The phrase “complex drug products that have not been fully characterized” is further defined in the bill to mean a drug for which: (1) the active ingredient has molecular diversity; (2) scientific analytic methodologies are unable to fully identify the molecular structures and physiochemical properties of the active ingredient; and (3) the nature of the active ingredient is not understood sufficiently to identify both the molecular components of the drug that are involved in producing the therapeutic effect, and the mechanisms of action that produce such effect.

At this level of scientific complexity, the old rules don’t apply. The Burgess bill is a timely (in fact, overdue) recognition of this hard truth.

The issues under debate are within Section 7002(e) of the Biologics Price Competition and Innovation Act of 2009. They concern the statutory definition of “biological product.”

The bill sets out two broad questions for the GAO:

1. With respect to non-biological complex drug products (NBCDs) that have not been fully characterized (such as glatiramer acetate, as an example), whether the listing of such drugs as reference products in generic drug applications presents unique challenges in meeting approval standards that are significantly different than the challenges presented by generic drug applications that list small-molecule reference products.

2. With respect to biological products that are within the scope of the exception under section 7002(e)(2) of Public Law 111-148, whether the listing of such biological products as reference products in generic drug applications presents unique challenges in meeting approval standards that are significantly different than the challenges presented by generic drug applications that list small-molecule reference products.

The FDA has more or less said that they’ve got the situation in hand and can get the job done on a case-by-case basis. In a letter to former Rep. John Dingell (D-Mich.), the agency wrote:

“FDA believes that it is possible for manufacturers to develop generic versions of complex large-molecule drugs that can be demonstrated to have the “same” active ingredient as the reference listed drug and meet the requirements for generic approval under section 505(j) of the FD&C Act and FDA regulations … FDA currently believes that it may be possible, with some complex products, for an applicant to demonstrate that its proposed drug product meets the standards for approval as a generic drug under section 505(j).”

And maybe they can. But this is just the kind of regulatory unpredictability that many parties in the healthcare policy ecosystem are pointing to as a major hurdle to advancing 21^st Century Cures. Greater predictability, in theory, will not only serve the public health, but also reassure those companies who want to make costly investments that there are rules to follow – and that those rules lead to outcomes that can be logically explained.

Significantly, the agency notes, “It is important to note that analytical methods, data analysis, and pharmaceutical manufacturing capability continue to evolve.”

Per the Burgess bill, if the GAO determines, after consulting with FDA and “appropriate public and private entities,” that the answer to the issues above is that “significantly different challenges are presented for patients when reference products are NBCDs that have not been fully characterized or when reference products are biological products that are within the scope of the exception under [BPCIA § 7002(e)(2)],” then that determination triggers a series of additional considerations, including:

1. What degree of characterization of the proposed follow-on version and the reference product should be required in order to determine the safety and effectiveness of the generic version?
2. What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product?
3. What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product?
4. What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product?
5. Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product; and
6. Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.

The GAO report addressing each of these issues would be due not later than two years after the enactment of the proposed Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015.

As Kurt Karst of Hyman, Phelps, & McNamara opines:

“With or without the passage of H.R. 1576, we’re likely to see some interesting questions and controversies crop up with the BPCIA’s transition provisions. For instance, what happens if FDA approves an A-rated generic version of a biological product that come March 2020 will be deemed a license under the PHS Act?  Does that A-rating transition into an interchangeable biological product or not given the statutory requirements for interchangeability?  And what about the applicability of pediatric exclusivity to patents currently listed in the Orange Book for biological products that will be deemed licensed under the PHS Act?  Does that exclusivity simply disappear given the BPCIA’s pediatric exclusivity limitation and lack of a patent listing mechanism?  Also, how will FDA treat any ANDAs or 505(b)(2) applications pending review on March 23, 2020?”

This level of complexity, left ad infinitum to “the discretion of the agency,” will be a boon for lawyers, a deterrent to the developers of lower-cost follow-on products, and result in higher costs for payers and patients. A dangerous triple play and, for Dr. Burgess, co-author of the BPCI Act, contrary to the spirit of the legislation.

Peter J. Pitts is  President of the Center for Medicine in the Public Interest and a former FDA Associate Commissioner.