Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
3Activity
0 of .
Results for:
No results containing your search query
P. 1

Ratings: (0)|Views: 1,889|Likes:
Published by jhardy1879

More info:

Published by: jhardy1879 on Sep 23, 2010
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

09/23/2010

pdf

text

original

 
77668
Federal Register
/Vol. 67, No. 244/Thursday, December 19, 2002/Rules and Regulations
(ii) One or more constructioncontracts (includes any contractawarded by the recipient) subject tosuch requirements or prohibitions had been awarded.(4) The Assistant Administrator forProcurement may exempt a particularproject, contract, or subcontract fromthis policy upon a finding that specialcircumstances require an exemption inorder to avert an imminent threat topublic health or safety, or to serve thenational security. A finding of 
‘‘
specialcircumstances
’’
may not be based on thepossibility or presence of a labor disputeconcerning the use of contractors orsubcontractors who are nonsignatoriesto, or otherwise do not adhere to,agreements with one or more labororganizations, or concerning employeeson the project who are not members of,or affiliated with, a labor organization.
PART 1274
 —
COOPERATIVEAGREEMENTS WITH COMMERCIALFIRMS
3. The authority citation for part 1274continues to read as follows:
Authority:
31 U.S.C. 6301 to 6308; 42U.S.C. 2451
et seq.
4. 1274.215 is added to read asfollows:
§
1274.215Federal and federally fundedconstruction projects.
(a) In accordance with E.O. 13202 of February 17, 2001,
‘‘
Preservation of Open Competition and GovernmentNeutrality Towards GovernmentContractors
Labor Relations on Federaland Federally Funded ConstructionProjects
’’
, as amended on April 6, 2001,the Government, or any constructionmanager acting on behalf of theGovernment, shall not
 (1) Require or prohibit recipients,potential recipients or subrecipients toenter into or adhere to agreements withone or more labor organizations (asdefined in 42 U.S.C. 2000e(d)) on thesame or other related constructionprojects; or(2) Otherwise discriminate againstrecipients, potential recipients orsubrecipients for becoming, refusing to become, or remaining signatories orotherwise adhering to agreements withone or more organizations, on the sameor other related construction projects.(b) Nothing in this section prohibitsthe recipient, potential recipients orsubrecipients from voluntarily enteringinto project labor agreements.(c) The Assistant Administrator forProcurement may exempt a constructionproject from this policy if, as of February 17, 2001
 (1) The agency or a constructionmanager acting on behalf of theGovernment had issued or was party to bid specifications, project agreements,agreements with one or more labororganizations, or other controllingdocuments with respect to thatparticular project, which contained anyof the requirements or prohibitions inparagraph (d)(1) of this section; and(2) One or more constructioncontracts (includes any contractawarded by the recipient) subject tosuch requirements or prohibitions had been awarded.(d) The Assistant Administrator forProcurement may exempt a particularproject, contract, or subcontract fromthis policy upon a finding that specialcircumstances require an exemption inorder to avert an imminent threat topublic health or safety, or to serve thenational security. A finding of 
‘‘
specialcircumstances
’’
may not be based on thepossibility or presence of a labor disputeconcerning the use of contractors orsubcontractors who are nonsignatoriesto, or otherwise do not adhere to,agreements with one or more labororganizations, or concerning employeeson the project who are not members of,or affiliated with, a labor organization.
[FR Doc. 02
31682 Filed 12
18
02; 8:45 am]
BILLING CODE 7510
 –
01
 –
P
DEPARTMENT OF HEALTH ANDHUMAN SERVICESFood and Drug Administration21 CFR Parts 314 and 320
[Docket No. 98N
 –
0778]RIN 0910
 –
AC47
Bioavailability and BioequivalenceRequirements; AbbreviatedApplications; Final Rule
AGENCY
:
Food and Drug Administration,HHS.
ACTION
:
Final rule.
SUMMARY
:
The Food and DrugAdministration (FDA) is amending itsregulations on bioavailability and bioequivalence and on the content andformat of an abbreviated application toreflect current FDA policy and to correctcertain typographical and inadvertenterrors. This action is intended toimprove the accuracy and clarity of theregulations.
DATES
:
This rule is effective February18, 2003.
FOR FURTHER INFORMATION CONTACT
:
 Christine F. Rogers, Center for DrugEvaluation and Research (HFD
7), Foodand Drug Administration, 5600 FishersLane, Rockville, MD 20857, 301
594
2041.
SUPPLEMENTARY INFORMATION
:
I. Background
FDA regulations require personssubmitting a new drug application(NDA) to provide bioavailabilityinformation (21 CFR 314.50(c)(2)(vi) and(d)(3)), and persons submitting anabbreviated new drug application(ANDA) to provide informationpertaining to bioavailability and bioequivalence (
§
314.94(a)(7) (21 CFR314.94(a)(7)).FDA regulations in part 320 (21 CFRpart 320) establish definitions andrequirements for bioavailability and bioequivalence studies. FDA finalizedthe bioavailability and bioequivalenceregulations on January 7, 1977 (42 FR1624), and amended these regulationson April 28, 1992 (57 FR 17950). The1992 amendments were designed toreflect statutory changes resulting fromthe Drug Price Competition and PatentTerm Restoration Act of 1984 (PublicLaw 98
417).In the
Federal Register
of November19, 1998 (63 FR 64222), FDA proposedto revise its regulations on bioavailability and bioequivalence andthe content and format of an ANDA toreflect current FDA policy and to correctcertain typographical and inadvertenterrors (the proposed rule). Thepublication of this final rule completesthis rulemaking.
II. Description of the Final Rule
FDA is finalizing the proposed rulewith the following revisions made inresponse to comments received on theproposal.As proposed, the final rule changesthe term
‘‘
enteric coated
’’
to
‘‘
delayedrelease
’’
and the term
‘‘
controlledrelease
’’
to
‘‘
extended release
’’
in
§
320.22(c). To conform to this change,the final rule also amends
§§
320.1,320.22(d)(2)(iv), 320.25(f),320.27(a)(3)(iv), 320.27(b)(2), 320.28,and 320.31 by changing
‘‘
controlledrelease
’’
to
‘‘
extended release.
’’
Toconform to the new terminology, thefinal rule also amends
§
320.25(f) bychanging
‘‘
noncontrolled release
’’
to
‘‘
nonextended release.
’’
The following new first sentence has been added to redesignated
§
320.25(a)(2):
‘‘
An in vivo bioavailability study is generally donein a normal adult population understandardized conditions.
’’
This sentenceis a necessary lead-in for the existingtext that refers to situations in which
VerDate 0ct<31>2002 15:15 Dec 18, 2002Jkt 200001PO 00000Frm 00018Fmt 4700Sfmt 4700E:\FR\FM\19DER1.SGM19DER1
 
77669
Federal Register
/Vol. 67, No. 244/Thursday, December 19, 2002/Rules and Regulations
 bioavailability studies may beconducted in patients.The proposed rule would haverevised
§
320.26(b)(2)(i) to require acustomary drug elimination period of five times, rather than at least threetimes, the half-life of the active drugingredient or therapeutic moiety, or itsactive metabolite(s). In response to acomment pointing out that a drugelimination period of five half-lives may be impractically long for a drug with along half-life, the agency has decidednot to revise
§
320.26(b)(2)(i).The proposed rule would haverevised
§
320.27(d)(1) and (d)(2) to statethat blood or urine samples should betaken on 3 or more consecutive days toestablish that steady-state conditionshave been achieved. Some commentsstated that obtaining samples onconsecutive days may be impracticaland, for drugs with long half-lives, may be less sensitive to the establishment of steady state than data obtained over alonger period of time. The final rulerequires that
‘‘
appropriate dosageadministration and sampling should becarried out to document steady state.
’’
 Specific advice about dosageadministration and sampling may beobtained from the appropriate reviewdivision for the drug product.
III. Comments on the Proposed Rule
The agency received seven commentsfrom pharmaceutical companies,pharmaceutical company tradeassociations, and a law firm.
A. Inactive Ingredients
Section 314.94(a)(9) establishesinformation requirements for thechemistry, manufacturing, and controlssection of an abbreviated application.Section 314.94(a)(9)(ii) through (v)provides that an abbreviated applicationmay have different inactive ingredientsthan the reference listed drug as long asthe applicant identifies andcharacterizes the inactive ingredients inthe proposed drug product and providesinformation demonstrating that theinactive ingredients do not affect thesafety of the drug product. The agencyproposed to amend this section torecognize the possibility that the use of different inactive ingredients can alsoaffect a product
s efficacy.(Comment 1) We received severalcomments about the addition of theword
‘‘
efficacy.
’’
One comment said thischange is unnecessary becausedemonstrating bioequivalence providesproof of efficacy. One commentinterpreted the change as suggesting thatFDA is departing from its position that bioequivalence shows that the genericproduct is as effective as its referencelisted drug. This comment asked whatadditional proof of effectiveness FDAwould require. One comment agreedwith the proposed change and askedthat it apply to pending ANDA
s. Thiscomment also stated that animal testsshould not be used to demonstrate thatdifferent inactive ingredients do notaffect safety or efficacy because the actprohibits the use of animal or clinicalstudies to establish that the drug is safeor effective. Another commentexpressed concern that the need to showthat a different inactive ingredient doesnot affect safety or efficacy makes itmore difficult to get approval for ageneric topical drug product becauseclinical trials must be conducted.As stated in the proposed rule, byadding the word
‘‘
efficacy,
’’
the agencyacknowledges the possibility that theuse of different inactive ingredients canalso affect a product
s efficacy. FDA isnot departing from its position that ageneric product that demonstrates bioequivalence to the reference listeddrug has shown that it is as effective asthat reference listed drug.The agency disagrees with thecomment stating the animal tests shouldnot be used in the process of assessingthe safety or efficacy of inactiveingredients that differ from those in thereference listed drug. In the preamble tothe proposed ANDA regulations, theagency suggested that data from animalstudies might be used as limitedconfirmatory testing to support anANDA suitability petition or an ANDAresulting from such a petition (54 FR28872 at 28880, July 10, 1989). Thepreamble cited as an example the use of limited confirmatory testing to showthat an approved change in an activeingredient did not have acute effects onthe safety of the product. In similarfashion, animal studies may be usefuland appropriate to assist FDA inevaluating the safety or the effect onefficacy of a changed inactiveingredient.Section 314.127 (21 CFR 314.127) liststhe reasons why FDA will refuse toapprove an ANDA. The agencyproposed to revise
§
314.127(a)(8) toclarify that, consistent with current FDApolicy, the applicant must show thatdifferent inactive ingredients would notaffect a product
s efficacy.(Comment 2) One comment statedthat the proposed change is consistentwith FDA
s current policy when appliedto parenteral and ophthalmic dosageforms, but otherwise is inconsistentwith current policy. Another commentsaid this change is unnecessary becausedemonstrating bioequivalence providesproof of efficacy.As stated in the proposed rule, and inthe response to the previous comment,the addition of the word
‘‘
efficacy
’’
 simply clarifies the current FDAapproach rather than effecting asubstantive change.
B. Pharmaceutical Equivalents
Proposed
§
320.1(c) revised thedefinition of 
‘‘
pharmaceuticalequivalents
’’
with regard to drugproducts that contain a reservoir thatfacilitates delivery or where residualvolume may vary.(Comment 3) One comment approvedof the change. The final rule isunchanged from the proposed rule.
C. Manufacturing Site Change
Section 320.21(c)(1) provides that anyperson submitting a supplementalapplication to FDA must provideevidence or information regarding theproduct
s bioavailability or bioequivalence if the supplementalapplication proposes
‘‘
[a] change in themanufacturing process, including achange in product formulation or dosagestrength, beyond the variations providedfor in the approved application.
’’
Theagency proposed to amend thisprovision to include a change in themanufacturing site because such achange may affect the bioavailability or bioequivalence of the drug product because of equipment, personnel, orenvironmental changes.(Comment 4) Several commentsasserted that this proposed change isinconsistent with FDA
s guidance
‘‘
Immediate Release Solid Oral DosageForms
Scale-Up and Post-ApprovalChanges: Chemistry, Manufacturing andControls; In Vitro Dissolution Testingand In Vivo BioequivalenceDocumentation
’’
(November 1995)(SUPAC
IR guidance), which does notspecify a demonstration of  bioequivalence for level 1
3 changes.The comments recommended that anychange to the regulation be consistentwith the SUPAC
IR guidance.FDA believes that this change isconsistent with the SUPAC
IRguidance. The SUPAC
IR guidancedescribes the levels of changes,recommended tests, and filingdocumentation that ensure continuingproduct quality and performancecharacteristics of an immediate releasedosage form for specific postapprovalchanges. Depending on the level of change and the solubility andpermeability characteristics of the activedrug substance, the SUPAC
IR guidancerecommends different levels of in vitrodissolution tests and/or in vivo bioequivalence studies. The addition of a change in the manufacturing site to
VerDate 0ct<31>2002 15:15 Dec 18, 2002Jkt 200001PO 00000Frm 00019Fmt 4700Sfmt 4700E:\FR\FM\19DER1.SGM19DER1
 
77670
Federal Register
/Vol. 67, No. 244/Thursday, December 19, 2002/Rules and Regulations
§
320.21(c)(1) does not mean that theagency would require an in vivodemonstration of bioequivalence in thecircumstances provided for in theSUPAC
IR guidance. For manufacturingsite changes, dissolution testing alone isgenerally sufficient to ensure unchangedproduct quality and performance for animmediate release solid oral dosageform. FDA expects to continue to followthe SUPAC
IR guidance inimplementing
§
320.21(c)(1) as revised.
D. Delayed Release and Extended Release Terminology 
The agency proposed to amend
§
320.22(c) to change
‘‘
enteric coated
’’
to
‘‘
delayed release
’’
and
‘‘
controlledrelease
’’
to
‘‘
extended release.
’’
(Comment 5) One comment statedthat these terms should also be replacedin
§
320.22(d)(2)(iv).FDA agrees with this comment. Thefinal rule amends
§
320.22(d)(2)(iv) bychanging
‘‘
enteric coated
’’
to
‘‘
delayedrelease
’’
and
‘‘
controlled release
’’
to
‘‘
extended release.
’’
The final rule alsoamends
§§
320.1, 320.25(f),320.27(a)(3)(iv), 320.27(b)(2), 320.28,and 320.31 by changing
‘‘
controlledrelease
’’
to
‘‘
extended release.
’’
Toconform to these changes, the final rulealso amends
§
320.25(f) by changing
‘‘
noncontrolled release
’’
to
‘‘
nonextended release.
’’
E. Bioavailability Is Measured 
Section 320.24 describes the types of evidence needed to establish bioavailability or bioequivalence.Instead of stating that bioavailability isdemonstrated or established, the agencyproposed to use the word
‘‘
measured.
’’
(Comment 6) One comment objectedto this across-the-board change,asserting that it is not possible to get aquantitative measure of bioavailabilityfrom an acute pharmacological effect, awell-controlled clinical trial, or an invitro test. The comment suggested thatthe words
‘‘
demonstrated
’’
or
‘‘
established
’’
be used in discussingthese types of evidence.FDA disagrees with this comment.Bioavailability is an observationalmeasure that always results in aquantitative figure. Therefore, the finalrule will remain as it was proposed.
F. Subjects for Bioavailability Studies
The agency proposed to remove
§
320.25(a)(2) and redesignate
§
320.25(a)(3) as
§
320.25(a)(2). Current
§
320.25(a)(2) provides in part that
‘‘
[a]nin vivo bioavailability study shall not beconducted in humans if an appropriateanimal model exists and correlation of results in animals and humans has beendemonstrated.
’’
(Comment 7) One comment proposedthe following new first sentence forredesignated
§
320.25(a)(2):
‘‘
An in vivo bioavailability study shall ordinarily bedone in normal adults understandardized conditions.
’’
The commentstated that this sentence is a necessarylead-in for the existing text that refers tosituations in which bioavailabilitystudies may be conducted in patients.FDA agrees with this comment andhas included similar language in thefinal rule.
G. Drug Elimination Period 
Proposed
§
320.26(b)(2)(i) stated thatthe customary drug elimination periodshould be five times the half-life of theactive drug ingredient or therapeuticmoiety, or its active metabolite(s).(Comment 8) FDA received severalcomments on this section. Onecomment approved of the change fromthe three half-lives in the currentregulation, while another commentrecommended four half-lives. Onecomment disagreed with using half-lifemultiples to establish the duration of sampling because the terminal half-lifeis a function of the study design and thesensitivity of the assay and, in manycases, represents the elimination of small amounts of drug from deepcompartments. In those cases, a fivehalf-life requirement may greatlyoverestimate the time needed tomeasure the area under the curve (AUC)extrapolated to infinity. The commentrecommended that the rule state:
‘‘
Theduration of blood sampling should beadequate to insure that the measuredAUC represents at least 90% of AUC(infinity)
’’
(AUC
). Another comment,noting that many drugs exhibitmultiexponential serum concentration-time profiles, asked FDA to substitute
‘‘
97% of the AUC
’’
for
‘‘
five times thehalf-life.
’’
The agency recognizes that for a drugwith a long half-life, a drug eliminationperiod of five half-lives may beimpractically long. FDA has concludedthat a drug elimination period of threehalf-lives, which characterizesapproximately 88 percent of the AUC
,is sufficent. Therefore, the final ruleleaves
§
320.26(b)(2)(i) unchanged.(Comment 9) One comment suggestedthat
§
320.26(b)(2) should use analternative phrase such as
‘‘
washoutperiod
’’
or
‘‘
time between dosings
’’
 rather than the term
‘‘
drug eliminationperiod
’’
because that term could beconfused with the concept of drugelimination. FDA disagrees with thiscomment. The term
‘‘
drug eliminationperiod
’’
has been used in
§
320.26(b)(2)since the bioequivalence regulationswere finalized in 1992, and the agencyhas not found that it causes confusion.Drug elimination is the metabolicprocess that eliminates the drug fromthe body. The drug elimination periodis the time allowed for subjects to clearthe first drug from the body beforegiving the second drug. The term
‘‘
drugelimination period
’’
is retained in thefinal rule.
H. Sampling to Establish Steady State
Proposed
§
320.27(d)(1) and (d)(2)would have required sampling on 3 ormore consecutive days to establish thatsteady-state conditions have beenachieved whenever comparison of thetest product and the reference materialis to be based on blood concentration-time curves at steady state or urinaryexcretion-time curves at steady state.(Comment 10) Several commentssuggested deleting the word
‘‘
consecutive
’’
from
§
320.27(d)(1). Onecomment stated that drugs with longhalf-lives accumulate slowly and theuse of data from consecutive days forsuch drugs is less sensitive to theestablishment of steady state than dataobtained over a longer period of time.Another comment said that the 3
consecutive-day requirement is oftennot practical, particularly for urinarycollection, and proposed dosing drugsfor five to six half-lives or 1 week,whichever is longer, and then sampling blood or urine over one dosing interval.One comment agreed that it isappropriate to obtain samples on 3 ormore consecutive days. This commentstated that sometimes predose bloodconcentrations may be below the limitof quantitation; then it would not bepossible to confirm attainment of steadystate. The comment recommended thatthe predose collection time should be ata time when the blood drugconcentrations are in the reliable rangeof quantitation of the assay and will beidentical on all 3 days for all subjects.Another comment stated that theproposed change to
§
320.27(d)(1)reflects current practice, but that therequirement for consecutive-day data in
§
320.27(d)(2) is unnecessarilyrestrictive. This comment proposedeliminating the word
‘‘
consecutive
’’
andinstead saying
‘‘
to define adequately thepredose blood concentration on 3 ormore days (or doses) to establish thatsteady-state conditions are achieved.
’’
The agency has carefully consideredthese comments and has decided not torequire that sampling be done on 3 ormore consecutive days. Therefore, FDAhas revised
§
320.27(d)(1) and (d)(2) tostate that
‘‘
* * * appropriate dosageadministration and sampling should becarried out to document attainment of steady state.
’’
VerDate 0ct<31>2002 15:15 Dec 18, 2002Jkt 200001PO 00000Frm 00020Fmt 4700Sfmt 4700E:\FR\FM\19DER1.SGM19DER1

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->