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Jun 15, 2009 (Vol. 29, No. 12)

Spotlight on the FDA

Biosimilars, Guidelines for Clinical Studies, and New Policies on cGMP Inspections and Reference-Listed Drug Choice

  • The Sameness Definition: FDA has always argued that an enantiomer, contained in a racemic mixture of an approved drug, is the same drug as in the original approved racemic mixture drug. The FDA, in approving a Spectrum Pharmaceutical NDA and granting seven years orphan drug exclusivity to Fusilev, a pharmacologically active enantiomer of leucovorin, held that the enantiomer was not the same drug as the original racemic mixture drug.

    Whether this approval of Fusilev is an exception to the policy stated in the FDA’s policy statement for the “Development of New Sterioisomeric Drugs” or a further definition of sameness, is difficult to ascertain at this time.

    Traditionally, sameness has meant having the identical chemical structure. However, based on this approval, an enantiomer in an existing approved drug is not the same as a new drug composed only of the enantiomer. Consider for a moment the consequence of this FDA decision on sameness regarding the microheterogeneity often seen in approved biologics, in terms of proteins having the same biological activity, but significant N-terminal degradation— an interesting thought when considering development of biosimilar proteins.

    Moving Non-U.S. Biosimilars Into the U.S. Market: A recent “BIO” session on biosimilars raised an interesting question as to whether companies generating biosimilars in India, China, or other countries need to collect adequate safety data to ultimately support bringing their biosimilars into the U.S. For example, will a non-U.S. company marketing a biosimilar product outside the U.S. need to collect sufficient safety data representative of its total sales to demonstrate adequate product safety?

    Chinese and Indian companies developing biosimilars see their local markets as their near-term markets and the U.S. and even Europe as long-term markets. The target price for biosimilars in local markets is typically between $50–100, whereas, such products in the U.S. and Europe may be sold for thousands of dollars/euros. 

    Biogenerics: The Holy Grail for biosimilars is substitutability (an AB rating), which will allow U.S. pharmacies to substitute a generic for the originator product. The FDA,  in its draft guidance of July 2, 1998, “Basis for 505(b)(2) NDA Approval of hGH and Insulin Drugs”, clearly indicated that the data hurdle for substitutability would be quite high.

    In fact, when asked about what amount and type of analytical, preclinical, and clinical data would be needed to demonstrate substitutability, an FDA official responded much like the U.S. Supreme Court when defining pornography—when a biosimilar company provides sufficient data to FDA, it will define substitutability when it sees the data.

    At the “BIO” sessions, presentations showed that non-U.S.-marketed biosimilars now claim substitutability in their local markets, but in the U.S. market they will be nonsubstitutable. Foreign biosimilar companies will thus need to partner with U.S. companies that have marketing capability for selling a nonsubstitutable (BX rating) drug.

  • Manufacturing Facilities’ Inspections

    FDA is now conducting more inspections of medical-device manufacturing facilities as part of its regulatory 510(k) clearance process. Warning letters to several device companies with pending 510(k) applications indicated that failure to have a finished design-history file with design inputs and outputs, verification, and risk analysis (among other things) as required by 21 CFR 820.30 (c)–(h) can be fatal flaws (Warning letter to W.H.P.M., March 19, 2009). 

    This is not an isolated case in that another Warning letter (IDEV Technologies, April 9, 2009) cited lack of adequate design validation and studies to address validation discrepancies.

    Frequently, in the corporate rush to submit a 510(k), the design-history files and cGMP compliance records are dealt with later. Companies can no longer afford to do this without jeopardizing the integrity of their 510(k) applications. The old regulatory rule of thumb, that compliance to cGMPs could be left to later since FDA did not inspect new medical-device companies for one to two years after the 510(k) clearance or establish registration and device listing, is obsolete.

    As a result, the costs for developing and submitting a 510(k) must now include adequate cGMP compliance prior to submission of the 510(k). 


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