KV Pharmaceutical Co.; Proposal To Withdraw Approval of Two Abbreviated New Drug Applications and One Abbreviated Antibiotic Drug Application; Opportunity for a Hearing

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 95N-0182]

KV Pharmaceutical Co.; Proposal To Withdraw Approval of Two

Abbreviated New Drug Applications and One Abbreviated Antibiotic Drug

Application; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to

withdraw approval of two abbreviated new drug applications (ANDA's) and

one abbreviated antibiotic application (AADA) held by KV Pharmaceutical

Co., 2503 South Hanley Rd., St. Louis, MO 63144 (KV). The grounds for

the proposed withdrawals are (1) that the applications contain untrue

statements of material fact; and (2) that based upon new information

evaluated together with the evidence available when the applications

were approved, there is a lack of substantial evidence that the drugs

will have the effect they purport or are represented to have under the

conditions of use prescribed, recommended, or suggested in their

labeling.

DATES: A hearing request is due on July 26, 1995; data and information

in support of the hearing request are due August 25, 1995.

ADDRESSES: A request for a hearing, supporting data, and other comments

should be identified with Docket No. 95N-0182 and submitted to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Harry T. Schiller, Center for Drug

Evaluation and Research (HFD-366), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

On February 4, 1992, FDA attempted to inspect KV to determine

whether or not the firm was following current good manufacturing

practice (CGMP) regulations. The firm, however, refused to provide

necessary records as required under the Federal Food, Drug, and

Cosmetic Act (the act). (See sections 505(k) and 704 of the act (21

U.S.C. 355(k) and 21 U.S.C. 374).) The agency, therefore, obtained

inspection warrants and inspected KV between March 11 and April 23,

1992. Despite the inspection warrants, KV failed to provide all of the

documents requested. FDA conducted another inspection of KV between

July 31 and November 3, 1992.

During the two 1992 inspections, the agency compared documents and

data found at the firm with records previously submitted to FDA in

support of KV's AADA and ANDA applications. The agency discovered that

KV had submitted false and misleading information in the following

applications:

1. AADA 62-047, Erythromycin Ethylsuccinate Oral Suspension, 200

and 400 milligrams (mg);

2. ANDA 71-929, Disopyramide Phosphate Extended Release Capsules,

100 mg; and

3. ANDA 86-538, Nitroglycerin Extended Release Capsules, 2.5 mg.

In support of the AADA and the two ANDA's listed above, KV

submitted analytical data necessary for approval and continued approval

of the applications, including stability data. During its inspections

of KV, the agency discovered documents that showed that KV had made

untrue statements in some of the stability data it had submitted in

supplements and amendments to the applications. The documents also

showed that KV had made untrue statements concerning stability data in

annual reports submitted to the applications.

In letters dated June 1, 1993, and November 12, 1993, FDA informed

KV that the agency intended to downgrade the therapeutic equivalency

rating of the products listed above in the agency's publication

``Approved Drug Products with Therapeutic Equivalence Evaluations''

(the ``Orange Book'') and to begin the administrative procedures

necessary to withdraw approval of the products. Accordingly, as

explained below, the Director of the Center for Drug Evaluation and

Research (the Director) is proposing to withdraw approval of the

products' applications.

II. Evidence That the Applications Contain Untrue Statements of

Material Fact

The first ground for withdrawing the AADA and two ANDA's listed

above is that the applications contain untrue statements of material

fact (21 U.S.C. 355(e)(5)). This section presents FDA's general

comments on untrue statements and materiality, and then sets forth the

specific false and misleading information in the three abbreviated

applications.

A. Untrue Statements

The untrue statements submitted by KV in its drug applications

include both stability test results that are inconsistent with

stability test results retained by the firm and selective or incomplete

reporting of stability date.

1. Conflicts Between Information Submitted to the Agency and

Information Retained by the Firm

The first type of untrue statement submitted in the drug

applications listed above consists of data that differ from data and

other primary source information discovered at the firm. The agency

concludes in such cases that, in the absence of a satisfactory

explanation, the discrepant information in the application is untrue.

Information in an AADA or ANDA, including the facts and data

covered by this notice, is generally derivative information. Such

information is often a restatement, summary, or copy of original data

or other underlying information such as that found in laboratory

notebooks not specifically included in the application. The agency

believes that original or underlying data generally have a higher

degree of reliability because they are the primary sources of the

information that are usually created contemporaneously with the event

the information describes. Restated, summarized, or copied information

submitted in the [[Page 32983]] application is transcribed, calculated,

or otherwise derived from the original or underlying sources and is

prepared after the events actually occurred and, therefore, is

generally less reliable in the event of a discrepancy or inconsistency.

Errors in the original or underlying data, even if discovered during

the preparation of an application, should be corrected with a proper

explanation.

2. Selective Reporting

The second type of untrue statement in the KV applications listed

above consists of selective or incomplete reports of stability data.

Selective reporting refers to reports that contain certain passing

results only. Selective reporting does not consistently contain failing

results and does not consistently contain a scientific justification

for rejecting the failing data. Selective reporting thus misrepresents

results, introduces bias into the studies' analysis, and may result in

erroneous conclusions about the stability of the product.

B. Material Fact

KV's ANDA's and AADA, filed under sections 505(j), 505(b), and 507

of the act and implementing regulations, did not require for their

approval the submission of animal toxicity studies, human safety

studies, and adequate and well-controlled clinical effectiveness

studies. Rather, the approval of an abbreviated application is based on

a showing that the generic drug is equivalent to the innovator drug on

certain key chemical and pharmacologic parameters, and, thus, will be

therapeutically equivalent to the innovator drug throughout the shelf

life of the generic product.

A finding that the generic and innovator drugs are chemically

equivalent with respect to the active ingredient and bioequivalent with

respect to the extent and rate of absorption of the active ingredient

includes adequate proof that the generic product will remain stable

throughout its labeled shelf life. Stability is demonstrated by showing

that the drug product will remain within specifications established to

ensure its identity, strength, quality, and purity throughout its

specified shelf life. The stability data help, therefore, to provide

assurance that a generic product will retain its physical, chemical,

and bioequivalent characteristics throughout its labeled shelf life.

To obtain FDA approval, an application for a generic drug must

demonstrate with reliable data and information (including stability

data) that the generic drug is equivalent to the innovator drug so that

the toxicity, safety, and effectiveness studies supporting the approval

of the innovator drug also support approval of the generic drug.

Moreover, FDA must have a reasonable basis on which to conclude that

data based on test batches of a generic product are representative of

the proposed commercial batches of that generic product.

To maintain continued approval of a drug, the sponsor must, among

other things, comply with various post-marketing reporting

requirements. Under 21 CFR 314.81, a sponsor must file annual reports,

which then become a part of the application; the failure to file such

annual reports may be grounds for withdrawing approval of the

application.

A fact is material if it has the natural tendency to influence or

be capable of affecting or influencing a government function. (See U.S.

v. Brittain, 931 F.2d 1413, 1415 (10th Cir. 1991); Gonzales v. United

States, 286 F.2d 118, 122 (10th Cir. 1960), cert. denied, 365 U.S. 878

(1961); Weinstock v. United States, 231 F.2d 699, 701-702 (D.C. Cir.

1956)). The statements submitted by KV about stability data are

required information for the approval or continued approval of an ANDA

or AADA (see 21 U.S.C. 355(j)(2)(A)(vi), 355(b)(1)(C), 355(b)(1)(D); 21

CFR 314.50(d)(1), 314.94(a)(9), 314.94(c), and 314.81).

Statements pertaining to stability are among the many statements in

an abbreviated application on which FDA relies when deciding whether or

not to approve an application for a generic product (see 21 U.S.C.

355(j)(3)(A) and 355(j)(3)(F); 21 CFR 314.94 and 314.125). Similarly,

when allowing a proposed tentative expiration dating period, FDA relies

on the manufacturer's written commitment in the application to conduct

or continue shelf life stability studies on at least the first three

production batches to establish the actual expiration dating period

(see 21 CFR 314.94(a)(9), 314.94(c), and 314.50(d)(1)). Moreover, FDA

relies on data submitted in annual reports to determine whether an

application should continue to be approved (see 21 U.S.C. 355(e),

355(k); 21 CFR 314.81, 433.1).

Because the statements in the applications that are the subject of

this notice were capable of affecting or influencing FDA's review of

the applications, they are material.

C. Specific Untrue Statements of Material Fact Contained in Each

Application

The specific untrue statements of material fact found in each

application are described below. KV received written notice of many of

these untrue statements in inspectional observations on Forms FDA-483

after FDA's inspections of March 11 through April 23, 1992, and July 31

through November 3, 1992.

1. AADA 62-047, Erythromycin Ethylsuccinate Oral Suspension, 200 and

400 mg

KV was not the original holder of this AADA. KV purchased the

original holder and its approved applications, including AADA 62-047,

the AADA for erythromycin ethylsuccinate oral suspension (EES). EES is

a drug recognized in the United States Pharmacopeia (U.S.P.), and,

therefore, the drug must meet the specifications regarding strength,

quality, and purity prescribed in the U.S.P. unless the deviations are

stated on the label. KV's EES product is labeled to indicate

conformance with such U.S.P. specifications, not deviations.

On August 2, 1989, KV submitted to FDA two supplements to AADA 62-

047, seeking approval for manufacturing changes (supplement S-006 for

its 200 mg EES and supplement S-007 for its 400 mg EES). After

evaluating KV's submissions, FDA issued a deficiency letter on

September 14, 1989, regarding a number of issues, including KV's

failure to provide adequate stability data for EES manufactured by KV's

proposed new process. KV amended these supplements on August 14, 1990,

and again on December 19, 1990. FDA approved the supplements in a

letter dated April 12, 1991.

Subsequently, during the inspections of March 11 through April 23,

1992, and July 31 through November 3, 1992, FDA compared the data

submitted in these supplements with records found at the firm. The

comparisons demonstrated that the data submitted in response to FDA's

1989 deficiency letter omitted failing stability results and falsely

reported failing results as passing. These data were false and

misleading and material to the approval of the AADA supplements.

In the August 14, 1990, amendment to its then pending AADA

supplement, KV provided results from freeze/thaw cycle stability

studies for lot L2072 (200 mg) and lot L2071 (400 mg), which were

performed by an independent contractor. Records discovered at KV,

however, showed that KV did not report failing freeze/thaw results done

by KV's lab. The selectively reported data submitted to FDA are

misleading because they do not reflect all of the stability testing

results of the lots, and, [[Page 32984]] thus, constitute untrue

statements of material fact.

In the August 14, 1990, amendment to its then pending supplement,

KV also selectively reported only a passing result for a 12-month

stability test for lot L2071 (400 mg) for methylparaben, an inactive

ingredient, although KV's records showed an initial unreported result

in which the lot failed to meet the firm's specifications approved in

the AADA for methylparaben.

In the August 14, 1990, amendment to its then pending supplement,

KV falsely reported that lot L2072 (200 mg) passed a 6-month stability

test for methylparaben. However, KV's records for the same time and

storage conditions showed that L2072 failed to meet the firm's

specifications as approved in the AADA.

FDA's inspection also established that KV made untrue statements in

certain annual reports by submitting false stability study results and

by omitting failing stability results for EES 200 mg and 400 mg. In

KV's April 30, 1991, annual report for its 200 mg EES product, the firm

falsely stated that lot L2510 passed an erythromycin assay at 3 months.

However, records from the outside contract laboratory that conducted

the 3-month assay show that the erythromycin assay results for lot

L2510 were below the U.S.P. specifications.

In KV's September 26, 1991, annual report for EES 400 mg, the firm

falsely reported that the assay of the active ingredient in lot L2071

passed stability testing at 18 months. Records at the firm, however,

showed that lot L2071 failed testing at 18 months because the results

were below U.S.P. specifications.

Records from KV show that EES lot L1791 (200 mg) failed assays for

erythromycin and for an inactive ingredient at 18 months. KV, however,

did not report these failures in its April 30, 1991, annual report as

required under 21 CFR 314.81. On April 28, 1992, KV recalled both

strengths of EES because of recurrent stability problems. Only after

this recall, in the firm's June 2, 1992, annual report, did KV report

the stability test failures of EES lot L1791.

The stability failures in 1990 and 1991 were capable of affecting

FDA's continued approval of the AADA because they provide evidence

directly relevant to the product's safety and effectiveness. KV's

omission in the April 30, 1991, annual report of the available

information about the 1990 and 1991 failures misrepresented the

product's quality at that time and, therefore, the applications contain

untrue statements of material fact.

2. ANDA 71-929, Disopyramide Phosphate Extended Release Capsules, 100

mg

FDA's inspections of KV revealed that the firm made untrue

statements about the stability of its Disopyramide Phosphate Extended

Release Capsules (100 mg) in its September 10, 1992, annual report, as

explained below. Disopyramide Phosphate Extended Release Capsules must

meet the specifications regarding strength, quality, and purity

prescribed in the approved ANDA, as amended. The stability data

submitted in the annual reports and discussed below are false and

misleading and are material to the continued approval of the ANDA

application.

First, KV reported that in December 1991, lot V1040 passed ANDA

specifications for 18-month drug release testing at 1, 4, and 8-hour

intervals. Records at the firm, however, showed that the six capsules

tested by KV on December 11, 1991, failed the 4-hour test both

individually and collectively. These failing data were lined through

and the notation ``Inconsistent with history and retest'' was added. No

other notation or explanation of KV's December 11, 1991, test results

was recorded. KV did not report this failure in the September 10, 1992,

annual record or record an explanation for omitting this failure from

the annual report. Five days later, on December 16, 1991, KV tested

another six capsules, which passed the 4-hour specifications. KV

selectively reported only the average of the passing test results in

the annual report, and the omission of failing data in the annual

report was misleading.

KV also reported in the September 10, 1992, annual report that in

April 1991, the 3-month drug release test for lot V1377 passed ANDA

specifications at the 4-hour interval. Records at the firm, however,

showed that on April 18, 1991, the aggregate average value of the six

capsules tested was below drug release specifications for the 4-hour

interval. Five of the six individual capsules were also below

specifications at 4 hours. These failing data were not reported in the

September 10, 1992, annual report.

Four months later, on August 18 and 19, 1991, KV reassayed the lot

three times and selectively reported only the results from the first

reassay. Furthermore, in the September 10, 1992, annual report, KV

falsely reported that the drug release test result had been obtained at

3 months, but KV's records showed that it had been obtained at 7

months.

KV also reported in the September 10, 1992, annual report that lot

V1497 passed both 4 and 8 hour, 12-month drug release tests in May

1992. KV's records, however, showed that a set of six capsules failed

the 8 hour, 12-month ANDA drug release test on July 21, 1992. On August

3, 1992, a second set of six capsules passed both 4 and 8 hour drug

release tests. However, these results were crossed out on the firm's

stability data report form. A handwritten note next to these results

reads ``Void. See recal using correct shell factor.'' On August 8,

1992, KV recalculated both the 4-hour and 8-hour drug release test

results. The aggregate averages for both 4 hour and 8 hour tests passed

specifications. However, two of the six capsules failed at 4 hours and

two of the six capsules failed at 8 hours. The notation ``Recal'' is

written beside this third set of data. KV selectively reported only the

passing 4 and 8 hour aggregate average results in the September 1992,

annual report.

3. ANDA 86-538, Nitroglycerin Extended Release Capsules, 2.5 mg

FDA's inspections of KV revealed that the firm made untrue

statements in certain annual reports about the stability of its

Nitroglycerin Extended Release Capsules. These untrue statements

consisted of false reporting and selective reporting of stability data,

including content uniformity data, which are material to the continued

conditional approval of the application.

In its April 29, 1988, annual report, KV reported that on July 28,

1987, the content uniformity test data for lot V8715 were not available

at 24 months. KV's records, however, included content uniformity test

results for this lot, which showed that lot V8715 failed to meet U.S.P.

specifications at 24 months. Although Nitroglycerin Extended Release

Capsules is not listed in the U.S.P., the standard test for content

uniformity of any product is described in the U.S.P., and KV's

submissions stated that it met the U.S.P. test.

In its June 6, 1989, annual report, KV reported that the 12-month

assay for nitroglycerin in lot V8648 tested within the ANDA

specifications. KV's records, however, showed that an assay result was

outside the ANDA assay limits. The passing result KV reported was an

average of the failing result and two additional assays it performed.

In the June 6, 1989, annual report, KV reported that a

nitroglycerin assay purportedly conducted at 9 months after lot V9527

was within ANDA specifications. KV's records, however, showed that the

KV lab test result, [[Page 32985]] which was dated March 3, 1988,

failed to meet ANDA specifications. KV records also showed that the

stability test result KV reported in its annual report was the average

of two retests performed by KV on April 19, 1988.

In the June 6, 1989, annual report, KV falsely reported that lot

V9133 conformed to U.S.P. specifications in a content uniformity test

conducted 6 months after the lot was manufactured. KV's records,

however, showed that the first 10 capsules of the lot failed U.S.P.

relative standard deviation (RSD) specifications and contained no

evidence that KV tested an additional 20 capsules. Without further

testing of an additional 20 capsules, the batch failed to meet U.S.P.

specifications. Therefore, lot V9133 did not conform to U.S.P.

specifications.

In its May 8, 1990, annual report KV reported that lot V9432 passed

a 24-month stability test in April 1989. Records at the firm, however,

show that the lot failed its stability test on May 15, 1989. During

retesting on June 5, 1989, the lot passed stability testing and met

assay specifications twice. KV averaged the passing tests and then

improperly averaged that resultant average with the failing result.

This final average was reported as a passing result in the May 8, 1990,

annual report.

KV reported in its May 8, 1990, annual report that lot V9527 met

ANDA assay specifications, purportedly in an 18-month stability test of

nitroglycerin conducted in February 1989. Records at the firm, however,

show that the lot failed the first stability test on May 15, 1989. The

lot passed the second and third stability tests, done on June 5, 1989.

KV improperly averaged the three test results and reported in the

annual report the average as a passing result. Furthermore, the retests

were conducted 21 and 22 months after the batch was manufactured, but

KV reported in the annual report that the tests were conducted at 18

months.

KV reported in an August 6, 1992, letter to the agency that lot

V9991 passed the 24-month content uniformity test and conformed to

U.S.P. specifications. Records at the firm, however, showed that the

group of capsules tested failed because its RSD was above U.S.P. RSD

specifications. In addition, the results of two individual capsules

were below U.S.P. specifications. According to U.S.P. specifications,

such failing results require testing an additional 20 capsules, which

KV did not do. Therefore, this lot did not conform to U.S.P.

specifications.

KV reported in an August 1, 1990, supplement that lot V9527 passed

a 12-month stability test for nitroglycerin. Records at the firm,

however, show that the lot failed a stability test on September 22,

1988, and thus did not meet the ANDA assay specifications. KV then

conducted two retests on October 4, 1988. KV selectively reported the

result of only one of the passing retests, and also falsely reported

the date of the test as August 15, 1988, which was 2 months before the

actual test date.

D. Conclusion

On the basis of the foregoing findings, the Director finds that KV

submitted untrue statements of material fact in the AADA and two ANDA's

listed above, and, therefore, proposes to withdraw the approval of

these applications under section 505(e)(5) of the act.

III. Evidence That the Drugs Lack Substantial Evidence of Effectiveness

Sction 505(e)(3) of the act provides that approval of an AADA or an

ANDA shall be withdrawn if, on the basis of new information, evaluated

together with the evidence available when the application was approved,

there is a lack of substantial evidence that the drug will have the

effect it purports or is represented to have. Because KV submitted

untrue statements regarding the stability of its product in annual

reports, supplements, and amendments to its applications, the agency

cannot be assured of the products' stability. Moreover, the agency can

no longer be assured as to the accuracy and validity of any of the data

used to support approval and continued approval of these applications.

Thus, the discovery of these untrue statements constitutes new

information demonstrating that there is a lack of substantial evidence

that the drugs will have the effects they purport or are represented to

have under the conditions of use prescribed, recommended, or suggested

in their labeling.

The reliability of stability data is of particular concern when, as

here, the results of multiple stability tests, both reported and

unreported, indicate a significant history of stability problems.

Without reliable stability data, FDA cannot be assured that a drug will

maintain the efficacy upon the basis of which the drug was approved.

Similarly, in the case of stability problems with generic drugs, FDA

cannot be assured that the drug will continue to be bioequivalent to

the innovator drug over a given period of time. In either case, an

unstable drug product may be more or less potent than the efficacy

parameters that the agency approved.

Because there are no reliable data or information to demonstrate

the stability and bioequivalence of these products to the listed drugs,

the three products listed above lack substantial evidence of

effectiveness.

IV. Proposed Action and Notice of Opportunity For a Hearing

The Director has evaluated the information discussed above

concerning the filing of untrue statements of material fact by KV and,

on the grounds stated, is proposing to withdraw approval of the

following AADA and ANDA's:

1. AADA 62-047, Erythromycin Ethylsuccinate Oral Suspension, 200

and 400 mg;

2. ANDA 71-929, Disopyramide Phosphate Extended Release Capsules,

100 mg; and

3. ANDA 86-538, Nitroglycerin Extended Release Capsules, 2.5 mg.

Notice is hereby given to the holder of the AADA and ANDA's listed

above and to all other interested persons that, based upon the

information discussed above concerning the filing of untrue statements

by KV and, on the grounds stated, the Director proposes to issue an

order under section 505(e) of the act withdrawing approvals, including

conditional approvals, of the foregoing AADA and ANDA's, and all

amendments and supplements thereto. The Director finds that: (1) The

applications contain untrue statements of material fact; and (2) on the

basis of new information before her with respect to the drugs,

evaluated together with the evidence available to her when the

applications were approved, there is a lack of substantial evidence

that the drugs will have the effects they purport or are represented to

have under the conditions of use prescribed, recommended, or suggested

in their labeling.

In accordance with section 505(e) of the act and 21 CFR part 314,

the applicant is hereby given an opportunity for a hearing to show why

approval of the AADA and ANDA's should not be withdrawn.

An applicant who decides to seek a hearing shall file: (1) On or

before July 26, 1995, a written notice of appearance and request for a

hearing, and (2) on or before August 25, 1995, the data, information,

and analyses relied on to demonstrate that there is a genuine issue of

material fact to justify a hearing. Any other interested person may

also submit comments on this notice. The procedures and requirements

governing this notice of opportunity for a hearing, a notice of

appearance and request for a hearing, submission of information

[[Page 32986]] and analyses to justify a hearing, other comments, and a

grant or denial of a hearing, are contained in 21 CFR 314.200 (except

that the limitations imposed by 21 CFR 314.200(d)(1) and (d)(2) do not

apply) and in 21 CFR part 12.

The failure of the applicant to file a timely, written notice of

appearance and request for a hearing, as required by 21 CFR 314.200,

constitutes an election by that person not to use the opportunity for a

hearing concerning the action proposed, and a waiver of any contentions

concerning the legal status of that person's drug products. Any new

drug product marketed without an approved new drug application is

subject to regulatory action at any time.

A request for a hearing may not rest upon mere allegations or

denials, but must present specific facts showing that there is a

genuine and substantial issue of fact that requires a hearing. In order

to raise a genuine and substantial issue of fact justifying a hearing

on the issue of whether the application contains untrue statements, the

applicant must specifically identify new evidence that supports its

position. Mere allegations and denials, arguments by counsel, or the

unsupported articulation of possible alternate inferences will not

suffice to obtain a hearing. See 21 CFR 12.24(b)(2); see also Cooper

Laboratories, Inc. v. Commissioner, Federal Food and Drug

Administration, 501 F.2d 772, 785 (D.C. Cir. 1974); Pineapple Growers

Ass'n v. Food and Drug Administration, 673 F.2d 1083-1085 (9th Cir.

1982); Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609,

620-621 (1973).

In order to obtain a hearing, the new evidence must do more than

reaffirm the applicant's belief that the information in the application

is true. As explained above, the Director's conclusion that the

applications contain an untrue statement of material facts is based on:

(1) Selective reporting of stability data without justification, (2)

omission of failing stability test results, and (3) actual conflicts

between stability data reported to FDA and stability data retained by

the firm.

In order to raise an issue of fact about whether the application

contains truthful information, the applicant's evidence should be

directed toward the basis of the Director's conclusion that the

statements in the application are untrue. The applicant's failure to

present evidence identifying a genuine and substantial issue of fact

with respect to the Director's conclusion that the applications listed

in this notice contain untrue statements of material fact, leaves the

basis for the conclusion intact, and will result in the denial of a

hearing on those issues.

In addition, the submission of truthful information to replace

untrue statements will not result in a finding that the previously

identified untrue statements are no longer material. If corrective

information could nullify the materiality of untrue statements, then

applicants could simply correct all untrue statements as soon as they

were discovered.

Should a hearing be held on these issues, the participants

requesting the hearing will bear the burden of proof with respect to

whether the applications contain untrue statements of material fact

and, ultimately, whether the drugs that are the subject of the

applications listed in this notice have been shown to be safe and

effective (21 CFR 12.87(d)).

If it conclusively appears from the face of the data, information,

and factual analyses in the request for a hearing that there is no

genuine and substantial issue of fact that precludes the withdrawal of

approval of the applications, or when a request for hearing is not made

in the required format or with the required analyses, the Commissioner

of Food and Drugs will enter summary judgment against the person(s) who

request the hearing, making findings and conclusions, and denying a

hearing.

Section 505(j)(6)(C) of the act requires that FDA remove from its

approved product list contained in FDA's publication the Orange Book

any drug that was withdrawn for grounds described in the first sentence

of section 505(e) of the act. If the agency determines that withdrawal

of the drugs subject to this notice is appropriate, FDA will announce

the removal of the relevant drugs from the list in the Federal Register

notice announcing the withdrawal of approval of the drugs.

All submissions pursuant to this notice of opportunity for hearing

are to be filed in four copies. Except for data and information

prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C.

1905, the submissions may be seen in the Dockets Management Branch

(address above) between 9 a.m. and 4 p.m., Monday through Friday.

This notice is issued under the Federal Food, Drug, and Cosmetic

Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the

Director of the Center for Drug Evaluation and Research (21 CFR 5.82).

Dated: June 13, 1995.

Murry A. Lumpkin,

Deputy Director, Center for Drug Evaluation and Research.

[FR Doc. 95-15539 Filed 6-23-95; 8:45 am]

BILLING CODE 4160-01-P