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FDA Official Says IND Hurdles for Oligos Similar to Other Drugs, Calls for Greater Awareness of Tech

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By Doug Macron

Though distinct from small molecules and biologics, oligonucleotide drugs face essentially the same regulatory hurdles as those other therapeutic modalities, revealing a more defined path toward the clinic than may be apparent on first pass, an official from the US Food and Drug Administration said this week.

Meanwhile, the FDA is working to better understand issues that may be specific to oligo medicines, which could not only improve the investigational new drug application-review process for these molecules, but also potentially lead to new guidance that addresses them, said Paul Brown, associate director for pharmacology and toxicology at the FDA's Center for Drug Evaluation and Research.

Speaking at the Drug Information Association/FDA Oligonucleotide-Based Therapeutics 2012 conference in Washington, DC, this week, Brown noted that while there has been a steady increase in the number of INDs for oligo drugs in recent years, these represent a small fraction of the overall number of such applications that the FDA receives.

In fact, because oligonucleotides “are a very small part of the overall CDER workload,” it is possible that an IND for this kind of drug candidate may go before an FDA reviewer who has never handled one before, according to Brown.

“Hopefully, that won't happen in most cases because divisions that have received them in the past are aware of which reviewers are familiar with them … and try to funnel them toward” those individuals, he added. Nevertheless, the possibility exists.

Yet those developing oligo therapeutics should bear in mind that their molecules aren't so different from traditional small molecules and biologics, at least from a regulatory standpoint.

To illustrate his point, Brown cited a review the agency conducted of recent INDs for oligo drugs, noting that while the majority of the applications were cleared, those that weren't usually failed due to the same safety, manufacturing, and clinical design issues that can plague other compounds.

Specific deficiencies in oligonucleotide INDs identified in the review included inappropriate margins between a toxic non-clinical dose and the proposed human dose; inadequate monitoring protocols for human studies; lower purity of a clinical drug batch versus the non-clinical batch; clinical protocols not being sufficiently designed to meet the study's objectives; and a clinical dosing schedule being too aggressive.

“None of these potential hold issues are unique to oligos,” Brown said. “These are the exact same things we see with all INDs, regardless of whether it is small molecule or large molecule.

“What that tells you is [that] a reviewer looks at these things pretty much the same way they look at anything,” he added. “They ask the same questions and want to see them addressed in the same way.”

This isn't to say that oligo drugs don't have their own issues of which developers and regulators alike must be aware. And the FDA is working to do so, he said, offering the possibility that guidance explicitly for oligo medicines may someday be released.

Brown conceded that, although oligonucleotides are specifically named in some of the guidances issued by the FDA, such mentions are only in passing and offer little in the way of useful direction. But this is more a reflection of the small number of oligonucleotide drugs that come before the agency, rather than disinterest, he said.

The FDA “prioritizes things, and there are always more things that people want to have guidances on” than can be reasonably provided, he said.

To prevent “that kind of marginalization … those of us interested in oligonucleotides, inside the FDA and outside ... have to think about the right strategy when thinking about policy and guidance,” he said.

That strategy should include being “alert to the possibilities to include oligos in discussions” and not “unnecessarily exclude oligos” from existing guidance.

“It is those sorts of practices, once they become an established routine, that could lead to [new] guidance,” Brown added.

At the same time, it could help streamline the regulatory process for oligonucleotide INDs.

“If we can get enough data to feel confident in setting up specifications, maybe we'll have something that we can use as a common practice,” he said. “If we can identify common practices that we have in different areas, maybe we can turn that into guidance."

He cautioned that the FDA won't necessarily release guidance solely for oligos, but indicated that this isn't an impossibility.

“We'll see if we can incorporate [an improved awareness of oligos] into what we have, and if there are outstanding issues that need independent guidance, I don't think it's out of the question,” Brown said.

Getting to that point, however, will benefit from the cooperation of industry, he said.

The FDA is unable to use data from one IND to support another without the approval of those who filed the applications, and protecting trade secrets always remains an issue, Brown noted. But drug developers should look to see “if there are ways … [to] share data” with the agency.

“The more you can share, the more it helps us,” he said.


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