Product Development
`Under the
`Animal Rule
`Guidance for Industry
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`October 2015
`Animal Rule
`
`Sandoz Inc.
`Exhibit 1046-0001
`
`JOINT 1046-0001
`
`

`
`Product Development
`Under the
`Animal Rule
`Guidance for Industry
`
`Additional copies are available J?om."
`
`Office of Communications, Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
`Silver Spring, MD 20993-0002
`Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
`Email: druginfo@fda.hhs.gov
`http://www~fda.g~v/Drugs/GuidanceC~mplianceRegulat~rv~nf~rmati~n/Guidances/default.htm
`
`or
`
`Office of Communication, Outreach and Development
`Center for Biologics Evaluation and Research
`Food and Drug Administration
`10903 New Hampshire Ave., Bldg. 71, Room 3128
`Silver Spring, MD 20993-0002
`Phone: 800-835-4709 or 240-402-8010
`Email." ocod@fda.hhs.gov
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`October 2015
`Animal Rule
`
`Sandoz Inc.
`Exhibit 1046-0002
`
`JOINT 1046-0002
`
`

`
`Contains Nonbinding Recommendations
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ............................................................................................................. 1
`
`THE ANIMAL RULE ...................................................................................................... 2
`
`III.
`
`REGULATORY CONSIDERATIONS .......................................................................... 7
`
`A.
`
`B.
`
`C.
`
`D.
`
`Drug Development Plan ................................................................................................................ 7
`
`Access to Investigational Drugs During a Public Health Emergency ....................................... 9
`
`Communications With FDA ........................................................................................................ 10
`
`Animal Model Qualification Program ....................................................................................... 10
`
`IV.
`
`ANIMAL STUDIES - GENERAL EXPECTATIONS ............................................... 12
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Animals Used in Investigations ................................................................................................... 12
`
`Study Conduct .............................................................................................................................. 13
`
`Types of Animal Care Interventions .......................................................................................... 14
`
`The Study Report ......................................................................................................................... 14
`
`Submission of the Study Report and Data ................................................................................. 15
`
`V.
`
`ESSENTIAL ELEMENTS OF AN ANIMAL MODEL .............................................. 16
`
`A.
`
`Elements Related to the Etiologic or Challenge Agent-Induced Disease or Condition ......... 17
`
`].
`
`Characteristics of the Etiologic or Challenge Agent That Influence the Disease or Condition .... 17
`a. The Challenge Agent ............................................................................................................... 17
`b. Pathophysiological Mechanisms of Toxicity or Virulence ..................................................... 18
`c. Route of Exposure ................................................................................................................... 18
`d. Dose and Quantification of Exposure ..................................................................................... 19
`Host Susceptibility and Response .................................................................................................. 19
`Natural History of the Disease or Condition Pathophysiological Comparability ...................... 20
`a. Time to Onset .......................................................................................................................... 21
`b. Progression .............................................................................................................................. 21
`c. Manifestations ......................................................................................................................... 22
`Trigger for Intervention ................................................................................................................. 22
`Elements Related to the Investigational Drug and the Selection of an Effective Dose in
`
`Uo
`
`Humans .................................................................................................................................................. 23
`
`1. The Investigational Drug ............................................................................................................... 23
`a. Mechanism of Action .............................................................................................................. 23
`b. Drug Class ............................................................................................................................... 24
`c. Dosage Form and Route of Administration ............................................................................ 24
`2. Selection of an Effective Dose in Humans ..................................................................................... 24
`a. PK and PD Information to Be Obtained in Animals and Humans .......................................... 25
`b. PK/PD Considerations for Human Dose Selection ................................................................. 26
`VI. DESIGN CONSIDERATIONS FOR THE ADEQUATE AND WELL-
`CONTROLLED EFFICACY STUDIES IN ANIMALS ......................................................... 30
`
`A. General Principles ........................................................................................................................ 31
`
`Sandoz Inc.
`Exhibit 1046-0003
`
`JOINT 1046-0003
`
`

`
`Contains Nonbinding Recommendations
`
`B. Dose Selection in Animals ........................................................................................................... 33
`
`VII. CONSIDERATIONS FOR PREVENTIVE VACCINES AND FOR CELLULAR
`AND GENE THERAPIES ......................................................................................................... 35
`
`A. Vaccines ........................................................................................................................................ 35
`
`B. Cellular and Gene Therapies ...................................................................................................... 36
`
`l. Cellular Therapy Products ............................................................................................................ 36
`2. Gene Therapy Products ................................................................................................................. 37
`VIII. HUMAN SAFETY INFORMATION ........................................................................... 38
`
`IX.
`
`CHECKLIST OF ESSENTIAL ELEMENTS OF AN ANIMAL MODEL .............. 41
`
`X. CHECKLIST OF ELEMENTS OF AN ADEQUATE AND WELL-CONTROLLED
`ANIMAL EFFICACY STUDY PROTOCOL .......................................................................... 42
`
`APPENDIX A: GENERAL PRINCIPLES FOR THE CARE AND USE OF ANIMALS IN
`BIOMEDICAL RESEARCH ..................................................................................................... 43
`
`APPENDIX B: TYPES OF ANIMAL CARE INTERVENTIONS ....................................... 46
`
`APPENDIX C: GENERAL EXPECTATIONS FOR NATURAL HISTORY STUDIES... 48
`
`APPENDIX D: ACRONYMS AND ABBREVIATIONS ....................................................... 49
`
`Sandoz Inc.
`Exhibit 1046-0004
`
`JOINT 1046-0004
`
`

`
`Contains Nonbinding Recommendations
`
`Product Development Under the Animal Rule
`Guidance for Industry1
`
`This guidance represents the current thinking of the Food and Drag Administration (FDA or Agency) on
`this topic. It does not create any rights for any person and is not binding on FDA or the public. You can
`use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To
`discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title
`page.
`
`I.
`
`INTRODUCTION
`
`This guidance2 provides information and recommendations on drug and biological product3
`development when human efficacy studies are not ethical or feasible. The regulations that set
`forth the pathway for approval4 of these products under 21 CFR 314.600 through 314.650
`(drugs) or 21 CFR 601.90 through 601.95 (biological products) are commonly referred to as the
`Animal Rule.
`
`This guidance does not address the following topics:
`
`¯ The chemistry, manufacturing, and controls or nonclinical pharmacology and toxicology
`studies necessary for drug development
`
`¯
`
`Issues related to initial proof-of-concept studies
`
`¯ The details of study design and conduct for drug-specific animal efficacy studies or for
`human pharmacokinetic (PK) and/or safety studies
`
`¯ Drug development in specific populations (e.g., pediatrics, geriatrics, and pregnant
`women)5
`
`¯ The development of combination products
`
`1 This guidance has been prepared by the Center for Dmg Evaluation and Research (CDER) in cooperation with the
`
`Center for Biologics Evaluation and Research (CBER) at the Food and Dmg Administration. The Office of Good
`Clinical Practice and the Office of Counterterrorism and Emerging Threats also provided input.
`2 This guidance finalizes the 2014 revised draft guidance for industry Product Development Under the Animal Rule,
`
`which replaced the 2009 draft guidance for industry AnimalModels Essential Elements’ to Address Efficacy Under
`the Animal Rule.
`
`As used in this guidance, all references to drugs include human dmgs, therapeutic biological products, cellular and
`gene therapies, and vaccines, unless otherwise specified.
`
`As used in this guidance, the term approval refers to approval or licensure.
`
`The Animal Rule applies equally to adult and pediatric populations.
`
`Sandoz Inc.
`Exhibit 1046-0005
`
`JOINT 1046-0005
`
`

`
`Contains Nonbinding Recommendations
`
`Requirements for procurement of medical countermeasures by the federal government
`(e.g., Strategic National Stockpile (SNS)6)
`
`The development of animal models for other purposes, such as for assessment of
`toxicology
`
`Information on FDA guidances is available on FDA’s Web page.7 In addition, FDA guidances
`related to medical countermeasures for chemical, biological, radiological, and nuclear (CBRN)
`agents can be accessed through FDA’s Medical Countermeasures Initiative (MCMi) Web page.
`
`In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
`Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
`as recommendations, unless specific regulatory or statutory requirements are cited. The use of
`the word should in Agency guidances means that something is suggested or recommended, but
`not required.
`
`II.
`
`THE ANIMAL RULE
`
`FDA’s regulations concerning the approval of new drugs when human efficacy studies are not
`ethical9 and field trials are not feasible are codified in 21 CFR 314.600 through 314.650 for
`drugs and 21 CFR 601.90 through 601.95 for biological products. Approval under the Animal
`Rule can be pursued only if human efficacy studies cannot be conducted because the conduct of
`such trials is unethical and field trials after an accidental or deliberate exposure are not feasible.
`The Animal Rule does not apply to drugs that can be approved for the proposed indication
`"based on efficacy standards described elsewhere in FDA’s regulations .... ,,10
`
`The Animal Rule states that for drugs developed to ameliorate or prevent serious or life-
`threatening conditions caused by exposure to lethal or permanently disabling toxic substances,
`when human efficacy studies are not ethical and field trials are not feasible, FDA may grant
`marketing approval based on adequate and well-controlled animal efficacy studies when the
`results of those studies establish that the drug is reasonably likely to produce clinical benefit in
`humans. Drugs evaluated for efficacy under the Animal Rule should be evaluated for safety
`under the existing requirements for establishing the safety of new drugs. The Animal Rule states
`
`6 Sponsors should discuss issues related to the SNS with the Department of Health and Human Services/Biomedical
`
`Advanced Research and Development Authority (HHS/BARDA and the Centers for Disease Control and
`Prevention (CDC).
`7 FDA guidances are updated periodically. The most recent versions are available at
`
`http ://www.fda. gov/Re~,ulatorvInformation/Guidance s/default, htm.
`s The MCMi Web page is available at
`
`http://www.fda, gov/emergencvpreparedness/medicalcountermeasures/default.htm.
`9 As described in the Scope of the Animal Rule, "... it would be unethical to deliberately expose healthy human
`
`volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance .... "
`See 21 CFR 314.600 for drugs and 21 CFR 601.90 for biological products.
`l o See 21 CFR 314.600 for drugs and 21 CFR 601.90 for biological products.
`
`Sandoz Inc.
`Exhibit 1046-0006
`
`JOINT 1046-0006
`
`

`
`Contains Nonbinding Recommendations
`
`that FDA will rely on evidence from animal studies to provide substantial evidence11 of
`effectiveness only when all of the following four criteria are met:
`
`1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of
`the substance and its prevention or substantial reduction by the product;
`
`The effect is demonstrated in more than one animal species expected to react with a
`response predictive for humans, unless the effect is demonstrated in a single animal
`species that represents a sufficiently well-characterized animal model for predicting the
`response in humans;
`
`3. The animal study endpoint is clearly related to the desired benefit in humans, generally
`the enhancement of survival or prevention of maj or morbidity; and
`
`4. The data or information on the kinetics and pharmacodynamics of the product or other
`relevant data or information, in animals and humans, allows selection of an effective dose
`in humans.12
`
`If all of these criteria are met, it is reasonable to expect the effectiveness of the drug in animals to
`be a reliable indicator of its effectiveness in humans.
`
`The use of the Animal Rule as a regulatory pathway to approval is intended for drugs developed
`to ameliorate or prevent serious or life-threatening conditions caused by chemical, biological,
`radiological, or nuclear substances regardless of whether the substances are considered potential
`threat agents for deliberate exposure (e.g., nerve agent, Bacillus anthracis) or threats to
`individuals’ health from accidental exposure (e.g., emerging infectious pathogens, snake venom,
`industrial chemicals), provided that human efficacy studies are not ethical and field trials to
`study effectiveness of the drug are not feasible.
`
`FDA will determine whether the previously noted criteria have been met and the Animal Rule
`can be used. In general, the determination of whether it is ethical to conduct deliberate exposure
`studies in humans is not difficult; however, the determination that human field trials are not
`feasible may be challenging. The feasibility issues to be considered will depend on the disease
`or condition to be studied and may change over time. For example, there may be circumstances
`that affect the feasibility of planning and conducting human field trials for the disease or
`condition, such as (1) a low prevalence and/or incidence, (2) an unpredictable incidence rate
`from year to year, (3) an inability to predict geographic locations where outbreaks may occur, (4)
`occurrences limited to areas lacking critical infrastructure, and/or (5) occurrences limited to areas
`
`11 The term substantial evidence has been defined previously in section 505(d) of the Federal Food, Drug, and
`
`Cosmetic Act (FD&C Act) (21 U.S.C. 355(d)) as follows: "... evidence consisting of adequate and well-controlled
`investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate
`the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such
`experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed,
`recommended, or suggested in the labeling or proposed labeling thereof."
`12 See 21 CFR 314.610(a) for drugs and 21 CFR 601.91(a) for biological products.
`
`Sandoz Inc.
`Exhibit 1046-0007
`
`JOINT 1046-0007
`
`

`
`Contains Nonbinding Recommendations
`
`in which there is some extraordinary threat to subj ect or investigator safety. However, the
`international collaboration in response to the 2014-2015 Ebola epidemic in West Africa
`highlights the fact that determination of infeasibility of clinical trials can change over time.
`Sponsors should provide FDA with a clear rationale to support the use of the Animal Rule for the
`development of their drug before proceeding with drug development.
`
`With regard to establishing evidence of efficacy, the Animal Rule states: "In assessing the
`sufficiency of animal data, the agency may take into account other data, including human data,
`available to the agency.’’13 Although data from different types of studies (e.g., in vitro studies,
`other types of animal studies, human studies) may be supportive, adequate and well-controlled
`animal efficacy studies are required for approval under the Animal Rule.
`
`Supportive human data can include clinical efficacy data either from available human data for
`the same indication (as was the case for the 2006 approval under the Animal Rule of Cyanokit
`(hydroxocobalamin) for the treatment of known or suspected cyanide poisoning), or from
`available human data for a relevant non-Animal Rule-based indication (as was the case for the
`2012 approval under the Animal Rule of Levaquin (levofloxacin) for the treatment of pneumonic
`and septicemic plague caused by gersiniapestis).
`
`For Cyanokit (hydroxocobalamin), efficacy was established in a dog model of cyanide poisoning
`that FDA considered sufficiently well-characterized for predicting the response in humans.
`Existing human data from open-label, uncontrolled studies using hydroxocobalamin to treat
`cyanide poisoning from smoke inhalation, cyanide ingestion, or cyanide inhalation provided
`additional support for its approval.
`
`For Levaquin (levofloxacin), efficacy was established in an African green monkey model of
`pneumonic plague that FDA considered sufficiently well-characterized for predicting the
`response in humans. Existing human data from its prior approvals for other respiratory
`infections (i.e., nosocomial and community-acquired pneumonias) provided additional support
`for its likely effectiveness in the treatment of pneumonic and septicemic plague.
`
`When human efficacy data from a relevant indication may support the approval of the Animal
`Rule-based indication, FDA encourages sponsors to evaluate the drug in an indication for which
`obtaining human data is possible under a traditional regulatory pathway.14 In addition to the
`previously discussed Levaquin (levofloxacin) example, another example of when human efficacy
`data obtained in a related human disease or condition may support the determination of efficacy
`for the Animal Rule-based indication is when the drug targets a pathway in the
`pathophysiological cascade that is common to both the disease or condition intended for
`evaluation under the Animal Rule and a disease or condition for which clinical trials are ethical
`and feasible.
`
`13 See 21 CFR 314.610(a) for drugs and 21 CFR 601.91(a) for biological products.
`
`14 As stated in the preamble to the final rule "New Drug and Biological Drug Products; Evidence Needed to
`
`Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible" (the final
`rule) (67 FR 37988 at 37990 footnote 2, May 31, 2002), "... with anti-infective drug products, it would usually be
`expected that human data on safety and effectiveness for other indications may be available."
`
`Sandoz Inc.
`Exhibit 1046-0008
`
`JOINT 1046-0008
`
`

`
`Contains Nonbinding Recommendations
`
`The Animal Rule specifies that the choice of species for the adequate and well-controlled
`efficacy studies must be appropriate with regard to the disease or condition of interest and the
`investigational drug.iS There is no requirement for the use of a specific species. For each animal
`species selected by sponsors, the sponsors should provide scientific justification that the animal
`species exhibits key characteristics of the human disease or condition when the animal is
`exposed to the challenge agent.16 In addition, the species should be selected based on an
`understanding of the drug’s mechanism of action, such that the drug’s effect in the animal
`species is expected to be predictive of its effect in humans, and to allow extrapolation from the
`animal data to the selection of an effective dose and regimen for humans.
`
`The number of animal species necessary to support approval of a drug under the Animal Rule
`depends on the nature and clinical significance of any differences between the animal models17
`and humans with regard to the essential elements as described in section V. Sponsors should
`provide data or information to demonstrate that each animal model reflects key aspects of the
`pathophysiology of the human disease or condition of interest and that the response to the
`investigational drug in each animal model is likely to predict the response in humans.
`
`FDA will evaluate the suitability of a proposed animal model on a case-by-case basis.
`Generally, the efficacy of the drug should be demonstrated in more than one animal species
`expected to react with a response predictive for humans. In certain circumstances, studies in
`more than two species may be necessary to model the relevant aspects of the human disease or
`condition and response to the investigational drug. If the effect is demonstrated in a single
`species that represents a sufficiently well-characterized animal model18 for predicting the
`response in humans, then the Animal Rule allows for approval based on substantial evidence of
`effectiveness demonstrated in studies conducted in that species. The acceptability of using a
`single animal species will require FDA review and agreement on the body of evidence
`supporting the adequacy of the model. As discussed in the preamble to the final rule: 19
`
`[The] circumstances in which the agency will rely on evidence from studies in
`one animal species to provide substantial evidence of the effectiveness of these
`products in humans would generally be limited to situations where the study
`model is sufficiently well-recognized so as to render studies in multiple species
`
`15 See 21 CFR 314.610(a) for drugs and 21 CFR 601.91(a) for biological products.
`
`16 As used in this guidance, the term challenge agent refers to the substance used to cause the disease or condition in
`
`the animal studies, whereas the term etiologic agent refers to the substance causing the disease or condition in
`humans.
`17 For the purpose of this guidance, an animal model is defined as a specific combination of an animal species,
`
`challenge agent, and route of exposure that produces a disease process or pathological condition that in multiple
`important aspects corresponds to the human disease or condition of interest.
`is In the preamble to the final rule (67 FR 37988 at 37989, May 31, 2002), a well-characterized animal model was
`
`defined as "meaning the model has been adequately evaluated for its responsiveness."
`
`See 67 FR 37988 at 37991, May 31, 2002.
`
`Sandoz Inc.
`Exhibit 1046-0009
`
`JOINT 1046-0009
`
`

`
`Contains Nonbinding Recommendations
`
`unnecessary. In addition, other human data for the product could provide
`support for such approvals.
`
`When efficacy is demonstrated in a single study conducted in a sufficiently well-characterized
`animal model, it may be necessary to conduct a confirmatory efficacy study in that animal
`model.2° The confirmatory study ideally should be conducted at a different laboratory, however,
`use of the same laboratory may be acceptable with justification. Supportive human efficacy data
`may negate the need for a confirmatory study, as was the case for Levaquin (levofloxacin) for
`pneumonic plague and Cyanokit (hydroxocobalamin) for cyanide poisoning.
`
`There may be situations in which the application of the Animal Rule requires a more complex
`development plan. For example, variola virus (the etiologic agent of smallpox) presents a unique
`challenge because humans are the only known natural host, no animal species has been found to
`have comparable susceptibility to variola virus, and naturally occurring smallpox has been
`eradicated. Therefore, efficacy of investigational drugs developed to treat smallpox needs to be
`studied using other orthopoxviruses in relevant animal species (e.g., monkeypox in nonhuman
`primates, rabbitpox in rabbits, ectromelia in mice). Depending on the strength of the animal
`studies and other supporting evidence, the efficacy findings from such studies may support
`approval of the drug against variola. As with all animal efficacy studies, FDA strongly
`recommends that in such situations, sponsors discuss the scientific approach under consideration
`with the review division before initiating the animal studies.
`
`Approval of a drug under the Animal Rule imposes three additional requirements, which are
`summarized below (for greater detail, see 21 CFR 314.610(b)(1) through (3) for drugs and 21
`CFR 601.91(b)(1)through (3) for biological products):
`
`Postmarketing studies (e.g., field studies) to provide evaluation of safety and clinical
`benefit if circumstances arise in which a study would be feasible and ethical (i.e., in the
`event an emergency arises and the drug is used). A plan or approach to conducting such
`a study must be included with the new drug application (NDA) or biologics license
`application (BLA).
`
`Restrictions to ensure safe use, if needed (e.g., restricting distribution to facilities or
`health care practitioners with special training, requiring specified types of follow up, or
`imposing record keeping requirements).
`
`Information to be provided in the labeling to patient recipients that explains that for
`ethical or feasibility reasons, the drug’s approval was based on efficacy studies conducted
`in animals alone. This drug labeling should also include all the other relevant
`information required by FDA at the time of approval (e.g., directions for use,
`contraindications, a description of any reasonably foreseeable risks, adverse reactions,
`
`20 AS stated in the preamble to the final role, "... the animal studies should be replicated or substantiated in each
`
`species as needed to ensure credible results... " (67 FR 37988 at 37991, May 31, 2002).
`
`Sandoz Inc.
`Exhibit 1046-0010
`
`JOINT 1046-0010
`
`

`
`Contains Nonbinding Recommendations
`
`anticipated benefits, and drug interactions). This information must be provided before
`administration or dispensing, if possible.
`
`Products approved under the Animal Rule are subj ect to postmarketing recordkeeping and safety
`reporting applicable to all approved drug and biological products.21 Information on withdrawal
`procedures, submission of promotional materials, and termination of certain requirements for
`products approved under the Animal Rule is specified in the regulations)~
`
`III. REGULATORY CONSIDERATIONS
`
`A.
`
`Drug Development Plan
`
`Obtaining the body of evidence necessary to support approval of a drug using the Animal Rule is
`a complex and iterative process. FDA strongly encourages sponsors to establish early and
`ongoing communications with the Agency. Sponsors also may wish to seek input from public
`health officials and/or the military about the potential need for, and operational use of, the
`investigational drug and discuss this with FDA. Developing a drug development plan will
`support the discussion of important issues, including, but not limited to, the following:
`
`¯ The proposed indication and whether a drug can be developed under the Animal Rule
`
`¯ The design of an animal study as it relates to the anticipated clinical use of the drug
`during an incident
`
`¯ The development and/or selection of the animal models, including, when necessary, the
`design of the natural history studies
`
`¯ The results of the proof-of-concept studies
`
`¯ The proposed methods for selecting an effective dose and regimen in humans
`
`¯ The design of the adequate and well-controlled animal efficacy studies intended to
`provide the primary evidence of effectiveness of the drug
`
`¯ The proposed approach for ensuring the quality and integrity of data~3
`
`¯ The size and composition of the human safety database
`
`21 See 21 CFR 314.630 for drugs and 21 CFR 601.93 for biological products.
`
`22 See 21 CFR 314.620, 21 CFR 314.640, and 21 CFR 314.650, respectively, for drugs and 21 CFR 601.92, 21 CFR
`
`601.94, and 21 CFR 601.95, respectively, for biological products.
`23 In issuing the Animal Rule, FDA stated that".., studies subject to this rule must be conducted in accordance
`
`with preexisting requirements under the good laboratory practices (21 CFR part 58) regulations... " (67 FR 37988
`at 37989, May 31, 2002). The good laboratory practice (GLP) regulations, however, were developed as a quality
`system for nonclinical safety studies. FDA’s current expectations are described in section IV.B.
`
`Sandoz Inc.
`Exhibit 1046-0011
`
`JOINT 1046-0011
`
`

`
`Contains Nonbinding Recommendations
`
`¯ Plans or approaches for conducting the required postmarketing studies (e.g., field studies)
`to demonstrate safety and clinical benefit when such studies are feasible and ethical24
`
`¯ Timelines and/or milestones for FDA feedback or meetings
`
`¯ Eligibility for expedited development and review designation programs
`
`¯ Additional issues critical to the sponsor’s funding agencies2~
`
`Drug development is data-driven; any development plan should allow for modification or
`refinement as data are gathered and analyzed and projections or expectations change. It is the
`sponsor’s responsibility to provide complete and accurate submissions. Sponsors should explain
`any proposed deviations from the recommendations expressed in this guidance. The potential
`impact of these deviations on the drug development program should be discussed with FDA
`before the conduct of the relevant studies.
`
`FDA strongly recommends that sponsors obtain Agency concurrence on the design of the
`adequate and well-controlled animal efficacy studies because these substitute for the efficacy
`trials in humans (see sections VI and X). Sponsors should allow adequate time for FDA review,
`comment, and agreement before initiating these studies to ensure that the study design is
`adequate to support the proposed indication.
`
`The protocols for animal efficacy studies intended to provide primary evidence of effectiveness
`are eligible for evaluation under special protocol assessment (SPA) provisions.26’27 Before
`submitting a Request for SPA, the sponsor should have FDA concurrence on the model proposed
`for use in the efficacy study (including, but not limited to, the species, the details of the challenge
`agent, the conditions of exposure) and the method that will be used to extrapolate from the
`animal data to select an effective dose and regimen in humans.
`
`Drugs developed under the Animal Rule may be eligible for two of the expedited development
`and review programs28 (fast track and priority review) or other FDA programs, such as orphan
`drug designation.29 Sponsors requesting these designations should use established procedures.
`Drugs being developed under the Animal Rule do not meet the statutory requirement for
`
`24 See 21 CFR 314.610(b)(1) for drugs and 21 CFR 601.91(b)(1) for biological products.
`
`25 Product development plans required by funding agencies for medical countermeasures against CBRN agen