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Summary Basis of Decision (SBD) for PrPROCHYMAL«

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

PrPROCHYMAL«

Remestemcel-L, Adult Human Mesenchymal Stem Cells (hMSCs)
100 × 106 hMSCs per 15 mL, cell suspension
Osiris Therapeutics, Inc.
Submission Control Number: 150026
Date Issued: 2012/10/05

Foreword

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. For information related to advisories, warnings and recalls as a result of adverse events (AE), interested parties are advised to access the Health Canada website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

Table of Contents

1 Product and Submission Information

Brand Name:
PrPROCHYMAL«
Manufacturer/Sponsor:
Osiris Therapeutics, Inc.
Medicinal Ingredient:
Remestemcel-L
Ex vivo Cultured Adult Human Mesenchymal Stem Cells (hMSCs)
International Non-proprietary Name:
Remestemcel-L
Adult Human Mesenchymal Stem Cells (hMSCs)
Strengths:
100 × 106 hMSCs per 15 mL,
2.5 × 106 hMSCs per mL after reconstitution
Dosage form:
Solution
Route of Administration:
Intravenous
Drug Identification Numbers (DINs):
02386380
Therapeutic Classification:
Allogeneic Cellular Therapy
Non-medicinal Ingredients:
Dimethyl sulphoxide (DMSO), human serum albumin (HSA), and Plasma-Lyte A
Submission Type and Control Number:
New Drug Submission, Control Number: 150026
Date of Submission:
2011/09/15
Date of Authorization:
2012/05/17

2 Notice of Decision

On May 17, 2012, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Osiris Therapeutics, Inc., for the drug product Prochymal. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for confirmatory studies to verify the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

Prochymal [remestemcel-L, adult human mesenchymal stem cells (hMSCs) for intravenous infusion] is a liquid cell suspension of ex vivo cultured adult hMSCs. The hMSCs are derived from the bone marrow of unrelated and human leukocyte antigen (HLA)-unmatched healthy adult donors.

Prochymal is indicated in the management of acute Graft versus Host Disease (aGvHD) in paediatric patients. Acute GvHD should be refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents. Prochymal may be used for Grades C and D of the disease in any organ. Prochymal may also be used in the management of Grade B aGvHD involving any visceral organ, including the gastrointestinal (GI) tract and the liver, but excluding skin. Prochymal is the first stem cell therapy indicated for clinical use in patients, specifically for children. It is also the first in a new class of therapeutic agents.

Acute GvHD is a progressive, debilitating, and lethal complication of bone marrow and haematopoietic stem cell transplantation that involves a reaction of donor immune cells against host tissues. It is graded from A-D based on the number and extent of organ involvement using the Center for International Bone Marrow Transplant Research (CIBMTR) grading system. The most severe grade is D. Patients with C/D aGvHD tend to have a very poor outcome. At the time of authorization, there were no approved therapies for aGvHD. Acute GvHD represents the largest component of transplant-related mortality. Prochymal is intended to modulate adverse immune and inflammatory responses, repair damaged or diseased tissues, and regenerate healthy tissue. Prochymal's activity against aGvHD, a T-cell mediated disease, is due to the immunomodulatory properties of hMSCs.

The market authorization was based on quality, non-clinical, and clinical information submitted. Data from two clinical studies provided evidence of efficacy for the use of Prochymal in the treatment of paediatric patients with refractory aGvHD. One study (Study 275) was a treatment protocol, single-arm, multicentre study that included 75 paediatric patients with Grades B-D aGvHD who failed to respond to steroid treatment and other therapies. The response outcome was improvement in clinical symptoms of aGvHD, measured by Overall Response (OR) defined as a Complete Response (CR) or Partial Response (PR) of aGvHD at Day 28 and Day 100 post-first infusion. The primary endpoint was the OR rate to Prochymal at Day 28. Furthermore, given that Study 275 was a single-arm study, an analysis was conducted to compare the Overall Survival (OS) rates (through 180 days post-aGvHD onset) of the patients with historical data (CIMBTR registry).

Another study (Study 280) was a Phase III, randomized, double-blind, placebo-controlled study that included 216 adult and 28 paediatric patients with Grades B-D aGvHD who had failed to respond to steroid treatment. This study did not meet statistical significance for its primary endpoint, a CR of ≥28 days duration within 100 days post-first infusion (p = 0.087 for per protocol population). A subset analysis of the paediatric patient subpopulation (14 patients treated with Prochymal plus standard of care and 14 patients treated with placebo plus standard of care) was conducted to evaluate additional efficacy endpoints in the paediatric subpopulation including OR (Overall Response) at Day 28 and Day 100.

Response to Prochymal treatment in Study 275 and in the paediatric subpopulation of Study 280 at Day 28 was similar, with 61-64% of previously refractory patients experiencing an OR. In comparison, the placebo arm for Study 280 had an OR of 36% in the paediatric subpopulation. By Day 100, response rates were further improved. Seventy-seven percent (77%) of the paediatric patients treated with Prochymal in Study 275 achieved an OR by Day 100. For Study 280, 86% of the paediatric patients treated with Prochymal achieved an OR by Day 100 as compared to 57% of paediatric patients treated with placebo. Complete response at 28 days, defined as the resolution of aGvHD in all evaluable involved organs, appears to be correlated with survival to 180 days, but has not been demonstrated to be causal.

For Study 275, survival was analyzed by comparing the treatment population to an historical control set provided by the CIBMTR. While certain limitations of the analysis exist, the data provides a useful benchmark for comparison. This analysis showed a benefit for Prochymal in OS at 180 days post-onset of aGvHD over the CIBMTR population. This benefit was most pronounced in patients with severe aGvHD (Grade D) where the probability of survival at 180 days post-onset of aGvHD was 51% for patients treated with Prochymal versus 31% for the historical control set.

To date, only preliminary evidence exists to indicate a potential therapeutic value for Prochymal; however, so far, Prochymal has not exhibited worrisome toxicity and has shown a relatively benign safety profile. Approval with conditions is based on clinical study of severe refractory aGvHD patients that demonstrated a clinically significant OR of their aGvHD 28 days following the start of Prochymal.

Prochymal (100 × 106 hMSCs per 15 mL, remestemcel-L) is presented as a cell suspension for intravenous infusion. Prochymal should be administered under the supervision of a qualified health professional experienced in the management of aGvHD. To reduce the potential for infusion reaction, it is recommended that patients receive premedication with hydrocortisone and diphenhydramine. Premedication should occur 30-60 minute prior to the administration of Prochymal. Dosing of Prochymal is based on body weight. The recommended dose of Prochymal is 2 × 106 hMSC/kg (actual body weight) administered intravenously at a controlled rate of 4-6 mL/minute by an infusion pump for patients weighing ≥35 kg. For patients <35 kg in weight, Prochymal should be infused over the course of 60 minutes. The recommended regimen is Prochymal twice per week for 4 consecutive weeks with infusions at least 3 days apart. A therapy assessment should be performed after the fourth week of treatment to determine whether continued treatment is warranted. Dosing guidelines are available in the Product Monograph.

Since Prochymal is indicated for use in refractory aGvHD, a life-threatening condition, there is no absolute contraindication. Prochymal should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Prochymal are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Prochymal is favourable for the indication stated above. As part of the market authorization, Health Canada has required a Risk Management Plan to ensure that the benefits continue to outweigh any risk, as well as post-market confirmatory studies and a Registry of treated patients.

3 Scientific and Regulatory Basis for Decision

On March 12, 2010, Osiris Therapeutics, Inc. submitted to Health Canada a clinical assessment package requesting Priority Review status for the drug product Prochymal as a rescue agent for refractory acute Graft versus Host Disease (aGvHD) in paediatric patients. Priority Review status was granted for Prochymal on April 30, 2010. On January 12, 2011, Health Canada issued a Notice of Non-Compliance (NON), outlining various deficiencies with the submission, including chemistry and manufacturing.

On June 30, 2011, Health Canada issued a NON-Withdrawal (NON/W) on the basis of outstanding issues related to clinical data, in particular efficacy. Following consultations in response to the issuance of the NON-W, Health Canada advised Osiris Therapeutics, Inc. to refile the submission for consideration under the Notice of Compliance with Conditions (NOC/c) Guidance. Accordingly, the sponsor re-filed the New Drug Submission (NDS) on September 15, 2011 and it entered the review stream. A Notice of Compliance with Conditions (NOC/c) was issued on May 17, 2012. A timeline of these events is documented in section 4 Submission Milestones.

3.1 Quality Basis for Decision

Prochymal is a liquid suspension of ex vivo cultured adult human mesenchymal stem cells (hMSCs) derived from the bone marrow of unrelated donors. These cells can modulate immune response, inhibit inflammation, and secrete factors that stimulate angiogenesis, tissue repair, and haematopoietic stem cell (HSC) engraftment. With low immunogenicity, hMSCs can be transplanted universally without donor-recipient human leukocyte antigen (HLA) compatibility matching with a low incidence of rejection. The drug product is intended to be used for the treatment of paediatric patients with aGvHD refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents. Acute GvHD is a life threatening immunological reaction which may occur following an allogeneic haematopoietic stem cell transplant (HSCT).

3.1.1 Drug Substance (Medicinal Ingredient)

Manufacturing Process and Process Controls

The starting material for production of the drug substance (hMSCs) is bone marrow aspirates from qualified healthy adult volunteer donors who have been tested for potential adventitious agents according to Health Canada's Safety of Human Cells, Tissues, and Organs for Transplantation Regulations. The hMSCs are isolated from the bone marrow aspirate, expanded to a homogeneous population of cells, harvested, formulated with 10% dimethyl sulfoxide (DMSO) and 5% human serum albumin (HSA) in Plasma-Lyte A, and sampled for lot release testing. In-process controls and lot release tests for the drug substance were established and validated.

The materials used in the manufacture of the drug substance (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Characterization

Detailed characterization studies were performed to provide assurance that the hMSCs consistently exhibit the desired phenotype, identity, and biological activity.

Appropriate tests are adequately controlling the levels of product- and process-related impurities.

Control of Drug Substance

In-process controls and lot-release tests for the drug substance were established and validated. The lot-release specifications include tests for drug substance potency and identity and purity, cell line species identity, sterility, mycoplasma, endotoxin, polymerase chain reaction (PCR) assays for various adventitious agents, in-vivo and in-vitro assays for viral contaminants, electron microscopic detection of viral particles, karyology, and appearance. Studies for aseptic processing validation, freezer and shipping validation, and batch analysis validation were performed.

The drug substance specifications and analytical methods used for quality control are considered acceptable. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is considered acceptable.

Stability

Based on the long-term and real-time stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance were supported and are considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Prochymal [remestemcel-L, hMSCs for intravenous (IV) infusion] is a liquid cell suspension of ex vivo cultured adult hMSCs derived from the bone marrow of unrelated and HLA-unmatched healthy adult donors. The active agent in Prochymal is remestemcel-L. Prochymal is supplied as a 15 mL formulation containing approximately 100 × 106 viable cells in Plasma-Lyte A containing 5% HSA and 10% DMSO.

Prochymal is packaged in Cryocyte™ freezing containers with a final volume of approximately 15 mL. Each Prochymal dose unit contains an overage of approximately 25 million hMSCs to account for any post-thaw viability loss.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of remestemcel-L with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

The labeling for Prochymal is 100 million hMSCs formulated in Plasma-Lyte A containing 5% HSA and 10% DMSO for storage at liquid nitrogen (LN2) vapor phase temperature (≤−135°C) until thawed and reconstituted shortly before administration.

Pharmaceutical Development

Preparation of Prochymal for administration involves thaw and reconstitution with Plasma-Lyte A or Plasmalyte 148. The total volume administered per infusion depends on dosage which is determined from the patient's weight in kilograms. The total volume of cell suspension required for administration is transferred to an infusion bag.

In Phase III clinical testing and an expanded access program for refractory aGvHD, a dose of 2 × 106 cells/kg was investigated for safety and efficacy. Selection of this dose was based upon clinical data from two Phase II clinical studies that compared two doses: 2 × 106 and 8 × 106 mesenchymal stem cells (MSCs) per kg. The results from those studies did not detect a difference in response of aGvHD between the two dose groups; however, the results suggested that more than two infusions may have benefit for patients with more severe disease. Similar results have been observed in the single-patient studies.

Based on clinical experience in refractory aGvHD, Prochymal should be administered twice weekly for four weeks.

All of the clinical lots produced and utilized in the Phase II and III clinical studies and expanded access program are comprised of the same formulation, that is (i.e.) 100 million hMSCs formulated in Plasma-Lyte A containing 5% HSA and 10% DMSO and an overage of approximately 25 million cells. This is the same formulation proposed for marketing in Canada.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.

Manufacturing Process and Process Controls

The ex vivo cultured adult hMSCs manufacturing process consists of two stages. The first stage is the production of the drug substance from the bone marrow aspirate. The second stage is the thawing and further culture of the drug substance to produce the final drug product. The two stage production results in a total of five cell passages. Following the harvest, the drug product is formulated and stored in quarantine pending release.

The validated process is capable of consistently generating product that meets release specifications. All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are acceptable. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

The specifications for all of the ingredients are approved in accordance with United States Pharmacopeia/National Formulary (USP/NF) or European Pharmacopoeia (Ph. Eur.) standards.

Control of Drug Product

In-process controls and lot-release tests for the drug product were established and validated. The lot-release specifications include tests for drug product potency, identity and purity, sterility, mycoplasma, endotoxin, residual bovine serum albumin and trypsin, appearance, and post-thaw viability.

Validation reports were submitted for in-process and release testing of the drug product and anomalies observed during the analytical method validation were appropriately investigated. The results for all of the batches were within the proposed specification limits; however, the sponsor has been asked to make a commitment to address a few outstanding issues post-approval to ensure that products manufactured in the future continue to meet the proposed specification limits.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. They were found to be within International Conference on Harmonisation (ICH)-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.

Stability

Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life at ≤−135°C in the vapour phase of a LN2 freezer for Prochymal is considered acceptable. The reconstituted product can be kept at room temperature and should be used within 5 hours from thaw.

The container closure system (Cryocyte™ freezing container) is non-pyrogenic and gamma sterilized. Extractables testing was performed by means of chemistry testing and Good Laboratory Practices (GLP) genotoxicity assays. Validation of the container closure system included studies for the container and seal integrity. The compatibility of the drug product with the container closure system was demonstrated through post-thaw viability studies and stability studies for confirmation of cell viability after cryopreservation, storage, and shipping. The container closure system met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

At the time of submission, Osiris Therapeutics, Inc. indicated that sufficient product had been manufactured, released, and placed in inventory to support the commercial launch, therefore manufacturing was not ongoing. Consequently, an On-Site Evaluation (OSE) was not scheduled. An OSE may be conducted at a later date once production commences.

The design, operations, and controls of the facilities and equipment that are involved in the production of Prochymal are considered suitable for the activities and products manufactured. Osiris Therapeutics, Inc. has indicated that all sites are compliant with Good Manufacturing Practices (GMP), and evidence of GMP compliance is pending.

3.1.4 Adventitious Agents Safety Evaluation

Programs are in place to control microbial and viral contamination and provide an ongoing assessment of the facilities, raw materials, process, and product (drug substance and drug product). More specifically, the manufacturing suites in which aseptic processing is performed for the drug substance and drug product are dedicated, validated International Organization for Standardization (ISO) Class 7 (FS 209E Class 10,000) Clean Rooms. Manufacturing areas and all manufacturing equipment are dedicated to hMSC manufacturing and any open process occurs within a biological safety cabinet under ISO Class 5 (FS 209E Class 100) conditions. Further, ex vivo culture expansion of hMSCs for manufacture of both the drug substance and drug product was designed and implemented with the goal of minimizing the risk of damage or contamination of the hMSCs, as well as, maximizing the safety of operators involved in the manufacturing process.

Aseptic Process Validation (APV) runs are conducted to validate that the process and personnel consistently produce sterile product. Environmental monitoring is also conducted and classified production areas are routinely monitored for air quality and bioburden.

Sterility tests are conducted by the manufacturer on all patient-contact materials (i.e. closure/container and excipients), and all product-contact raw materials that are part of the aseptic manufacturing processes.

Materials of biological origin are properly sourced and tested.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Prochymal has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-clinical Basis for Decision

3.2.1 Pharmacodynamics

In vitro and in vivo non-clinical data indicate that Prochymal has the potential to treat an inflammatory, immune-mediated disease such as aGvHD due to its cellular properties of inhibition of immune and inflammatory responses at target sites, protection of inflamed tissue from collateral damage, and facilitation of damaged tissue repair. Eleven published studies were provided by the sponsor at the time of submission which demonstrated the potential of MSCs as treatment for aGvHD in vitro and in vivo, including homing, immune suppression, and tissue repair.

Two studies demonstrated homing of the MSCs to the gut and skin in vivo. Macaques or baboons received autologous or allogeneic MSCs following total body irradiation. Mesenchymal stem cell engraftment was detected in many tissues including the skin, liver, and gut. Mesenchymal stem cells have shown the ability to modulate T cells by prolonging the survival of an allogeneic skin graft in a baboon model of skin graft rejection. In one study baboons received autologous or allogeneic MSCs following total body irradiation. Transgene could be detected in bone marrow as long as 511 days post-transplant.

Five studies examined the immunodulatory effects of MSCs in vitro. Baboon MSCs and hMSCs suppressed the response of the immune cells [including peripheral blood mononuclear cells, T cells, Natural Killer (NK) cells, and dendritic cells] to alloantigen and mitogen stimulation in vitro. The suppressed proliferative activity of allogeneic T lymphocytes likely occurred through secreted factors [including prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO)] in a dose-dependent and genetically unrestricted manner.

Mesenchymal stem cells provide tissue protection and tissue repair effects, through reduction of pro-inflammatory cytokines and secretion of factors including keratinocyte growth factor (KGF) [also known as fibroblast growth factor-7 (FGF-7)], and vascular endothelial growth factor (VEGF). They have been shown to stimulate the growth of new blood vessels, a process crucial to tissue repair, in a mouse model of ischaemia, through secretion of factors such as VEGF. In one in vivo study, the protective tissue properties of MSCs were exhibited as secreted recombinant human KGF protected graft versus host mice from mortality and progressive wasting syndrome; however, pathological changes still developed. Two studies examined tissue repair in vivo and demonstrated that hMSCs secrete factors that help tissue repair in vivo after irradiation or ischaemia. MSCs have been shown to promote regeneration of tissue in the gut as indicated by repair of irradiation-damaged small intestinal mucosa in mice.

Safety Pharmacology

Two safety pharmacology studies (one for pulmonary and one for cardiac safety) were submitted. Although limited, the data from the pulmonary safety study in rats at doses of up to 25 × 106 cells/kg suggested that infusion of allogeneic MSCs may result in death at doses of 16 and 25 million cells/kg in rats. Eleven of 40 rats died shortly following infusion of allogeneic MSCs. The clinical findings suggested pulmonary/respiratory distress due to potential cell clumping in the vascular system. There were no histo-pathological findings related to MSCs. While respiratory rates and tidal volumes were influenced by MSCs delivery, they stayed within normal ranges. Pulmonary safety should be investigated and evaluated in further detail in animal and clinical study.

The cardiac safety pharmacology study was conducted in swine at doses up to 10 × 106 cells/kg. Intravenous infusion of porcine MSCs did not cause electrocardiogram (ECG) disturbances, changes in haemoglobin saturation, heart rate, or respiration rate. There was no acute infusional toxicity and no other toxicities observed at 6 and 24 weeks after infusion.

3.2.2 Pharmacokinetics

Three non-Good Laboratory Practices (GLP) biodistribution studies and seven published study reports were submitted to describe the non-clinical pharmacokinetics following the administration of hMSCs. The studies were conducted in rats, fetal lambs, mice, dogs, baboons, and monkeys. The biodistribution results were consistent between the studies. Radiolabeling, genetic analysis through fluorescence in situ hybridization (FISH), deoxyribonucleic acid (DNA) analysis, magnetic resonance imagining (MRI), and fluorescent labelling, were performed to determine the distribution profile of Prochymal. The studies demonstrated that hMSCs clear from the blood within hours of administration. Mesenchymal stem cells infused into the venous system experience a significant pulmonary first-pass effect, initially distributing to the lungs within minutes of infusion. This is the result of the physical size of the cells passing through the pulmonary capillary bed, which is the first capillary system the cells encounter. At 24 hours post-infusion, a majority of the cells are found in the lungs with lesser amounts in the liver, kidneys, and spleen. At 48 hours, cells are detected at similar levels in the lungs and liver.

3.2.3 Toxicology

In vivo toxicity studies were conducted to evaluate the safety of Prochymal following administration to mice, rats, dogs, and baboons. Additional safety data were obtained in safety pharmacology studies in rats and swine.

Single-Dose Toxicity

In a single-dose toxicology study in rats, the no-observed adverse effect level (NOAEL) following IV administration was 40 × 106 MSC/kg and the maximum tolerated dose (MTD) was 65 × 106 MSCs/kg.

Repeat-Dose Toxicity

In a repeat-dose toxicology study in rats, NOAEL following IV administration was a cumulative dose of 80 × 106 MSC/kg when dosing twice per week. There were no effects on host immune cell quantities or host immune system functionality, and no biologically significant alloantibody formation was found. A 6-month immunotoxicology study in normal, healthy baboons supports these findings.

Genotoxicty, Carcinogenicity, Tumorigenicity and Ectopic Tissue Formation

Standard genotoxicity and 2-year carcinogenicity studies were not conducted as they were not relevant for a cell therapy. Ectopic tissue formation was evaluated in non-clinical toxicology studies and clinical studies. A standard 6-week tumorigenicity study in nude mice was performed. There was no evidence of tumor formation attributed to hMSCs. In addition, there has been no evidence of tumor or ectopic tissue formation in long-term dosing studies (up to 12 months) in canine, swine, and baboon models. No cases of ectopic tissue formation were observed due to product administration in clinical studies.

Reproductive and Development Toxicity

Animal reproduction and developmental toxicology studies were not conducted as they were not relevant for the aGvHD patient population.

3.2.4 Conclusion

The non-clinical pharmacodynamics, pharmacokinetics, and toxicology database was considered adequate to assess the safety profile of remestemcel-L and support its use in humans.

3.3 Clinical Basis for Decision

3.3.1 Pharmacodynamics

Currently there are no techniques available to measure the pharmacodynamic effects of hMSCs in patients with aGvHD. At present, the effects of MSCs are measured through clinical outcomes.

The hMSCs administered with each Prochymal dose are derived from the bone marrow of unrelated and HLA-unmatched healthy adult donors. Patient-specific blood type or HLA matching is not required for the administration of hMSCs due to the product's low immunogenic profile. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. The immunomodulatory functions of hMSCs were examined by co-culturing them with purified subpopulations of immune cells. The hMSCs altered the cytokine secretion profile of immune cells to induce a more anti-inflammatory or tolerant phenotype. This insight into the interactions between allogeneic MSCs and immune cells provides the mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that appears to be therapeutic for reduction of aGvHD, rejection, and modulation of inflammation.

3.3.2 Pharmacokinetics

Pharmacokinetic studies for Prochymal are limited to tissue distribution studies as explained in the pharmacokinetics summary in section 3.2.2 Pharmacokinetics. Currently there are no techniques available to measure the distribution of hMSCs in patients with aGvHD.

3.3.3 Clinical Efficacy

The information provided in support of the efficacy for Prochymal consists of studies that differ in their thrust from the commonly filed pivotal trials for an NDS. Prochymal was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence and the need for confirmatory studies to verify the clinical benefit. Data from the treatment protocol for paediatric patients with Grades B-D aGvHD who failed to respond to steroid treatment and other therapies (Study 275) and the paediatric patient subpopulation enrolled in the Phase III study (Study 280) provided preliminary evidence of efficacy for the use of Prochymal in the treatment of paediatric patients with refractory aGvHD.

Acute GvHD is staged and graded by the number and extent of organ involvement. The result is an overall aGvHD grade, ranging from A to D [according to the Centre for International Blood and Marrow Transplant Research (CIBMTR) grading system], which correlates with the severity of aGvHD and is predictive of ultimate outcome. Acute GvHD can also be graded I-IV using the Glucksberg's scale, where Grade IV would be comparable to Grade D.

Study 275

Study 275 was a treatment protocol, single-arm, multicentre study that included 75 paediatric patients with Grades B-D aGvHD who failed to respond to steroid treatment and other therapies. Patients were evaluated for efficacy and safety until death, withdrawal, or for 100 days post-first infusion of Prochymal (Day 0), whichever occurred first. The response outcome was an improvement in clinical symptoms of aGvHD and was measured at Day 28 and Day 100 post-first infusion. The primary endpoint was the Overall Response (OR) [Complete Response (CR) or Partial Response (PR)] rate to Prochymal at Day 28. The OR rate through Day 100 was evaluated as a secondary endpoint. Furthermore, given that Study 275 was a single-arm study, an analysis was conducted to compare the Overall Survival (OS) rates (through 180 days post-aGvHD onset) of the patients with historical data from the CIMBTR registry.

The median duration of aGvHD prior to study entry was 30 days and patients failed a median of three lines of therapy prior to entry. The most frequently used drugs were steroids for 3 to 7 days. If there was failure to respond, then second-line (unauthorized for the indication and potentially toxic) drugs such as Infliximab, Tacrolimus, Mycophenolate, Mofetil, and Daclizumab were used. Despite these attempted treatments, 97% of these patients were classified as having aGvHD that was not improving or was worsening prior to Prochymal therapy.

At the time of this submission, the paediatric patients treated with Prochymal [total number (n) = 75] had achieved response rates as follows: OR (61%); stable/mixed response (19%); and worsening of condition (20%). In addition, survival was analyzed by comparing the treatment population to an historical control set provided by the CIBMTR. While certain limitations of the analysis exist, the data provides a useful benchmark for comparison. This analysis showed a benefit for Prochymal in OS at 180 days post-onset of aGvHD over the CIBMTR population. This benefit was most pronounced in patients with severe aGvHD (Grade D) where the probability of survival at 180 days post-onset of aGvHD was 51% for patients treated with Prochymal versus (vs.) 31% for the historical control set.

Study 280

Study 280 was a Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Prochymal in patients with Grade B-D aGvHD who had failed to respond to steroid treatment. There were 216 adult and 28 paediatric patients enrolled. Secondary to allogeneic HSCT or donor leukocyte infusion (DLI), patients were randomized 2:1 to receive Prochymal plus standard of care or placebo plus standard of care. Randomization was stratified by grades of aGvHD (B and C/D). Efficacy and safety were evaluated until death, withdrawal, or 180 days post-first infusion of Prochymal, whichever occurred first. The primary efficacy endpoint was durable CR (DCR), defined as the resolution of aGvHD in all evaluable involved organs, of ≥28 days duration within 100 days post-first infusion. Additional efficacy endpoints included OR for each organ at Day 28 and Day 100.

Study 280 did not meet statistical significance for the primary endpoint (DCR within 100 days post-first infusion). Durable CR was 40% in the Prochymal group and 28% in the placebo group (p = 0.087 for per protocol population). In a post hoc subset analysis of the paediatric subpopulation, for the additional endpoint of OR at any time to Day 100, 12 Prochymal-treated patients (86%) and 8 placebo-treated patients (57%) had an OR through Day 100 demonstrating a possible trend toward clinical benefit.

Analysis of Study 275 and 280

There were two main differences in patient characteristics between Studies 275 and 280: severity of disease and treatment refractory status. Patients in Study 275 had more severe aGvHD than those in Study 280. Additionally, most patients (60%) in Study 275 were refractory to three agents including steroids. In contrast, patients in Study 280 were randomized immediately after failing steroids only.

Response to Prochymal treatment in the paediatric patient subpopulation of Study 280 and in Study 275 at Day 28 was similar, with 61-64% of previously refractory patients experiencing an OR. In comparison, the placebo arm for Study 280 had an OR of 36% in the paediatric subpopulation. By Day 100 response rates were further improved. Seventy-seven percent (77%) of the paediatric patients treated with Prochymal in Study 275 achieved an OR by Day 100. For Study 280, 86% of the paediatric patients treated with Prochymal achieved an OR by Day 100 as compared to the 57% of paediatric patients treated with placebo. Complete Response at 28 days appears to be correlated with survival to 180 days, but a direct relationship has not been demonstrated.

Based on the data, and while many questions remain, Prochymal may be a useful addition to the treatment of aGvHD. It may represent another modality for paediatric patients with aGvHD refractory to treatment with steroids and/or other immunosuppressive agents used off-label, when other medications have failed. In keeping with the provisions of the NOC/c Guidance and as per the Expert Advisory Panel Report Recommendations, the sponsor must develop a strong clinical study design that will demonstrate efficacy of Prochymal in the paediatric or steroid refractory aGvHD population. This could take the form of either a randomized clinical study comparing Prochymal vs. the best standard of care or a properly conducted case control study with appropriately matched concurrent or historical controls. The sponsor must commit to provide substantial data that show statistical significance in the efficacy of Prochymal in an aGvHD patient population that is steroid refractory. The final study report will be provided as a Supplemental New Drug Submission - Confirmatory (SNDS-c) by June 2016.

3.3.4 Clinical Safety

The clinical safety of Prochymal was evaluated in the studies described in section 3.3.3 Clinical Efficacy.

Study 276

No adverse events (AEs) or adverse reactions were reported. All the AEs reported for this study were serious adverse events (SAEs). The most common SAEs were respiratory failure and multi-organ failure. The SAEs that were assessed as at least possibly related to Prochymal were neutropaenia, pulmonary hemorrhage, hypertension, and infusion-related reaction. There was one case of pulmonary hemorrhage that led to death.

Overall, these events were typical for patients with aGvHD of this level of severity. Ectopic tissue formation was not observed up to 180 days after the first infusion. There were no longer term data as the study was ongoing at the time of the review of this submission. Potential risks are ectopic tissue, hypersensitivity to porcine/bovine components, and other risks such as infusional toxicity. There was one case of recurrent acute lymphocytic leukaemia leading to death.

There was no reported infusional toxicity, ectopic tissue formation, or relapse of underlying disease in the paediatric patient subpopulation. There were no effects of treatment on laboratory parameters, vital signs, or ECG findings.

In addition to aGvHD, safety information is being gathered in studies with myocardial infarction, Type 1 diabetes mellitus, and chronic obstructive lung disease.

Study 280

All paediatric patients in this study experienced at least one treatment-emergent adverse event (TEAE). The total number of reported TEAEs was 121 and 102, for the Prochymal and placebo groups, respectively. The most commonly reported TEAEs, by system-organ class (SOC), were gastrointestinal (GI) disorders; infections and infestations; and respiratory, thoracic, and mediastinal disorders.

For the paediatric patient subpopulation, there was no difference between the Prochymal and placebo treatment groups overall for any of the TEAE analyses.

The majority of TEAEs were unrelated to the investigational agent. The percentage of patients who experienced TEAEs that were deemed related to the investigational agent was 28.6% for the Prochymal group and 23.1% for the placebo groups.

The number of SAEs between the Prochymal and placebo treatment groups was similar. The most common SAEs, by SOC, were in the gastrointestinal disorders class, and the infections and infestations class. The number and frequency of these events were similar between treatment groups during the treatment phase of the protocol.

According to the sponsor's interpretation of AEs, no deaths in the paediatric patient population were deemed related to the investigational agent.

Immuno-compromised patients commonly suffer from viral, bacterial, and fungal infections. Adverse event rates for infections and infestations were slightly elevated in patients receiving Prochymal (88.3%) versus placebo (81.5%) in this study, indicating a possible increased risk of infection. Given that infection is a common and expected event following HSCT and steroid and other immunosuppressant agent treatment for aGvHD, it is difficult to attribute cause in such a heavily confounded population.

Single Patient Emergency Use of Prochymal

Prochymal was well tolerated in 12 paediatric patients who participated in single-patient, emergency-use protocols. Patients in these studies received between 3 and 21 infusions (average of 11 infusions) of Prochymal. All patients had failed previous treatments for aGvHD.

There were no reports of infusion reactions, even after repeated exposures to the product. The most common SAEs reported were infectious and respiratory in nature. There was no trend toward a specific type of SAE, nor to an increase in the incidence of events with increased exposure to Prochymal.

Four SAEs were assessed by the investigator as possibly or probably related to Prochymal: respiratory failure, cytomegalovirus encephalitis, aGvHD and mass (DNA from the Prochymal MSC donor was not detected in the mass).

Other

There are no data on the use of Prochymal in patients with: renal dysfunction; pre-existing neoplasm or active relapse of underlying disease; or those who have received HSCT with solid tumour.

No formal drug-drug interaction studies have been performed for Prochymal. Patients in clinical studies of Prochymal concomitantly received medications used in the standard of care of patients who receive HSCT, including medications to prevent and treat aGvHD and infections and to treat pain. Specific drug-drug interactions with Prochymal have not been observed. As Prochymal is administered intravenously, interaction with food or drink is not expected. It is suggested that Prochymal not be administered simultaneously with any other treatment.

Dose-limiting toxicity, as determined from animal studies, is due to the accumulation of MSCs in the microvasculature of the lungs leading to breathing difficulty and pulmonary collapse. Dose-limiting toxicity has not been determined clinically. Prochymal should be administered intravenously at a controlled rate and under the supervision of a qualified health professional who is experienced in the management of aGvHD. It is recommended that oxygen saturation be monitored by pulse oximetry during infusion of the product. If there are signs of adverse reaction, discontinue the infusion.

In keeping with the provisions of the NOC/c Guidance and as per the Expert Advisory Panel Report Recommendations, the sponsor must develop a formal long-term registry to monitor the safety of Prochymal. The registry would also facilitate tracing back all activities retrospectively and help gather information on patient populations excluded from the studies (and/or those in whom Prochymal was used off-label). In specific cases where patients are autopsied, the lungs should be screened to look for the potential presence of residual Prochymal cells.

To date, there have not been any reported toxicities specific to Prochymal and its safety profile appears acceptable when compared to other therapies used off-label. Potential toxicities with low frequency associated with the administration of Prochymal are not fully understood, but they are acceptable in a situation with a life-threatening disease.

3.3.5 Additional Issues

In keeping with the provisions outlined in the NOC/c Guidance, the sponsor is required to undertake the following studies:

  1. As per the Expert Advisory Panel Report Recommendations the sponsor must develop a strong clinical study design that will demonstrate efficacy of Prochymal in the paediatric or steroid refractory aGvHD population. This could take the form of either a randomized clinical study comparing Prochymal vs. the best standard of care or a properly conducted case control study with appropriately matched concurrent or historical controls. The sponsor must commit to provide substantial data that show statistical significance in the efficacy of Prochymal in an aGvHD patient population that is steroid refractory. The final study report should be provided as an SNDS-c by June 2016.
  2. As per the Expert Advisory Panel Report Recommendations, the sponsor must develop a formal long-term registry to monitor the safety of Prochymal. The registry would also facilitate tracing back all activities retrospectively and help gather information on patient populations excluded from the studies (and/or those in whom Prochymal was used off-label). In specific cases where patients are autopsied, the lungs should be screened to look for the potential presence of residual Prochymal cells.

The sponsor has also agreed to Health Canada's requests to:

  • Report of all serious Adverse Reactions (AR) that occur in Canada and all serious unexpected ARs that occur outside of Canada should be forwarded, within 15 days, to Health Canada.
  • Submit Periodic Safety Update Reports for NOC/c Products (PSUR-Cs) for Prochymal on an annual basis until such time as conditions associated with the market authorization are removed.
  • Implement the Risk Management Plan (RMP) in Canada with the following recommendations and provide an updated RMP:
    1. The Product Monograph needs to be updated to reflect the potential for risks identified within the RMP submitted.
    2. Consideration should be given to including pregnant or nursing women in the RMP as a potential safety concern for which safety information is missing.
    3. The possibility of off-label use is always present, especially after issuance of the Notice of Compliance (NOC). Consideration should be given as to how any off-label use will be monitored and reported. The population size for which the authorized indication is being requested is small resulting in a limited safety database. Therefore, it is expected that rare, potentially significant signals would not have been detected prior to the issuance of the NOC pursuant to the NOC/c Guidance. The possibility of detecting new signals or AEs when a larger population is involved is increased and, therefore, a better indication for level of safety can be elucidated.
    4. It was indicated that donor suitability will be assessed according to the United States Food and Drug Administration (FDA) Donor suitability Guidance. Details regarding donor screening should be provided in a revised RMP to demonstrate how these criteria are aligned with those in Canada.
    5. Given the human origin of these cells, there is an inherent risk of donor-transmitted infections. The current RMP provides no information on how such events would be investigated or traced back. In fact, it is unclear whether a traceability system is planned or not. Health Canada has asked the sponsor whether archived blood samples from donors will be retained in the event that additional testing is required at a later date. The sponsor has also been asked to ensure that all applicable ethical considerations are dealt with, described and respected.
    6. As also noted by the Expert Advisory Panel, the sponsor should clarify how the potential late development of ectopic tissue will be followed longer-term.
  • As per the Expert Advisory Panel Recommendations the sponsor should address in their Letter of Undertaking how Osiris Therapeutics, Inc. will limit the distribution of Prochymal to only paediatric blood and marrow transplant centres in Canada as Prochymal will only have an indication for aGvHD in children.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

In view of the fact that this is a new product in a new class, and in view of the severity and seriousness of the condition that is being treated, external advice was sought to help in deciding on the disposition of the product.

Acute GvHD is a progressive, debilitating, and lethal complication of bone marrow transplantation which may occur following an allogeneic HSCT. Acute GvHD manifests as a reaction of donor immune cells against host tissues. The exact risk is dependent on the stem cell source, age of the patient, conditioning treatment to prepare patients for bone marrow transplantation, and aGvHD prophylaxis used.

Acute GvHD results from an inflammatory cascade [a cytokine storm including tumour necrosis factor-alpha (TNF-α)] that begins with the preparative immunosupressive regimen. Activated donor T cells damage host epithelial cells. Patients can have involvement of three organs: skin (rash/dermatitis); liver (hepatitis/jaundice); and gastrointestinal tract (abdominal pain/diarrhoea which may become bloody). One or more organs may be involved. Graft versus Host Disease is a clinical diagnosis that is best supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic aGvHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash).

In Canada, the incidence of aGvHD is about 50 paediatric (age 2 months to 17 years) cases per year. Up to 50% of HSCT recipients will develop aGvHD, usually within 100 days of their transplant. Patients with Grade III/IV or C/D aGvHD tend to have a very poor outcome.

Generally the aGvHD patient is treated by optimizing their immunosuppression and adding steroids. Only about 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or have not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Additional management issues in aGvHD patients include attention to wound infections in skin and fluid/nutrition management.

About 50% of patients with steroid-resistant aGvHD will eventually have lifelong manifestations of chronic aGvHD. About 50% will die, most commonly from ongoing aGvHD or opportunistic infections in these immunocompromised hosts. End stage disease (Grade C/D or lll/lV) is painful and debilitating with a median survival of less than 6 months. The median survival for severe refractory aGvHD is <100 days.

There are no therapies specifically approved for aGvHD (acute or otherwise) and beyond steroids, there is no standard of care. Tacrolimus, Mycophenolate, also monoclonal antibodies such as Infliximab and Daclizumab, as well as numerous other potent second-line therapies have been tried empirically for this disease. All these drugs (used off-label) have significant toxicities and contribute to potentially fatal opportunistic infections.

Prochymal is presented as salvage therapy for aGvHD after failure of steroids and resistance to second line drugs. The large number of second line drugs is an indication that no single drug is outstandingly or even significantly effective. There is an unmet need for a new therapeutic agent, in particular if this new therapy is confirmed to show greater efficacy with lesser toxicity than current treatments.

Prochymal is the first of a new kind of therapy. Prochymal consists of ex vivo cultured hMSCs derived from bone marrow aspirate of healthy adult donors. The drug product is intended to modulate adverse immune and inflammatory responses, repair damaged or diseased tissues, and regenerate healthy tissue.

Prochymal is the first stem cell therapy indicated for clinical use in patients, specifically for children. As such, it is the first in a new class of therapeutic agents.

Clinical studies demonstrated that Prochymal achieves an OR of 61-64% in previously refractory paediatric patients at Day 28. In comparison, the placebo arm for Study 280 had an OR of 36% in the paediatric subpopulation. By Day 100 response rates were further improved. Seventy-seven percent (77%) of the paediatric patients treated with Prochymal in Study 275 achieved an OR by Day 100. For Study 280, 86% of the paediatric patients treated with Prochymal achieved an OR by Day 100 as compared to 57% of paediatric patients treated with placebo. Complete response at 28 days appears to be correlated with survival to 180 days, but has not yet been demonstrated to be directly related. Response may include some or all of the following: clearing and healing of skin lesions; reduction in number of stools; reduction in stool volume; and resolution of liver dysfunction.

The exact risk is considered dependent on the stem cell source, age of the patient, preparative regimen for transplant, and aGvHD prophylaxis used.

One risk with Prochymal treatment is donor-infection transmission. Donors are pre-screened extensively for communicable disease risk factors. A sample of the isolated MSCs is tested again for adventitious agents prior to release of MSCs for clinical use. Protocols are in place if any infection is revealed at any point in the drug lifecycle also protocols for look back/trace back action.

There is potential for transmission of infectious agents. Cells grown and expanded outside the body have the potential to be contaminated and infection could be introduced to the patient at the time of infusion. This risk is reduced by processing cells in a production facility that is GMP-compliant and is a semi-closed system.

It is important to consider that the risks attributed to Prochymal can be confounded by the complex clinical status of aGvHD patients.

The standard of care for patients undergoing treatment for aGvHD in the post-HSCT setting is at the most advanced, sophisticated levels of medical care. The transplant specialists and physicians responsible for care of patients receiving Prochymal routinely perform a high degree of clinical monitoring for potential infections.

Toxicities with low frequency are not fully understood; but, these potential toxicities appear benign relative to a life-threatening disease.

End stage disease (Grade C/D or III/IV) is painful and debilitating with a median survival of less than 6 months. In this setting, spontaneous remission does not occur. Prochymal induced a response in more than 60% of treatment refractory end-stage patients. In a previous study evaluating 864 patients with predominantly mild to moderate aGvHD the response rate for steroids was 65%. Prochymal can produce comparable response rates in a significantly more severe and refractory population, that has failed one or more therapeutic modality. The numbers to date are too small for an analysis by race or ethnicity.

So far, Prochymal has not demonstrated any specific worrisome toxicity and has shown a relatively benign safety profile, particularly when compared to alternative "off-label" therapies which are unauthorized, unproven and whose toxicity profile is relatively well-known in other settings. However, the number of patients treated is small and there are still many unknowns in the area of cell therapy related to safety.

Based on the data, and while many questions remain, Prochymal may be a useful addition to the treatment of aGvHD. Prochymal is not a cure for aGvHD disease. It may represent another modality for the treatment of paediatric patients with aGvHD refractory to treatment with systemic corticosteroid therapy (and/or other immunosuppressive agents). To date, only preliminary evidence exists to indicate a potential therapeutic value for Prochymal; however, given that Prochymal has not exhibited any worrisome toxicity and has shown a benign safety profile, the benefit-risk balance is in favour of the use of Prochymal for the approved indication.

In order to monitor that the benefits of Prochymal continue to outweigh any risk, an RMP has been requested that includes several post-approval recommendations. In addition, Health Canada has requested that future RMPs address the issues listed in section 3.3.5 Additional Issues, which includes post-market confirmatory studies and a recommended Registry of treated patients.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Prochymal is favourable in the management of aGvHD in paediatric patients. Acute GvHD should be refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents. Prochymal may be used for Grades C and D of the disease in any organ. Prochymal may also be used in the management of Grade B aGvHD involving any visceral organ, including the GI tract and the liver, but excluding skin.

Prochymal has been granted marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization. This New Drug Submission qualifies for authorization under the Notice of Compliance with Conditions (NOC/c) Policy. The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.

In keeping with the provisions outlined in the NOC/c Guidance, the sponsor has agreed to submit the results of the confirmatory studies listed as well as the additional data listed in Section 3.3.5 Additional Issues.

4 Submission Milestones

Submission Milestones: Prochymal
Submission Milestone Date
Control Number: 135496: Pre-submission meeting: 2010/02/03
Control Number: 137287: Request for priority status
Filed: 2010/03/16
Approval issued by Director, Centre for Blood and Tissues Evaluation: 2010/04/13
Control Number: 138759: Submission filed: 2010/06/15
Screening 1
Screening Acceptance Letter issued: 2010/07/16
Review 1
Quality Evaluation complete: 2011/01/12
Clinical Evaluation complete: 2011/01/12
Notice of Non-Compliance (NON)/ issued by Director General (safety and efficacy): 2011/01/12
Response filed: 2011/03/07
Screening 2
Screening Acceptance Letter issued: 2011/04/01
Review 2
Quality Evaluation complete: 2011/06/30
Clinical Evaluation complete: 2011/06/30
Notice of Non-Compliance/Withdrawal (NON/W) issued by Director General (safety and efficacy issues): 2011/06/30
Control Number: 150099: Pre-submission meeting: 2011/08/03
Acceptance of Advance Consideration under the Guidance document: Notice of Compliance with Conditions (NOC/c): 2011/09/16
Control Number: 150026: Submission Filed: 2011/09/15
Screening
Screening Acceptance Letter issued: 2011/09/22
Review
Quality Evaluation Complete: 2012/04/09
Clinical Evaluation Complete: 2012/04/09
Labelling Review Complete: 2012/04/19
Expert Advisory Panel meeting held: 2012/01/26
Notice of Compliance with Conditions/Qualifying Notice (NOC/c-QN) issued: 2012/04/04
Response filed: 2012/04/17
Notice of Compliance (NOC) issued by Director General under the Guidance Document: Notice of Compliance with Conditions: 2012/05/17

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