Debate regarding follow-on biologics and how the FDA will regulate them continues to rage in the halls of Washington and in the boardrooms of biologics manufacturers. But what are the legal issues surrounding follow-on biologics, and what is the likely result of FDA deliberation on the issue?
Because of the differences between regular drugs and biologics, it is impossible to guarantee that biologics from different manufacturers are identical. For this reason, the provisions of the Hatch-Waxman Act permitting an abbreviated approval process for generic drugs that can be shown to be the same as brand-name pioneers cannot currently be applied to biologic products. Brand-name biologics are thereby largely protected from the generic competition common to ordinary prescription drugs.
Because these follow-ons are not identical to the original biologic products, the FDA currently approves and licenses these products only after submission of a complete new drug application (NDA) or a biologic license application (BLA).
Proponents of the application of the abbreviated generic drug approval process to biologic products assert, however, that since these products resemble each other in much the same way that brand and generic drugs do, it is possible that these drugs could be approved without the full complement of safety and efficacy trials required for the submission of a full NDA or BLA.
To do so, however, would require a change in the way sameness or bioequivalence is currently determined under the generic approval provisions of the Hatch-Waxman Act. Such a shift would have serious repercussions on the delicate legal balance struck between the interests of innovators and the makers of generic drugs by the current policy. Thus, the FDA is attempting to play it as safely as is possible by taking a wait-and-see approach to the whole affair.
The Generic Pharmaceutical Association (GPhA) has, expectedly, made the availability of generic biologics a top priority, while the Biotechnology Industry Organization (BIO) has committed to trying to avoid their appearance. In 2003, BIO filed a citizen petition urging the FDA to act to prevent generic competition for biologics.
BIO asserted that the current state of scientific knowledge does not permit the adequate characterization of biologics, therefore clinical trials are necessary to determine safety and efficacy since even minor differences in composition can be clinically significant. The FDA denied the petition, asserting its authority to approve generic biologics. At other times, the FDA has stated that legislation is required to provide an NDA process for those products regulated solely as biologics.
Speaking before the GPhA in February of last year, acting FDA Commissioner Lester Crawford announced the agencys intention to provide the industry with guidance and specification for follow-on biologics including: a policy-guidance document outlining the FDAs current position, a background document describing the FDAs previous policies and actions on the issue fairly soon, and draft guidance, including immunogeneticity and chemistry, several months later.
The FDA has dragged its feet on the issue, however, and after changing its position throughout the last year has recently refused to comment on whether or not they are able to allow follow-on biologics through the 505(b)(2) loophole.
The Sandoz Case
A lawsuit by Sandoz Pharmaceuticals filed in September regarding the human growth hormone Omnitrope could complicate matters, as Sandoz alleges that the FDA has taken too long in either approving the drug or providing reasons for its disapproval. The NDA on Omnitrope was filed over two years ago and is still pending resolution.
The defendants actions could result in the effective institution of an uncodified policy that the existing 505(b)(2) pathway cannot be used prospectively for protein-based technologies under Section 505, said Sandoz.
In October, Scott Gottlieb, the deputy commissioner for medical and scientific affairs, announced that the FDA did not have the authority to approve follow-on biologics under the Public Health Services Act, stating that there are still too many legal, scientific, and regulatory questions that need to be addressed before they are prepared to make more decisions on the issue. The science will continue to be developed, and well continue to work through some of the policy questions, some of the legal questions, and regulatory questions that exist around exactly what the authority is there and what the appropriate framework and policy environment is to enable that, said Gottlieb.
The EU has moved forward with its own abbreviated approval process for generic versions of certain biologic products. In 2005, the European Medicines Agency released draft guidance documents containing requirements for the approval of biosimilar versions of four biologic products. Since then, at least one company has obtained European approval for the marketing of a generic biologic product under this abbreviated approval program.
What does this mean for the future of follow-on biologics in the U.S.? It is still too early to tell. Certainly, it is important to make sure that any testing procedure takes into account full clinical trials and provides for both efficacy and safety, but there is no need to institutionalize a redundant method and waste money and time for both government agencies and drug companies. For now, at least, the FDA appears to be silent on the issue, and may continue waiting for years to come before reaching a ruling on where the authority lies for approving these revolutionary new treatments and therapies.