Posted: 04 Nov 2015 09:22 PM PST
By Kurt R. Karst –
Earlier this week FDA finally released its Manual of Policies and Procedures (“MAPP”) on NDA Classification Codes (MAPP 5018.2) – formerly called “Chemistry Classification Codes.” The MAPP has been under development for quite some time . . . . and there’s a lot of history behind it. And although the “Background” section of the MAPP warns that “NDA classification codes are not determinative of classification for purposes of exclusivity,” and that they “are not indicative of the extent of innovation or therapeutic value that a particular drug represents,” the MAPP is chock-full of goodies for exclusivity junkies.
As FDA explains in MAPP 5018.2, an NDA Classification Code is assigned by the Agency’s Center for Drug Evaluation and Research (“CDER”) to an NDA based on certain characteristics of the product described in the application, and is a way of categorizing NDAs. “The code evolved from both a management and a regulatory need to identify and group product applications based on certain characteristics, including their relationships to products already approved or marketed in the United States,” explains FDA in the MAPP. “Classifying applications based on these characteristics contributes to the management of CDER’s workload, promotes consistency across review divisions, enables retrospective analysis of trends, and facilitates planning and policy development.”
What is now MAPP 5018.2 started off as an FDA Staff Manual Guide (“SMG”) published on August 31, 1976 (SMG No. BD 4820.3) by the then-Bureau of Drugs. Another version of SMG BD 4820.3 came out on February 19, 1982. Fast-forward some years and SMG BD 4820.3, or the then-equivalent MAPP, seems to have vanished from public view. We would see references here and there in FDA NDA review documents to a draft MAPP – one draft dated April 18, 2003 (see here PDF page 5), and another draft MAPP identified as “new MAPP 7500.3” from around 2007 (see here PDF page 18) – but the MAPP languished in draft form. Then in 2009, FDA produced a draft version of MAPP 7500.3, titled “Drug and Application Classification,” as part of litigation over FDA’s decision to grant a period of 5-year New Chemical Entity (“NCE”) for VYVANSE (lisdexamfetamine dimesylate) Capsules (see our previous posts here and here). But even after that litigation concluded, the MAPP still languished in draft form for many years. . . . until November 2015.
MAPP 5018.2, like draft MAPP 7500.3, lays out the various NDA Classification Codes FDA uses, but the new MAPP has new and refined codes:
What we find most interesting about MAPP 5018.2, however, is FDA’s comments in a “Points to Consider” section of the document. There, FDA provides the Agency’s current thinking on esters and metal-containing substances:
When it comes to metal-containing substances, active moiety determinations are complex (pardon the pun). For example, take a look at FDA’s 2003 Chemical Classification Determination for RADIOGARDASE (insoluble Prussian blue) Capsules (NDA 021626) (see here at PDF pages 36-42). And we’re all still waiting for FDA to update the Orange Book with an exclusivity determination for AURYXIA (ferric citrate) Tablets. FDA approved that drug under NDA 205874 on September 5, 2014, but has been silent as to whether or not 5-year NCE exclusivity will be granted.
Earlier this week FDA finally released its Manual of Policies and Procedures (“MAPP”) on NDA Classification Codes (MAPP 5018.2) – formerly called “Chemistry Classification Codes.” The MAPP has been under development for quite some time . . . . and there’s a lot of history behind it. And although the “Background” section of the MAPP warns that “NDA classification codes are not determinative of classification for purposes of exclusivity,” and that they “are not indicative of the extent of innovation or therapeutic value that a particular drug represents,” the MAPP is chock-full of goodies for exclusivity junkies.
As FDA explains in MAPP 5018.2, an NDA Classification Code is assigned by the Agency’s Center for Drug Evaluation and Research (“CDER”) to an NDA based on certain characteristics of the product described in the application, and is a way of categorizing NDAs. “The code evolved from both a management and a regulatory need to identify and group product applications based on certain characteristics, including their relationships to products already approved or marketed in the United States,” explains FDA in the MAPP. “Classifying applications based on these characteristics contributes to the management of CDER’s workload, promotes consistency across review divisions, enables retrospective analysis of trends, and facilitates planning and policy development.”
What is now MAPP 5018.2 started off as an FDA Staff Manual Guide (“SMG”) published on August 31, 1976 (SMG No. BD 4820.3) by the then-Bureau of Drugs. Another version of SMG BD 4820.3 came out on February 19, 1982. Fast-forward some years and SMG BD 4820.3, or the then-equivalent MAPP, seems to have vanished from public view. We would see references here and there in FDA NDA review documents to a draft MAPP – one draft dated April 18, 2003 (see here PDF page 5), and another draft MAPP identified as “new MAPP 7500.3” from around 2007 (see here PDF page 18) – but the MAPP languished in draft form. Then in 2009, FDA produced a draft version of MAPP 7500.3, titled “Drug and Application Classification,” as part of litigation over FDA’s decision to grant a period of 5-year New Chemical Entity (“NCE”) for VYVANSE (lisdexamfetamine dimesylate) Capsules (see our previous posts here and here). But even after that litigation concluded, the MAPP still languished in draft form for many years. . . . until November 2015.
MAPP 5018.2, like draft MAPP 7500.3, lays out the various NDA Classification Codes FDA uses, but the new MAPP has new and refined codes:
- Type 1 — New Molecular Entity
- Type 2 — New Active Ingredient
- Type 3 — New Dosage Form
- Type 4 — New Combination
- Type 5 — New Formulation or Other Differences (e.g., new indication, new applicant, new manufacturer)
- Type 6 — New Indication or Claim, Same Applicant
- Type 7 — Previously Marketed But Without an Approved NDA
- Type 8 — Rx to OTC
- Type 9 — New Indication or Claim, Drug Not to be Marketed Under Type 9 NDA After Approval
- Type 10 — New Indication or Claim, Drug to be Marketed Under Type 10 NDA After Approval
- Medical Gas — A Designated Medical Gas Certification Request Submitted Under Section 576 of the FD&C Act
The terms New Molecular Entity (NME) and New Chemical Entity (NCE) are sometimes used interchangeably; however, they are distinct. An NCE is defined in 21 CFR 314.108(a) as “a drug that contains no active moiety that has been approved by the FDA in any other application submitted under 505(b) of the Act.” The term NME is not defined in the statute or regulations. An NME is an active ingredient that contains no active moiety that has been previously approved by the Agency in an application submitted under section 505 of the Act or has been previously marketed as a drug in the United States. [(Italics in original)]And an answer to the question: “How far back does FDA look to determine whether or not an active ingredient or active moiety was approved?” “This applies to applications approved or deemed approved from 1938 to the present,” says FDA in the MAPP. That would seem to preclude a grant of 5-year NCE exclusivity for a product like KYBELLA (deoxycholic acid) Injection, which FDA approved under NDA 206333 on April 29, 2015, and for which FDA still has not updated the Orange Book to reflect an exclusivity determination. On September 23, 1940, FDA approved NDA 003044 for a drug product purportedly containing deoxycholic acid as an active ingredient.
What we find most interesting about MAPP 5018.2, however, is FDA’s comments in a “Points to Consider” section of the document. There, FDA provides the Agency’s current thinking on esters and metal-containing substances:
ESTERS
FDA’s regulations at 21 CFR 314.108(a) define the term “active moiety” to mean “the molecule or ion, excludingthose appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” Esters are, thus, the only molecules containing only covalent bonds for which the active moiety is not the entire molecule. Esters are comprised of an alcohol and an acid fragment, and because either or both of the fragments may be “responsible for the physiological or pharmacological action of the drug substance,” either or both may be considered an “active moiety.” Whether the ester is stable in vivo, i.e., not metabolized to its constituent alcohol and acid fragments, is not a consideration in the “active moiety” determination. For example, the Agency determined that for purposes of NCE exclusivity, fluticasone furoate contained a previously approved “active moiety,” fluticasone, despite the fact that there is no evidence of in vivo cleavage of the ester.
METAL-CONTAINING SUBSTANCES
In the case of drugs containing metals, other than salts, the active moiety may be a coordination complex or chelate of the metal (e.g., gadobutrol), rather than the metal ion itself. This is the case when the complex or chelate has at least one metal-ligand bond that can be considered to be a covalent bond.
To determine whether a metal-ligand bond is covalent, the Agency applies a “weight-of-evidence” test for covalency based on a consideration of data based on factors, such as:
Evidence of bond energies, and inter-atomic distances consistent with covalent bonds;
Evidence of existence as independent entity (e.g., elutes in a single chromatographic peak);
A substantially large equilibrium constant for dissociation of the complex in water (e.g., on the order of 10exp20 for gadolinium contrast agents);
Observed geometry predicted by theory; and
A well-defined stoichiometry.
When it comes to metal-containing substances, active moiety determinations are complex (pardon the pun). For example, take a look at FDA’s 2003 Chemical Classification Determination for RADIOGARDASE (insoluble Prussian blue) Capsules (NDA 021626) (see here at PDF pages 36-42). And we’re all still waiting for FDA to update the Orange Book with an exclusivity determination for AURYXIA (ferric citrate) Tablets. FDA approved that drug under NDA 205874 on September 5, 2014, but has been silent as to whether or not 5-year NCE exclusivity will be granted.
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