Medicare and Medicaid. ([A#2015500087])

Boucher said IDSA will continue to advocate for broader stewardship requirements – “acute care hospitals and all health care systems.” Cempra Inc. CEO Prabha Fernandes also mentioned the long-term care proposal and said a similar program for acute care is expected. CMS’ July 31 interim final rule covering acute care hospitals did not include the stewardship proposal from the long-term care rule.

With respect to other ways to ensure use is limited, Fernandes noted that surveillance is a crucial part of PATH. Fernandes also discussed “appropriate pricing.” High price points are “important for both drug developers to develop products as well as for stewardship,” she said. “If priced appropriately, a new antibacterial will not get used away from what it is intended for. Despite high costs, access would not be a problem because the appropriate patients are in the hospital in acute care situations where the hospital will be involved in making the selections.

Expansion of LPAD To Other Classes Beyond Antibiotics

FDA is treating LPAD as a careful extension of its experience with drugs for rare diseases and recent more targeted approvals as part of the precision medicine approach.

However, LPAD also furthers a model that could eventually be used for other drug classes. That is why it is being attacked by critics as a nose-under-the-tent move to lower approval standards and supported by other groups as a way to give FDA more flexibility for some approval decisions.

One example that has been used in the past is obesity. Trust for America’s Health Executive Director Jeff Levi spoke at a 2012 Congressional briefing on the precursor to the current LPAD proposal suggesting such a pathway could be used in chronic conditions like obesity, where FDA doesn’t currently have the authority to say a drug should be used only for the morbidly obese.

In the House-passed bill, FDA can expand the limited use pathway if the agency determines, based on a formal assessment process, that the public health would benefit from the expansion.

The assessment of the program essentially delays the decision on whether other types of drugs should be considered for limited-access approval for about five years.

An assessment from FDA of the antibacterial program would be due four years after the bill is enacted. Then FDA would be required to hold a public meeting within three months. After that, the agency would have a solid foundation to start the process to expand the LPAD approach to other classes.

The idea of applying the limited use pathway outside antibiotics is embraced more fully by the Senate PATH Act proposal – the alternative starting point for consideration of the provision in the Senate.

PATH has a provision that the pathway will be expanded to apply to approval of “other drugs intended to treat a serious or life-threatening illness” beginning on a fixed date (October 1, 2016 in the point of departure version) unless FDA gives Congress a report before then “explaining why such pathway should not be used for other therapeutic areas in addition to antibacterial infections.”

FDA Prepares For LPAD: Orphan Drug Approvals Are Model

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