March 20, 1991

Dear Sir or Madam:

This is the seventh in a series of policy letters regarding the
implementation of the Generic Animal Drug and Patent Term Restoration
Act (GADPTRA), which was signed into law on November 16, 1988.

We are introducing four policy statements (refer to attachment) which
address our continuing implementation of the new law. The policy
statements are entitled as follows:

1)  "Guidance for Analytical Methods for ANADA's"

2)  "Hybrid Applications"

3)  "ANADA's, NADA's and Supplemental Approval for

> Subtherapeutic Antibiotics"

4)  "Waivers of *In Vivo* Bioquivalence Studies for Topical Products"

We welcome comments and questions from all interested parties. If any
changes are made, the revised policy statements will be placed on public
display, and a notice of availability will be published in the FEDERAL
REGISTER.

Comments on the policy statements may be submitted to:

Dockets Management Branch

HFA-305, Room 4-62

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

We will continue to announce the availability of our policy statements
regarding the new law.

Sincerely yours,

/s/

Gerald B. Guest, DVM

Director, Center for

Veterinary Medicine

Attachment

1\) [GUIDANCE FOR ANALYTICAL METHODS FOR ANADA's]{.underline}

Sponsors of abbreviated new animal drug applications (ANADA's) should
discuss any questions or problems concerning analytical methodology with
CVM before undertaking pivotal bioequivalence or residue studies. Early
discussion of the issues relevant to analytical methods can lead to the
solution of any actual or potential analytical problems which could
invalidate the animal drug studies.

The purpose of this guidance is to outline technical items that should
be addressed when developing and validating analytical methods for
bioequivalence studies for generic animal drugs. Details on the
requirements for analytical methods are specified in the "Guideline for
the Approval of a Method of Analysis for Residues", available from CVM's
Industry Information Staff.

The guidance presented here is not intended to specify the techniques
that should be used in developing or validating analytical methods.
Rather, the guidance is intended to characterize the type of information
needed to validate analytical methods. The technology used to develop an
analytical method and the tests and experiments used to establish the
performance characteristics of the analytical method are the decision of
the drug sponsor.

In general, there are six important aspects that should be addressed in
assessing method performance:

1\. [The concentration range of the analyte, or any designated
metabolite, and demonstration of linearity over the concentration
range.]{.underline} This range can be determined by conducting recovery
studies using the sample and method.

2\. [The limit of detection (LOD)]{.underline}. This is the minimum
level of the marker drug in the target matrix that can be discriminated
from background to some level of statistical confidence. The 95%
confidence level is typically used.

3\. [The limit of quantition (LOQ)]{.underline}. This is the minimum
level of marker drug in the target matrix that can be quantitated to
some level of statistical confidence. The 95% confidence level is
typically used.

4\. [Accuracy]{.underline}. This is usually determined at various drug
concentrations in the target matrix within the concentration range of
the method. "Accuracy" is also referred to as "recovery."

5\. [Specificity]{.underline}. This is an estimate of the extent to
which the method responds only to the drug of interest. Specificity
should also assess interferences that may be caused by potential
degradation products and/or the matrix, e.g. tissue, feed, blood, and
urine.

6\. [Reproducibility.]{.underline} This is an estimate of precision.
This is usually expressed as a coefficient of variation or relative
standard deviation.

FDA reviewers will evaluate the data on the above six items to establish
whether the proposed method is scientifically sound and is appropriate
for the intended measurement. Items 1 through 6 above should be the
basic elements in a validation plan for analytical methods that are
either newly developed or are newly modified versions of existing
methods.

If existing methods which have been previously satisfactorily validated
are to be used verbatim, then quality assurance procedures should be
established to assure that the method is operating in a state of control
every time the method is used in a study. In this case, the FDA reviewer
would typically verify that a quality assurance (QA) procedure has been
developed and is part of the operational instructions for the method.
Good quality assurance procedures do not have to be elaborate or
complicated. The core of a quality assurance plan is the types of
control samples, materials and techniques that are used to assess that
the method is performing satisfactorily. The purpose of the controls is
to show that the equipment and reagents are performing as intended, and
that the method is responding acceptably to the analyte and is free of
interferences. All validated methods should have a quality assurance
assessment as part of the standard operating procedures (SOP's) for the
method application.

2\) [HYBRID APPLICATIONS]{.underline}

Section 512(n)(3) of the act provides for suitability petitions which
may be filed to request permission to submit an abbreviated new animal
drug application (ANADA) for certain changes in the listed (pioneer)
animal drug. The suitability petition can be approved only if the
proposed changes do not require investigations other than bioequivalence
or tissue residue for approval of the new product. However, an applicant
may wish to make a modification in an approved animal drug, which would
require investigations beyond bioequivalence and tissue residue studies.
For example, an applicant may wish to obtain approval of a new
indication for a listed animal drug.

Following the approval of an ANADA, the holder of the approved ANADA may
seek approval of a supplemental application that contains reports of
clinical investigations needed for approval of the new indication.
Because such a supplement would require the review of data, FDA would
treat it as a submission under section 512(b)(1) of the act.

An applicant may also wish to seek approval of, for example, a new
dosage form of a listed animal drug that requires the review of
investigations. The statute could be interpreted to require such an
applicant to first obtain approval of an ANADA for the listed animal
drug's approved dosage form, and then file a 512(b)(1) supplement to the
approved ANADA containing clinical data to obtain approval of the new
dosage form. If the applicant did not first obtain an ANADA for the
approved dosage form, the applicant could be required to submit a full
new animal drug application (NADA) under section 512(b)(1) of the act
for the new dosage form and duplicate the basic safety and effectiveness
studies conducted on the listed animal drug. FDA has concluded that such
an interpretation would be inconsistent with the legislative purposes of
the 1988 Amendments because it would serve as a disincentive to
innovation and would require needless duplication of research.

FDA believes that a more consistent, less burdensome interpretation of
the 1988 Amendments is to allow a generic applicant to submit a
512(b)(1) application for a change in an already approved animal drug
that requires the submission and review of investigations conducted by
or for the applicant, without first obtaining approval of an ANADA for a
duplicate of the listed animal drug. Therefore, FDA proposes to accept
applications for changes requiring the review of investigations
conducted by or for the applicant, including changes in dosage form,
strength, route of administration, and active ingredients (in a
combination product), as well as new indications and new species. These
applications will be known as "hybrid" applications. Like similar
supplements to approved ANADA's, these applications will rely on the
approval of the listed animal drug, together with the data needed to
support the change. The applicant will thus be relying on the approval
of the listed animal drug only to the extent that such reliance would be
allowed under section 512(n) of the act: to establish the safety and
effectiveness of the underlying animal drug. FDA notes, however, that it
will not accept such an application for an animal drug that differs from
the listed animal drug only in that its extent of absorption is
significantly less than that of the listed animal drug.

An application that relies in part on the approval of a listed animal
drug, is, for this purpose, considered an application described in
section 512(b)(2) and must make a certification as to any relevant
patents that claim the listed animal drug. In addition, the date of
submission and effective approval of these applications may, under
section 512(c)(2)(D), be delayed to give effect to any patent or period
of exclusivity accorded the listed animal drug.

Because these hybrid applications will be reviewed in part as
applications under section 512(b)(1) of the act, they will be subject to
the statutory and regulatory requirements applicable to such
applications, including the patent submission requirements of sections
512(b)(1) and (c)(3) of the act, and may be eligible for 3 years of
exclusivity under sections 512(c)(2)(F)(ii) and (iii) of the act.

The exact requirements for a hybrid application will depend upon the
proposed new animal drug product in question. However, in general, the
hybrid application may include a bioequivalence study, tissue residue
study, and the additional studies the Center deems necessary for
approval of the innovative product.

All applicants should consult with CVM to determine the types of studies
required for approval of the hybrid application. The general content and
format described for the ANADA in the second generic policy letter
(dated June 7, 1989) can be used for submission of the hybrid
application. However, the environmental assessment should follow the
requirements for the 512(b)(1) supplemental application.

3\) [ANADA's, NADA's AND SUPPLEMENTL APPROVALS FOR SUBTHERAPEUTIC
ANTIBIOTICS]{.underline}

# Background

> FDA regulation 21 CFR 558.15 provides that new animal drug
> applications (NADAs) for the subtherapeutic use of antimicrobials in
> animal feed would not be approved after specified dates in 1973 unless
> specific data were submitted to resolve questions concerning
> transferable resistance. FDA has, since 1973, not approved NADAs for
> subtherapeutic use of drugs containing penicillin or the
> tetracyclines, including combinations^\*^ containing those drugs. This
> restriction has applied both to original NADAs and those filed under
> the Drug Effectiveness Study Implementation (DESI) program. These
> drugs are the subjects of notices of opportunity for hearing (NOOHs),
> published in 1977, on FDA's proposal to withdraw their approvals.

# ANADAs

Drugs for subtherapeutic use that contain penicillin and the
tetracyclines that have been approved for safety and effectiveness are
eligible to be, and are, "listed" drugs under the Generic Animal Drug
and Patent Term Restoration Act (GADPTRA) of 1988. A drug that was
subject to the DESI review is "approved for safety and effectiveness" if
FDA, based upon its review of, for example, a DESI-conforming
supplemental application, has approved the application. Listed drugs can
be the subject of abbreviated new animal drug applications (ANADAs)
unless FDA has issued a notice of hearing (NOH) concerning such drugs.
Because NOHs have not been issued for drugs providing for subtherapeutic
use of penicillin and the tetracyclines, ANADAs for those drugs that
have been approved for safety and effectiveness can be submitted and
approved under the 1988 Act starting January, 1991.

# NADA's

FDA will continue to refuse to approve original applications for drugs
providing for subtherapeutic use of penicillin and the tetracyclines,
pending resolution of the resistance transfer issues.

# Supplemental Applications

> Consistent with the provisions of 21 CFR 558.15, FDA has, since 1973,
> not approved supplemental applications for new uses of penicillin and
> tetracycline containing drugs for subtherapeutic use, although the
> agency has approved certain other kinds of supplemental applications
> for such drugs. "New uses" refers to new combinations,^\*^ new
> indications and use in additional species.
>
> FDA has concluded that 21 CFR 558.15 requires the agency to continue
> to refuse to approve supplemental applications (including supplements
> to NADA's, ANADA's, and hybrid applications) for new uses of
> penicillin- and tetracycline- containing drugs for subtherapeutic use,
> pending resolution of the resistance transfer issues.
>
> However, FDA will continue to consider the following types of NADA or
> ANADA supplements for changes relating to the manufacture of drug
> products currently listed in 21 CFR 558.15:

-   Bulk drug shipments

-   Changes in:

-   repacking operations

-   containers \-- size, style, material, type

-   equipment (for any operation in the manufacturing process)

-   batch sizes

-   analytical control procedures (for the new drug substance,

> raw materials, and finished dosage form)

-   manufacturing processes

> \- new technology
>
> \- new equipment
>
> \- revision of procedures

-   record keeping

-   reprocessing/reworking

-   raw materials/specifications

-   product storage requirements

-   new drug substance synthesis or fermentation

-   Addition of alternate sources of the new drug substance

-   Addition of alternate manufacturing, packaging, labeling and

> Testing facilities

\- Export of product as approved

> \- Updating/revision of analytical methods for the release of the
>
> finished drug product

Supplemental NADA's or ANADA's for drug products subject to 21 CFR
558.15 will also continue to be considered for the following:

-   change in Type A medicated article concentration

-   new therapeutic uses for less than 14 days duration of use.

-   new combination products which include oxytetracycline at

> 75-80 mg/head/day for liver abscesses in cattle

GADPTRA permits a generic applicant to petition for certain changes from
the listed drug it is proposed to copy, i.e. for a different dosage
form, route of administration, strength or substitution of an active
ingredient in a combination drug (including substitution in a feed-mixed
combination). FDA has concluded that, if it permits generic sponsors to
make any of the aforementioned changes in drugs containing penicillin or
tetracycline for subtherapeutic use, it will also permit the sponsor of
the "listed" drugs to submit supplemental applications for the same
changes.

> \*New combinations have not been allowed, with the exception of new
> combination products which include oxytetracycline at 75-80
> mg/head/day for liver abscesses in cattle.
>
> 4\) WAIVERS OF IN VIVO BIOEQUIVALENCE STUDIES FOR TOPICAL PRODUCTS
>
> CVM will consider requests for waivers of *in vivo* bioequivalence
> studies for abbreviated new animal drug applications (ANADA's) for
> topically applied products intended for local therapeutic effects in
> non-food animals. Waivers will be considered for all dosage forms of
> topicals, including dermatologic, ophthalmic, and otic preparations.
>
> The proposed generic product must be the same as the pioneer product
> in concentration and identity of active ingredients, as well as in
> dosage form (i.e., pioneer ointment and generic ointment, pioneer
> cream and generic cream).
>
> The inactive ingredients should be the same in the pioneer and generic
> products whenever possible. However, certain differences in the
> inactive ingredients may be allowed in the formulation of the generic
> product being considered for a waiver. The specifics of the allowable
> changes will depend upon the drug product in question.
>
> The request for waiver of the *in vivo* bioequivalence study may be
> filed in the INAD or the ANADA. The request for waiver should provide
> information about the differences in the pioneer and generic product
> formulations and a justification for granting the waiver.
>
> To request a change in dosage form for topical products (e.g., pioneer
> ointment and generic cream), a suitability petition (as described in
> 21 CFR 10.30) must be filed. For a change in dosage form for a topical
> product, an *in vivo* bioequivalence study will ordinarily be
> required.