FDA's decision to develop guidance for development of follow-on versions of biologics approved under the Food, Drug & Cosmetic Act indicates the agency has accepted section 505(b)(2) of the FD&C Act as a viable pathway for approval of such products.

"We are in the process of writing overall guidance on the process of and scientific approach to follow-on proteins under 505(b)(2)," FDA Chief Medical Officer Janet Woodcock testified March 26 at the House Oversight and Government Reform Committee hearing on generic biologics.

The agency's decision to embrace the 505(b)(2) pathway appears to be somewhat of a change of position. Following approval of Sandoz's human growth hormone follow-on Omnitrope (somatropin [rDNA origin]) via 505(b)(2), FDA emphasized that the approval was not establishing a pathway (¹ Also see "FDA Clears Omnitrope; Product Is Not The Process, But Nor Is It A Pathway" - Pink Sheet, 5 June, 2006., p. 3). FDA has previously approved other follow-ons under 505(b)(2), including hyaluronidase products and calcitonin.

FDA's plans to develop guidance on 505(b)(2) also represent the latest in a series of shifts in FDA's strategy for developing an approval process for follow-on biologics.

At different times, the agency has said it would issue a historical white paper, general guidance on follow-on biologic approval standards, and guidances addressing specific products such as HGH and insulin (² Also see "FDA Sees Critical Path Opportunity To Address Follow-On Biologics" - Pink Sheet, 10 April, 2006., p. 13).

In written testimony for the hearing, Woodcock acknowledged FDA's change in direction regarding the 505(b)(2) pathway. "As our knowledge of this issue expanded, we reconsidered our focus and determined it would be more appropriate to initially promulgate guidance that is more broadly applicable to follow-on protein products in general," she said.

FDA plans to follow up its general 505(b)(2) guidance document with guidances on technical issues such as the immunogenicity of proteins and physical characterization methods, Woodcock said.

While an established pathway for approval under 505(b)(2) would affect relatively few products - only compounds referencing biologics approved under the FD&C Act such as HGH and insulin - any approval standards laid out in the guidance could have important implications for the development of a broader regime for approval of generic biologics.

The prospects for generic biologics legislation have received a major boost from the change in control of Congress. House Government Reform Committee Chairman Henry Waxman, D-Calif., has introduced legislation that would grant FDA broad authority to establish criteria for approval of follow-on versions of biologics approved under the Public Health Service Act (³ Also see "Generic Biologics Bill’s Key Battleground May Be Senate Health Committee" - Pink Sheet, 19 February, 2007., p. 3).

During the hearing, Waxman asked Woodcock if FDA would be ready to review applications immediately if the bill were to become law and not require additional guidance or regulation from the agency.

"FDA currently ... reviews applications and also inquiries from companies and so forth providing guidance under the 505(b)(2) regimen, so we have the technical expertise to perform" the task, she responded.

Woodcock indicated that FDA would favor a relatively flexible framework for approving generic biologics, leaving most decisions regarding approval requirements up to the agency.

"From my point of view, flexibility in enabling us to incorporate new science into the regulatory process and as science evolves and becomes available - it is in the best interest of the public as well as the agency and industry," Woodcock said.

Rep. Paul Hodes, D-N.H., suggested that legislation limiting FDA's flexibility in establishing approval standards, such as language requiring all follow-on sponsors to conduct clinical trials, could have adverse consequences. "If a follow-on statute required a clinical trial in every case, could it end up requiring perhaps unnecessary and therefore potentially unethical trials in the future?" he asked.

"When trials aren't needed, it is a question of ethics," Woodcock responded. "The use of human subjects for trials that are not needed, [to] simply check a box for a regulatory requirement, is not desirable."

Waxman inquired whether the agency will be able to better assess if clinical tests will be required to demonstrate comparability as science evolves.

"The ability to physically characterize a protein molecule and other complex substances has evolved and continuously evolves and so, over time, we're going to be able to do a better and better job of controlling the quality of these products and allowing continuous improvement" to the process, Woodcock responded.

The FDAer's testimony noted that the agency's ability to predict the clinical comparability of two complex protein products is hindered by the lack of advanced technology. Stakeholders have suggested that FDA's guidance on establishing comparability for biologics undergoing manufacturing changes could serve as a basis for the agency's comparability standards for generic biologics (see ⁴ Also see "FDA Biologic Manufacturing Comparability Policy May Apply To Follow-Ons" - Pink Sheet, 2 April, 2007.).

Aside from current technologies that allow FDA to assess the amino acid sequence of a recombinant protein, "conclusive analysis of other aspects of a protein's structure requires much more sophisticated technologies and is fraught with uncertainties that are proportional to the size and complexity of the protein itself," Woodcock's testimony said.

Committee Ranking Member Tom Davis, R-Va., asked when such technology would become available.

"It's going to be a continuum," Woodcock replied. "Right now with very short peptides, which are as small as ranitidine [GSK's Zantac and generics] ... or anything ballpark, we can do right now, but those are very small compared to the erythropoietin molecule, so it's going to be a stepwise progression over a decade or so."

Woodcock noted that in the absence of additional tools it is unlikely manufacturers will be able to demonstrate interchangeability.

"Because of the variability and complexity of protein molecules, current limitations of analytical methods, [and] the difficulties in manufacturing a consistent product, it is unlikely that, for most proteins, a manufacturer of a follow-on product could demonstrate that its product is identical to an already approved product," she said.

However, Woodcock acknowledged it may be possible to establish interchangeability via clinical trials.

"The situation in health care right now is that products that are interchangeable, they need to be repeatedly switched back and forth, and we're in a situation where we have a number of similar products on the market with the same indication, and they're very similar. It might be that they could be switched back and forth amongst one another multiple times ... depending on the plan and who they contract with and so on."

However, "in some cases, there may be ethical issues that would have to be addressed very carefully" with such a trial, she said. "We would not want to set the patient up for harm."

Woodcock said another issue the agency would have to become more comfortable with before interchangeability could be established is assessing immunogenicity.

"The innovator product could cause antibodies to the follow-on product or vice versa, and we think we have to ... make sure that we think it would be feasible to do those tests," she said.

Rep. Darrell Issa, R-Calif., asked if clinical trial data is currently necessary to establish the relative immunogenicities of an innovator product and a follow-on.

"We have very limited understanding of immune response and we are not able to predict immuno-genicity from non-clinical data," Woodcock responded.

However, during a separate panel, Tekgenics President Bill Schwieterman, a former FDA reviewer, asserted that clinical trials would not always be necessary to test immunogenicity.

"It would depend upon the nature of the case. It would depend upon the data that were there, and I think there are ways and methods to be sure beyond clinical trials to determine immunogencity. In fact, clinical trials have limitations in this regard," he said.

Independent consultant Theresa Gerrard, a former FDA reviewer and a director at Amgen, agreed. "FDA can assess the risk for immunogenicity when it reviews the products for purity, safety and overall quality and can request additional clinical data when necessary," her written testimony states. "While immunogenicity is an important consideration for biogenerics, it is certainly not a hurdle in their development."

- Kathryn Phelps

505(b)(2) Resurrection, FDA Guidance To Bless Follow-On Biologics Pathway

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