Emerging Sponsors And FDA: Will Better Communication Under PDUFA V Ease Inherent Tensions?

New communication mechanisms built into the Prescription Drug User Fee Act V agreement are unlikely to be the panacea for the regulatory, economic and public relations challenges created when a small company attempts to bring its first drug to market.

FDA and industry are hopeful that new communication mechanisms built into the Prescription Drug User Fee Act V agreement will aid small, emerging companies’ ability to bring drugs to market. Yet, it seems these new interactions may go only so far in easing the various regulatory, economic and public relations tensions between agency staff and sponsors.

Discussion by FDA, biotech and venture capital representatives at Elsevier Business Intelligence’s FDA/CMS Summit on Dec. 8-9 highlighted a number of areas of strain between the agency and small sponsors, some of which are not likely to dissolve in a sea of increased communication envisioned under PDUFA V.

The PDUFA V agreement is due to be finalized and transmitted to Congress this month for inclusion in an omnibus user fee reauthorization bill later this year. The agreement includes establishment of new FDA liaison staff focused on getting sponsors’ questions answered quickly. It also gives sponsors new opportunities for meetings with the agency, including one late in the application review process.

It is hard to envision how improved communication will ease fundamental tensions underlying the relationship between a small company strapped for capital and a regulator seeking more evidence.

Nevertheless, it is hard to envision how increased sponsor/agency interactions will ease the fundamental tension present when a small company struggling to preserve capital and get to market with its first product runs up against FDA’s requirement for substantial evidence of efficacy and safety.

While improved communications may help keep sponsors from getting hit with what they consider to be a surprise “complete response” letter, it will not solve the underlying funding pressures they face when a key pipeline product hits a regulatory delay.

It also remains to be seen whether and how sponsors will publicly disclose details about their increased interactions with agency review staff under PDUFA V.

Growing Role Of Emerging Sponsors

Issues stemming from the growing role of emerging sponsors in drug development were hot topics for discussion during the Summit.

FDA Office of New Drugs Director John Jenkins kicked off the meeting by observing that the growing trend of emerging sponsors taking drugs through the development and approval process on their own, without a big pharma partner, is creating challenges for the agency (Also see "“Emerging Sponsors” Pose Regulatory, Public Relations Challenges For Drug Review Process, FDA’s Jenkins Says" - Pink Sheet, 8 Dec, 2011.).

Emerging sponsors are companies that previously did not hold approved applications to market a drug. As of early December, approximately one-third of the 30 new molecular entities and novel biologicals approved in 2011 were submitted by emerging sponsors, Jenkins said.

However, these small companies often need more hand-holding to navigate the regulatory process. “Inexperienced companies need more advice and meetings with us than the large companies do who have more experience, and we also find that these smaller companies need greater clarity from us in the advice they receive,” Jenkins said.

Emerging companies also seem to be more transparent when it comes to reporting their interactions with FDA to the public, Jenkins observed, terming this phenomenon “drug development by press release.”

However, these public statements “are often overly optimistic in their characterization of the interaction and don’t capture the nuance of what we actually talked about or the advice we actually gave,” he said, adding that FDA is limited in its ability to monitor and correct such statements.

It’s About Economics, Not Experience

Jenkins’ remarks about the experience level of emerging sponsors brought pushback from representatives of the venture capital and biotech communities.

Ed Mathers, a partner in the venture capital firm NEA, said that VCs look to invest in companies that have experienced teams of people who have successfully taken drugs through the regulatory process. “You might characterize them as inexperienced in terms of never having a drug approved as a company, but I would submit that the teams running these companies now are very experienced at what they do.”

Similarly, NuPathe Inc. CEO Jane Hollingsworth said the implication that regulators need to treat emerging companies differently because of their level of expertise “is a little bit off the mark.”

For emerging companies to secure financing and fund product development, “we have to have people that are really good and very well proven and have been very successful at what they do. I don’t think we’re any different from anybody else. So the level of expertise isn’t the issue.”

Rather, the issue is the different fiscal environments in which small and large companies operate, she said.

Since the 2004 withdrawal of Merck & Co. Inc.’s Vioxx, FDA has been viewed as taking a more conservative approach to drug approvals, Hollingsworth said, adding that this can result in additional regulatory hurdles that small companies can ill afford.

“While FDA has to treat everyone equally, we can’t accept necessarily a more cautious approach, whether it’s rational or irrational, the same way a [large] company may be able to because they have the capital to withstand that,” Hollingsworth said.

No Lowering Of Evidentiary Standards

Jenkins said the agency regularly hears about, and is sympathetic to, the financial constraints that small companies face but is limited in its ability to respond as these sponsors would like.

“The other thing we hear a lot from small companies is, ‘Can’t you change your standards? We can’t afford to do that,’ or ‘We’re going to be out of business if we can’t get an SPA [special protocol assessment] from you.’ That’s one thing we can’t compromise on, is the standard,” Jenkins said.

“When companies tell us, ‘If you don’t agree with us, we’re going to go out of business next week,’ it’s hard for us to respond to that,” OND Director Jenkins said.

“We don’t have a standard for Pfizer that’s different from a standard for a venture capital virtual company that has two employees. The standards have to be the same. We have flexibility. We work with companies to try to make development programs efficient and high quality, but when companies tell us, ‘If you don’t agree with us, we’re going to go out of business next week,’ it’s hard for us to respond to that. We understand. Sometimes we’re just as frustrated as they are that a good idea may not go anywhere. But we can’t change the standards to accommodate that lack of funding.”

Jenkins said he believes financial considerations, such as the costs of conducting additional clinical trials following a “complete response” action, are spurring emerging sponsors to pursue dispute resolution of unfavorable review decisions. “It’s easy and cheap, I guess, to dispute, rather than to actually go off and do the work,” he said.

End-Of-Review “Surprises”

Hollingsworth and Acorda Therapeutics Inc. CEO Ron Cohen attributed some of the regulatory hurdles experienced by emerging sponsors to poor communication both within FDA and with sponsors.

NuPathe was on the receiving end of a “complete response” letter in August for its lead product, Zelrix, a transdermal sumatriptan patch for treating migraines. The company said FDA raised questions primarily about chemistry, manufacturing and safety, but that additional Phase I and/or non-clinical studies may be needed to address other issues (Also see "NuPathe Must Patch Together New Zelrix Launch Timetable After "Complete Response" Letter" - Pink Sheet, 30 Aug, 2011.).

Hollingsworth said FDA’s action came as a surprise because some matters cited in the letter could and should have been raised by agency staff earlier in the development and review process.

Acorda has had similar experiences with the agency, Cohen said, adding, “I think its endemic across the entire industry.” Acorda’s Ampyra (dalfampridine), a drug that improves walking ability in multiple sclerosis patients, received a first-cycle approval in January 2010 following a refuse-to-file action on the original submission (Also see "Acorda Builds Ampyra Promotion On Years Of MS Outreach" - Pink Sheet, 1 Feb, 2010.).

“Time and time again you wind up with issues that delay you by six months, a year or more that certainly could have and should have been brought up much earlier in the process,” Acorda’s Cohen said.

“Time and time again you wind up with issues that delay you by six months, a year or more that certainly could have and should have been brought up much earlier in the process,” Cohen said. “The impression one gets is of terrible inefficiencies within the agency itself so that people raise their hand and bring up issues way later than would make sense or that one should rightfully expect.”

Such issues can be fatal for small companies, Cohen stressed. “Bigger companies roll with it because they have the infrastructure and certainly the cash to do so, but a six-month delay for a start-up company without a product on the market can be fatal and has been fatal.”

Cohen acknowledged that sponsors could do a better job at addressing issues earlier in the process, “but right now there’s really very little room in the system for getting guidance from the people who know best about this” at the agency “at an early stage.”

Both biotech execs said the ability to have informal conversations with agency staff has all but disappeared, particularly now that so many formal meetings are required under PDUFA.

“Our perception is there used to be more informal ongoing communication,” Hollingsworth said. “As that communication became more constrained because there needed to be more formality in the system, it tended to shut down. So you didn’t find out about things until at the end of the day, which is deadly.”

In an effort to address some of these types of communications difficulties, industry secured an agreement under PDUFA V for FDA to add liaison staff focused on dealing with simple and clarifying questions from emerging as well as experienced sponsors (Also see "PDUFA V: Emerging Sponsor Communication Issue Resolved And Expanded" - Pink Sheet, 6 Jun, 2011.).

Discussing the new liaison staff under PDUFA V, Cohen said: “It shows that you can arrive at reasonable approaches that everyone on each side will agree to, but you have to have those conversations and you have to have a system that allows this” to occur.

Center for Drug Evaluation and Research Deputy Director for Regulatory Programs Douglas Throckmorton said he believes the PDUFA V proposal to set up liaison communications teams will give sponsors a mechanism for getting their questions answered, but in a way that does not make agency reviewers feel badgered.

“I see that as a real opportunity for answering a lot of those questions, with enough structure that both parties get what they need out of it,” he said.

Public Disclosure About Late-Cycle Meetings

The PDUFA V agreement also provides for increased communication between FDA and sponsors through a pre-submission meeting, mid-cycle review communication and a late-cycle review meeting (Also see "Pre-NDA Work Takes Added Importance As PDUFA V Stretches Review Cycle" - Pink Sheet, 9 May, 2011.).

Jenkins said it remains to be seen whether these late-cycle meetings will serve as an impetus for further press release activity by sponsors.

In those late-cycle meetings, sponsors will “get the most information they’ve ever received to date on our thinking about the status of their application and what the issues are, and there’s going to be questions about communication of that publicly,” Jenkins said.

“How much Pfizer may say about those meetings versus how much a venture capital-based company may say about those meetings is going to be quite interesting.”