Guidance for IndustryClinical Development Programs forDrugs, Devices, and BiologicalProducts for the Treatment ofRheumatoid Arthritis (RA)U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Devices and Radiologic Health (CDRH)February 1999Clin 7
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`Guidance for IndustryClinical Development Programs for Drugs,Devices, and Biological Products for theTreatment of Rheumatoid Arthritis (RA)Additional copies of this Guidance are available from: Office of Training and Communications Division of Communications Management Drug Information Branch, HFD-210Center for Drug Evaluation and ResearchFood and Drug Administration 5600 Fishers Lane, Rockville, MD 20857 (Phone 301-827-4573)Internet: http://www.fda.gov/cder/guidance/index.htm.or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448 Internet: http://www.fda.gov/cber/guidelines.htm. Fax: 1-888-CBERFAX or 301-827-3844 Mail: the Voice Information System at 800-835-4709 or 301-827-1800.orThe Division of Small Manufacturers Assistance (DSMA), HFZ-220Center for Devices and Radiological HealthFood and Drug Administration1350 Piccard Drive, Rockville, MD 20850800-638-2041 or 301-443-6597Internet: DSMA@CDRH.FDA.GOVFax: 1-301-443-8818Facts-On-Demand (FAX) at 800-899-0381 or 301-827-0111U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Devices and Radiological Health (CDRH) February 1999
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`iTABLE OF CONTENTSI. INTRODUCTION.....................................................1II. NEW CLAIMS FOR THE TREATMENT OF RA.............................2A. Reduction in the Signs and Symptoms of RA...........................2B. Major Clinical Response...........................................3C. Complete Clinical Response........................................4D. Remission......................................................4E. Prevention of Disability...........................................4F. Prevention of Structural Damage....................................5III. CONSIDERATIONS IN RA PRODUCT DEVELOPMENT.....................6A. Preclinical Considerations..........................................7B. Pharmacokinetic/Pharmacodynamic Strategies.........................11C. Considerations in Phase 1 Trials....................................11D. Considerations in Phase 2 Trials....................................14E. Efficacy Trial Considerations......................................16F. Safety Analysis.................................................30IV. SPECIAL CONSIDERATIONS FOR BIOLOGICAL PRODUCTS ..............32A. Species Specificity..............................................32B. Dose Responses................................................32C. Toxicity Response..............................................32D. Product Homogeneity ...........................................32E. The Role of Antibodies...........................................32V. SPECIAL CONSIDERATIONS FOR MEDICAL DEVICES...................33A. Background...................................................33B. Efficacy Considerations..........................................33C. Safety Considerations............................................34VI. SPECIAL CONSIDERATIONS FOR JUVENILE RHEUMATOID ARTHRITIS....35A. Background...................................................35B. Applicability of Pediatric Regulation and Impact onTrial Design for JRA Studies......................................36C. Outcome Variables and Claims.....................................37D. Trial Design Issues..............................................39E. Concurrent Antirheumatic Agent Administration.......................40F. Multicenter Trials and Center Effects................................40REFERENCES............................................................42APPENDIX A: COMPARATIVE TRIAL RESPONSE RATES......................45
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` This guidance has been prepared by the Rheumatology Working Group of the Medical Policy Coordinating1Committee (MPCC) of the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation andResearch (CBER), and the Center for Devices and Radiological Health (CDRH). This guidance document represents theAgency’s current thinking on Clinical Development Programs for Drugs, Devices, and Biological Products Intended forthe Treatment of Rheumatoid Arthritis. It does not create or confer any rights for or on any person and does not operateto bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of theapplicable statute, regulations, or both. Guidance for Industry1 Clinical Development Programs forDrugs, Devices, and Biological Products Intended for theTreatment of Rheumatoid Arthritis (RA) I.INTRODUCTIONThis guidance is intended to assist developers of drugs, biological products, and medical devicesintended for the treatment of rheumatoid arthritis (RA). The document discusses the types oflabel claims that can be considered for such products and provides guidance on the clinicaldevelopment programs to support those claims.The central purpose of label claims is to inform prescribers and patients about the documentedbenefits of a product. Because RA is a chronic, symptomatic disease that can result in a variety ofoutcomes with different chronologies, severities, and overall patient effects, any number ofdifferent clinical outcomes could provide the basis for a label claim.Relief of symptoms — the signs and symptoms claim — is a central therapeutic effect of mostRA therapeutics marketed circa 1997. The claim structure proposed in this document, however,incorporates a wider range of patient outcomes than previously allowable RA claims. As a result,guidance is provided for demonstrating patient benefit of greater magnitude than is needed for aclaim of symptomatic relief. For example, the claims major clinical response, complete clinicalresponse, and remission (the same criteria as complete clinical response while off allantirheumatic drugs) reflect enhanced effects on the signs and symptoms of disease. The claimprevention of structural damage is documented by various radiographic techniques. The claimprevention of disability is intended to reflect longer term benefits on disease course. The claimsand clinical development programs discussed in this draft guidance for industry represent thecurrent views of Agency rheumatologists about achievable and clinically relevant overalloutcomes that can be evaluated in clinical trials.Traditionally, RA therapeutics have been categorized as disease modifying antirheumatic drugs(DMARDs) or as nonsteroidal anti-inflammatory drugs (NSAIDs). As a result of the ongoingsearch for more effective therapeutics that have a positive impact on the natural history of thedisease, promising new therapies are currently being tested in the clinic. Many of the novel agents
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`2under study for the treatment of RA defy categorization by putative mechanism of action. As aresult, the usefulness of classifying them in the traditional manner may be limited. For this reason,information being provided in labeling about the onset and duration of action and the durability ofresponse of therapeutic interventions is intended to reflect the data that were gathered in clinicaltrials. Because of this, some of the claims described in this document incorporate responseduration times within their structure.Over the past decade, there has been a search for better measures to describe patient outcomes inRA clinical trials. A number of organizations, including the European League AgainstRheumatism, the International League Against Rheumatism, the American College ofRheumatology (ACR), and the Outcome Measures in Rheumatoid Arthritis Clinical Trials(OMERACT) group, have attempted to define core groups of measures, as well as compositeindices, that describe patient outcomes. As a result of these efforts, several new measures havebeen described and validated with clinical data. With the hope that these measures will providemore useful information about patient outcomes, this document provides guidance about the useof these new measures in clinical trials to support label claims. One outcome measure that is not fully relied upon as a stand-alone claim is general health-relatedquality of life (HR-QOL). Since RA affects so many domains of a patient’s life, it is hoped thatsuch HR-QOL measures may provide an integrated assessment of the long-term impact ofintervention. However, not enough information is available on the performance of general HR-QOL measures in longer term arthritis trials. The incorporation of such measures in planned trialsis encouraged.II.NEW CLAIMS FOR THE TREATMENT OF RAA number of new claims are now being evaluated in clinical trials during drug development. Descriptions of the claims and acceptable outcome measures to support each claim are discussedin the following sections.A.Reduction in the Signs and Symptoms of RAThis claim is intended to reflect the demonstration of symptomatic benefit or benefits thatincludes improvement in signs of disease activity as well as symptoms. Reduction in signsand symptoms may ordinarily be the initial claim granted for marketing approval.Ordinarily, this claim is established by trials of at least six months' duration, unless theproduct belongs to an already well-characterized pharmacologic class (e.g., NSAIDs) forwhich trials of three months' duration are sufficient to establish efficacy for signs andsymptoms. Six-month trials are desirable for several reasons. First, RA is a disease oflong duration. Interventions that provide only short-term, time-limited benefit are unlikelyto have overall value to patients. In addition, products with the potential to elicit antibodyformation should be assessed for durability, since antibodies may block effectiveness. Inevaluating signs and symptoms, methods that evaluate response over time are preferable tomethods that incorporate only the baseline value and the final observation, unless there is a
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` The ACR definition of improvement (ACR 20) is 20 percent improvement in tender and swollen joint counts2and 20 percent improvement in three of the five remaining core set measures: patient and physician globals, pain,disability, and an acute phase reactant (Felson 1993, 1995). For specific details on individual measures, e.g., disability,acute phase reactant, refer to Felson 1995. 3reason to weight symptoms at the last visit more than intermediary symptoms. Acceptableoutcome measures that would support claim A include:l.Validated composite endpoints or indices of signs and symptomsThese composites may be used to construct categorical endpoints for patientsuccess or failure. For example, the Paulus criteria (1990) or the ACR definitionof improvement (ACR 20) could be used to assess a patient's response.2Illustration: Success for each patient in a six-month trial could be defined asmeeting the criteria for improvement over baseline in at least four of six monthlyobservations and not dropping out because of toxicity.2.Well-accepted sets of signs/symptoms measuresThe four measures previously recommended in the 1988 CDER Guideline for theClinical Evaluation of Anti-Inflammatory and Antirheumatic Drugs (FDA 1988)— joint counts: pain, tenderness, and swelling and global assessments: physicianand patient — or the ACR core set are examples of well-accepted sets of signs andsymptoms measures. The criteria for success and the methods for statisticalanalysis should be prospectively defined and agreed upon. For example,historically, in using joint counts and global assessments, a statistically significantdifference between the control and the treatment group in change from baseline inat least three of the four measures has been used as the criterion for a successfultrial. However, as stated above, comparison of only the baseline and lastobservation may not be the best way to construct the analysis since this methodleaves out all intervening efficacy observations.For both the above measures, using 66- or 28-joint count is appropriate (Smolen1995).B.Major Clinical ResponseThis claim is intended to reflect the demonstration of a continuous six-month period ofsuccess by the “ACR 70," which is defined entirely parallel to the ACR 20, except 70percent improvement, rather than 20 percent, is needed for the component assessed. Thisclaim is based on statistically significant improvement in response rates by the continuoussix-month ACR 70 definition compared to background therapy in a randomized controlgroup. For reference, the number of patients satisfying various definitions of ACR
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`4responses from ACR 20 to ACR 70 in two historic databases are given in Appendix A ofthis document. Trial duration should be a minimum of seven months for an agentexpected to have a rapid onset of action and longer for agents with less prompt effects. C.Complete Clinical ResponseThis claim is intended to describe a therapeutic benefit of greater magnitude than themajor clinical response claim. Complete clinical response and remission (see below) areidentically defined as a continuous six-month period of both remission by ACR criteriaand radiographic arrest (no radiographic progression [Larsen 1977] or modified Sharpmethods [1985]). Complete clinical response connotes a benefit requiring ongoing drugtherapy; remission is defined by the same result while off all antirheumatic drugs. The1981 ACR remission criteria (Pinals 1981) require at least five of the following: morningstiffness less than 15 minutes, no fatigue, no joint pain by history, no joint tenderness orpain on motion, no swelling of joints or tendon sheaths, and erythrocyte sedimentationrate (ESR) less than 20 for males or less than 30 for females. The duration of trialsdesigned to support this claim will vary depending upon the rate of onset of effect of thetest product. For all but the most rapid-onset agents, trials of one year’s duration shouldbe planned. Longer trials may be needed for very slow-acting agents. Trials evaluatingcomplete clinical response would use a categorical endpoint (patient complete response ortreatment failure) as the primary outcome measure. D. RemissionThis claim is defined as both remission by ACR criteria and radiographic arrest (noradiographic progression by Larsen or modified Sharp method) over a continuoussix-month period while off all antirheumatic therapy. Remission is not intended to implycure, and a remission claim could be granted even if patients relapse after six months ormore of remission. The duration of trials designed to support a remission claim will vary,depending upon the rate of onset of effect of the test product. Ordinarily such trialsshould be at least one year in duration, and longer trials may be needed for slow-actingagents.E.Prevention of DisabilityThis claim is intended to encourage long-term trials in RA. Currently, the HealthAssessment Questionnaire (HAQ) (Fries 1982) and the Arthritis Impact Measure Scales(AIMS) (Meenan 1982) are adequately validated measures for use as the primary outcomemeasure in these trials. Studies should be two to five years in duration. Sponsors seekingthis claim should plan to have demonstrated previously, or to demonstrate concomitantly,improvement in signs and symptoms. Since the full effect of RA on a patient is notcaptured without the use of more general HR-QOL measures, a validated measure such asthe SF-36 should also be collected and patients should not worsen on these measures overthe duration of the trial.
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`5F. Prevention of Structural DamagePrevention of structural damage is an important goal of RA therapy. Trials evaluating thisoutcome should be at least one year in duration.The following are examples of outcome measures that could be used to supportprevention of structural damage claims.1.Slowing X-ray progression, using either the Larsen, the modified Sharp, oranother validated radiographic indexRadiographic claims should be based on comparisons of films taken at one year(and subsequent yearly points) with those taken at baseline. All randomizedpatients should have films at both time points, regardless of whether they arecontinuing treatment. Patients dropping out of the trial should have films taken atthat time. Prespecification of the handling of dropouts is especially important inthese trials.2.Prevention of new X-ray erosions — maintaining an erosion-free state orpreventing new erosionsTrials evaluating this claim would ordinarily use a categorical endpoint to assign astatus of progression or nonprogression to each patient, comparing the final stateto the baseline state.3.Other measurement tools (e.g., MRI)Other measures, such as MRI (magnetic resonance imaging) or ultrasonography,could be employed. However, because of the technique's potential for identifyingsmall, albeit statistically significant changes, the magnitude of the difference thatwould reflect actual patient benefit is unclear and needs to be established.Because slowing of radiographic progression does not in itself define a patient benefit, it isexpected that the claim of prevention of structural damage would be submitted for anagent that has been shown (previously or concomitantly) to be effective for one of theother claims (e.g., prevention of disability). However, some agents are not intended toaffect acute inflammation, but are designed to prevent or slow joint destruction by othermeans. The first indication that such an agent is clinically useful might be slowing ofradiographic progression. Nevertheless, the ultimate goals of slowing joint destruction areto improve symptoms and to preserve functional ability. Therefore, slowing radiographicprogression of disease is considered a surrogate marker for overall patient benefit in RA.Under 21 CFR 314, subpart H and 21 CFR 601 subpart E, FDA can approve drugsintended to treat serious and life-threatening diseases based on an effect on a surrogatemarker, provided that certain criteria are met and that there is a commitment to define the
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`6actual clinical benefit of the agent in studies completed after marketing. A demonstrationof significant slowing of radiographic progression in a seriously affected population of RApatients would qualify for consideration under these regulations. Sponsors are urged toconsult with the relevant FDA staff before embarking on a clinical program based on theseregulations. One example of a significant effect on radiographic progression might be thedemonstration, in a randomized controlled trial, of maintenance of an erosion-free state ina large majority of treated patients when control patients develop multiple erosions. Themethods of measurement of the radiographic finding, the magnitude of change consideredto be clinically significant (whether a by-patient measure or treatment group means), andthe methods of statistical analysis should be prospectively defined in the clinical protocol,and the sponsor should seek Agency concurrence with the plan for evaluating efficacy. The use of the accelerated approval pathway would necessitate timely completion ofphase 4 studies using acceptable clinical endpoints evaluating signs and symptoms orprevention of disability. It is anticipated that these investigations would be extensions ofthe one-year studies used for the accelerated approval. III.CONSIDERATIONS IN RA PRODUCT DEVELOPMENTThe following information on preclinical and early clinical product development pertains primarilyto pharmaceuticals (drugs and biologics). Except in the first two sections, the general principlesoutlined below also apply to devices. For information specific to the development of devices,refer to the section in this document entitled "Special Considerations for Medical Devices." Developers of products that combine therapeutic modalities (e.g., biologics and devices) mayrequest assistance from FDA in designating a lead center for review of the product. Suchrequests should be submitted to: Office of the Chief Mediator and Ombudsman (HF-7), Food andDrug Administration, 5600 Fishers Lane, Rockville, MD 20857.Frequently encountered issues in RA product development include:1.Selecting appropriate in vitro (animal or human systems) and in vivo animal models forscreening potentially active agents.2.Designing and performing appropriate preclinical safety studies to support the use of anew molecular entity in human volunteers or patients.3.Balancing the potential need for therapeutic intervention early in the disease course withthe need to avoid exposing patients with mild disease to agents that have toxicities or littlerecord of safety.4.Identifying the potential risks associated with combination therapies, particularly thosewith shared target organ toxicity or potential for pharmacokinetic interactions.
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` ICH documents are available via the FDA Internet home page at http://www.fda.gov/cder or cber.375.Designing adequate and practical long-term safety monitoring.6.Designing trials that definitively show clinical efficacy.The following sections discuss approaches to the above issues. A.Preclinical ConsiderationsThis section focuses on preclinical issues that are specific to the clinical development ofantirheumatic therapies. In designing toxicity studies and the timing of such studies,consultation with the Agency is recommended concerning the current recommendationsand guidances that address drugs, devices, and biological products. Guidance onpreclinical safety testing, addressing the need for and design of toxicokinetic, reproductivetoxicity, genotoxicity, and carcinogenicity studies has been developed by the InternationalConference on the Harmonization (ICH) of Technical Requirements for Pharmaceuticals. Because biologics can pose unique challenges in animal study design (for example,species-specific binding or immunogenicity of human proteins in animals), a specific ICHdocument is available that addresses the safety evaluation of biotechnology-derivedpharmaceuticals (ICH S6 1997). 31.PharmacokineticsAnimal studies of drug absorption, distribution, metabolism, and excretion areimportant during the early investigational new drug (IND) phase to aid in toxicitystudy interpretation, but need not all be completed prior to phase 1. Generally, forinitial studies in humans, determining pharmacokinetic (PK) parameters, such asarea under the curve (AUC), maximum concentration (C ), and half-life (t ) inmax 1/2animals, is sufficient to provide a basis for predicting safe clinical exposure. In the past, preclinical testing of combinations of drugs (or biologics) to be used inpatients with RA has not often been done prior to the initial clinical trials. However, given the variety of drugs, including NSAIDs, analgesics,corticosteroids, and DMARDs currently used to treat RA patients, it would beuseful to consider this testing of common combinations both preclinically andclinically. In addition, to evaluate potential interactions, information on the impactof concomitant therapies on pharmacokinetics may be needed to optimize dosingregimens and to identify potential safety concerns. Metabolic interactions oftenmay be assessed in an in vitro system using animal or human liver slices,microsomal preparations, or purified P450 enzymes (FDA 1997).Interactions may also result from the presence of individual- or disease-specific factors, such as rheumatoid factor, which may bind to various
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`8monoclonal antibody therapeutics; in such cases in vitro binding studies thatidentify patients with high titers may be useful in identifying patients who mayexhibit unique pharmacokinetics or patterns of clinical response.2.Biological activity The biological activity of a potential antirheumatic therapy should be establishedusing multiple preclinical model systems (i.e., in vitro, in vivo, ex vivo). In vitroscreens can use cells or tissues derived from animal or human sources and aregenerally used to select candidate drugs that have a desired effect on a moleculartarget. Such assays can also be used to devise appropriate bioassays for theselected agent. Animals, either healthy, with rheumatic disease (spontaneous orinduced), or genetically modified, are subsequently used to determine whether thebiological effect can be demonstrated in vivo. While the in vivo system usedshould mimic one or more aspects of rheumatoid arthritis or its etiology, it isexpected that each animal model will have limitations. a.In vitroData from in vitro studies can be useful in defining the potential mechanismof action of a drug or biologic and for determining relevance of a particularanimal species for in vivo assessment of activity or safety. These data areespecially useful if a potential surrogate marker can be identified inpreclinical studies. For example, if the product is intended to affect theCD4 receptor on lymphocytes, this receptor can be used as a surrogatemarker for both activity and certain toxicities.Several in vitro tests could be used, depending on the mechanism of actionof the drug or biologic. For example, binding assays may be useful fordeveloping receptor antagonists or monoclonal antibodies. In vitrofunctional assays (e.g., platelet and neutrophil aggregation) may be usefultests for identifying inhibitors of inflammatory mediators. Enzymaticassays (e.g., in vitro or ex vivo inhibition of cyclooxygenase, lipoxygenase,and phospholipase) may also be useful for determining selectivity for theinhibition of isozymes. b.In vivoSelection of animal models should be made on the basis of pharmacodynamic (PD) responses, similarity of animal disease etiology toclinical disease, and/or to define mechanism-based toxicity. Ideally,products that are targeted for a subset of arthritic patients should bedeveloped in an experimental model(s) that is most relevant to that subset. For example, rats are not sensitive to drugs that inhibit 5-lipoxygenase.
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`9Therefore, mouse or rabbit models are more relevant to evaluate the anti-inflammatory activity of leukotriene inhibitors.The development of rheumatic disease models to allow screening for potential RAcandidate drugs is encouraged. The following examples are meant only toillustrate some models in current use and are not intended to suggest excluding theuse of others.Collagen-induced arthritis (CIA):Collagen-inducted arthritis is often considered to be a suitable model for studyingpotential drugs or biologics active in human rheumatoid arthritis because of theinvolvement of localized major histocompatibility, complete class II-restricted Thelper cell activation, and the similarity of histopathological lesions. Radiographsof joints affected by CIA often show erosive changes similar to those seen inhuman rheumatoid arthritis. The progressive arthritis often results in RA-like jointdeformity and dysfunction. Anticollagen antibodies, which occur in some patientswith RA, develop in the CIA model.The CIA model has been useful for assessing immunosuppressants and steroidhormones as well as inhibitors of inflammatory mediators. Since this model can beinduced in several animal species, it may be especially useful for evaluating drugsthat are species-specific (e.g., leukotriene antagonists and 5-lipoxygenaseinhibitors). In addition, although functional tests are not routinely used in thismodel, incorporation of measures of mobility and joint function may enhance thepredictive value of the model.Naturally occurring arthritis or autoimmune response:MRL/lpr mice, Biozzi H mice and DBA/1 mice have been used to examine theonset of drug-induced tolerance and immunosuppressant drug effects onautoimmunity. The MRL/lpr mouse model has been useful for evaluatingimmunosuppressants and hormones.Rat carrageenin-induced acute model of inflammation:This model has been useful in assessing anti-inflammatory activity ofcyclooxygenase inhibitors. Most of the animal models that involve inflammation inthe paw may be used for measuring antiphlogistic action of a drug.Adjuvant-induced arthritis in rats (AA):AA in rats has been frequently used for screening nonsteroidal anti-inflammatorydrugs and inhibitors of inflammatory cytokines as well as antimetabolite-likeimmunosuppressants.
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`10Streptococcal cell wall-induced arthritis:This model has been used for developing cytokine inhibitors.Experimental organ transplant in animals:This model has been used to identify the activity of immunosuppressants andantimetabolites, particularly those directed at cytolytic cellular immune processes.Transgenic animal models:A number of transgenic animal models are being developed for the study ofrheumatoid arthritis and may prove useful over the next decade. Some examplesinclude transgenic mice that carry genes for the env-Px region of the human T cellleukemia virus type I genome, human TNF, CD4, and HLA B-27.3.ToxicologyPreclinical toxicology studies of a drug or biological product are designed tocharacterize general and specific toxicity using dosing routes and regimens assimilar as possible to the proposed clinical trials with consideration of thedemographics and disease status of the intended patient population. For instance,the prevalence of RA is high in females. Therefore, reproductive toxicity studiesshould be completed early in clinical development to support the inclusion ofwomen of childbearing age in early phases of clinical trials. The need forreproductive studies for biological products is likely to be case-specific due tocomplications arising from immunogenicity and species selectivity. Therefore,standardized study designs, such as those recommended in the ICH reproductivetoxicology guidance, may not be feasible or clinically relevant for biologics (ICHS5 1994). The need, and specific designs, for these studies may be discussed withAgency review staff.Immunomodulatory or immunosuppressive agents administered to RA patients asmonotherapy or in combination raise concerns about the adverse effects ofprolonged immunosuppression. For example, malignancies (i.e., lymphomas) are aknown risk of long-term, nonselective immunosuppression used for treatment ofgraft recipients. Investigational drug-related opportunistic infections and mortalityrelated to immunosuppression have occurred in RA patients. Sponsors areencouraged to identify and use animal models that assist in selecting drugcandidates that selectively inhibit cells and processes responsible for RA. Antirheumatic drugs are often used in combination in an attempt to improveoutcomes and minimize toxicities. However, drug interactions may result inincreased toxicity, even at lower than previously evaluated doses of either agent. This concern is especially evident for agents that have long half-lives or
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`11nonselective activity, or for drugs that share common target organ toxicity. Preclinical toxicity studies that evaluate the use of combined agents may be helpfulin predicting clinical safety hazards. The duration of toxicity dosing of animals isusually linked to patient dosing regimens. Development and validation of in vitroor whole animal models is encouraged to address concerns regarding short- orlong-term toxicity and to identify surrogate markers for patientimmunocompetence. B. Pharmacokinetic/Pharmacodynamic StrategiesIn vivo pharmacokinetic studies should be used to evaluate drug disposition andmetabolism, degree of linearity and accumulation, dose proportionality, and, for oraldosage forms, food interactions (Peck 1992). Some of these data can be gathered in asingle study designed to evaluate a number of parameters. During formulationdevelopment, bioequivalence studies linking formulations may be recommended. A particular concern with biological agents is the development of antibodies that mayaccelerate drug clearance or alter its distribution, resulting in changes in therapeuticbenefit over time, or following repeated courses of treatment. To address thisconsideration, it is desirable for sponsors to build into their repeat-dose clinical protocols acoordinated evaluation of drug