E. Animal Efficacy RuleIn May 2002, FDA promulgated a rule allowing for approval of new drug products based on animal data when adequate and well-controlled efficacy studies in humans cannot be ethically conducted because the studies would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers, and field trials are not feasible before approval. The intent of the Animal Efficacy Rule[23] is to facilitate the development of medical countermeasures to treat or prevent injury from chemical, biological, nuclear, or radiological agents. The rule does not apply to products that can be approved based on other efficacy standards (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation of the products to which it does apply. Emergencies may arise necessitating human use of a decorporation agent still under development and for which approval under the Animal Efficacy Rule is not immediately feasible. Should this situation arise, it is conceivable that the product could be used under FDA's investigational new drug regulations in 21 CFR part 312 or under the emergency use authorization provision in section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3). 1. Applying the Animal Efficacy Rule to Decorporation AgentsFor decorporation agents used to enhance elimination or excretion of absorbed radioactive contaminants, animal studies may be used to provide substantial evidence of effectiveness only when (1) there is a reasonably well-understood pathophysiologic mechanism of the toxicity of the radioactive contaminant and its elimination or excretion by the decorporation agent, (2) 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, and (4) pharmacokinetic and pharmacodynamic data or information in animals and humans are sufficient to allow selection of an effective dose in humans. It should be noted that animal efficacy studies are subject to the same good laboratory practice (GLP) requirements as animal toxicology studies (see Subsection III.D below). In some situations, human efficacy studies using nontoxic levels of the radioactive contaminant or a stable, nonradioactive counterpart may be feasible and ethical. In such cases, approval could be based on efficacy standards described elsewhere in FDA's regulations, and evidence of effectiveness from animal studies alone would not be sufficient to support approval of a new product or a new indication for an already marketed product. Human efficacy studies would be needed to support marketing approval (see 21 CFR 314.600). Even if a new decorporation agent is eligible for approval under the Animal Efficacy Rule, that agent must still be evaluated for safety in humans; animal data is not sufficient to demonstrate safety (21 CFR 314.600). Products evaluated for effectiveness under the Animal Efficacy Rule must be evaluated for safety under preexisting requirements for establishing the safety of new drug products (21 CFR 314.600). FDA believes that the safety of these products (unlike their effectiveness) can be studied in human volunteers. 2. Three Requirements for Approval under the Animal Efficacy RuleApproval of a decorporation agent under 21
CFR part 314 subpart I requires: (1) submission of a plan or
approach to postmarketing studies that would be feasible should an
accidental or intentional release of radiation occur; (2)
postmarketing restrictions to ensure safe use, if deemed
necessary; and (3) product labeling intended for the patient to be
provided before product administration or dispensing, advising,
among other things, that the product’s approval was based on
efficacy studies conducted in animals alone. III. PRODUCT DEVELOPMENT PLAN FOR AN NDA or an EFFICACY SUPPLEMENTWe recommend that a sponsor planning to develop a decorporation agent for submission as a new drug application (NDA) or an efficacy supplement for a marketed product in support of a new use as a decorporation agent, meet with representatives of the Division of Medical Imaging and Hematology Products and the Office of Counter-Terrorism and Pediatric Drug Development in CDER regarding the specifics of a product’s development plans. This is particularly important if the sponsor intends to seek approval under the Animal Efficacy Rule. A comprehensive search of the medical literature and available scientific databases may reveal important information regarding a product’s chemistry, animal safety pharmacology, toxicology and efficacy, or human pharmacology and safety and inform the sponsor regarding additional studies that may be needed. Sponsors are encouraged to attempt to access primary data and perform an independent review of published findings to the extent possible. In most instances, literature references alone will not provide substantial evidence of effectiveness of a new product or new use, and additional well-controlled, animal efficacy and human pharmacology and safety studies will be needed.[24] We believe a well-planned and executed development program to prospectively assess product efficacy in animals and safety in humans is preferable to the post-event collection and analysis of data that has characterized the data supporting prior product approvals. A. Study SequenceA typical sequence for the requisite animal and human studies to support approval under the Animal Efficacy Rule is represented below. Additional detailed information is contained in the specified subsection. · Search of the published literature and available scientific databases and review of source documents, if available. · Tests of effectiveness in vitro; assay development and validation (i.e, chemistry, manufacturing, and controls) (Subsection III.B). · Preliminary or exploratory animal efficacy studies, typically in rodents or other suitable small animal model (Subsection III.C). · Animal safety pharmacology and toxicology studies (Subsection III.D). · Single-dose, dose escalation, safety, and tolerability studies in humans (initial first in human studies), using doses supported by animal data, as required (Subsection III.E). · Selection of the most appropriate animal species for the efficacy studies supporting approval; the animal species selected should be similar to humans with respect to the pharmacokinetic profile of the decorporation agent and the distribution of the radioactive contaminant (Subsection III.C). · Efficacy studies supporting approval, conducted in the most appropriate animal species (Subsection III.C). · Safety studies in humans; these studies should be conducted at the highest dose anticipated to be marketed and be performed in parallel with the animal efficacy study or studies intended to support approval, assuming the product is reasonably likely to produce clinical benefits in humans (Subsection III.F). B. Chemistry, Manufacturing, and ControlsThe same standards for chemistry, manufacturing, and controls (CMC) apply to decorporation agents as with other pharmaceuticals. Sponsors should consult the appropriate FDA guidances for drug substances and drug products. We also recommend that sponsors consider developing pediatric-appropriate dosage forms (e.g., liquid preparations, powder formulations for suspension), as appropriate. Specifications for new drug substances (also referred to as new chemical entities) and new indications for previously approved drug products should be adequate for the intended dosage form and route of administration to ensure identity, strength, quality, purity, and potency.[25] FDA recommends that sponsors develop and validate in vitro tests intended to predict the effectiveness of isotope (radioactive or nonradioactive) uptake by a decorporation agent. FDA also urges sponsors to establish the time course of uptake, generally as part of the specification for product release and stability. For example, in the case of Prussian blue, FDA used the mass uptake of nonradioactive cesium per gram of Prussian blue as a function of time as a measure of its probable effectiveness. This in vitro test measures not only the total uptake of cesium, but also the kinetics of the solution to solid (heterogeneous) exchange reaction. The synthetic procedure for manufacturing Prussian blue can produce insoluble solids of highly variable particle size, porosity, hydration, and defect impurities. In FDA’s experience, it was important to consider the effects of all these factors on Prussian blue’s cesium exchange properties. C. Animal Efficacy StudiesUnder the Animal Efficacy Rule, a sponsor can rely on animal studies to provide substantial evidence of effectiveness for certain new drug products intended to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances. Under §§ 314.610(a)(2), one of the requirements for approval based on effectiveness data from animals alone is that the effect be 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. Determination of the number of animal studies needed to support approval of a particular NDA will be made on a case-by-case basis, as will the determination of what constitutes a sufficiently well-characterized animal model for a given product or indication. In FDA's experience, animal efficacy studies found in the published literature or conducted without the express purpose of supporting regulatory submissions have often lacked adequate scientific rigor. Furthermore, unless there are sufficient pharmacokinetic and/or pharmacodynamic data to conclude that a rodent species will adequately predict the human response, FDA believes that the effectiveness of a proposed decorporation agent will need to be demonstrated in a second, probably nonrodent, animal species. 1. Considerations Regarding Efficacy Studies Supporting ApprovalThe following considerations and study characteristics are important in designing and interpreting the animal studies that will be used to support product approval (this list is not comprehensive): 1. Evaluation of efficacy in an appropriate animal species; the pharmacokinetic profile of the product and the distribution of the radioactive contaminant in the selected species should be similar to what is observed or expected in humans. 2. Inclusion of both male and female animals; the number of animals and the inclusion of appropriate controls should be adequate for proper statistical analysis. 3. Use of a test product that is pharmaceutically equivalent to that intended for humans. 4. Evaluation of a range of doses and calibration of a dose-response relationship. 5. Use of a dosing frequency and route of administration that are similar, if not identical, to that intended for humans; determination of the efficacy window (i.e., the timing of product administration relative to radioactive contamination and duration of treatment). 6. Efficacy can be based on direct measurement of the elimination of the radioactive contaminant through feces and/or urine (or exhalation, as appropriate) at various time points after administration of the decorporation agent; alternatively, the residual body burden may be measured. These measurements can then be used to calculate changes in whole-body committed radiation dose following product administration. It is generally acknowledged that the long-term risk of cancer is a function of the radiation dose received. Clinically meaningful reduction in whole-body committed radiation dose (see Glossary definition) following administration of a decorporation agent in the animal efficacy study or studies intended to support approval is “clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity” (21 CFR 314.610(a)(3)).[26] 7. Designing the study using the relevant characteristics of an adequate and well-controlled study as described in 21 CFR 314.126, including reduction of bias, a clear protocol, and a statistical plan. To support approval, the decorporation agent should demonstrate statistically significant and clinically meaningful reduction in whole-body committed radiation dose compared to the control. 2. Good Laboratory Practice (GLP) ComplianceBecause efficacy studies will not be conducted in humans when a product is approved under the Animal Efficacy Rule, it is essential to ensure the quality and reliability of the animal efficacy data. Therefore, efficacy studies supporting approval must be conducted in compliance with GLPs (see 21 CFR part 58). D. Animal Safety Pharmacology and Toxicology StudiesSponsors must conduct animal safety studies to define pharmacological and toxicological effects before initiation of first-in-human clinical trials to establish a safe starting dose for decorporation agents that are new molecular entities (see 21 CFR 312.23(a)(8)). The product used for definitive animal safety pharmacology and toxicology studies should be pharmaceutically equivalent to the product proposed for human studies. If the decorporation agent is a product that has already been approved for marketing, or if comprehensive animal or human data are available under another NDA that the sponsor either owns or has a right of reference to, additional safety pharmacology and toxicology studies may not be required, unless the route of administration, dosing regimen, and/or formulation is new. 1. Safety Pharmacology StudiesSafety pharmacology studies investigate potential undesirable pharmacodynamic effects on physiologic functions in relation to exposure in the therapeutic range and above. FDA recommends that sponsors perform safety pharmacology studies assessing effects on the cardiovascular, central nervous, pulmonary, and renal systems before first administration in humans.[27],[28] Follow-up or supplemental studies may also be needed if there is cause for concern. Information from adequately designed and conducted toxicology studies that address safety pharmacology endpoints may result in reduction or elimination of some of the safety pharmacology studies. [27] For products that are not systemically absorbed, it may be necessary to conduct safety studies using intravenous administration to assess the potential risk that may arise in special populations (e.g., ulcerative colitis patients). Sponsors should thoroughly evaluate local gastrointestinal toxicity for such products. 2. Toxicokinetic and Pharmacokinetic StudiesFDA recommends that exposure in animals be evaluated before human safety studies.[29] FDA believes that absorption, distribution, metabolism, and excretion (ADME) data in animals should be available to compare human and animal pharmacokinetic profiles. 3. Toxicology StudiesToxicology studies should include the following: · Expanded single- and repeat-dose toxicity studies in two mammalian species (one nonrodent). The duration of the repeat-dose toxicity studies should be equal to or exceed the duration of the intended treatment in humans.[30] · Genotoxicity studies in vitro and in vivo[31],[32] · Reproductive toxicity studies (Segment I & II).[33],[34] For oral decorporation agents that are not systemically absorbed, reproductive studies may not be needed. · Local tolerance studies in animals using routes relevant to the proposed clinical route of administration. The assessment of local tolerance may be part of other toxicity studies. · Safety studies in juvenile animals if the decorporation agents are likely to be used in pediatric populations.[35] · Carcinogenicity studies, but only if there is cause for concern, such as evidence of preneoplastic lesions in repeat-dose toxicity studies. Any special toxicology study requirements will be determined on a case-by-case basis, depending on product characteristics. Animals used to determine efficacy may also be assessed for toxicity. For example, safety endpoints may include assessment of physiologic functions during the study, as well as determination of histology of tissues obtained at necropsy. Sponsors should refer to the appropriate Agency guidances for information regarding (1) the conduct of safety pharmacology and toxicology studies, (2) the timing of these studies relative to the initiation of human studies, and (3) appropriate methods for dose extrapolation that may be used for estimating a safe starting dose in human clinical trials.[36] E. Clinical Pharmacology and Biopharmaceutics StudiesUnder § 314.610(a)(4), the data or information on the kinetics and pharmacodynamics of a decorporation agent in humans, as well as in animals, must allow selection of an effective dose in humans. Sponsors should attempt to evaluate as heterogeneous a human study population as possible, with a reasonable balance of males and females, young and elderly, and members of differing racial groups. FDA believes that a complete clinical pharmacology and biopharmaceutics evaluation of a decorporation agent will provide detailed information on (1) general attributes, (2) general clinical pharmacology, (3) extrinsic and intrinsic factors, (4) general biopharmaceutics, and (5) bioanalytical methods. In particular, sponsors should consider the following issues relating to these topics: General attributes, including the physicochemical properties of the drug substance and the formulation of the drug product. General clinical pharmacology, including (1) the proposed mechanism or mode of action of the product and (2) the proposed human dosage regimen and its justification. The pharmacologic assessment should address the following in detail: 1. The basis for selecting the response endpoints in animal models and how they are extrapolated to humans; establishment of pharmacokinetic (PK)/pharmacodynamic (PD) relationships in animals; time to the onset and offset of the pharmacological response. 2. Product absorption, distribution, metabolism, and excretion in humans (a mass balance study using radiolabeled product would be useful in this regard). FDA believes that the route of administration should be designated and be the same in both animal and human studies. 3. Identification and quantification of the active moieties in plasma (or other appropriate biological fluid) and characterization of pharmacokinetic parameters in humans, including the following: · The degree of linearity or nonlinearity in the dose-concentration relationship evaluated in a dose escalation study. · The change in pharmacokinetic parameters with time following multiple dosing, if multiple dosing is indicated. · The metabolic profile, pharmacokinetic parameters, and plasma protein binding in humans as compared to animals. · Characteristics of the exposure-response relationships (i.e., dose-response or concentration-response) for safety parameters. Extrinsic and intrinsic factors, including the effect of age, gender, race, and organ dysfunction (e.g., renal impairment and hepatic impairment) on exposure, as necessary; evaluation of drug-drug interactions, as appropriate. General biopharmaceutics, including the solubility, permeability, and dissolution of the drug product, if applicable; the effect of food on bioavailability of the drug product, if applicable. Bioanalytical methods for determination of active moiety and metabolite(s). Sponsors should provide the rationale for selecting metabolites for analysis and describe the range of the standard curve and curve fitting techniques. They should also identify the upper and lower limits of quantification (ULOQ/LLOQ) and describe the accuracy, precision, and selectivity of analytical methods at these limits. In addition, sponsors should address sample stability during freeze-thaw cycles, sample transport, and long-term storage. F. Safety Assessment in HumansThe goal of human safety studies is to characterize the adverse effects of the product in humans, so that this toxicity can be weighed, to the extent possible, against the benefits of use, both generally and for particular patients. When designing safety studies for decorporation agents that may be approved under the Animal Efficacy Rule, sponsors should consider the following: 1. What safety information should be generated preapproval, and in particular, what specific safety risks or animal findings should be explored preapproval? 2. What safety information reasonably may be delayed to postmarketing studies? Considerations for Safety Studies Supporting Approval. At a minimum, sponsors should conduct a randomized, placebo-controlled safety study in humans to support approval of a product under the Animal Efficacy Rule. Additional safety studies may be needed to address specific concerns not addressed by, or raised by, the results of the placebo-controlled trial. Sponsors should consider the following factors in the design and interpretation of human safety studies that will support product approval (this list is not comprehensive): 1. Use of a test product that is bioequivalent to, and delivered by the same route of administration and dosing regimen as, that intended for marketing. 2. Focused evaluation of the planned human dose; evaluation of a range of doses and establishment of a dose-response relationship for any observed adverse events would also be useful. 3. Inclusion of complete physical examinations with vital signs, ECGs, and laboratory parameters (e.g., electrolytes, chemistry and hematology profiles, tests of renal and liver function) as part of the clinical evaluation. Additional evaluations may be needed, as appropriate. FDA recommends that evaluations be performed at baseline and at specified follow-up time points, as dictated by the dosing regimen and preclinical or other available human safety findings. 4. Incorporation of population PK/PD studies using sparse sampling techniques. Such studies may be useful in identifying factors causing intersubject variability and in relating individual drug exposure to safety outcomes. 5. Monitoring for adverse events that includes collection of the following: the timing of the event relative to product administration, the duration and severity of the event, clinical management of the event, outcomes (e.g., need for hospitalization, event resolved spontaneously). Sponsors should refer to the FDA guidance, Premarketing Risk Assessment, for more information on preapproval risk assessment, including generation, analysis, and presentation of human safety data in an application for approval. Size of the NDA Safety Database. We recommend that a sponsor planning to submit an NDA for a new decorporation agent, or an efficacy supplement for a previously marketed product in support of a new use as a decorporation agent, under the Animal Efficacy Rule or other regulatory mechanism, meet with the appropriate representatives in CDER to discuss the size of the human safety database. The following factors may increase or decrease the size of the requisite NDA safety database (this list is not comprehensive): 1. Whether additional studies focused on risks to a specific target organ or addressing specific animal or clinical safety concerns are needed preapproval 2. Whether the product is intended to treat otherwise healthy individuals on a large scale or a defined, seriously ill subpopulation for whom some risk would be acceptable 3. Whether the product will be used chronically or for acute, one time only use 4. Whether the product treats a condition for which there are no available therapies 5. Whether the product meets an unmet medical need (e.g., is superior in efficacy to or avoids serious toxicities associated with available therapies, or provides benefits to patients who are unresponsive to or intolerant of available therapies)[37] 6. Whether the product is already marketed and known to have an acceptable safety profile for the populations that would be given it as a decorporation agent 7. Whether the product is first in its class or relatively similar to other products on the market An NDA safety database generally will include human subjects exposed to a variety of product doses as well as placebo-treated subjects. Although the requisite number of subjects will vary across applications for the reasons cited above, for products that (1) are intended to treat conditions for which there are no available therapies, (2) meet an unmet medical need, (3) are intended for short-term use, or (4) have a well-defined and acceptable toxicity profile in animals, 200 to 300 subjects may be sufficient to support approval, if those subjects have been exposed to the decorporation agent at doses and durations comparable to those anticipated in marketed use and have had an adequate battery of safety testing. G. Benefit-Risk AssessmentBenefit-risk
assessment relates the potential or actual benefit that a
particular patient or population derives from using a product to
the risks incurred through its use. If a decorporation agent is
highly effective in eliminating absorbed radiocontaminants from
the body and is relatively free of risk, its benefit-risk
assessment would be highly favorable. Such a product would
provide enormous benefit, especially to those most heavily exposed
to radioactive contamination, or to those who might suffer greater
consequences as a result of even lesser amounts of exposure (e.g.,
pediatric populations). Situations may arise, however, in which
there is a question of whether to administer such a product to a
less heavily exposed population. Therefore, there is a great need
for a careful assessment of benefit-risk in populations with
varied levels of radioactive contamination. If a product's
approval is subject to the Animal Efficacy Rule, before its
approval such assessments will generally be based primarily on
experience with animal models. In the event of accidental or
nonaccidental radioactive contamination, serious efforts to
evaluate the benefit-risk of a decorporation agent in humans
should be made, to the extent possible. IV. POSTAPPROVAL COMMITMENTS FOR PRODUCTS APPROVED UNDER THE ANIMAL EFFICACY RULESponsors planning to submit an NDA for a new decorporation agent, or an efficacy supplement for a marketed product in support of a new use as a decorporation agent, for approval under the Animal Efficacy Rule23 are encouraged to meet with the appropriate representatives in CDER regarding the specifics of postapproval commitments. Postapproval issues for products approved under the Animal Efficacy Rule are discussed in §§ 314.610(b). One of the requirements for approval under the Animal Efficacy Rule is that sponsors must conduct postmarketing studies to verify and describe a decorporation agent’s clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical (see § 314.610(b)(1)). Except in the case of accidental or nonaccidental radioactive contamination, such studies would be infeasible. Under the rule, sponsors must, therefore, include as part of their NDA or efficacy supplement a plan for conducting postmarketing studies. Such studies could include field studies of subjects with radioactive contamination. Sponsors should anticipate and plan for data collection under emergency use conditions and develop methods for maximizing information collection. At a minimum, sponsors should design postmarketing studies to collect the following information on subjects with radioactive internal contamination: [38]
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