Vol. 59
`
`No. 216
`
`Wednesday
`November 9,1994
`
`United States
`G overnm ent
`Printing Office
`SUPERINTENDENT
`OF DOCUMENTS
`Washington, DC 20402
`
`OFFICIAL BUSINESS
`Penalty for private use, $300
`
`SECOND CLASS NEWSPAPER
`Postage and Fees Paid
`U.S. Government Printing Office
`(ISSN 0097-6326)
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`“
`
`11-9-94
`No. 216
`Vol. 59
`Pages 55807-55984
`
`Wednesday
`November 9, 1994
`
`Briefings on How To Use the Federal Register
`For information on briefings in New York. NY and
`Washington, DC. see announcement on the inside cover
`of this issue.
`
`
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`II
`
`: Federal Register / Vol. 59, No. 216 / Wednesday, November 9, 1994
`
`FEDERAL REGISTER Published daily, Monday through Friday,
`(not published on Saturdays, Sundays, or on official holidays), by
`the Office of the Federal Register, National Archives and Records
`Administration, Washington, DC 20408, under the Federal Register
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`

`

`Contents
`
`Agricultural Marketing Service
`RULES
`Peanuts, domestically produced, 55808-55810
`
`Agriculture Department
`See Agricultural Marketing Service
`See Forest Service
`See Rural Telephone Bank
`NOTICES
`Agency information collection activities under OMB
`review, 55830
`
`Civil Rights Commission
`NOTICES
`Meetings; State advisory committees:
`Nevada, 55833
`
`Coast Guard
`PROPOSED RULES
`Vessel identification system:
`Expanded hull identification number and certificates of
`origin requirements
`Workshop, 55823-55824
`NOTICES
`Great Lakes icebreaking requirements; review and comment
`request, 55906-55907
`
`Commerce Department
`See National Oceanic and Atmospheric Administration
`NOTICES
`Agency information collection activities under OMB
`review, 55833-55834
`
`Committee for the Implementation of Textile Agreements
`NOTICES
`Cotton, wool, and man-made textiles:
`Indonesia, 55834-55836
`Sri Lanka, 55834
`
`Commodity Futures Trading Commission
`NOTICES
`Meetings; Sunshine Act, 55908
`
`Consumer Product Safety Commission
`NOTICES
`Settlement agreements:
`Concord Enterprises, Inc., 55836-55838
`
`Drug Enforcement Administration
`NOTICES
`Applications, hearings, determinations, etc.:
`Johnson Matthey, Inc., 55856-55857
`
`Employment and Training Administration
`NOTICES
`Meetings:
`Apprenticeship Federal Committee, 55857
`
`Energy Department
`See Federal Energy Regulatory Commission
`
`Federal Register
`Vol. 59, No. 216
`Wednesday, November 9, 1994
`
`III
`
`Environmental Protection Agency
`RULES
`Air programs:
`Stratospheric ozone protection—
`Refrigerant recycling, 55912-55927
`Clean Air Act:
`State operating permits programs—
`Washington, 55813-55820
`PROPOSED RULES
`Air pollution control; new motor vehicles end engines:
`Gasoline spark-ignition and diesel compression-ignition
`marine engines; emission standards, 55930-55966
`Air quality implementation plans; approval and
`promulgation; various States:
`Connecticut, 55824-55826
`NOTICES
`Agency information collection activities under OMB
`review, 55843-55844
`Executive Office of the President
`See Presidential Documents
`Federal Aviation Administration
`RULES
`Class D airspace, 55810-55811
`Federal Communications Commission
`PROPOSED RULES
`Radio services, special:
`Amateur services—
`Visiting foreign amateur operators; licensing procedure;
`termination, 55828-55829
`Federal Energy Regulatory Commission
`NOTICES
`Environmental statements; availability, etc«
`Grand River Dam Authority, 55841-55842
`Hydroelectric applications, 55842-55843
`Applications, hearings, determinations, etc.:
`Acme Power Marketing, Inc., 55840
`Algonquin Gas Transmission Co., 55839
`Iroquois Gas Transmission System, L.P., 55840-55841
`NorAm Gas Transmission Co., 55839
`Texas Eastern Transmission Corp., 55840
`Transcontinental Gas Pipe Line Corp., 55838, 55841
`Trunkline Gas Co., 55838
`Williston Basin Interstate Pipeline Co., 55839-55840
`Federal Maritime Commission
`PROPOSED RULES
`Manne earners in domestic offshore commerce:
`Coloading practices by non-vessel operating common
`earners; shipper affiliate access to service contracts,
`55826-55828
`Federal Railroad Administration
`NOTICES
`Grants and cooperative agreements; availability, etc.:
`Next generation high-speed rail program, 55907
`Federal Reserve System
`NOTICES
`Meetings; Sunshine Act, 55908-55909
`
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`IV
`
`Federal Register / Vol. 59, No. 216 / W ednesday, November 9, 1994 / Contents
`
`Applications, hearings, determinations, etc.:
`Banterra Corp., 55844
`FCNB Corp. et al., 55844
`
`Federal Trade Commission
`NOTICES
`Competition and consumer protection order duration;
`policy statement and comment request, 55844-55845
`
`Fish and Wildlife Service
`n o tic e s
`Endangered and threatened species permit applications,
`55851-55852
`Environmental statements; availability, etc.:
`Incidental take permits—
`Barton Creek Development, Travis County, TX; golden­
`cheeked warbler, 55852
`
`Food and Drug Administration
`NOTICES
`Debarment orders:
`Copanos, John D., 55846-55847
`Harmonisation International Conference; guidelines
`availability:
`Dose-response information to support drug registration,
`55972-55976
`Medical devices; premarket approval:
`Sonic Accelerated Fracture Healing System (SAFHS),
`55847-55848
`
`f
`
`"
`
`Forest Service
`NOTICES
`Appealable decisions; legal notice:
`Southern region, 55830—55833
`Health and Human Services Department
`S e e Food and Drug Administration
`See National Institutes of Health
`NOTICES
`Privacy Act:
`Systems of records, 55845—55846
`Housing and Urban Development Department
`NOTICES
`Grant and cooperative agreement awards:
`Public and Indian housing—
`Crime prevention through environmental design
`program, 55849—55850
`Public housing resident patrol training of trainers and
`technical assistance program, 55849
`
`-
`
`Immigration and Naturalization Service
`ru les
`Nonimmigrant classes:
`Temporary alien workers seeking H—IB, O and P
`classifications
`Correction, 55910
`
`Indian Affairs Bureau
`NOTICES
`Tribal-State Compacts approval; Class III (casino) gambling:
`Choctaw Indians, MS, 55970
`Tonkawa Tribe, OK, 55968
`
`Interior Department
`See Fish and Wildlife Service
`See Indian Affairs Bureau
`See Land Management Bureau
`
`International Trade Commission
`NOTICES
`Import investigations
`Drawer slides from—
`China, 55852-55853
`Import investigations:
`Diltiazem hydrochloride and diltiazem preparations,
`55854
`Disposable lighters from—
`Thailand, 55853-55854
`Lamb meat—
`Competitive conditions affecting U.S. and foreign lamb
`industries, 55854—55855
`fylicrosphere adhesives, process for making same,
`including self-stick repositionable notes, 55855
`Wheel inserts from—
`Taiwan, 55856
`Interstate Commerce Commission
`NOTICES
`Environmental statements; availability, etc.:
`Atchison, Topeka & Santa Fe Railway Co. et al., 55856
`
`Justice Department
`See Drug Enforcement Administration
`See Immigration and Naturalization Service
`
`Labor Department
`See Employment and Training Administration
`See Veterans Employment and Training, Office of Assistant
`Secretary
`See Workers’ Compensation Programs Office
`
`Land Management Bureau
`RULES
`Public land orders:
`Arizona, 55821
`Wyoming, 55820-55821
`NOTICES
`Closure of public lands:
`Colorado, 55850—55851
`Realty actions; sales, leases, etc.:
`Oregon, 55851
`Library of Congress
`RULES
`Procedures and services:
`Name, seal, or logo use; credit and recognition policy,
`55811-55813
`National Aeronautics and Space Administration
`NOTICES
`Patent licenses; non-exclusive, exclusive, or partially
`exclusive:
`Pacific Scientific Co., 55859
`Veatronics Corp., 55859
`
`National Institutes of Health
`NOTICES
`Meetings:
`Research Grants Division special emphasis panels,
`55848-55849
`National Oceanic and Atmospheric Administration
`RULES
`Fishery conservation and management:
`Bering Sea and Aleutian Islands groundfish, 55822
`Summer flounder; correction, 55821-55822
`
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`Federal Register / Vol. 59, No. 216 / W ednesday, November 9, 1994 / Contents
`
`V
`
`Tuna, Atlantic bluefin fisheries, 55821
`National Science Foundation
`NOTICES
`Agency information collection activities under OMB
`review, 55860
`Meetings; Sunshine Act, 55909
`
`Nuclear Regulatory Commission
`NOTICES
`Agency information collection activities under OMB
`' review, 55860
`Environmental statements; availability, etc.:
`Illinois Power Co. et al., 55864-55865
`Philadelphia Electric Co., 55863-55864
`Operating licenses, amendments; no significant hazards
`considerations; biweekly notices, 55865-55900
`Petitions; Director’s decisions:
`Southern California Edison Co. et al., 55900-55901
`Regulatory guides; issuance, availability, and withdrawal,
`55901
`Applications> hearings, determinations, etc,:
`Baltimore Gas & Electric Co., 55861
`Commonwealth Edison Co., 55860-55861
`Old Forge Testing Co., 55862-55863
`Personnel Management Office
`RULES
`Voluntary separation incentive payments repayment;
`waiver, 55807-55808
`Presidential Documents
`PROCLAMATIONS
`Special observances:
`American Indian Heritage Month, National (Proc. 6756),
`55983-55984
`Women Veterans Recognition Week, National (Proc.
`6755), 55981
`ADMINISTRATIVE ORDERS
`Foreign Operations, Export Financing, and Related
`Programs Appropriations Act; memorandum to
`Secretary of State (Presidential Determination No. 9 5 -
`2 of November 1, 1994), 55979
`Public Health Service
`See Food and Drug Administration
`See National Institutes of Health
`Railroad Retirement Board
`NOTICES
`Agency information collection activities under OMB
`review, 55901
`Meetings; Sunshine Act, 55909
`
`*
`
`Rural Telephone Bank
`NOTICES
`Meetings; Sunshine Act, 55908
`
`Securities and Exchange Commission
`NOTICES
`Investment companies; deregistration:
`Jupiter National, Inc., 55905
`Self-regulatory organizations; proposed rule changes:
`National Association of Securities Dealers, Inc., 55905-
`55906
`Applications, hearings, determinations, etc.:
`Action Performance Companies, Inc., 55902
`
`PMC Capital, Inc., 55904-55905
`TSX Corp., 55902
`Weatherford International Inc., 55902
`Woodward Funds, 55902-55904
`
`Textile Agreements Implémentation Committee
`See Committee for the Implementation of Textile
`Agreements
`
`Transportation Department
`See Coast Guard
`See Federal Aviation Administration
`See Federal Railroad Administration
`
`Treasury Department
`RULES
`Government Securities Act; implementation
`Correction, 55910
`
`Veterans Employment and Training, Office of Assistant
`Secretary
`NOTICES
`Meetings:
`Veterans’ Employment and Training Advisory Committee,
`55857-55858
`
`Workers’ Compensation Programs Office
`NOTICES
`Privacy Act:
`Computer matching programs, 55858-55859
`
`Separate Parts In This Issue
`
`Part II
`Environmental Protection Agency, 55912-55927
`
`Part III
`Environmental Protection Agency, 55930-55966
`
`Part IV
`Department of the Interior, Bureau of Indian Affairs, 55968
`Part V
`Department of the Interior, Bureau of Indian Affairs, 55970
`
`Part VI
`Department of Health and Human Services, Food and Drug
`Administration, 55972-55976
`
`Part VII
`The President, 55977-55984
`
`Reader Aids
`Additional information, including a list of public laws,
`telephone numbers, and finding aids, appears in the Reader
`Aids section at the end of this issue.
`
`Electronic Bulletin Board
`Free Electronic Bulletin Board service for Public Law
`numbers, Federal Register finding aids, and a list of
`documents on public inspection is available on 202-275-
`1538 or 275-0920.
`-
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`VI
`
`Federal Register / Voi. 59, No. 216 / Wednesday, November 9, 1994 / Contents
`
`CFR PARTS AFFECTED IN THIS ISSUE
`
`A cumulative list of the parts affected this month can be found in the
`Reader Aids section at the end of this issue.
`
`■*
`
`.................... ....... ...55807
`
`
`
`
`
`
`
`.55808
`
`
`
`
`
`
`
`
`
`
`
`55910
`
`..._____
`
`
`
`55810
`
`
`
`....55910
`
`
`
`55823
`
`
`
`
`
`55813
`55912
`
`3 CFR
`Proclamations:
`6755 ..... ...............................55981
`6756 ..... .............................. 55983
`Administrative Orders:
`Presidential Determinations:
`No. 95-2 of November
`1,1994.......... .................55979
`5 CFR
`576..
`7 CFR
`997.............
`8 CFR
`214......
`14 CFR
`71..
`17 CFR
`405............................
`33 CFR
`Proposed Rules:
`181................
`36 CFR
`701............................... ...„.55811
`40 CFR
`70..
`.......
`82..
`....
`Proposed Rules:
`52 ................ :.......... ............55824
`89 ..........................................55930
`91...................
`
`55930
`43 CFR
`Public Land Orders:
`7100..
`........„..................55820
`7101.........
`
`.........55821
`46 CFR
`Proposed Rules:
`514.....................
` „55826
`
`55826
`
`580
`...........
`
`581 .......................„......„..55826
`47 CFR
`Proposed Rules:
`97__
`
`50 CFR
`285..........................
`625...................
`
`675......
`
`
`
`
`
`
`
`
`
`
`„...55828
`
`
`
`
`
`55821
`„„55821
`55822
`
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`5 5 9 7 2
`
`Federal Register / Vol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`Food and Drug Administration
`[Docket No. 93D-Q194]
`International Conference on
`Harmonisation; Dose-Response
`Information to Support Drug
`Registration; Guideline; Availability
`AGENCY: Food and Drug Administration,
`HHS.
`ACTION: Notice.
`
`SUMMARY: The Food and Drug
`Administration (FDA) is publishing a
`final guideline entitled “Dose-Response
`Information To Support Drug
`Registration.” The guideline is
`applicable to both drugs and biological
`products. This guideline was prepared
`by the Efficacy Expert Working Group of
`the International Conference on
`Harmonisation of Technical
`Requirements for Registration of
`Pharmaceuticals for Human Use (ICH).
`The guideline describes why dose-
`response information is useful and how
`it should be obtained in the course of
`drug development. This information can
`help identify an appropriate starting
`dose as well as how to adjust dosage to
`the needs of a particular patient. It can
`also identify the maximum dosage
`beyond which any added benefits to the
`patient would be unlikely or would
`produce unacceptable side effects. This
`guideline is intended to help ensure that
`dose response information to support
`drug registration is generated according
`to sound scientific principles.
`EFFECTIVE DATE: November 9,1994.
`ADDRESSES: Submit written comments
`on the guideline to the Dockets
`Management Branch (HFA-305), Food
`and Drug Administration, 12420
`Parklawn Dr., rm. 1-23, Rockville, MD
`20857. Copies of the guideline are
`available from the CDER Executive
`Secretariat Staff (HFD-8), Center for
`Drug Evaluation and Research, Food
`and Drug Administration, 7500 Standish
`PL, Rockville, MD 20855.
`FOR FURTHER INFORMATION CONTACT:
`Regarding the guideline: Robert
`Temple, Center for Drug Evaluation
`and Research (HFD-100), Food and
`Drug Administration, 5600 Fishers
`Lane, Rockville, MD 20857, 301-
`443-4330.
`Regarding ICH: Janet Showalter,
`Office of Health Affairs (HFY-1),
`Food and Drug Administration,
`5600 Fishers Lane, Rockville, MD
`20857,301-443-1382.
`SUPPLEMENTARY INFORMATION: In recent
`years, many important initiatives have
`
`been undertaken by regulatory
`authorities and industry associations to
`promote international harmonization of
`regulatory requirements. FDA has
`participated in many meetings designed
`to enhance harmonization and is
`committed to seeking scientifically
`based harmonized technical procedures
`for pharmaceutical development. One of
`the goals of harmonization is to identify
`and then reduce differences in technical
`requirements for drug development.
`ICH was organized to provide an
`opportunity for harmonization
`initiatives to be developed with input
`from both regulatory and industry
`representatives. FDA also seeks input
`from consumer representatives and
`others. ICH is concerned with
`harmonization of technical
`requirements for the registration of
`pharmaceutical products among three
`regions: The European Union, Japan,
`and the United States. The six ICH
`sponsors are the European Commission,
`the European Federation of
`Pharmaceutical Industry Associations,
`the Japanese Ministry of Health and
`Welfare, the Japanese Pharmaceutical
`Manufacturers Association, FDA, and
`the U.S. Pharmaceutical Research and
`Manufacturers of America. The ICH
`Secretariat, which coordinates the
`preparation of documentation, is
`provided by the International
`Federation of Pharmaceutical
`Manufacturers Associations (IFPMA).
`The ICH Steering Committee includes
`representatives from each of the ICH
`sponsors and IFPMA, as well as
`observers from the World Health
`Organization, the Canadian Health
`Protection Branch, and the European
`Free Trade Area.
`At a meeting held on March 8, 9, and
`10,1993, the ICH Steering Committee
`agreed that the draft tripartite guideline
`entitled “Dose-Response Information To
`Support Drug Registration” should be
`made available for comment. (The
`document is the product of the Efficacy
`Export Working Group of ICH.)
`Subsequently, the draft guideline was
`made available for comment by the
`European Union and Japan, as well as
`by FDA (see 58 FR 37402, July 9,1993),
`in accordance with their consultation
`procedures. The comments were
`analyzed and the guideline was revised
`as necessary. At a meeting held on
`March 10,1994, the ICH Steering
`Committee agreed that this final
`guideline should be published.
`With this notice, FDA is publishing a
`final guideline entitled “Dose-Response
`Information To Support Drug
`Registration.” It is applicable to both
`drugs and biological products. This
`guideline has been endorsed by all ICH
`
`sponsors. The guideline describes the
`value and uses of dose-response
`information and the kinds of studies
`that can obtain such information, and
`gives specific guidance to manufacturers
`on the kinds of information they should
`obtain.
`In the past, guidelines have generally
`been issued under § 10.90(b) (21 CFR
`10.90(b)), which provides for the use of
`guidelines to state procedures or
`standards of general applicability that
`are not legal requirements but that are
`acceptable to FDA. The agency is now
`in the process of revising § 10.90(b).
`Therefore, the guideline is not being
`issued under the authority of current
`§ 10.90(b), and it does not create or
`confer any rights, privileges, or benefits
`for or on any person, nor does it operate
`to bind FDA in any way.
`As with all of FDA’s guidelines, the
`public is encouraged to submit written
`comments with new data or other new
`information pertinent to this guideline.
`The comments in the docket will be
`periodically reviewed, and where
`appropriate, the guideline will be
`amended. The public will be notified of
`any such amendments through a notice
`in the Federal Register'.
`Interested persons may, at any time,
`submit written comments on the
`guideline to the Dockets Management
`Branch (address above). Two copies of
`any comments are to be submitted,
`except the individuals may submit one
`copy. Comments are to be identified
`with the docket number found in
`brackets in the heading of this
`document. The guideline and received
`comments may be seen in the office
`above between 9 a.m. and 4 p.m.,
`Monday through Friday.
`The text of the final guideline follows:
`Dose-Response Information to Support Drug
`Registration
`I. Introduction
`Purpose o f Dose-Response Information
`Knowledge of the relationships among
`dose, drug concentration in blood, and
`clinical response (effectiveness and
`undesirable effects) is important for the safe
`and effective use of drugs in individual
`patients. This information can help identify
`an appropriate starting dose, the best way to
`adjust dosage to the needs of a particular
`patient, and a dose beyond which increases
`would be unlikely to provide added benefit
`or would produce unacceptable side effects.
`Dose-concentration, concentration- and/or
`dose-response information is used to prepare
`dosage and administration instructions in
`product labeling. In addition, knowledge of
`dose-response may provide an economical
`approach to global drug development, by
`enabling multiple regulatory agencies to
`make approval decisions from a common
`database.
`
`.
`
`Page 9 of 13
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`SLAYBACK EXHIBIT 1031
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`

`

`Federal Register 7 Vol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
`
`5 5 9 7 3
`
`Historically, drugs have often been initially-
`marketed at what were later recognized as
`excessive doses (i.e., dosés well onto the
`plateau of the dose-response curve for the
`desired effect), sometimes with adverse
`consequences (e.g., hypokalemia and other
`metabolic disturbances with thiazide-type
`diuretics in hypertension). This situation has
`been improved by attempts to find the
`smallest dose with a discernible useful effect
`or a maximum dose beyond which no further
`beneficial effect is seen, but practical study
`designs do not exist to allow for precise
`determination of these doses. Further,
`expanding knowledge indicates that the
`concepts of minimum effective dose and
`maximum useful dose do not adequately
`account for individual differences and do not
`allow a comparison, at various doses, of both
`beneficial and undesirable effects. Any given
`dose provides a mixture of desirable and
`undesirable effects, with no single dose,
`necessarily optimal for all patients.
`Use o f Dose-Response Information in
`Choosing Doses
`What is most helpful in choosing the
`starting dose of a drug is knowing the shape
`and location of the population (group)
`average dose-response curve for both
`desirable and undesirable effects. Selection
`of dose is best based on that information,
`together with a judgment about the relative
`importance of desirable and undesirable
`effects. For example, a relatively high starting
`dose (on or near the plateau of the
`effectiveness dose-response curve) might be
`recommended for a drug with a large
`demonstrated separation between its useful
`and undesirable dose ranges or where a
`rapidly evolving disease process demands
`rapid effective intervention. A high starting
`dose, however, might be a poor choice for a
`drug with a small demonstrated separation
`between its useful and undesirable dose
`ranges. In these cases, the recommended
`starting dose might best be a low dose
`exhibiting a clinically important effect in
`even a fraction of the patient population,
`with the intent to titrate the dose upwards as
`long as the drug is well tolerated. Choice of
`a starting dose might also be affected by
`potential intersubject variability in
`pharmacodynamic response to a given blood
`concentration level, or by anticipated
`intersubject pharmacokinetic differences,
`such as could arise from nonlinear kinetics,
`metabolic polymorphism, or a high potential
`for pharmacokinetic drug-drug interactions.
`In these cases, a lower starting dose would
`protect patieûts who obtain higher blood
`concentrations. It is entirely possible that
`different physicians and even different
`regulatory authorities, looking at the same
`data, would make different choices as to the
`appropriate starting doses, dose-titration
`steps, and maximum recommended dose,
`based on different perceptions of risk/benefit
`relationships. Valid dose response data allow
`the use of such judgment.
`In adjusting the dose in an individual
`patient after observing the response to an
`initial dose, what would be most helpful is
`knowledge of the shape of individual dose-
`response curves, which is usually not the
`same as the population (group) average dose-.
`
`response curve. Study designs that allow
`estimation of individual dose-response
`curves could therefore be useful in guiding
`titration, although experience with such
`designs and their analysis is very limited.
`In utilizing dose-response information, it is
`important to identify, to the extent possible,
`factors that lead to differences in
`pharmacokinetics of drugs among
`individuals, including demographic factors
`(e.g., age, gender, race), other diseases (e.g.,
`renal or hepatic failure), diet, concurrent
`therapies, or individual characteristics (e.g.,
`weight, body habitus, other drugs, metabolic
`differences).
`Uses o f Concentration-Response Data
`Where a drug can be safely and effectively
`given only with blood concentration
`monitoring, the value of concentration-
`response information is obvious. In other
`cases, an established concentration-response
`relationship is often not needed, but may be
`useful: (1) For ascertaining the magnitude of
`the clinical consequences of pharmacokinetic
`differences, such as those due to drug-disease
`(e.g, renal failure) or drug-drug interactions;
`pr (2) for assessing the effects of the altered
`pharmacokinetics of new dosage forms (e.g.,
`controlled release formulation) or new
`dosage regimens without need for additional
`clinical trial data, where such assessment is
`permitted by regional regulations.
`Prospective randomized concentration-
`response studies are obviously critical to
`defining concentration monitoring
`therapeutic “windows,” but are also useful
`when pharmacokinetic variability among
`patients is great; in that case, a concentration-
`response relationship may in principle be
`discerned in a prospective study with a
`smaller number of subjects than could the
`dose-response relationship in a standard
`dose-response study. Note that collection of
`concentration-response information does not
`imply that therapeutic blood level
`monitoring will be needed to administer the
`drug properly. Concentration-response
`relationships can be translated into dose-
`response information. Concentration-
`response information can also allow selection
`of doses (based on the range of
`concentrations they will achieve) most likely
`to lead to a satisfactory response.
`Alternatively, if the relationships between
`concentration and observed effects (e.g., an
`undesirable or desirable pharmacologic
`effect) are defined, the drug can be titrated
`according to patient response without the
`need for further blood level monitoring.
`Problems With Titra tion Designs
`A study design widely used to demonstrate
`effectiveness utilizes dose titration to some
`effectiveness or safety endpoint. Such
`titration designs, without careful analysis, are
`usually not informative about dose-response
`relationships. In many studies, there is a
`tendency to spontaneous improvement over
`time that is not easily distinguishable from
`an increased response to higher doses or
`cumulative drug exposure. This leads to a
`tendency to choose, as a recommended dose,
`the highest dose used in such studies that
`was reasonably well tolerated. Historically,
`this approach has often led to a dose that was
`
`well in excess of what was really necessary,
`resulting in increased undesirable effects,
`e.g., to high-dose diuretics used for
`hypertension. In some cases, notably where
`an early answer is essential, the titration-to-
`highest-tolerable-dose approach is
`acceptable, because it often requires a
`minimum number of patients. For example,
`the first marketing of zidovudine (AZT) for
`treatment of people with acquired immune
`deficiency syndrome (AIDS) was based on
`studies at a high dos