International Consortium For Innovation & Quality in Pharmaceutical Development

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1 International Consortium For Innovation & Quality in Pharmaceutical Development s on Draft Guidance: FDA Draft Guidance: Investigational Enzyme Replacement Therapy Products: Nonclinical Assessment (draft May 2015) We are pleased to offer the following comments, prepared by the IQ Consortium. The IQ Consortium is a technically focused organization of pharmaceutical and biotechnology companies, whose mission is to advance science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide. We very much appreciate the opportunity to review the draft proposed guidance and share our feedback. Specific concerns and feedback on the draft guidance follow. Please contact Dr. Maggie Liu at the IQ Secretariat with any questions: Maggie.liu@dbr.com or The draft guidance clearly demonstrates FDA recognition of the unique nature of storage disorders and the challenges associated with developing effective and safety therapies. The draft guidance further reflects the need for rapid advancement of the development of enzyme replacement therapies (ERTs). The flexibility inherent in the guidance along with the recommendation for sponsors to dialog with the review division to develop the most appropriate nonclinical strategies supports the out-of-the-box strategies that best suit the urgency for the patient population. The progressive nature of these diseases, that often leads to rapid debilitation and death, warrant rapid advancement of therapies to clinical trials and registration. The requirement for toxicity studies of 3-months duration (or potentially longer) is considered to be too cautious. It is recommended that ICH S9 for Oncology products should be considered a guide for how nonclinical studies can support rapid development of ERTs while insuring a robust nonclinical evaluation. For patients with advanced disease, treatment upon entry into Phase 1 clinical trials should be allowed to continue according to the patient s response without initiating a new toxicology study. The nonclinical data for supporting Phase 1 along with the clinical data obtained from Phase 1 should be considered sufficient for patients to enter Phase 2 trials. To support Phase 3 clinical trials a study of 3 months duration in a single relevant species would be considered the maximum duration of nonclinical toxicity studies to support clinical trial entry as well as drug registration. As ERTs consist of replacement of an endogenous enzyme, the side effect profile is expected to be fairly benign and easily monitored for adverse effects that warrant discontinuation of treatment. Therefore, ICH S9 is a suitable model for establishing a drug development paradigm that appropriately balances benefit and risk. 1

2 Furthermore, the requirement for studies in two species is also considered overly cautious and we believe alignment with ICH S6(R1) for biotherapeutic products is a preferred approach. ERTs by their nature are human enzyme replacements that have well understood biological activities. This aligns closely with ICH S6(R1) recommendations on choice of relevant species and justification for use of a single species for safety evaluations. Moreover, the nature of these products supports a side effect profile that is expected to be fairly benign and amendable to biomonitoring. Further consideration of need for two species is warranted. We believe the default expectation of conducting a battery of reproduction and development studies should be reconsidered for ERTs as it is overly cautious. Since ERT s would be a replacement of an endogenous enzyme and in most cases they are not expected to cross the placenta, the battery of reproductive toxicology studies recommended (ICH-S5 (R1) and the timing of when such studies need to be conducted (ICH-M3(R2)) are also considered conservative and cautious even though there are provisions for waiving or delaying such studies until after licensure. Furthermore, the intended patient population should be considered when determining the need for reproductive and developmental toxicity testing. An example of the overcautious default recommendation for a battery of reproductive toxicity studies are cases where an endogenous human enzyme is administered to a pediatric patient population that has a low probability of surviving past adolescence. Additional comments for consideration regarding specific aspects of the draft guidance are provided below. The IQ Consortium appreciates the opportunity to review and comment on the draft guidance for Investigation Enzyme Replacement Therapy Products: Nonclinical Assessment. (Docket No. FDA-2015-D-1246) Lines 88 Nonclinical Program Objectives: General : Recommend adding that the objective of safety assessment should also be to evaluate potential safety concerns due to rapid clearance of accumulated lysosomal storage substrates that can be evaluated in the animal disease models. 2

3 Recommendations for General Nonclinical Program Design. General s: Since approximately 2/3 of LSDs involve disease progression in the CNS that is unamenable to systemically administered ERT, direct CNS administration of ERT will play an increasing role in treatment. Whenever possible, the same route of administration and similar delivery device(s) should be used in the nonclinical studies as in the proposed clinical trial. In some cases, technical considerations may limit use of certain delivery devices in animal models. Justification should be provided for the relevance of selected routes/delivery device(s) in animal models compared to the intended use of the device in patients. It would be helpful to note that high dose levels in nonclinical CNS studies may be maximum feasible doses due to limitations of achievable enzyme concentration, dose volume, and/or infusion rate/time in the nonclinical species. Nonhuman primates are considered to have the closest CNS to human and should be considered for CNS distribution studies for ERT; adding toxicity endpoints could provide additional information for characterization of safety endpoints Selection of Animal Species: Recommend clarification as follows: (3) natural immune tolerance to the ERT product and feasibility of administration agents to control immune reactivity and/or hypersensitivity eg: anti-histamines 3

4 Animal Models of Disease Use of animal models of disease can be valuable adjunct to use of normal healthy animals. As defined by Morgan et. al., the appropriateness of including toxicity endpoints in these models requires consideration of the models suitability for evaluation of the intended endpoints. In general, the text in this section is unclear regarding expectations and circumstances, in which animal models of disease should be considered. Because only limited numbers of animals may be available in these models we recommended that expectations should be established around the suitability of using them for hazard identification as opposed to establishing safety margins and the suitability of a limited data set to enabling FIH clinical trials. Recommend adding following bullets Animal models of disease may provide more relevant safety assessments because of similar ongoing disease processes as human patients that may affect safety, PK, and/or distribution of ERT. Should these models be used a therapeutic index could be derived based on the minimum efficacious dose and the NOAEL dose in the study Interpretation of studies in animal models using CNS administration should take into account differences in the CNS parameters of the nonclinical species vs. human, including brain size/weight/volume, CSF volume, and CSF turnover rate. These CNS parameters should be considered when estimating clinical doses for patients and for estimation of safety margins between doses used in toxicology studies and first in human clinical studies. eg: mcg or mg of drug / gram of brain weight When using animal disease models consideration should be given to adding wild-type or litter mate controls to be treated with ERTs as a healthy group to characterize response differences in disease versus healthy state. 4

5 Inclusion of a section addressing the potential need for safety pharmacology is recommended and that it could be inserted between Section III.B.4 and III.B.5. Recommend the following text be added: It is important to investigate the potential for undesirable pharmacologic activity in appropriate animal models, and, where necessary, to incorporate particular monitoring for these activities in POC, toxicology, or clinical studies. Safety pharmacology studies measure functional indices of potential toxicity. If needed, functional indices to evaluate effects on major physiological systems should be incorporated in the design of POC or toxicity studies if possible. Stand-alone studies are generally not warranted for ERT products Toxicology Studies Recommend addition of the following bullet point to ensure adequacy of consideration for toxicokinetic data: Toxicokinetic evaluation should be included to inform the clinical dosing regimen. In studies involving direct CNS administration of ERT, toxicokinetic assessments should be considered for both the systemic (plasma) and CNS (CSF) compartments Toxicology Studies Add the following recommendation: When considering the suitability of animal models of disease it is recommended that background data be collected on the ERT mechanism of action to ensure the ability to detect a response as well as evaluation of toxicologic endpoints (e.g., histopathology) to establish baseline response. 5

6 Recommend addition as follows: POC studies in relevant animal disease model(s) modified to prospectively asses toxicology endpoints, including clinical pathology and microscopic examination of select tissues from key target organs (disease or toxicity) may be adequate to evaluate toxicity and would be considered supportive for initiation of human clinical trials General : Recommend adding further clarification on the extent of safety data from adult animals and adult patients that would support a waiver of juvenile toxicology studies General : Recommend including a comment that when considering use of an antihistamine control group to limit hypersensitivity response it may not be necessary to include the control group if the effects of anti-histamine treatment in animal species is reasonably well understood based on prior studies and/or historical controls. 6

7 General comments on Dose Selection: ICH M3(R2) and the associated Q&A are not appropriate references for dose selection in toxicity studies. This guidance is primarily focused on small molecules and much less applicable to enzymes and proteins. Moreover, the intent of M2(R2) is to identify target organ toxicity by maximizing the dose, which is somewhat counter to the situation with biopharmaceuticals. More applicable is ICH S6 for biopharmaceuticals that refers to a dose that either achieves the maximum pharmacological dose or a dose which approximates a 10-fold exposure multiple over the estimated clinical exposure. Use of some multiple on line 253 is too vague to provide useful guidance. The implication seems to be that it is not necessary to identify target organ toxicity, which it counter to stated intent of the guidance and leaves the reader confused and uncertain regarding dose selection and with no choice but to initiate the formal dialog process with the review division. As this is an important, if not critical, point for designing toxicity studies more clarity regarding the expectation is warranted. Furthermore, in certain circumstances we recommend consideration of a less than 10-fold margin either from systemic exposure or at the local site of administration as long as the maximum feasible dose is able to be delivered. 7

8 General : We believe that a 1-year timeline to death or irreversible morbidity is too specific as a criterion. We recommend that expected to rapidly progress is sufficient to specify this situation as it allows the sponsor and FDA to mutually define the cases where this approach is acceptable. Also since ERT products will be biologics, we believe a sentence should be added regarding the case where there is only one pharmacologically relevant species. Furthermore, the request for 3-mo or longer studies to support long term dosing in patients should be considered too cautious for disease conditions with less than 12 mo (or even out to 2-3 years) survival or progression window to irreversible effects. For patients with advanced disease in Phase 1 clinical trials treatment should be allowed to continue according to the patient s response without initiating a new toxicology study (this would align with ICH S9 language and intent). The nonclinical data to support Phase 1 and clinical data from Phase 1 should be considered sufficient for patients to enter Phase 2 trials. To support Phase 3 clinical trial a study of 3 mo duration in a single relevant species would be considered he maximum duration of nonclinical toxicity studies to support clinical trial entry as well as drug registration. Recommend the following changes: If the entry criteria define a phenotype that can be expected to rapidly progress to death or substantive irreversible morbidity over the course of 1 year, then repeat-dose toxicology studies in a single human relevant species may be sufficient to initiate clinical trials and support continued treatment should treatment be safe and effective. 8

9 Duration of Dosing: The conduct of 3-mo or longer studies to support long term dosing in patients is considered overly cautious for disease conditions with short survival windows. The draft guidance on lines indicated this as 1 year or less. We believe this survival and progression window should be expanded to well beyond 1 year, with a time frame of 3-5 years or even longer being warranted. It is further recommended that for patients with advanced disease in Phase 1 clinical trials treatment should be allowed to continue according to the patient s response without initiating a new toxicology study (this would align with ICH S9 language and intent). The nonclinical data to support Phase 1 and clinical data from Phase 1 should be considered sufficient for patients to enter Phase 2 trials. To support Phase 3 clinical trial a study of 3 mo duration in a single relevant species would be considered the maximum duration of nonclinical toxicity studies to support clinical trial entry as well as drug registration The following changes are recommend to reflect standard toxicology practices: Safety endpoints that capture potential toxicities. Standard parameters evaluated should include mortality (with cause of death determined, if possible), clinical observations, body weights, physical examinations, food consumption, or appetite, water consumption (as applicable), clinical pathology (serum chemistry, hematology, coagulation, urinalysis), organ weights, gross pathology, and histopathology. Additional developmental endpoints maybe appropriate when conducting juvenile animal studies, with specific endpoints dependent on organ systems targeted by ERT and timing of when these organ systems are known to develop either pre or post-nataly in animal species compared to humans 9

10 Recommend the following addition to clarify the extent of the nonclinical studies needed to support registration: For diseases with slow progression, if no safety concerns are identified in animal toxicology studies of 3 month duration in rodent and non-rodent species or in animal models of disease, and no safety concerns from chronic dosing in patients are identified, then the nonclinical studies may be sufficient to support registration 10

11 Battery of Reproductive Toxicity Studies We believe the default expectation of conducting a battery of reproduction and development studies should be reconsidered for ERTs as it seems overly cautious since many ERTs are identical to or closely mimic the target human enzyme. For ERTs that diverge from this or contain conjugated small molecule components could be addressed on a case by case basis relative to their impact on reproductive tissues. Providing a recommendation to include collection of reproductive tissues in studies using animal disease models would provide the opportunity to evaluate the impact rapid clearance of substrates on reproductive tissues, which could influence a decision on waiving the reproductive toxicity battery. In addition, the intended patient population should be considered when determining the need for reproductive and developmental toxicity testing. In cases where an endogenous human enzyme is administered to a pediatric patient population that doesn t survive past adolescence, histopathological evaluation of reproductive organs from the pivotal toxicology study(ies) may be sufficient to enable registration. In general we believe ICH S5(R2) should be referenced and would provide guidance that would avoid unnecessary conduct of a battery of reproductive toxicity studies. We recommend the following changes: In general, we recommend conducting reproductive and developmental toxicity studies according to the strategic principles and timing described in ICH S6(R1), and the methodological principles described in ICH S5(R2). Flexibility in timing or requirements for specific studies may be warranted in most cases with adequate justification. Most studies can be waived or delayed until after licensure or approval depending on the indicated patient population. 11

12 We believe the statement regarding evaluation of carcinogenic potential is inconsistent with ICH S6(R1), which states that when an assessment for a biologic product is warranted according to ICH S1A (based on intended clinical population and treatment duration), the sponsor should design a strategy to address the potential hazard. We recommend the following correction: Evaluation of carcinogenic potential generally is not needed to support a markeing application. The need for a product-specific assessment of the carcinogenic potential of the ERT product should be determined with regard to the intended clinical population and treatment duration (see ICH S1A). As described in ICH S6(R1), when an assessment is warranted, a weight of evidence approach should be taken, including a review of all relevant literature, with subsequent testing strategies dependent on the assessment outcome 12