55972
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`Federal Register / Vol. 59, No. 216 / Wednesday November 9. 1994 / Notices
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`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
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`Food and Drug Administration
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`[Docket No. 930-0194]
`international conference on
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`Hannonlsation; Dose-Response
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`intomiation to Support Drug
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`Registration; Guideline; Availability
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`AGENCY: Food and Drug Administration,
`HHS.
`Ac‘i1ON: Notice.
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`SUMMARY’ The Food and Drug
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`Administration (FDA) is publishing a
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`final. guideline entitled “Dose-Response
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`Information To Support Drug
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`Registration." The guideline is
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`applicable to bothdrugs and biological
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`products. Tlns guideline was_prepared
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`by the Efficacy Expert Working Group of
`the International Conference on
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`Harmonisation of Technical
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`Requirements for Registration of
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`Pharmaceuticals for Human Use (ICH).
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`The guideline describes why dose-
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`response information is useful and how
`it should be obtained in the course of
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`drug development. This information can
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`help identify an appropriate starting
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`dose as well as how to adjust dosage to
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`the needs of a particular patient. It can
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`also identify the maximum dosage
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`beyond which any added benefits to the
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`patient would be unlikely or would
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`produce unacceptable side effects. This
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`guideline is intended to help ensure that
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`dose response information to support
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`drug registration is generated according
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`to sound scientific principles.
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`EFFECTIVEDATE: November 9, 1994.
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`ADDRESSES: Submit written comments
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`on the guideline-to the Dockets
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`Management Branch (HFA—305), Food
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`and Drug Administration, 12420
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`Parklawn-Dr., rm. 1-23, Rockville, MD
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`20857 Copies of the guideline are
`available from the CDER Executive
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`Secretariat Staff (HFD—8), Center for
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`Drug Evaluation and Research, Food
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`and Drug Admimstration, 7500 Standish
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`Pl., Rockville, MD 20855.
`FOR FURTHER INFORMATION CONTACT:
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`Regarding the guideline: Robert
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`Temple, Center for Drug Evaluation
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`and Research (HFD-100), Food and
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`Drug Administration, 5600 Fishers
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`Lane, Rockville, MD 20857 -301-
`443-4330.
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`Regarding ICH: Janet Showalter,
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`Office‘ of Health Affairs ,(HFY—1),
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`Food and Drug Administration,
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`5600 Fishers Lane. Rockville, MD
`20857 301-443-1382.
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`SUPPLEMENTARY INFORMATION: In recent
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`years, many important initiatives have
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`beenundertaken by regulatory
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`authorities and industry associations to
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`promote international harmonization of
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`regulatory requirements. FDA has
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`participated in many meetings designed
`to enhance harmonization and is
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`committed to seeking scientifically
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`based harmonized technical procedures
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`for pharmaceutical development. One of
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`the goals of harmomzation Is to identify
`and then reduce differences in technical
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`re uirements for drug development.
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`CH was organized to provide an
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`opportunity for harmonization
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`initiatives to be developed with input
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`from both regulatory and industry ,
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`representatives. FDA also seeks input
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`from consumer -representatives and
`others. ICH is concerned with
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`harmonization of technical
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`requirements for the registration of
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`pharmaceutical‘ products among three
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`regions: The European Union, Japan,
`and the United States. The six ICH
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`sponsors are the European Commission.
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`the European Federation of
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`Pharmaceutical Industry Associations,
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`the Japanese Ministry of Health and
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`Welfare, the Japanese Pharmaceutical
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`Manufacturers Association. FDA, and
`the U.S. Pharmaceutical Research and
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`Manufacturers of America. The ICH
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`Secretariat. which coordinates the
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`preparation of documentation, is
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`provided by the International
`Federation of Pharmaceutical
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`Manufacturers Associations (IFPMA).
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`The ICH Steering Committee includes
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`representatives from each of the ICH
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`sponsors and IFPMA, as well as
`observers from the World Health
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`Orgamzation, the Canadian Health
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`Protection Branch, and the European
`Free Trade Area.
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`At a meeting held on March 8, 9, and
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`10, 1993, the ICH Steering Committee
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`agreed that the draft tripartite guideline
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`entitled “Dose-Response Information To
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`Support Drug Registration" should be
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`made available for comment. (The
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`document is the product of the Efficacy
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`Export Working Group of ICH.)
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`Subsequently the draft guideline was
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`made available for comment by the
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`European Union and Japan, as well as
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`by FDA (see 58 FR 37402, July 9, 1993),
`in accordance with their consultation
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`procedu.res..The comments were
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`analyzed and the guideline was revised
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`as necessary. At a meeting held on
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`March 10, 1994, the [CH Steering
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`Committee agreed that this final
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`guideline should be published.
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`With this notice, FDA is publishing a
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`final guideline entitled “Dose-Response
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`Information To Support Drug
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`Registration.” It is applicable to both
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`drugs and biological products. This
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`guideline has been endorsed by all ICH
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`sponsors. The guideline describes the
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`value and uses of dose-response
`information and the kinds of studies
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`that can obtain such. information, and
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`gives specific guidance to manufacturers
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`on the kinds of information they should
`obtain.
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`In the past, guidelines have generally
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`been issued under § 10.90(b) (21 CFR
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`-10.90(b)), which provides for the use of
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`guidelines to state procedures or
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`standards of general applicability that
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`are not legal requirements but that are
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`acceptable to FDA. The agency is now
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`in the process of revising § 10.90(b).
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`Therefore, the guideline is not being
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`issued under the authority of current
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`§ 10.90(b). and it does not create or
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`confer any rights, privileges.-oi‘ benefits
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`for or on any person, nor does it operate
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`to bind FDA in any way.
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`As with all of FDA’s guidelines, the
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`public is encouraged tosubmit written
`comments with new data or other new
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`information pertinent to this guideline.
`The comments in the docket will be
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`periodically reviewed, and where
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`appropriate, the guideline will be
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`amended. The public will be notified"of
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`any such amendments through a notice
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`in the Federal Register.
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`Interested persons may at any time,
`submit written comments on the.
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`guideline to the Dockets Management
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`Branch (address above). Two copies of
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`any comments are to be submitted,
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`except the individuals may submit one
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`copy. Comments are to be identified
`with the docket number found in
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`brackets in the heading of this
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`document. The guideline and received
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`comments may be seen in the office
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`above between 9 a.m. and 4 p.m.,
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`Monday through‘Friday.
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`The text of the final guideline follows:
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`Dose-Response Information to Support Drug
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`Registration
`1. Introduction
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`Purpose of Dose-Response Information
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`Knowledge of therelationships among
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`dose. drug concentration in blood, and
`clinical response (effectiveness and
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`undesirable effects) is important for the safe
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`and effective use of drugs in individual
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`patients. This information can help identify
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`an appropriate starting dose, the best way to
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`adjust dosage to the needs of a particular
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`patient, and a dose beyond which increases
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`would be unlikely to provide added benefit
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`or would ‘produce unacceptable side effects.
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`Dose-concentration, concentration- and/or
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`dose-response information is used to prepare
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`dosage and administration instructions in
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`product labeling. In addition. knowledge of
`dose-response may provide an economical
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`approach to global drug development. by
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`enabling multiple regulatory agencies to
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`make approval decisions from a common
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`database.
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`Biogen Exhibit 2059
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`Coalition v. Biogen
`IPR2015-01993
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`Page 1 of 5
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`Biogen Exhibit 2059
`Coalition v. Biogen
`IPR2015-01993
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`response curve. Study designs that allow
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`estimation of individual dose-response
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`curves could therefore be useful in guiding
`titration, although experience with such
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`designs and their analysis is very limited.
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`In utilizing dose-response information, it is
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`important to identify, to the extent possible,
`factors that lead to differences in
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`pharrnacokinetics of drugs among
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`individuals, including demographic factors
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`(e.g., age, gender, race). other diseases (e.g.,
`renal or hepatic failure). diet, concurrent
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`therapies, or individual characteristics (e.g.,
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`weight, body habitus, other drugs, metabolic
`differences).
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`well in excess of what was really necessary,
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`resulting in increased undesirable effects,
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`-e.g., to high-dose diuretics used for
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`hypertension. In some cases, notably where
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`an early answer is essential, the titration-to-
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`highest-tolerable-dose approach is
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`acceptable, because it often requires a
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`minimum number of patients. For example,
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`the first marketing of zidovudine (AZT) for
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`treatment of people with acquired immune
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`deficiency syndrome (AIDS) was based on
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`studies at a high dose; later studies showed
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`that lower doses were as effective and far
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`better tolerated. The urgent need for the first
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`effective anti-HIV (human immunodeficiency
`virus) treatment made the absence of dose-
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`response information at the time of approval
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`reasonable (with the condition that more data
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`were to be obtained after marketing), but in
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`less urgent cases this approach is
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`discouraged.
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`I
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`55973
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`Federal Register / Vol. 59, No. 216 I Wednesday November 9, 1994 /- Notices
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`Historically, drugs have often been initially
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`marketed at what were later recogniied as
`excessive doses (i.e., doses well onto the
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`plateau of the dose-response curve for the
`desired effect), sometimes with adverse
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`consequences (e.g., hypokalemia and other
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`metabolic disturbances with thiazide-type
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`diuretics in hypertension). This situation has
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`been improved by attempts to find the
`smallest dose with a discernible useful effect
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`or a maximum dose beyond which no further
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`beneficial effect is seen, but practical study
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`designs do not exist to allow for precise
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`determination of these doses. Further,
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`expanding knowledge indicates that the
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`concepts of minunum effective dose and
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`maximum useful dose do not adequately
`account for individual differences and do not
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`allow a comparison, at various doses, of both
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`beneficial and undesuable effects. Any given
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`dose provides a mixture of desirable and
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`undesirable effects, with no single dose
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`necessarily optimal for all patients.
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`Use of Dose-Response Information in
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`Ch oosmg Doses
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`‘What is most helpful in choosing the
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`starting dose of a drug is knowing the shape
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`and location of the population (group)
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`average dose-response curve for both
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`desirable and undesirable effects. Selection
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`of dose is best based on that information,
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`together with a iudgment about the relative
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`importance of desirable and undesirable
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`effects. For example, a relatively high starting
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`dose (on or near the plateau of the
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`effectiveness dose-response curve) might be
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`recommended for a drug with a large
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`demonstrated separation between its useful
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`and undesirable dose ranges or where a
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`rapidly evolving disease process demands
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`rapid effective intervention. A high starting
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`dose, however, might be a poor choice for a.
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`drug with a small demonstrated separation
`between its useful and undesirable dose
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`ranges. In these cases, the recommended
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`starting dose might best be a low dose
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`exhibiting a clinically important effect in
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`even a fraction of the patient population,
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`with the intent to titrate the dose upwards as
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`long as the drug is well tolerated. Choice of
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`a starting dose might also be affected by‘
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`potential intersubiect variability in
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`pharmacodynamic response to a given blood
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`concentration level, or by anticipated
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`intersubiect pharmacokinetic differences,
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`such as could arise from nonlinear kinetics,
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`metabolic polymorphism, or a high potential
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`for pharmacokinetic drug-drug interactions.
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`In these cases, a lower starting dose would
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`protect patients who obtain higher blood
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`concentrations. It is entirely possible that
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`different physicians and even different
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`regulatory authorities, looking at the same
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`data, would make different choices as to the
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`appropriate starting doses, dose-titration
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`steps, and maximum recommended dose,
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`based on different perceptions of risk/benefit
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`relationships. Valid dose response data allow
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`the use of such iudgnent.
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`In adjusting the dose in an individual
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`patient after observing the response to an
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`initial dose, what would be most helpful is
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`knowledge of the shape of individual dose-
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`response curves, which is usually not the
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`same as the population (group) average dose-
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`Uses of Concentration-Response Data
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`Where a drug can be safely and effectively
`given only with blood concentration
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`monitoring, the value of concentration-
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`response information is obvious. In other
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`cases, an established concentration-response
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`relationship is often not needed, but may be
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`useful: (1) For ascertaining the magnitude of
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`the clinical consequences of phannacokinetic
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`differences, such as those due to drug-disease
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`(e.g, renal failure) or drug-drug interactions;
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`or (2) for assessing the effects of the altered
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`pharmacokinetics of new dosage forms (e.g.,
`controlled release formulation) or new
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`dosage regimens without need for additional
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`clinical trial data, where such assessment is
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`permitted by regional regulations.
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`Prospective randomized concentration-
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`response studies are obviously critical to
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`defining concentration monitoring
`therapeutic "windows, but are also useful
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`when pharmacokinetic variability among
`patients is great; in that case, a concentration-
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`response relationship may in principle be
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`discerned in a prospective study with a
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`smaller number of subiects than could the
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`dose-response relationship in a standard
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`dose-response study. Note that collection of
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`concentration-response information does not
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`imply that therapeutic blood level
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`monitoring will be needed to administer the
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`drug properly. Concentration-response
`relationships can be translated into dose-
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`response information. Concentration-
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`response information can also allow selection
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`of doses (based on the range of
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`concentrations they will achieve) most likely
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`to lead to a satisfactory response.
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`Alternatively, if the relationships between
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`concentration and observed effects (e.g., an
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`undesirable or desirable pharinacologic
`
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`effect) are defined, the drug can be titrated
`
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`according to patient response without the
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`need for further blood level monitoring.
`
`
`
`Problems With Titration Designs
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`A study design widely used to demonstrate
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`effectiveness utilizes dose titration to some
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`effectiveness or safety endpoint. Such
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`titration designs, without careful analysis, are
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`usually not informative about dose-response
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`relationships. In many studies, there is a
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`tendency to spontaneous improvement over
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`time that is not easily distinguishable from
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`an increased response to higher doses or
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`cumulative drug exposure. This leads to a
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`tendency to choose, as a recommended dose.
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`the highest dose usedin such studies. that
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`was reasonably well tolerated. Historically,
`this approach has often led to a dose that was
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`Interactions Between Dose-Response and
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`Time
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`The choice of the size of an individual
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`dose is often intertwined with the frequency
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`of dosing. In general, when the dose interval
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`is long compared to the half-life of the drug,
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`attention should be directed to the
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`pharmacodynamic basis for the chosen
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`dosing interval. For example, there might be
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`a comparison of the long dose interval
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`regimen with the same dose in a more
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`divided regimen, looking. where this is
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`feasible, for persistence of desired effect
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`throughout the dose interval and for adverse
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`effects associated with blood level peaks.
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`Within a single dose interval, the dose-
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`responsa relationships at peak and trough
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`blood levels may differ and the relationship-
`could-depend on the dose iriterval chosen.
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`Dose-response studies should take time
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`into account in a variety of other ways. The
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`study period at a given dose should be long
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`enough for the full~effect to be realized,
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`whether delay is the result of
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`pharmacokinetic or pharmacodynamic
`
`
`factors. The dose-response may also be
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`different for morning versus evening dosing.
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`Similarly, the dose-response relationship
`
`
`during early dosing may not be the same as
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`in the subsequent maintenance dosing
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`period. Responses could also be related to
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`cumulative dose, rather than daily dose, to
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`duration of exposure (e.g., tachyphylaxis,
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`tolerance, or hysteresis) or to the
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`relationships of dosing to meals.
`
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`
`
`II. Obtaining Dose-Response Information
`
`
`Dose-Response Assessment Should Be an
`
`
`
`
`Integral Part of Drug Development
`
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`
`
`Assessment of dose-response should be an
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`
`
`integral component of drug development
`
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`with studies designed to assess dose-
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`response an inherent part of establishing the
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`safety and effectiveness of-the drug. If
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`development of dose-response information is
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`built into the development process it can
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`usually be accomplished with no loss of time
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`and minimal extra effort compared to
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`development plans that ignore dose-
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`response.
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`Studies in Life-Threatening Diseases.
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`In particular therapeutic areas, different
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`therapeutic and investigational behaviors
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`Page 2 of 5
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`Page 2 of 5
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`

`

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`Federal Register / Vol. 59, No. 216’ I ‘Wednesday November 9, 1994 I Notices55974 -~
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`some cases to derive, retrospectively, blood
`
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`concentration-response relationships from
`the variable concentrations attained in a
`
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`fixed-dose trial. While these analyses are
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`potentially confounded by disease severity or
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`other patient factors. the information can be
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`useful and can guide‘ subsequent studies.
`
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`Conducting dose-response studies at an early
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`stage of clinical development may reduce the
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`
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`number of failed Phase 3 trials, speeding the
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`drug development process and conserving
`
`development resources.
`
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`Pharmacokinetic information can be used
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`to choose doses that ensure adequate spread
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`of attained concentration-response values
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`and diminish or eliminate overlap between
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`attained concentrations in dose-response
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`trials. For drugs with high pharmacokinetic
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`variability, a greater spread of doses could be
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`chosen. Alternatively, the dosing groups
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`could beindividualized by adjusting for
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`pharmacokinetic covariates (e.g., correction
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`for weight’, lean body mass, or renal function)
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`or a concentratiomcontrolled study could be
`carried out.
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`As a practical matter, valid dose-response
`
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`data can be obtained more readily when the
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`response is measured by a continuous or
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`categorical variable, is relatively rapidly
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`obtained after therapy is started, and is
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`rapidly dissipated afier therapy is stopped
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`(e.g., blood pressure, analgesia,
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`bronchodilation). In this case, a wider range
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`of study designs can be used and relatively
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`small, simple studies can give useful
`information. Placebo-controlled individual
`
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`subiect titration designs typical of many early
`
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`drug -development studies, for example,
`
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`properly conducted and analyzed
`
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`(quantitative analysis that models and
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`
`estimates the population and individual.
`
`
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`dose-response reletionship_s),. can give
`
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`guidance for more definitive parallel, fixed-
`
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`
`
`dose, dose-response studies or may be
`definitive on their. own.
`
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`In contrast, when the study endpoinfor
`
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`adverse effect is delayed, persistent, or
`
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`irreversible (e.g., stroke or heart attack
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`prevention, asthma prophylaxis, arthritis
`
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`treatments with late onset response, survival
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`in cancer, treatment of depression), titration
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`and simultaneous assessment of response is
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`usually not possible, and the parallel dose-
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`response study is usually needed. The
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`parallel dose-response study also offers
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`protection against missing an effective dose
`
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`because of an inverted “U-shaped" (umbrella
`
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`or bell-shaped) dose-response curve, where
`
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`higher doses are less effective than lower
`
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`doses, a response that can occur, forexample,
`
`
`with mixed agonist-antagonists.
`
`
`Trials intended to evaluate dose- or
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`
`concentration-response should be well-
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`controlled, using randomization and blinding
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`(unless blinding is unnecessary or
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`impossible) to assure comparability of»
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`treatment groups and to minunize potential
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`patient, investigator, and analyst bias, and
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`should be of adequate size:
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`It is important to choose astwide a range‘
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`of doses as is compatible:.with practicality
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`and patient safety to. discern clinically
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`meaningful differences. This is especially
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`important where. there are nopliarmacolagic
`
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`.».. ........-.-. --
`or plausible surrogatsendpoints to give
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`initial guidance as to dose.
`'3.
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`range (but without valid dose response
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`
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`information) might be appropriate where
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`benefit frorii a new therapy in treating or
`
`
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`
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`preventing a serious disease is clear.
`
`
`
`
`Examining tIie.§nti'rie Database for Dose-
`
`‘Hesponse Information
`
`
`
`
`In addition to seeking dose-response
`
`
`
`information from studies specifically
`
`
`
`
`
`
`designed to provide it, the entire database
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`
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`
`
`should be examined intensively for possible
`
`
`
`dose-response effects. The limitations
`
`
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`
`
`imposed by certain study design features
`
`
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`
`
`should, of course, be appreciated. For
`
`
`
`
`
`example, many studies titrate the dose
`
`
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`
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`upward for safety reasons. As most side
`
`
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`
`
`
`effects of drugs occur early and may
`
`
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`
`
`disappear with continued treatment,‘ this can
`
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`
`
`result in a spuriously higher rate of
`undesirable effects at the lower doses.
`
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`Similar1y,.in'studies where patients are
`
`
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`-titrated to a desired response, those patients
`
`
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`
`
`relatively unresponsive to the drug are more
`
`
`
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`
`
`
`likely to receive the higher dose, giving an
`
`
`
`
`apparent, but misleading, inverted “U-
`
`
`
`
`shaped" dose-response curve. Despite such»
`limitations, clinical data from all sources
`
`
`
`
`
`
`
`
`
`
`should be analyzed for dose-related effects
`
`
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`using. multivariate or other approaches, even
`
`
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`
`
`.if the analyses can yield principally
`
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`
`
`hypotheses, not definitive conclusions. For
`
`
`
`
`
`
`example, an inverse relation of effect to
`
`
`
`
`
`
`weight or creatinine clearance could reflect a
`
`
`
`dose-related covariate relationship. If
`
`
`
`pharrnacokinetic screening (obtaining a small
`
`
`
`
`number of steady-state blood concentration
`measurements in most Phase 2 and Phase 3
`
`
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`
`
`
`
`
`
`
`
`
`
`study patients) is carried out, or if other
`
`
`
`
`approaches to obtaining drug concentrations
`
`
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`
`
`
`during trialsare used, a relation of effects
`
`
`
`
`(desirable or undesirable) to blood
`
`
`
`
`concentrations may be discerned. The
`
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`
`‘relationship may by itself be a persuasive
`
`
`
`
`description of concentration-response or may.
`
`
`suggest further study.
`
`
`
`
`
`III. Study Designs for Assessing Dose
`Response
`General
`
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`
`
`
`
`The choice of study design and study
`
`
`
`
`population in dose-response trials will
`
`
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`
`
`depend on the phase of development, the
`
`
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`therapeutic indication under investigation,
`
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`
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`
`and the severity of the disease in the patient
`
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`
`
`population of interest. For example, the lack
`
`
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`
`
`of appropriate salvage therapy for life-
`
`
`
`
`-threatening or serious conditions with
`
`
`
`
`irreversible outcomes may ethically preclude
`conduct of studies at doses below the
`
`
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`
`
`
`maximum tolerated dose. A homogeneous
`
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`
`
`
`_patient population will generally allow
`
`
`
`
`
`achievement of study objectives with small
`
`
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`
`
`numbers of subjects given each treatment. On
`
`
`
`
`
`the other hand. larger, more diverse
`
`
`
`
`populations allow detection of potentially
`
`
`important covariate effects.
`
`
`
`In general, useful dose-response
`information is best obtained from trials
`
`
`
`
`
`
`
`
`specifically designed:.to compare several
`
`
`
`
`
`.doses. A cornparison.of‘results from two or
`
`
`
`
`
`
`more controlled trials with single fixed doses
`
`
`
`
`
`might sometimesabe informative, e.g., if
`
`
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`
`
`control groups -were similar, although even in
`
`
`
`
`
`that case, the many across-study differences
`
`
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`
`
`
`that occur in separatetrials usually make this
`
`
`
`
`
`
`approach unsatisfactoi-y..!t is also possible in
`
`have evolved; these affect the kinds of
`
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`
`
`
`
`studies typically carried out. Parallel dose-
`
`
`
`
`
`
`response study designs with placebo, or
`
`
`
`placebo-controlled titration study designs
`
`
`
`
`
`(very effective designs, typically used in
`studies of angina, depression, hypertension,
`
`
`
`
`
`etc.) would not be acceptable in the study of
`
`
`
`
`
`
`
`some conditions, such as life-threatening
`
`
`
`
`
`
`infections or potentially curable tumors, at
`
`
`
`least if there were effective treatments
`
`
`
`
`
`known. Moreover, because in those
`
`
`
`
`
`
`
`
`therapeutic areas considerable toxicity could
`
`
`
`
`
`
`be accepted, relatively high doses of drugs
`
`
`
`
`are usually chosen to achieve the greatest
`
`
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`
`
`
`possible beneficial effect rapidly. This
`
`
`
`
`
`approach niaylead to recommended doses
`
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`
`
`that deprive some patients of the potential
`
`
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`
`
`benefit of a drug by inducing toxicity that
`
`
`
`
`leads to cessation of therapy. On the other
`
`
`
`
`
`
`
`hand, use of low, possibly subeffective,
`
`
`
`doses, or of titration to desired effect may be
`
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`
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`
`
`
`unacceptable, as aninitial failure in these‘
`
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`
`
`
`
`cases may represent an opportunity for cure
`forever lost.
`
`Nonetheless,-even for life-threatening
`
`
`
`
`
`diseases. drug developers should always be,
`
`
`
`
`
`
`
`
`-weighing the gains and disadvantages of
`
`
`
`
`
`varying regimens and considering how best
`to choose dose, dose-interval and dose-
`
`
`
`
`
`escalation steps. Even in indications
`
`
`
`
`
`
`
`involving life-threatening diseases, the
`
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`
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`
`
`highest tolerated dose, or the dose with the
`
`
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`
`
`
`largest effect on a surrogate marker will not
`
`
`
`
`
`
`
`always be the optimal dose. Where only a
`
`
`
`
`
`single dose is studied, blood concentration
`data, which will almost always show-
`
`
`
`
`
`considerable individual variability due to
`
`
`
`
`
`
`pharmacokinetic differences, may
`
`
`
`
`retrospectively give clues to possible
`r
`concentration-response relationships.
`
`
`
`
`
`
`
`
`
`Use of just a single dose hasbeen typical
`
`
`
`
`of large-scale intervention studies (e.g., post-
`
`
`
`
`
`
`myocardial infarction studies) because of the
`
`
`
`
`
`
`large sample sizes needed. In planning an
`‘intervention study. the potential advantages
`
`
`
`
`
`
`
`
`
`
`of studying more than a single dose should
`be considered. In some cases, it may be
`
`
`
`
`
`
`
`
`
`
`
`
`
`possible to simplify the study by collecting
`
`
`
`
`
`less information on each patient, allowing
`
`
`
`
`
`study of a larger population treated with
`several doses without significant increase in
`
`
`
`
`
`costs.
`
`
`
`
`Regulatory Considerations When Dose-
`
`
`
`Response Data Are Imperfect
`
`
`
`
`Even well-laidplans are not invariably
`
`successful. An otherwise well-designed dose-
`
`
`
`
`
`
`
`
`
`
`response study may have utilized doses that
`
`
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`
`
`
`
`
`were too high, or too close together, so that
`
`
`
`
`
`all appear equivalent (albeit superior to
`
`
`
`
`
`
`
`placebo). In that case, there is the possibility
`that the lowest dose studied is still greater
`
`
`
`
`
`
`
`
`
`
`
`
`than needed to exert the drug's‘ maximum
`
`
`
`
`effect. Nonetheless, an acceptablebalance of
`
`observed undesired effects and beneficial
`
`
`
`
`-effects mi
`
`
`
`
`
`
`
`ght make. marketing at one of the
`doses studied reasonable. This decision
`
`
`
`
`
`
`
`would be easiest,,of course, if the drug had
`
`
`
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`
`
`
`
`
`
`
`
`
`special value. but even if it did not, in light
`
`
`
`
`
`
`
`of the studies that partly defined the proper
`
`
`
`
`
`dose range. further dose-finding might be
`
`
`
`
`pursued in the postrnarketing period.
`
`
`
`
`Similarly, although seeking dose response
`
`
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`data should be a goal of every development
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`program, approval based on data from studies
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`using afixed single dose or a defined dose
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`Federal Register / Vol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
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`55975
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`Specific Trial Designs
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`A number of specific study designs can be
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`used to assess dose-response. The same
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`approaches can also be used to measure
`concentration-response relationships.
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`Although not intended to be an exhaustive
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`list, the following approaches have been
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`shown to be useful ways of deriving valid
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`dose-response information. Some designs
`outlined in this guidance are better
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`established than others, but all are worthy of
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`consideration. These d