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Federal Register / Vol. 49, No. 107 / Friday, June 1, 1984 .1 Rules and Regulations DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 630 [Docket No. 84N-0178] Additional Standards for Viral Vaccines; Poliovirus Vaccine, Live, Oral AGENCY: Food and Drug Administration. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the regulation governing testing of Poliovirus Vaccine, Live, Oral used in clinical trials performed for determining the antigenicity of the vaccine. The amendment eliminates the provision that the five lots of poliovirus vaccine used in clinical trials be manufactured as consecutive lots and that the five lots be shown to have satisfactory results in all prescribed tests. FDA is amending the regulation because of questions concerning the proper interpietation of clinical data used in the early 1960's as part of the basis for licensure of the sole Poliovirus Vaccine, Live, Oral, Trivalent product that is currently licensed for sale in the United States. The amendment also makes the requirements concerning clinical studies more flexible and consistent with current scientific knowledge. FDA will, however, continue to have authority to ensure that poliovirus vaccine used in clinical trials shows satisfactory results in all tests necessary to assure the safety, purity, and potency of the vaccine. DATES: Effective June 1, 1984; comments by July 31, 1984. ADDRESS: Written comments to the Dockets Management Branch (HFA- 305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Steven F. Falter, Center for Drugs and Biologics (formerly National Center for Drugs and Biologics) (HFN-368), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443- 1306., SUPPLEMENTARY INFORMATION: I. Background History of Poliomyelitis Vaccine Three monovalent f6rms of Poliovirus Vaccine, Live, Oral were first licensed for use in the United States in August 1961. A vaccine consisting of each of the monovalent forms, called Poliovirus Vaccine, Live, Oral, Trivalent (hereafter "oral poliovirus vaccine"), was licensed initially in June 1963. Since .introduction of the oral poliovirus vaccine, it has largely replaced the killed-virus, injectable vaccine, often called the "Salk Vaccine," as the vaccine of choice for the immunization of children. The selection of oral poliovirus vaccine as the principal polio vaccine in the United States has been made by virious public health organizations including the Committee on Infectious Diseases of the American Academy of Pediatrics (Ref. 1), the Immunization Practices Advisory Committee (Ref. 2), and a special expert committee of the Institute of Medicine, National Academy of Sciences (Ref. 3]. All 50 States require that children be immunized with oral poliovirus vaccine as a prerequisite to entering elementary school. Over 95 percent of the children entering school in the United States have completed primary immunization with oral polio.virus vaccine. Currently only one manufacturer holds a U.S. license for the manufacturer and sale of oral poliovirus vaccin6. The initial results of immunization with killed-virus, injectable poliovirus vaccine and subsequent results with oral poliovirus vaccine have been dramatic. In 1954, the last year before general immunization programs against polio began, over 18,000 cases of paralytic poliomyelitis were reported in the United States; in 1983, only 8 cases of paralytic poliomyelitis were reported (Ref. 4). Thus, concerted immunization programs, using an oral poliovirus vaccine which has been consistently safe and nearly 100 percent effective, have resulted in virtual elimination of paralytic poliomyelitis in the United States. However, several minor outbreaks of poliomyelitis, occurring in 1970, 1972, and 1979 in unimmunized populations in the United States and abroad, indicate the importance of maintaining the polio immunization programs in the United States. II. Amendments to 21 CFR 630.11 In addition to published general standards for all biological products and requirements contained in the license issued to the manufacturer, FDA's regulations contairi specific standards for the safety, purity, and potency of Poliovirus Vaccine, Live, Oral (both monovalent and trivalent). These additional standards are set forth in 21 CFR 630.10 through 630.17. The additional standards for oral poliovirus vaccine originally were issued on March 25, 1961, and were subsequently recodified in Title.21 of the Code of Federal Regulations. Section 630.11 of the additional standards contains requirements concerning clinical trials for determining the antigenicity of oral poliovirus vaccine that must be performed to qualify the vaccine for licensure. The antigenicity of a vaccine is its ability to induce the production of specific, protective antibodies in human recipients. These clinical trials are designed to demonstrate the effectiveness of the oral poliovirus vaccine. Included in § 630.11 is a requirement that the clinical trials be conducted using five consecutive lots of poliovirus vaccine, all manufactured by the same methods, and each of which has shown satisfactory results in all prescribed tests. FDA has determined that two amendments to this requirement should be made. A. The "Consecutive Manufacture" Requirement FDA is amending § 630.11 by removing the word "consecutive" so that the five lots of ordl poliovirus vaccine used in clinical trials need not be consecutively manufactured. This "cbnsecutive manufacture" requirement is contained in a number of additional standards for vaccines, and is intended generally to assure that the manufacturer can control the manufacturing process. The agency has concluded, however, that this requirement is unnecessary to assure the safety, purity, and potency of the oral poliovirus vaccine used in clinical trials and could be the cause of a meaningless waste of effort and vaccine by a manufacturer conducting clinical studies in the United States or abroad. The manufacture of a viral vaccine is a complex operation involving living organisms. Therefore, it is inevitable that occasionally an attempt to manufacture a safe, pure, and poteit oral poliovirus vaccine will be unsuccessful depite the use of good manufacturing practices. Under current § 630.11, a failure to manufacture successfully one lot could result in the consecutive sequence of lot manufacture being broken and the use of the remaining lots in a clinical trial would be prohibited. Thus, the lots of vaccine that were properly manufactured would be wasted and any clinical studies already under way would not be acceptable to FDA because they would not comply with § 630.11. There Is, however, no scientific justification for rejecting the use of such lots of vaccine in clinical studies or the results of such studies. FDA has therefore concluded that the requirement that the five lots 23004 HeinOnline -- 49 Fed. Reg. 23004 1984

HHS & FDA 1984

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In 1984 the Department of Health and Human Services along with the Food and Drug Administration ruled, “…any possible doubts, whether or not well founded, about the safety of the vaccine cannot be allowed to exist in view of the need to assure that the vaccine will continue to be used to the maximum extent consistent with the nation’s public health objectives” (HHS, 1984).This statement by our health authority clearly indicates they are biased, and driven by a utilitarian philosophy.

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Federal Register / Vol. 49, No. 107 / Friday, June 1, 1984 .1 Rules and Regulations

DEPARTMENT OF HEALTH ANDHUMAN SERVICESFood and Drug Administration21 CFR Part 630[Docket No. 84N-0178]

Additional Standards for ViralVaccines; Poliovirus Vaccine, Live,OralAGENCY: Food and Drug Administration.ACTION: Final rule.

SUMMARY: The Food and DrugAdministration (FDA) is amending theregulation governing testing ofPoliovirus Vaccine, Live, Oral used inclinical trials performed for determiningthe antigenicity of the vaccine. Theamendment eliminates the provisionthat the five lots of poliovirus vaccineused in clinical trials be manufacturedas consecutive lots and that the five lotsbe shown to have satisfactory results inall prescribed tests. FDA is amendingthe regulation because of questionsconcerning the proper interpietation ofclinical data used in the early 1960's aspart of the basis for licensure of the solePoliovirus Vaccine, Live, Oral, Trivalentproduct that is currently licensed forsale in the United States. Theamendment also makes therequirements concerning clinical studiesmore flexible and consistent withcurrent scientific knowledge. FDA will,however, continue to have authority toensure that poliovirus vaccine used inclinical trials shows satisfactory resultsin all tests necessary to assure thesafety, purity, and potency of thevaccine.DATES: Effective June 1, 1984; commentsby July 31, 1984.ADDRESS: Written comments to theDockets Management Branch (HFA-305), Food and Drug Administration, Rm.4-62, 5600 Fishers Lane, Rockville, MD20857.FOR FURTHER INFORMATION CONTACT:Steven F. Falter, Center for Drugs andBiologics (formerly National Center forDrugs and Biologics) (HFN-368), Foodand Drug Administration, 5600 FishersLane, Rockville, MD 20857, 301-443-1306.,SUPPLEMENTARY INFORMATION:I. Background History of PoliomyelitisVaccine

Three monovalent f6rms of PoliovirusVaccine, Live, Oral were first licensedfor use in the United States in August1961. A vaccine consisting of each of themonovalent forms, called PoliovirusVaccine, Live, Oral, Trivalent (hereafter

"oral poliovirus vaccine"), was licensedinitially in June 1963.

Since .introduction of the oralpoliovirus vaccine, it has largelyreplaced the killed-virus, injectablevaccine, often called the "Salk Vaccine,"as the vaccine of choice for theimmunization of children. The selectionof oral poliovirus vaccine as theprincipal polio vaccine in the UnitedStates has been made by virious publichealth organizations including theCommittee on Infectious Diseases of theAmerican Academy of Pediatrics (Ref.1), the Immunization Practices AdvisoryCommittee (Ref. 2), and a special expertcommittee of the Institute of Medicine,National Academy of Sciences (Ref. 3].All 50 States require that children beimmunized with oral poliovirus vaccineas a prerequisite to entering elementaryschool. Over 95 percent of the childrenentering school in the United Stateshave completed primary immunizationwith oral polio.virus vaccine. Currentlyonly one manufacturer holds a U.S.license for the manufacturer and sale oforal poliovirus vaccin6.

The initial results of immunizationwith killed-virus, injectable poliovirusvaccine and subsequent results withoral poliovirus vaccine have beendramatic. In 1954, the last year beforegeneral immunization programs againstpolio began, over 18,000 cases ofparalytic poliomyelitis were reported inthe United States; in 1983, only 8 casesof paralytic poliomyelitis were reported(Ref. 4). Thus, concerted immunizationprograms, using an oral poliovirusvaccine which has been consistentlysafe and nearly 100 percent effective,have resulted in virtual elimination ofparalytic poliomyelitis in the UnitedStates. However, several minoroutbreaks of poliomyelitis, occurring in1970, 1972, and 1979 in unimmunizedpopulations in the United States andabroad, indicate the importance ofmaintaining the polio immunizationprograms in the United States.II. Amendments to 21 CFR 630.11

In addition to published generalstandards for all biological products andrequirements contained in the licenseissued to the manufacturer, FDA'sregulations contairi specific standardsfor the safety, purity, and potency ofPoliovirus Vaccine, Live, Oral (bothmonovalent and trivalent). Theseadditional standards are set forth in 21CFR 630.10 through 630.17. Theadditional standards for oral poliovirusvaccine originally were issued on March25, 1961, and were subsequentlyrecodified in Title.21 of the Code ofFederal Regulations.

Section 630.11 of the additionalstandards contains requirementsconcerning clinical trials for determiningthe antigenicity of oral poliovirusvaccine that must be performed toqualify the vaccine for licensure. Theantigenicity of a vaccine is its ability toinduce the production of specific,protective antibodies in humanrecipients. These clinical trials aredesigned to demonstrate theeffectiveness of the oral poliovirusvaccine. Included in § 630.11 is arequirement that the clinical trials beconducted using five consecutive lots ofpoliovirus vaccine, all manufactured bythe same methods, and each of whichhas shown satisfactory results in allprescribed tests. FDA has determinedthat two amendments to thisrequirement should be made.A. The "Consecutive Manufacture"Requirement

FDA is amending § 630.11 byremoving the word "consecutive" sothat the five lots of ordl poliovirusvaccine used in clinical trials need notbe consecutively manufactured. This"cbnsecutive manufacture" requirementis contained in a number of additionalstandards for vaccines, and is intendedgenerally to assure that themanufacturer can control themanufacturing process. The agency hasconcluded, however, that thisrequirement is unnecessary to assurethe safety, purity, and potency of theoral poliovirus vaccine used in clinicaltrials and could be the cause of ameaningless waste of effort and vaccineby a manufacturer conducting clinicalstudies in the United States or abroad.

The manufacture of a viral vaccine isa complex operation involving livingorganisms. Therefore, it is inevitablethat occasionally an attempt tomanufacture a safe, pure, and poteitoral poliovirus vaccine will beunsuccessful depite the use of goodmanufacturing practices. Under current§ 630.11, a failure to manufacturesuccessfully one lot could result in theconsecutive sequence of lot manufacturebeing broken and the use of theremaining lots in a clinical trial wouldbe prohibited. Thus, the lots of vaccinethat were properly manufactured wouldbe wasted and any clinical studiesalready under way would not beacceptable to FDA because they wouldnot comply with § 630.11. There Is,however, no scientific justification forrejecting the use of such lots of vaccinein clinical studies or the results of suchstudies. FDA has therefore concludedthat the requirement that the five lots

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used in clinical trials be of consecutivemanufacture is unnecessarily restrictive.

The agency believes that any five lotsof poliovirus vaccine manufacturedusing the same methods, regardless ofthe sequence of manufacture, areappropriate for use in clinical trials todemonstrate antigenicity. Indeed, theremay be some scientific advantages toconducting clinical trials using oralpoliovirus vaccine that has beenmanufactured over a long period of time.FDA believes that clinical trialsconducted using vaccine manufacturedover several years, rather than severalmonths, may provide a better indicationof the manufacturer's ability to produceconsistently a fully safe and antigenicvaccine.

The agency emphasizes that thisamendment will not affect the regulatoryrequirements for the consistency ofmanufacture of licensed oral poliovirusvaccine for commercial use. FDA willcontinue to impose the requirements in§ 630.17(b) for the release of individuallots of vaccine. These requirementsinclude the requirement that each lot beone of five consecutive lots that havebeen manufactured satisfactorily. Inaddition, FDA inspections ofmanufacturing facilities will assure theconsistency of manufacture of licensedoral poliovirus vaccine.

In addition to assuring the continuedsafety, purity, and potency of oralpoliovirus vaccine used in clinical trials,the amendment will providemanufacturers greater flexibility inscheduling clinical trials. Theopportunity to conduct clinical trials of avaccine is often limited by such factorsas difficulty in identifying a suitable,unimmunized test population and ashortage of qualified clinical scientiststo conduct the trials. By removing theconsecutive lot requirement, thesponsoring manufacturer will havegreater.flexibility in selecting theappropriate times and opportunities forconducting the required clinical trials.

The agency further notes that, sincethe agency first issued § 630.11, anumber of clinical studies have beenperformed in other countries todemonstrate the antigenicity of variousoral poliovirus vaccines. Some of thestudies were performed to qualify thevaccine for approval in the host nation.Other clinical studies have beenperformed on approved oral poliovirusvaccines to assure that the vaccinecontinues to display adequateantigenicity in humans. FDA hasdetermined that many of these clinicalstudies provide an appropriatedemonstration of the antigenicity of thevaccine. Therefore, FDA should be ableto rely on the data from these clinical

trials as part of the basis for approvingU.S. licensure of the manufactureres oralpoliovirus vaccine. However, becausethese studies generally were notperformed on five consecutive lots ofvaccine, the studies would not meet therequirements of § 630.11. By removingthe "consecutive manufacture"requirement, in addition to theamendment discussed later in thispreamble, FDA can accept appropriateclinical studies performed in othercountries as part of the basis ofapproval for U.S. licensure.B. The Testing Requirement

FDA is also amending § 630.11 byremoving the provision that the five lotsof oral poliovirus vaccine used in therequired clinical trials each showsatisfactory results in all prescribedtests.

This change is prompted by questionsconcerning whether all lots ofpoliovirous vaccine used in clinicaltrials in 1961 and 1962 as a basis for thecurrently licensed oral poliovirusvaccine showed satisfactory results inseveral tests. This change will alsofacilitate FDA's ability to rely on oralpoliovirous vaccine clinical studiesperformed in other nations.

In tort litigation involving the Federalgovernment and private parties,questions have been raised concerningwhether some of the lots of vaccine usedin the 1961 and 1962 clinical trials metthe test standard for neurovirulenceprescribed in § 630.16(b)(1). The purposeof the neurovirulence tests, which isperformed in monkeys, is to assure thatthe live virus used in the oral poliovirusvaccine is properly attenuated(nonvirulent). In 1962, the reviewingscientists in the Public Health Service,the responsible regulating agency at thattime, judged that the test resultsdemonstrated that the poliovirusvaccine used in clinical trials forantigenicity was of acceptably lowneurovirulence.

FDA has reviewed the data and hasconcluded that, although there may be aquestion as to whether the results of allof the neurovirulence tests met thestandard in the regulations, there is nodoubt that the oral poliovirus vaccineused in the clinical trials involving195,000 subjects was of acceptably lowneurovirulence. FDA's conclusion wasconfirmed by an FDA advisorycommittee, the Panel on Review of ViralVaccines and Rickettsial Vaccines,which, as part of its general review ofthe safety and effectiveness of viralvaccines, reexamined the datasupporting the licensure of the currentlyavailable oral poliovirus vaccine. Asstated in its final report published in the

Federal Register of April 15.1930 (45 FR25652), the panel found that the data metthe requirements of § 630.11 and foundthe vaccine to be fully safe andeffective.

Nevertheless, for the oral poliovirusvaccine used in the initial clinical trials,the results of the test for monkeyneurovirulence are open tointerpretation and might be considerednot to meet the specific terms of§ 630.16[b)(1). Continued uncertaintyabout whether technical conformity withthis requirement was achieved when thelicense was first issued couldunjustifiably diminish public confidencein the proven safety of the vaccine andthe vital public health program to which -it is indispensable. Because the vaccineused in the initial clinical trials was notneurovirulent in the subjects tested andbecause the oral poliovirus vaccinecurrently in use in the United States issafe and effective, FDA has concludedthat it is in the best interest of the publichealth to amend § 630.11 to eliminate-the unnecessary requirement that thevaccine used in clinical trials showsatisfactory results in all testsapplicable to lots used in clinical trials.and thus avert any possible loss ofconfidence in the polio immunizationprogram.

The agency emphasizes that there isno basis for concern about the actualsafety of oral poliovirus vaccine. Thebest indication of the lowneurovirulence of licensed oralpoliovirus vaccine is the history of itsuse. It is characteristic of any live oralpoliovirus vaccine that, in rareinstances, the vaccine recipient or aclose contact of the vaccine recipientwill contract paralytic poliomyelitis.During the clinical trials conducted priorto licensure, no cases of paralyticpoliomyelitis associated with thevaccine were reported. For many years,the Centers for Disease Control (CDC] ofthe Public Health Service have closelymonitored the incidence of poliomyelitisin the United States, including theincidence of poliomyelitis in the UnitedStates. including the incidence ofvaccine-associated paralyticpoliomyelitis. In the 12-year period 1969through 1980, approximately 290 milliondoses of oral poliovirus vaccine weredistributed and 92 cases of paralyticpoliomyelitis associated with thevaccine were reported to CDC (1 caseper 3.3 million doses distributed). In1933, a total of eight cases of paralyticpoliomyelitis were reported to CDC. In1982, the World Health Organization(WHO) Consultive Group on LivePoliomyelitis Vaccine (Sabin Strains)published a 10-year study comparing the

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incidence of vaccine-associatedpoliomyelitis among 13 nations (Ref. 5).'The study shows that the safety(neurovirulence) of the vaccine used inthe United States compares favorablywith that of the oral poliovirus vaccinesused by other nations in the study.Accordingly, FDA finds that the lowneurovirulence of the currently licensedoral poliovirus vaccine has beendemonstrated thoroughly throughout itshistory of manufacture.

The agency further emphasizes thatthis amendment will not compromise thesafety, purity, or potency of oralpoliovirus vaccine used in any futureclinical trials. The agency has authorityunder the licensing provisions of thePublic Health Service Act (42 U.S.C.262(a)) to ensure the safety, purity, andpotency of the poliovirus vaccine usedin clinical trials. Section 601.2 of FDA'sregulations (21 CFR 601.2) requires that,to obtain a license, manufacturerssubmit "data derived from nonclinicallaboratory and clinical studies whichdemonstrate that the manufacturedproduct meets prescribed standards ofsafety, purity, and potency * * Inaddition, under the applicablerequirements of 21 CFR Part 312 ofFDA's investigational new drugregulations, FDA will continue to assurethat an investigational oral poliovirusvaccine has been shown by appropriatemethods to be ofacceptably lowneurovirulence and otherwise safe foradministration to humans before " '

permitting its use in a clinical trial in theUnited States.

FDA believes that pliminating therequirement that the oral poliovirusvaccine used in clinical trials showsatisfactory results in all prescribedtests will also facilitate FDA's ability torely on clinical trials performed inforeign countries in support of an -application for a U.S. license. Theseclinical trials are usually performed inaccordance with the applicableregulations of the foreign country inwhich the study is conducted and theWHO's requirements for oral poliovirusvaccine (Ref. 6). The regulationssometimes differ in certain technicalrespects from FDA's regulations, and therevision of FDA's regulations willenable FDA to accept clinical trials thathave been performed using a vaccinethat has been shown to be of adequatesafety, but has not been subjected Jo theprecise battery of tests required by FDAfor clinical trials. Such clinical trialswould also be required to meet FDA'sregulations concerning foreign clinicalstudies of investigational new drugs(§ 312.20; see also proposed § 312.120published as part of a proposal to revise

Part 312 in the Federal Register of June9,1983 (48 FR 26720)).

FDA again emphasizes that thisamendment will not change therequirements that apply to themanufacture of licensed oral poliovirusvaccine. FDA will continue to requirethat each lot of licensed oral poliovirusvaccine meet the lot release criteria of§ 630.17(b), including the requirementsthat each monovalent pool contained inthe vaccine be one of five consecutivepools meeting the criteria ofneuovirulence for monkeys in§ 630.16(b)(1),and for in vitro markersprescribed in § 630.16(b)(3).

For many years, because of carefulselection by the vaccine manufacturersof virus seed strains for use in thevaccine, licensed oral poliovirus vaccinehas demonstrated a markedly lowneurovirulence and, if properlymanufactured, can readily meet therequirements of § 630.16(b)(1).Continuation of the current lot releaserequirements will assure consistency ofmanufacture of the licensed product.

At a later time, FDA intends topublish a proposed rule to revise theadditional standards for other viralvaccines, consistent with theamendments made to § 630.11 in' thisfinal rule. The additional standards forMeasles, Mumps, Rubella, and Measles-Smallpox Vaccines contained in§ § 630.31, 630.51, 630.61, and 630.81,respectively, inlucde provisions similarto those in § 630.11. FDA believes it isappropriate to amend those sectionsconsistent with the amendments madeto § 630.11. However, FDA finds thatthese amendments are not immediatelynecessary for the protection of thepublic health and, in order to expeditethe revisions for oral poliovirus vaccine,will initiate procedures for revising theadditional standards for the other viralvaccines at a later date.III. References.

The following information has beenplaced on display in the DocketsManagement Branch (address above)and may be seen by interested personsbetween 9 a.m. and 4 p.m., Mondaythrough Friday.1. American Academy of Pediatrics, "Report

of the Committee on InfectiousDiseases," 19th Ed., Evanston, IL 1982.

2. "Recommendation of the Immunizatio'-Practices Advisory Committee (ACIP)-Poliomyelitis Prevention," Morbidity andMortality Weekly Report, 31:12-34,1982.

3. Nightingale, E. L., "Recommendations for aNational Policy on PoliomyelitisVaccination," The New England fournal

'of.Medicine, 297:249-253.1977.4. Centers for Disease Control, "Corrected

Cumulative 1983 Totals for Tables I and

II," Morbidity and Mortality WeeklyReport. 33:63. 1984.

5. WHO Consultive Group, "The RelationBetween Acute Persisting SpinalParalysis and Poliomyelitis Vaccine--Results of a Ten-Year Enquiry," Bulletinof the World Health Organization,60(2):231-242,1982.

6. WHO Expert Committee on BiologicalStandardization, "Requirements forPoliomyelitis Vaccine (Oral): Thirty-Third Report," Technical Report Series687. pp. 107-174,1983.

IV. Economic, Environmental, andProcedural Considerations

The agency has determined pursuantto 21 CFR 25.24(d)(10) (proposedDecember 11, 1979; 44 FR 71742) that thisaction is of a type that does notindividually or cumulatively have asignificant impact on the humanenvironment. Therefore, neither anenvironmental assessment nor anenvironmental impact statement isrequired.

The agency has examined theeconomic impact of this rule and hasdetermined that it does not requireeither a regulatory impact analysis, asspecified in Executive Order 12291, or aregulatory flexibility analysis, asdefined in the Regulatory Flexibility Act(Pub. L. 96-354). The amendmentremoves unnecessary restrictions fromthe regulations and makes theregulations more consistent with currentscientific knowledge. Therefore, theagency concludes that this final rule isnot a major rule as defined in ExecutiveOrder 12291. One large manufacturer isaffected by the regulation. Accordingly,the agency certifies that even if this rulewere subject to the RegulatoryFlexibility Act because it was precededby a proposed rule, it will not have asignificant economic impact on asubstantial number of small entities, asthese terms are used in the RegulatoryFlexibility Act. This rule does notimpose any paperwork requirements,

Under the Administrative ProcedureAct (5 U.S.C. 553(b) and (d)), FDA findsthat notice, public procedure, anddelayed effective date for theamendment of § 630.11 are contrary tothe public interest. Section 553(b)(B)

..provides that the notice and commentprovisions in section 553(b) are notrequired to be followed where th6agency "for good cause finds (andincorporates the finding and a briefstatement of reasons therefor in therules issued) that notice and publicprocedure thereon are impracticable,unnecessary, or contrary to the publicinterest." Section 553(d) allows tinagency to make a rule effective less than30 days after publication if it relieves a

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restriction or the agency otherwise findsgood cause for the earlier effective date.

FDA believes that delaying the changemade by the amendment to § 630.11would be contrary to the public interest.As discussed above, questions havebeen raised in litigation about whetherthe vaccine used in the clinical trialsconducted in 1962 for the approval of thesole license for oral poliovirus vaccinemet all of the technical requirements in§ 630.11. FDA believes it is in theinterest of the public health to make theamendment effective as soon aspossible to make certain that questionsconcerning whether the vaccine lotsused in the original clinical trialstechnically conformed with therequirements of the additional standardsin 21 CFR 630.10 to 630.17 do not castdoubt on the safety of the vaccine andon the continued viability of the polioimmunization program. As noted above,oral poliovirus vaccine is the vaccine ofchoice in the United States. As a resultof the use of the vaccine, cases ofparalytic poliomyelitis have beenreduced from 18,000 in 1953 to only 8cases in 1983. Moreover, the severalminor outbreaks of poliomyelitis arisingin 1970,1972, and 1979 in unimmunizedpopulations in the United States andabroad make clear that theimmunization program is essential to theprotection of the public health. FDAemphasizes that the lots used in theclinical trials submitted in support of thelicense were properly judged to be safefor purposes of the initial licensuredecision and that, in view of thetechnical nature of any possible

.deficiencies in the lots, FDA does notbelieve, that action to revoke the licenseunder § 601.5 is warranted. However,although the continued availability ofthe vaccine may not be in immediate

jeopardy, any possible doubts, whetheror not well founded, about the safety ofthe vaccine cannot be allowed to existin view of the need to assure that thevaccine will continue to be used to themaximum extent consistent with thenation's public health objectives.Accordingly, because of the importanceof the vaccine and of maintaining publicconfidence in the immunization programthat depends on it, good cause emsts toissue these amendments as a final ruleeffective immediately. The fact that theamendment relieves a restriction alsojustifies making the rule effectiveimmediately.List of Subjects in 21 CFR Part 630

Biologics.Therefore, under the Federal Food,

Drug, and Cosmetic Act (secs. 201, 502.505, 701, 52 Stat. 1040-1042 as amended.1050-1053 as amended, 1055-1056 asamended by 70 Stat. 919 and 72 Stat. 948(21 U.S.C. 321, 352, 355, 371)), the PublicHealth Service Act (sec. 351, 58 Stat. 702as amended (42 U.S.C. 262)), and theAdministrative Procedure Act (secs. 4,10, 60 Stat. 238 and 243 as amended (5U.S.C. 553, 701-708)) and under authoritydelegated to the Commissioner of Foodand Drugs (21 CFR 5.10), Part 630 isamended by revising § 630.11, to read asfollows:

PART 630-ADDITIONAL STANDARDSFOR VIRAL VACCINE§ 630.11 Clinical trials to qualify forlicense.

To qualify for license, the antigenicityof the vaccine shall have beendetermined by clinical trials of adequatestatistical design conducted incompliance with Part 56 of this chapterunless exempted under § 56.104 or

granted a waiver under § 55.105, andwith Part 50 of this chapter. Suchclinical trials shall be conducted withfive lots of poliovirus vaccine whichhave been manufactured by the samemethods. Type specific neutralizingantibody shall be induced in 80 percentor more of susceptibles whenadministered orally as a single dose, orin 90 percent or more of susceptibleswhen administered orally after a seriesof doses. A separate clinical trial shallhave been conducted for eachmonovalent and each polyvalentvaccine for which a license applicationis made.

Interested persons may, on or beforeJuly 31,1934, submit to the DocketsManagement Branch (address above]written comments regarding thisrulemaking. Two copies of anycomments are to be submitted, exceptthat individuals may submit one copy.Comments are to be identified with thedocket number found in brackets in theheading of this document. Suchcomments will be considered indetermining whether the amendmentmade in this document should bemodified. Received comments may beseen in the office above between 9 a.m.and 4 p.m., Monday through Friday.

Effective date. This regulation iseffective June 1,1984.(Secs. Z.01. 502 505,701.52 Stat. 1040-1042 asamended. 1050-1053 as amended. 1035-1036as amended by 70 Stat 919 and 72 StaL M4g(21 U.S.C. 321. 352. 355, 371); se. 351.53 StaL702 as amended (42 U.S.C. 2621; secs. 4,10, 60StaL 238 and 243 as amended (5 US.C. 553.701-70))

Dated. May 29, 194.Mark Nolvitch.Acting ConmssionerofFoadandDrugs.

ir D:. e4lO F41.0t51-C44.O Ff1B!WHS~ COce 4160,-01-U

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Heather White