Generic biologicto some, they are fighting words, to others an oxymoron. But no matter what their personal or professional bias, the experts interviewed for this article agreed, the traditional pathway of a generic drug in the United States is not readily amenable to the production of "substitutable" biologics. And, according to the Waxman-Hatch Generic Drug Act of 1984, "substitutable" is the distinguishing criteria that determines a generic drug.
Nevertheless, in 2002 alone, perhaps $l0 billion worth of biologics went off patent, increasingly focusing the attention of manufacturers, consumers, and payers on the possibility/desirability of "generic" biologics. The Biotechnology Industry Organization (BIO) is adamant: There can be no such thing as a generic biologic. To understand the differences between conventional drugs and biologics, see the table on page 23s.
"The key distinction of biologics is they're regulated under the Public Health Service Act," said Gillian R. Woollett, M.A., D.Phil., VP-Science and Regulatory Affairs, BIO. Drugs are regulated under the Food, Drug, and Cosmetic Act. So you get a license for a biologic, and it's based on purity, potency, and identity. Whereas, a drug [license] is based on safety and efficacy."
Purity, potency, and identityin the opinion of BIOare inextricably linked to the manufacturing process. Without an identical manufacturing process, you cannot produce a bioequivalent ("generic") biologic. When the innovator's patent expires, similar products ("follow-ons") can be marketed.
Follow-on biologics may or may not be intended to be molecular copies of the innovator's product. They do depend on the same mechanism of action and, as a result, are intended for the same indication. However, follow-ons are not considered bioequivalent or substitutable. And they are approved or licensed by the Food & Drug Administration upon submission of a full product license application (either New Drug Application or Biologic License Application)there is currently no mechanism for an abbreviated approval.
Comparability for biologics is a bit different from that for conventional drugs. "Bioequivalence in conventional drugs means two products containing the same drug substance but in different formulations or from different manufacturers are bioequivalent," stated Yuan-yuan Chiu, Ph.D., Office of Pharmaceutical Science, Center for Drug Evaluation and Research, FDA. "Bioequivalence in therapeutic biologics is often used to demonstrate pharmaceutical equivalence of two products [i.e., the drug substance, or active ingredients, in the two products are the same]. The two products could be from the same manufacturer, but before and after manufacturing changes."
But Robert Bell, Ph.D., chair of the American Association of Pharmaceutical Scientests (AAPS), noted that pharmaceutical equivalence might not sufficiently determine substitutability. "Pharmaceutical equivalence is very good up to a certain point, up to about 300 amino acids. There's really not that much of a problem, but, again, you get these huge molecules where there are internal bonds and there's inherent heterogenicity." He believes that manufacturers need to demonstrate more than bioequivalence. "I've often recommended pharmacodynamic studies," he said.
However, Bell believes bioequivalent products can be made. "Contract labs wouldn't exist if they couldn't do it"most of our defense vaccines are coming from contract labs, he said. The key is "well-characterized proteins can be characterized well." But, he acknowledged, at present, not all proteins are characterized well.
Complicating the issue of substitutability of biologics is a paucity of standards. Help may be forthcoming from the United States Pharmacopeia (USP), the nongovernment agency that promotes public health by establishing state-ofthe-art standards to ensure the quality of the nation's medicines and healthcare technologies. These standards include the development of public monographs containing analytical standards for many biologic and biotechnology products, including proteins, vaccines, blood products, and cell and gene therapy.
Roger Williams, M.D., CEO of USP, stated, "There's an aspect of the monograph that in my mind is a presumption of equivalence. If you look at a monograph that has a name, if you do all the tests in the monograph, you have confirmed that you have the named article. That means if you had two manufacturers creating something that conformed to the tests in the monograph that they should have the same therapeutic outcome." He acknowledged that much more characterization is needed, "but still it is a start."
The regulatory approval pathway is another hurdle for a generic biologic. FDA chief Mark McClellan has expressed the opinion that legislative action will be required to establish generic biologics. And everyone interviewed agreedthe road to the first generic biologic is likely to be littered with lawsuits.
"Provisions of Waxman-Hatch do not provide for biologics," Bell said. "If you go to the Public Health Service Act, it doesn't prevent the use of a biologic generic, but it doesn't provide a path. Then you go to FDA Modernization Act in 1997 that incorporates a biologic as a drug. If you truly kept to the letter of the law, there's an AB provision for it. So we have a bit of confusion on the regulatory pathway."
Bell noted that even with an abbreviated pathway, biologics are likely to require various sorts of testingabove and beyond that of conventional drugs. "You'll have to do some clinical trials, because most of the drugs are chronically administered," he explained. "It's one thing if you're taking oral, but here you're injecting something chronically. Over years, most people develop antibodies. The point is, over time, will this product, if it's made from a different cell line and has different impurities, cause different immunogenicity in a patient?"
Both Steve Bende, Ph.D., VP of scientific affairs, Generic Pharmaceutical Association, and Bell acknowledged that the FDA already publishes comparability protocols that manufacturers use when they make changes. Bende noted that recombinant human insulin, glucagon, and the new flu vaccine are examples of products that have been approved every year with scaled-back clinical programs.
Another example is Xigris (drotrecogin alfa, activated) by Eli Lilly & Co. "During the pivotal clinical trial in the approval process, they changed the master cell bank they used to make the product," said Bende. "They also changed the trial protocol a bit, and they saw an increase in efficacy." Based on a physical-chemical characterization of the product, and the changes made to the protocol, the FDA was willing to say that the increase in efficacy was not due to a change in the product from changing the master cell bank. "So the point is that the FDA is more than willing to allow physical-chemical data to characterize a molecule" even in the middle of the pivotal clinical trial, he said.
Recently, BIO filed a citizen's petition with the FDA. Woollett stated, "What we've been saying to the FDA is please have a public participatory process that asks, 'What are we even talking about?' Because our worry is that you've basically got presumptive economic incentive, and we're not sure the science is ready."
Still, the FDA is showing signs of moving forward. According to one report, data requirements to approve generic biologics under the Waxman-Hatch Act will be taken up within the next six months. Center for Drug Evaluation & Research director Janet Woodcock, M.D., told analysts on a Smith Barney-sponsored conference call May 16 that the question is "How much data would be required for a follow-on biologic approved through the Waxman-Hatch 505(b)(2) process" in determining AB equivalence? The amount of data required is likely to affect whether companies strive for "substitutability" or branded generic status.
Bell stated, "If you're going to go through all this [to attain substitutability], why not become a brand? If you can do comparability and become a branded generic, that's a huge enough hurdle [in the marketplace] ... you might be competitive in the market rather than as most generics arecoming in and gutting one another."
Whether biologics can be determined to be substitutable is a heated topic. Bell commented that he is presenting two sessions on "biogenerics" at the AAPS biotech meeting in 2004. By then, he joked, the issue may heat up to "where people are bringing eggs and tomatoes."
|Made by||Conventional drug Chemical synthesis||Biologic Living cells or bacteria|
|Characterization||Often lesser molecular weight and structural complexity than a biologic; homogenous molecules||Often large molecular weight, high structural complexity; heteroge molecules|
|Basis for approval||Food, Drug and Cosmetic Act: Safety and efficacy||Public Health Services Act: Purity potency, identity*|
|Assurance of safety||Clinical testing; quality manufacturing||Adherence to process/clinical testing used to make and test each batch; quality manufacturing|
|Assurance of efficacy||Clinical testing||Clinical testing|
|Assurance of identity, purity, quality||Monographs/specifications/testing; quality manufacturing (GMP, GCP, GLP)||Adherence to process/testing; quality manufacturing (GMP GCP, GLP)|
|Generic status||Waxman-Hatch 505(j); AB rating= substitutability; typical generic application has no safety and efficacy data||Unknown; different biologic salts sometimes rated BX to themselves|
Kathy Hitchens. Push for generic biologics gaining momentum. Drug Topics Generic Supplement;147:22s.