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

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 The FDA,  in its draft guidance of July 2, 1998, “Basis for 505(b)(2) NDA Approval of hGH and Insulin Drugs”, clearly indicated that the data hurdle for substitutability would be quite high.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). 

Conducting Clinical Studies—Ignoring the Basics Is Perilous

Terrence Chew, M.D.

Biomedical companies, especially start-ups new to or unfamiliar with the FDA environment, that are developing a new drug/device combination or a nutritional product may enter a clinical trial unaware of regulatory requirements or may feel their company is too small to be subject to the usual requirements. This is not true—FDA maintains a single set of standards to which all companies, regardless of size, must adhere.

In order to ensure clinical trial compliance, the FDA has an ongoing bioresearch-monitoring program that includes inspections designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects have been protected. FDA periodically publishes findings of inspections, which is a great resource to assess potential investigative sites or pharmaceutical partners.

A recent inspection of a small pharmaceutical company revealed that the company had failed to submit an IND for the conduct of a clinical investigation with an investigational new drug. In addition, it failed to obtain necessary documentation to ensure compliance with the clinical protocol and subject protection such as a Statement of investigator that includes a commitment from the investigator to comply with the protocol, personally oversee the investigation, meet informed consent requirements, ensure that IRB review and approval requirements are addressed, and disclose financial information. 

In addition, the sponsor did not maintain adequate records regarding investigational drug disposition and did not monitor the progress of the trial with a qualified monitor. All of the above are required by law and relevant FDA guidelines. Companies often feel that they are exempt from these regulations as they are not developing a new drug or they are just conducting pilot studies to make decisions. 

Common clinical investigator compliance issues include failure of the investigators to conduct the study in compliance with the protocol and signed investigator plans. In addition, investigators may incorrectly feel that they can modify the protocol for specific patients, which is different from the protocol’s standard of care. FDA inspectors compare the protocol inclusion and exclusion criteria versus the patient records to look for such violations.

Although, investigators may ask the sponsor for an exemption—these must be considered carefully to determine their impact on the study results and statistics.  FDA may examine the quality of the informed consent for adequacy in terms of explaining risk, and to ensure that informed consent was obtained prior to the patient being treated on the protocol. FDA may also audit IRB adherence to its own rules and regulations. 

Companies that sponsor clinical trials are responsible for the compliance of their investigators. Since many trials are being performed outside the U.S., companies must ensure that investigators are properly trained equivalent to U.S. medical standards of practices and monitored to maintain compliance.

Although costs may be less in certain ex-U.S. regions, this must be balanced by the increased cost of properly monitoring distant sites. There are many valid reasons to conduct trials outside of the U.S., but sponsor companies must be sure that the lower cost is not due to lower quality, especially since EMEA and FDA have increased the inspection of non-U.S. pivotal studies.

Terrence Chew, M.D. (
[email protected]), is a clinical development expert with over 25 years experience in FDA regulatory and clinical studies issues.

FDA’s RLD Choice Policy and Change Prohibition: A New Tool in the Lifecycle Management Toolbox

Kurt R. Karst

On November 25, 2008, the FDA granted a citizen petition submitted by Osmotica Pharmaceutical requesting that FDA determine that any company with a pending ANDA for a proposed venlafaxine HCl extended-release tablet drug product be required to submit a new ANDA to FDA citing Osmotica’s approved venlafaxine HCl extended-release tablets drug product as the reference listed drug (RLD). The company also asked that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to Osmotica’s approved drug product. 

FDA’s petition decision: (1) affirms the agency’s longstanding RLD Change Policy, which requires a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the agency approves an application for the drug product covered by the suitability petition; (2) affirms FDA’s RLD Choice Policy, under which a generic applicant must choose the most pharmaceutically equivalent listed drug as the RLD; and (3) implements FDC Act §505(j)(2)(D)(i), which was added to the statute in 2003 by the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) and precludes an applicant with a pending ANDA from amending that application to change RLD.

Osmotica’s citizen petition concerned FDA’s May 2008 approval of the company’s 505(b)(2) application for venlafaxine HCl extended-release tablets and FDA’s March 2005 decision to approve a suitability petition submitted pursuant to FDC Act §505(j)(2)(C) for a dosage form change from Venlafaxine HCl extended-release cpsules (i.e., Wyeth’s Effexor XR) to Venlafaxine HCl Extended-Release Tablets.

A generic company, Sun Pharmaceutical, had submitted an ANDA to FDA pursuant to FDA’s suitability petition decision seeking approval of Venlafaxine HCl extended-release tablets—pharmaceutically the same drug product FDA approved under Osmotica’s NDA.

Under FDA’s RLD Choice Policy, a generic applicant should refer to the approved pharmaceutical equivalent designated by FDA as the RLD as its basis for ANDA submission. As FDA explained in its RLD Choice Petition Response:

“if a tablet and a capsule are approved for the same moiety with patents listed for the tablet and none listed for the capsule, an ANDA applicant seeking approval for a tablet should cite the approved tablet as the [RLD].  It should not circumvent the patents on the tablet by citing the capsule as the [RLD] and filing a suitability petition under [FDC Act § 505(j)(2)(C)] and 21 CFR 314.93 seeking to change to a tablet dosage form.

Under FDA’s longstanding RLD Change Policy, the agency has required a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the agency approved an application for the drug product covered by the suitability petition. For example, after FDA approved NDAs for carboplatin injection drug products that were also the subject of pending ANDAs submitted pursuant to an approved suitability petition, the agency required generic applicants to change RLD.

FDA has also required generic applicants to take the same action in an Rx-to-OTC switch scenario, where the agency approved a new NDA for an OTC drug product, thus creating a new RLD listed in the Orange Book that generic applicants must cite.

FDA’s RLD Change Policy became particularly important with the enactment of the MMA in 2003. The MMA amended the FDC Act to add §505(j)(2)(D)(i), which states: “[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA].”

A similar provision was added to FDC Act §505(b)(4)(A) with respect to 505(b)(2) applications. That provision states: “[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA].” Thus, given FDA’s RLD Change and Choice Policies, a generic applicant must cite the most appropriate RLD, and must change RLD (for a pending application) when a pharmaceutically equivalent listed drug is approved. 

The MMA, however, precludes an ANDA applicant (and a 505(b)(2) applicant) with a pending application from changing RLD. Instead, Osmotica argued in its citizen petition that a new application must be submitted citing the appropriate RLD, and such application must contain the required bioequivalence data comparing the proposed generic drug to the new RLD (in this case, Osmotica’s approved venlafaxine HCl extended-release tablets drug product).

FDA concluded in its November 2008 petition response that:     

“our requirement that an applicant with a pending ANDA subject to an approved suitability petition change the RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition reflects the Agency’s judgment that considerations regarding an ANDA’s limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder

“this approach reduces the potentially confusing proliferation of pharmaceutically equivalent drug products that have not demonstrated therapeutic equivalence, and ensures that ANDAs for venlafaxine HCl extended-release tablets will be therapeutically equivalent and thus substitutable for the RLD, Osmotica’s venlafaxine HCl extended-release tablets”

“FDA’s policy of requiring all pending ANDA applicants to change their basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition is intended to ensure that ANDA applicants do not circumvent the patent certification requirements of section 505(j)(2)(A)(vii)-(viii) of the Act through the suitability petition process. In addition, our policy would appropriately protect any marketing exclusivity that has been granted to the newly approved RLD.”

In the case of Sun’s pending ANDA for venlafaxine HCl extended-release tablets, FDA determined that:

“an ANDA for venlafaxine HCl extended-release tablets submitted based upon an approved suitability petition that was pending at the time of approval of Osmotica’s NDA 22-104 and that seeks approval for a pharmaceutically equivalent drug product must be withdrawn, as the ANDA is required to reference the corresponding approved strengths of Osmotica’s venlafaxine HCl extended-release tablets as its RLD, and section 505(j)(2)(D)(i) of the Act precludes such a change from being submitted as an amendment to an ANDA. If Sun or any other applicant wishes to pursue approval of an ANDA for venlafaxine HCl extended-release tablets, it must submit a new ANDA containing data and information required by section 505(j) of the Act for approval (including, but not limited to, a demonstration of bioequivalence to the RLD, Osmotica’s venlafaxine HCl extended-release tablets).”

FDA’s citizen petition response also applies to 505(b)(2) applications pursuant to FDC Act §505(b)(4)(A). FDA stated that:

“We note that our interpretation of § 505(b)(4)(A) of the Act, also added by the MMA, for 505(b)(2) applications is influenced by and intended to be consistent with section 505(j)(2)(D)(i) regarding ANDAs. Accordingly, a 505(b)(2) applicant may not amend or supplement a 505(b)(2) application to seek approval of a drug that relies on the Agency’s finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.”

Thus, if at any time before approval of an ANDA (subject to an approved suitability petition) or a 505(b)(2) application, another drug product is approved that is the pharmaceutical equivalent—or that is more pharmaceutically similar to the product in a pending 505(b)(2) application—FDA could, as a result of the agency’s RLD choice policy, require the applicant to cite a new RLD, and, as a result of the statutory prohibition on amending an application to change RLD, FDA could require the applicant to submit a new application containing a certification or statement to any relevant Orange Book-listed patents (as well as required bioequivalence/bioavailability information). 

The importance of FDA’s citizen petition response cannot be overstated. It has significant implications—and creates significant risk—for generic companies that rely on the suitability petition process. For 505(b)(2) applicants, it also creates a risk of application resubmission and underscores the importance of carefully choosing the appropriate listed drug(s) and creates a new lifecycle management tool for innovator companies. 

Kurt R. Karst ([email protected]) is an associate at Hyman, Phelps & McNamara. Web: www.hpm.com

Bruce F. Mackler, Ph.D., J.D., a senior advisor in FDA matters, is lead contributor to GEN’s “Spotlight on the FDA” column. Web: www.brucemackler.net.

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