It’s always an exciting day when FDA issues the new annual edition of the Orange Book!  (At least for me, and I’m sure also for Kurt Karst, over at FDA Law Blog.)  There are a lot of changes in store at the Orange Book in the next year, all of which will get fanfare and attention, but this post is about the little changes in the annual edition (print and PDF) that don’t get called out.  It’s prompted by the fact that FDA deleted a sentence in the preface last year, without telling anyone.  (I had quoted it in an expert report, just a few months earlier and was annoyed to see it deleted.)  I resolved that going forward I would electronically compare every new annual edition to the last year’s edition, and so I spent my Saturday doing exactly this with the new edition — and crashing my computer repeatedly.  The results after the jump.

But first, what sentence did FDA remove?

The preface to the Orange Book is a lengthy essay on the principles and policies reflected in the publication, including FDA’s approach to therapeutic equivalence determinations.  For years it included the sentence, “Therapeutic equivalence determinations are not made for unapproved, off-label uses.”  This principle remains true, but the sentence was dropped in the 37th edition of the Orange Book (reflecting 2017 and published at the beginning of 2018).

Ok, so what changed from 2018 to 2019?

As was true last year, there are a lot of wording changes in the Preface this year.  Section 1, which is the first part of the preface, is 21 pages long, and Adobe marked 180 changes.  (Last year: 193.)  Some of these are ghosts – Adobe misread some things as deletions/insertions, when in fact nothing changed.  But the vast majority are actual changes.

Updates.  Of course, there are simple updating changes, as from 2018 to 2019.

Corrections and insertions to improve accuracy.  There are a number of these.

• For instance, in discussing the background of the publication, the preface has previously stated that the January 1979 proposed Orange Book included only prescription drugs approved by FDA under NDAs and ANDAs under section 505 of the FDCA.  That was amended to say section 505 of the Act “and FDA regulations at the time” — an important correction, because the statute did not authorize ANDAs at the time, though FDA’s regulations did.
• Another example is changing “withdrawn for safety or effectiveness reasons” to “withdrawn from sale for safety or effectiveness reasons.”

Fiddling.  I don’t know what else to call these edits.  Last year, someone with a penchant for visual complexity made changes like code to code(s) and time to date/time. That person also changed “minor” and “rare” to “certain,” a meaningless adjective if ever there was one.  (My former students and former associates would not be surprised to learn that I would jump at an opportunity to rewrite the Preface from scratch.  It is dreadful.)  Anyway, this year there were a number of changes that appear to be nothing more than wording changes.

• For instance, from “regulatory action through administrative or judicial means” to “regulatory action being taken administratively or judicially.”
• Or from “the concept of therapeutic equivalence, as used to develop the Orange Book, applies only to . . . “ to “the concept of therapeutic equivalence applies only to …”

FDA added a reference to § 505(x) of the FDCA. 

The Orange Book lists the date each new drug was approved.  In the Improving Regulatory Transparency for New Medical Therapies Act, Congress added subsection (x) to section 505.  This states that for a drug subject to scheduling under the Controlled Substances Act, FDA approval doesn’t take effect until the interim final rule controlling the drug is issued.  And the phrase “date of approval” for purposes of section 505 means the later of (1) the date the FDA application was approved and (2) the date of issuance of the interim final rule controlling the drug. (What does this all mean?  In simple English, the company can’t market the drug until DEA finishes scheduling the drug.  This change to the statute means that the clock on the drug’s statutory exclusivity doesn’t start until the scheduling happens.) 

FDA has now written in the preface of the Orange Book:

“In addition, we note that Section 505(x) of the FD&C Act affects the date of approval for certain drug products subject to scheduling under the Controlled Substances Act. The Agency will list the drug product in the Orange Book and the date of approval as determined under Section 505(x).”

** NB: FDA has not changed the dates listed for already approved drugs (and there’s been a dispute about whether the change in the law was meant to be retroactive, see Kurt Karst’s discussion). As a practical matter, if you are relying on the Orange Book for research, you will need to remember that if the drug is a controlled substance, an “approval date” before November 25, 2015, is reliably the date of FDA’s action letter . . . but an “approval date” after then might not be. If you want to know for sure when FDA acted, you will have to check Drugs@FDA.

There are also changes relating to the meaning of pharmaceutical “equivalents” and “alternatives.”

FDA changed the definition of pharmaceutical equivalents.

• Old: “Drug products are considered pharmaceutical equivalents if they contain the same active ingredients, are of the same dosage form and route of administration, and are formulated to contain the same amount of active ingredient and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity).”
• New: “Pharmaceutical equivalents are drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where the residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.”

FDA changed the definition of pharmaceutical alternatives.

• Old: “Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths”
• New: “Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form, or the same salt or ester.  Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.”

What’s going on here?

Nothing, really. These are not substantive changes in practice.  These definitions now simply match the definitions added to FDA’s regulations in October 2016. See 21 C.F.R. § 314.3. (The administrative law professor in me finds it curious that it took FDA an additional 27 months to change a document that doesn’t go through notice and comment.)

And there are corresponding changes to the actual discussion of therapeutic equivalents.

The second criteria for a finding of therapeutically equivalents (the one that corresponds to “pharmaceutical equivalence”) was changed, to conform in part to the change noted above.  Thus “identical amounts of the same active drug ingredient in the same dosage form” was changed to “identical amounts of the identical active drug ingredient in the identical dosage form.”

And there was this change:

• Old:  FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product.
• New: FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product can be expected to have the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions of use specified in the labeling.

Finally, there’s a (non-significant) change under practitioner/user responsibilities.

• Old: Products evaluated as therapeutically equivalent can be expected, in the judgment of FDA, to have equivalent clinical effect and no difference in their potential for adverse effects when used under the conditions of their labeling.
• New: Products evaluated as therapeutically equivalent can be expected, in the judgment of FDA, to have the same clinical effect and no difference in their potential for adverse effects when used under the conditions of their labeling.

Two edits — removing references to drug costs — piqued my curiosity, though.

First, under General Policies and Legal Status, the agency changed how it refers to state substitution laws.  “Therapeutic equivalence evaluations are a scientific judgment based upon evidence,” the publication has said in the past (and still says).  In the past, it also added that “generic substitution may involve social and economic policy administered by the states, intended to reduce the cost of drugs to consumers.”  This year, someone changed this to say “generic substitution may involve social and economic policy administered by the states, e.g., reducing the cost of drugs to consumers.” 

Exempli gratia . . . for example.  If the editor used “e.g.” mindfully [something I am not entirely willing to assume], this edit acknowledges that state generic substitution laws might be intended to further social policies unrelated to reducing the cost of drugs to consumers. 

Second, after stating that therapeutic equivalents can be substituted with the full expectation that they will have the same clinical effect and safety profile, the Orange Book notes (as it has in the past) that these products may nevertheless differ in other characteristics (such as shape and scoring) and that substitution in these situations can result in patient confusion.  The final sentence of the paragraph previously added that there could also be “differences in cost to the patient.”  The new edition drops the mention of cost differences.

What does all of this mean? 

Probably just that I had too much time on my hands today.