Special To BioWorld Today

Editor's Note: This is part one of a two-part series on follow-on biologics and their pathway to regulatory approval. Part two will run in Monday's issue.

The design and production of protein-based biotechnology-derived compounds - in other words, biologics - is entering a new era. In the U.S., there are about 500 biologic products in various stages of clinical development, and the demand for biologics is expected to exceed $56 billion in 2006.

In that lucrative market and with biologics patents that have an estimated total worth of more than $10 billion set to expire at 2006's end, generic manufacturers are eager to jump aboard. The clock is ticking, and the debate over generics has been pushed to the forefront.

For that debate, here's some background.

Biologics generally are large molecular mixtures derived from living organisms, while chemical pharmaceuticals typically are smaller, synthesized molecules. Biologics license applications (BLAs) are used to approve biologics, whereas new drug applications (NDAs) are used for chemical drugs.

BLAs differ from NDAs in many respects. For example, in addition to providing safety and efficacy data, the facilities in which a biologic is processed must meet strict regulatory standards. Consistent with those stricter requirements, the Center for Biologics Evaluation and Research (CBER) has long held that in biologic manufacturing, "the product is inexorably linked to the process." Even companies licensed to manufacture a biologic are subject to a new facility approval if they want to shift the manufacturing site.

Today, manufacturers of generic or follow-on biologics cannot be granted expedited FDA approval, but generic chemical pharmaceutical manufacturers can. The Drug Price Competition and Patent Term Restoration Act of 1984 (commonly known as "Hatch-Waxman") and amendments such as the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, granted companies manufacturing generic chemical pharmaceuticals the option of filing an abbreviated new drug application (ANDA) - a far less complex application than the NDA required for pioneer chemical drug manufacturers.

Under Hatch-Waxman, a generic form of a chemical drug must contain the same active ingredient as an innovator product, be bioequivalent to that innovator drug, and must have the same dosage form, strength, and route of administration, labeling, and conditions of use. By establishing in the ANDA that the generic chemical pharmaceutical drug product is the same as the approved innovator drug, the applicant can rely on the FDA's findings of safety and effectiveness for the brand-name drug. Establishing bioequivalence certainly is less of a burden than what is required for an NDA. In that way, generic manufacturers are spared the lengthy and expensive preclinical and clinical trial processes.

That's what Hatch-Waxman did for chemical drugs when it was enacted in 1984. The problem for biologics is that not many existed at that time and they weren't well understood. In the late 1970s and early 1980s, recombinant proteins and monoclonal antibodies were just being developed. Back then, biologics, such as hormones, were regulated by the Center for Drug Evaluation and Research (CDER) under the FDCA, and biologics, such as cytokines and blood proteins, were regulated by CBER under the PHSA.

In 1993, CDER and CBER agreed to move all recombinant proteins and antibodies to CBER - except insulin and human growth hormone, which remained regulated by CDER. In 2003, recombinant therapeutic proteins regulated by CBER were transferred to CDER, but there was no change in the applicable approval authority: The PHSA still regulates all biologics, excluding insulin and human growth hormone.

But since Hatch-Waxman amended the FDCA and not the PHSA, follow-on biologics are not covered by Hatch-Waxman. Today's arguments over follow-on biologics seem to mirror to a large degree those surrounding Hatch-Waxman and chemical drugs 20 years ago: What is the proper balance between allowing cheaper access to products while still protecting the owner's intellectual property? Also, can follow-on drugs be more affordable while still having the same bioequivalency as brand-name drugs?

Hatch-Waxman Might Not Be Answer

Generic manufacturers of chemical pharmaceuticals have never been privy to the manufacturing processes for pioneer drugs. However, they do obtain a reasonable amount of information. As a result of Hatch-Waxman, chemical pharmaceuticals approved by the FDA (via NDAs or ANDAs) are published in the "Approved Drug Products with Therapeutic Equivalence Evaluations," more commonly known as "The Orange Book." It is available online and lists patent information applicable to each approved NDA, a list of approved ANDAs, and the patents corresponding to them. There is no Orange Book for biologics.

At the center of the generic biologics conflict is the feasibility of determining bioequivalence without requiring extensive clinical testing. How should generic companies prove that complex biogenerics are equivalent to, and as safe as, branded counterparts? Biotech firms and the Biotechnology Industry Organization (BIO) are of the view that generic biologic manufacturers cannot guarantee bioequivalence to pioneer products unless they use the exact proprietary technology employed by brand-name manufacturers. Genentech Inc., Pfizer Inc., Pharmacia Corp., and BIO all have written citizens petitions setting forth their positions.

Generic companies agree that the biologics are more complex than chemical pharmaceuticals, but say technology has progressed so that while some independent testing might be required, generic biologics should not need the same degree of clinical testing as required for brand-name biologics.

Biologics have proved to be efficacious therapies for complicated, debilitating diseases such as diabetes, arthritis, multiple sclerosis and various cancers. Amgen Inc., for instance, produces two of the best-known biologic drugs, Epogen and Neupogen, which are used in patients with renal disease and cancer. The drugs brought Amgen $4 billion last year but soon are to come under heavy generic pressure.

The problem before biotechnology and the drug world is how to protect the type of innovation found in Amgen's products vs. allowing access to drugs at lower prices for the patients who need them. However, it is worth mentioning that allowing generic biologics under an abbreviated approval process might not guarantee better affordability: The economics of a generic biologic do not mirror that of a generic chemical pharmaceutical.

For example, in the case of manufacturers of human growth hormone, interferons or growth factors, each generic manufacturer's price has been similar to that of the innovator's price. Considering the manufacturing costs of biologics and the legal obstacles to generic biologics being legislatively created with a Hatch-Waxman-type "formula," there is no basis to predict whether prices of generic biologics likely are to be lower than their brand-name counterparts. Hence, Hatch-Waxman may be an inappropriate model for fashioning follow-on biologics regulation. n

Eugene Trogan is a technology specialist at Fish & Richardson P.C. in New York. The views expressed here are his own.

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