[Federal Register Volume 62, Number 60 (Friday, March 28, 1997)]
[Notices]
[Pages 14917-14918]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-7912]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket Nos. 95P-0262 and 96P-0317]


Citizen Petitions Concerning Therapeutic Equivalency Ratings 
Between Tablets and Capsules; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is requesting comments 
on two citizen petitions that ask the agency to revise its current 
policy concerning therapeutic equivalency ratings between tablets and 
capsules. The petitions propose that a tablet and a capsule containing 
the same active ingredient in the same dosage strength that have been 
demonstrated to be bioequivalent be listed as therapeutic equivalents 
in the publication ``Approved Drug Products with Therapeutic 
Equivalence Evaluations.'' FDA is seeking public comment in order to 
assist the agency in deciding whether to revise its current policy.

DATES: Submit written comments by June 26, 1997.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, 
MD 20857.

FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-5644.

SUPPLEMENTARY INFORMATION: The publication ``Approved Drug Products 
with Therapeutic Equivalence Evaluations'' (the Orange Book) identifies 
drug products approved on the basis of safety and effectiveness by FDA 
under the Federal Food, Drug, and Cosmetic Act. The Orange Book also 
contains therapeutic equivalence evaluations for approved multisource 
prescription drug products. These evaluations are prepared to serve as 
public information and advice to State health agencies, prescribers, 
and pharmacists, to promote public education in the area of drug 
product selection, and to foster containment of health costs.
    For two drug products to be listed as therapeutically equivalent in 
the Orange Book, the products, among other criteria, must be 
pharmaceutical equivalents. FDA regulations define pharmaceutical 
equivalents as follows:
    Pharmaceutical equivalents means drug products that contain 
identical amounts of the identical active drug ingredient, i.e., the 
same salt or ester of the same therapeutic moiety, in identical 
dosage forms, but not necessarily containing the same inactive 
ingredients, and that 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.
(see 21 CFR 320.1(c))
Tablets and capsules containing the same active ingredient in the same 
dosage strength are defined as pharmaceutical alternatives rather than 
pharmaceutical equivalents. Pharmaceutical alternatives are defined as 
follows:
    Pharmaceutical alternatives means drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily 
in the same amount or dosage form or as 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.
(see 21 CFR 320.1(d))

[[Page 14918]]

Pharmaceutical equivalents and pharmaceutical alternatives are defined 
similarly in the Orange Book. Under these definitions, a tablet and a 
capsule cannot be rated as therapeutic equivalents in the Orange Book 
even if they have been demonstrated to be bioequivalent.
    FDA has received two citizen petitions asking the agency to revise 
the current policy that does not permit tablets and capsules to be 
rated as therapeutically equivalent. Kleinfeld, Kaplan and Becker 
(Kaplan) submitted a petition dated August 11, 1995, that asks FDA to 
take the following actions: (1) Revise the Orange Book to specify 
therapeutic equivalence evaluations for products that contain the same 
active ingredient, but are in a different solid oral dosage form (i.e., 
tablets and capsules); (2) change the Orange Book designations 
``Tablet, Oral'' and ``Capsule, Oral,'' to ``Solid, Oral''; and (3) 
change the definitions of ``Pharmaceutical equivalents'' and 
``Pharmaceutical alternatives'' in FDA's regulations in 21 CFR 320.1(c) 
and (d) and in the Orange Book to accommodate the requested changes. 
The petition suggests, as an alternative, that FDA could rule that 
tablets and capsules are the same dosage form (i.e., solid oral) and 
are thus pharmaceutical equivalents. Under the latter approach, grant 
of a suitability petition (under section 505(j)(2)(C) of the act (21 
U.S.C. 355(j)(2)(C)) and 21 CFR 314.93) would not be a prerequisite for 
FDA to approve a tablet form of a capsule product, or vice versa.
    The National Association of Pharmaceutical Manufacturers (NAPM) 
submitted a citizen petition dated August 27, 1996, requesting that 
``FDA deem all solid oral dosage form drug products (e.g., tablets and 
capsules) as the same dosage form, which, upon a showing of 
bioequivalence, will be considered in all respects to be 
`pharmaceutical equivalents.''' NAPM argues that tablets and capsules 
are ``more properly regarded as a single dosage form, i.e., solid oral 
dosage forms.'' Both petitions assert that there is no scientific basis 
for distinguishing between tablets and capsules that have been 
demonstrated to be bioequivalent.
    Recently, the issue of whether tablets and capsules can be listed 
in the Orange Book as therapeutically equivalent has taken on added 
significance. Some innovator firms, whose period of marketing 
protection (either through patent or exclusivity) is about to expire, 
have succeeded in delaying generic competition by, for example, 
voluntarily withdrawing the new drug application (NDA) for the tablet 
formulation of a product and submitting a second NDA for the drug 
product in capsule form. In such a case, if there are already filed 
abbreviated new drug applications (ANDA's) for the tablet product, 
these ANDA's cannot be approved immediately upon expiration of the 
innovator's period of market protection. Before these ANDA's can be 
approved, an interested party must file a petition asking the agency to 
determine whether the innovator product was withdrawn for reasons of 
safety or effectiveness. The agency must then determine that the 
product was not withdrawn for these reasons, publish that 
determination, and relist the product in the Orange Book. Even after a 
withdrawn product has been relisted in this way, generic competition 
may still be affected. For example, if physicians continue to write 
prescriptions by brand name rather than by generic name, substitution 
of the generic tablet for the brand name capsule may not be permitted 
under the applicable State drug product selection statute.
    FDA is soliciting public comment on the two citizen petitions 
discussed above. Among the questions the agency would particularly like 
to see addressed are the following:
    1. Should any potential change in current FDA policy be limited to 
permitting bioequivalent tablets and capsules to be listed as 
therapeutic equivalents in the Orange Book, or should FDA regard 
tablets and capsules as the same (i.e., solid oral) dosage form?
    2. What would be the implications of regarding all tablets and 
capsules as the same dosage form?
    3. Is there a sound scientific basis for the current distinction 
between tablets and capsules?
    4. What would be the impact on patients of rating bioequivalent 
tablets and capsules as therapeutically equivalent, or of adopting the 
term ``solid oral'' as a dosage form? Are there reasons for some 
patients or health care practitioners to prefer either tablets or 
capsules?
    5. How would listing tablets and capsules as therapeutic 
equivalents in the Orange Book affect current substitution practices 
under State drug product selection statutes? What would be the impact 
on drug selection by formularies?
    6. What would be the economic impact of various proposed changes?
    7. How would FDA action in this area relate to United States 
Pharmacopoeia (USP) monographs?
    Interested persons may, on or before June 26, 1996, submit to the 
Dockets Management Branch (address above) written comments regarding 
this notice. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Requests and comments are to be 
identified with the docket numbers found in brackets in the heading of 
this document. The NAPM and Kaplan petitions and received comments may 
be seen in the office above between 9 a.m. and 4 p.m., Monday through 
Friday. Copies of the citizen petitions may be requested in writing 
from the Freedom of Information Office (HFI-35), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.

    Dated: March 21, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-7912 Filed 3-27-97; 8:45 am]
BILLING CODE 4160-01-F