Summary Basis of Decision for Rekovelle

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Rekovelle is located below.

Recent Activity for Rekovelle

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Rekovelle

Updated:  2024-11-04

The following table describes post-authorization activity for Rekovelle, a product which contains the medicinal ingredient follitropin delta. For more information on the type of information found in PAATs, please refer to theFrequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN) :

  • DIN 02474077 - 72 µg/2.16 mL follitropin delta, solution, subcutaneous administration
  • DIN 02474085 - 36 µg/1.08 mL follitropin delta, solution, subcutaneous administration
  • DIN 02474093 - 12 µg/0.36 mL follitropin delta, solution, subcutaneous administration
  • DIN 02487462 - 12 µg/0.36 mL follitropin delta, solution, subcutaneous administration, (prefilled pens)
  • DIN 02487470 - 36 µg/1.08 mL follitropin delta, solution, subcutaneous administration, (prefilled pens)
  • DIN 02487489 - 72 µg/2.16 mL follitropin delta, solution, subcutaneous administration, (prefilled pens)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 264553 2022-05-30 Issued NOC
2023-11-03		 Submission filed as a Level II – Supplement (Safety) to remove the cartridge presentations from the PM following the cancellation of the DINs, and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued.
DINs 02474077, 02474085, 02474093 cancelled (post-market) Not applicable Discontinuation date: 2021-05-06 The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
Drug product (DIN 02487462, 02487470, 02487489) market notification Not applicable Date of first sale:
2019-11-01		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 228904 2019-06-20 Cancellation Letter Received
2019-07-26		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer a quality control test to a new facility. The sponsor cancelled the submission.
NC # 228718 2019-06-17 Cancellation Letter Received
2019-07-26		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer a quality control test to a new facility. The sponsor cancelled the submission.
NC # 228606 2019-06-12 Issued NOL
2019-06-25		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 225671 2019-03-13 Issued NOL
2019-05-10		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 220986 2018-10-15 Issued NOC
2019-04-18		 Submission filed as a Level I - Supplement for a new presentation. The information was reviewed and considered acceptable. An NOC was issued. New DINs (02487462, 02487470, 02487489) were issued for the new presentation.
NC # 219059 2018-08-09 Cancellation Letter Received
2018-08-20		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a new product format and manufacturing site. The submission exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor, so as to be filed as an SNDS.
Drug product (DINs 02474077, 02474085, 02474093) market notification Not applicable Date of first sale:
2018-05-23		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 188743 2015-12-09 Issued NOC
2018-03-22		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Rekovelle

Date SBD issued: 2018-06-02

The following information relates to the new drug submission for Rekovelle.

Follitropin delta
12 µg/0.36 mL, 36 µg/1.08 mL and 72 µg/2.16 mL, solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02474077 - 72 µg/2.16 mL, solution
  • DIN 02474085 - 36 µg/1.08 mL, solution
  • DIN 02474093 - 12 µg/0.36 mL, solution

Ferring Inc.

New Drug Submission Control Number: 188743

On March 22, 2018, Health Canada issued a Notice of Compliance to Ferring Inc. for the drug product Rekovelle.

The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Rekovelle is favourable for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

1 What was approved?

Rekovelle, a gonadotropin, was authorized for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Rekovelle is contraindicated in the following situations:

  • Hypersensitivity to the active substance or to any of the excipients
  • Tumours of the hypothalamus or pituitary gland
  • Ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome
  • Gynaecological hemorrhages of unknown etiology
  • Ovarian, uterine or mammary carcinoma
  • Pregnancy and lactation

In addition, Rekovelle must not be used when an effective response cannot be obtained, as in:

  • Primary ovarian failure
  • Malformations of sexual organs incompatible with pregnancy
  • Fibroid tumours of the uterus incompatible with pregnancy

Rekovelle is not indicated for use in the geriatric and pediatric population.

Rekovelle was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Rekovelle (12 µg/0.36 mL, 36 µg/1.08 mL and 72 µg/2.16 mL follitropin delta) is presented as a solution. In addition to the medicinal ingredient, the solution contains phenol, polysorbate 20, L-methionine, sodium sulphate decahydrate, disodium hydrogen phosphate dodecahydrate, phosphoric acid, sodium hydroxide, and water for injection.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Rekovelle Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Rekovelle approved?

Health Canada considers that the benefit-risk profile of Rekovelle is favourable for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Exogenous recombinant human follicle-stimulating hormone (rhFSH) is administered to stimulate multifollicular development in women undergoing ART. The controlled ovarian stimulation allows a cohort of mature oocytes to be retrieved for fertilization and cultured into embryos that can be transferred to the uterus in a fresh cycle or cryopreserved for later use.

Rekovelle (follitropin delta) is the first rhFSH to be derived from a human cell line and to be administered with an individualized dosing regimen, based on the patient's serum anti-Müllerian hormone level and body weight. With these parameters, a specific daily dose of Rekovelle is determined for each patient from the start of the ART cycle and fixed throughout stimulation.

A number of rhFSH preparations are currently available in Canada, including Gonal-F (follitropin alpha), Puregon (follitropin beta), and Pergoveris (follitropin alfa 150 IU/lutropin alfa 75 IU).

The market authorization of Rekovelle was primarily based on efficacy and safety data derived from the pivotal Phase III clinical trial ''Evidence-based stimulation trial with human rFSH in Europe and rest of world 1'' (ESTHER-1). The ESTHER-1 trial demonstrated non-inferiority of Rekovelle compared to Gonal-F with respect to ongoing pregnancy rate and ongoing implantation rate in women undergoing controlled ovarian stimulation for IVF/ICSI. Another Phase III clinical trial, ESTHER-2, demonstrated that the immunogenicity of Rekovelle was comparable to Gonal-F in women undergoing repeated controlled ovarian stimulation cycles. The efficacy of Rekovelle was acceptable for the indication sought.

The major risk for patients undergoing fertility treatment with Rekovelle is development of ovarian hyperstimulation syndrome. The Warnings and Precautions section of the Rekovelle Product Monograph emphasizes the value of careful and frequent monitoring of follicular development (with ultrasound alone, or in combination with measurement of serum estradiol levels) in order to reduce the risk of ovarian hyperstimulation syndrome.

A Risk Management Plan (RMP) for Rekovelle was submitted by Ferring Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

As part of the marketing authorization for Rekovelle, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing an updated Canadian RMP for Rekovelle to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies (see What follow-up measures will the company take?).

The submitted inner and outer labels, package insert and Patient Medication Information section of the Rekovelle Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look alike Sound alike brand name assessment was performed and the proposed name Rekovelle was accepted.

Rekovelle has an acceptable safety profile based on the non-clinical data and clinical studies. Safe and effective use of Rekovelle requires monitoring of ovarian response with ultrasound alone, or in combination with measurement of serum estradiol levels, on a regular basis. Appropriate warnings and precautions are in place in the Rekovelle Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Rekovelle?

During the review of the New Drug Submission for Rekovelle, a Notice of Deficiency (NOD) was issued on November 21, 2016, based on the fact that the selected co-primary efficacy endpoints in the pivotal clinical trial ESTHER-1 were judged not to be appropriate to support the proposed indication. Health Canada's comments were further discussed with the sponsor in an NOD response meeting on February 17, 2017. The sponsor's response to the NOD has been reviewed as part of this submission and judged to be acceptable. The main deficiency issues were addressed and the minor deficiency issues were mitigated via revisions to the proposed Product Monograph. A Notice of Compliance was issued for Rekovelle on March 22, 2018.

Submission Milestones: Rekovelle

Submission Milestone Date
Submission filed: 2015-12-09
Screening 1  
Screening Acceptance Letter issued: 2016-01-29
Review 1  
On-Site Evaluation: 2016-06-03 - 2016-06-06
Quality Evaluation complete: 2016-10-07
Clinical Evaluation complete: 2016-11-16
Review of Risk Management Plan complete: 2016-09-10
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2016-10-10
Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (efficacy and quality issues): 2016-11-21
Response filed: 2017-04-11
Screening 2  
Screening Acceptance Letter issued: 2017-05-26
Review 2  
Quality Evaluation complete: 2018-03-22
Clinical Evaluation complete: 2018-03-22
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-03-22
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-03-22

The Canadian regulatory decision on the non-clinical and clinical review of Rekovelle was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency (EMA) was used for consultation during the review of the quality data submitted for Rekovelle.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

As part of the marketing authorization for Rekovelle, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • Submitting to Health Canada a formal population pharmacokinetic report of the Phase III study 00004 within 3 to 4 months after Notice of Compliance (NOC) issuance.

  • Providing Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies.

  • Providing Health Canada with the Rekovelle medical educational materials for review prior to the launch of the product.

  • Providing Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Rekovelle annually. Each PSUR/PBRER will include an analysis of all adverse drug events that may be related to the safety profile (e.g., ovarian hyperstimulation syndrome, cardiovascular events, etc.) and other adverse events related to the potential risks identified in the label and the RMP.

  • Providing Health Canada with all reports/correspondence pertaining to post-approval commitments from major regulatory agencies, e.g., United States Food and Drug Administration (US FDA), European Medicines Agency (EMA), Australia's Therapeutic Goods Administration (TGA), etc.

  • Providing Health Canada with the final results of any clinical trials conducted in North America as per the US FDA requirements.
5 What post-authorization activity has taken place for Rekovelle?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Rekovelle is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

Follitropin delta, the medicinal ingredient in Rekovelle, is a recombinant human follicle-stimulating hormone (rhFSH) produced in a human cell line by recombinant deoxyribonucleic acid (DNA) technology. Follicle-stimulating hormone (FSH) is one of the key hormones regulating reproductive functions both in females and in males. In females, the ovary is the target organ, where binding of FSH to the FSH receptor triggers intracellular mechanisms that drive the hormonal and cellular events regulating the maturation of Graafian follicles and granulosa cell estrogen production. Follitropin delta has the amino acid sequence identical to the endogenous human FSH for both α and β subunits but it is distinct from other recombinant FSH products, produced in a non-human cell line (such as follitropin alfa and follitropin beta) by sialic acid pattern, isoforms, and glycosylation profiles of the FSH protein. Comparisons of follitropin delta versus follitropin alfa indicate that the differences in glycosylation influence both the pharmacokinetic and pharmacodynamic profile.

The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies. The data support the use of Rekovelle for the recommended indication.

Three (Phase I, Phase II, and Phase III) formulations were used during the clinical development of Rekovelle. Although the sponsor did not conduct a standard clinical pharmacokinetic bioequivalence study to bridge the formulations, the proposed commercial formulation of Rekovelle was used in the Phase III trials, which provides appropriate data in lieu of bridging studies. Three strengths are intended for marketing, i.e., 12 µg, 36 µg and 72 µg in 0.36 mL, 1.08 mL and 2.16 mL, respectively. All contain the same protein concentration of 33.3 µg/mL.

Clinical pharmacokinetic and pharmacodynamic properties of Rekovelle were characterized in healthy female subjects using the Phase I formulation (Studies CS01, CS02, CS03) or Phase II formulation (Study 00020) and in patients undergoing controlled ovarian stimulation for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using the Phase II formulation (Study 00009). A study report to characterize the pharmacokinetics of the Phase III formulation was not submitted in this new drug submission. However, no marked pharmacokinetic difference between the Phase II and III formulations is expected since the two formulations only differ slightly in protein content (i.e., 34.5 µg/mL vs. 33.3 µg/mL) and their comparability was demonstrated by bioanalytical assessment.

For further details, please refer to the Rekovelle Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Rekovelle was primarily evaluated in the pivotal Phase III clinical trial ''Evidence-based stimulation trial with human rFSH in Europe and rest of world 1'' (ESTHER-1).

Another clinical trial, ESTHER-2, evaluated the immunogenicity of Rekovelle and Gonal-F based on the presence of anti-FSH antibodies and their neutralizing capacity in women undergoing repeated controlled ovarian stimulation cycles. Efficacy was evaluated as a secondary objective in an exploratory manner.

ESTHER-1 trial

ESTHER-1 was a randomized, controlled, assessor-blind, parallel-group, multicentre, multinational trial comparing the efficacy and safety of Rekovelle with follitropin alfa (Gonal-F). The trial included 1,326 women aged 18 to 40 years who were undergoing their first cycle of controlled ovarian stimulation for IVF/ICSI following a gonadotropin releasing hormone (GnRH) antagonist protocol. There were 665 patients treated with Rekovelle and 661 with Gonal-F.

The primary objective of the trial was to demonstrate non-inferiority of Rekovelle compared to Gonal-F with respect to (i) ongoing pregnancy rate and (ii) ongoing implantation rate in a fresh cycle in women undergoing controlled ovarian stimulation for IVF/ICSI.

Enrolled patients had regular menstrual cycles of 24-35 days, presumed to be ovulatory, and had been infertile for 3 years (average). They had been diagnosed with unexplained infertility (42%), tubal infertility (14%), endometriosis stage I/II (4%), or had partners diagnosed with male factor infertility (40%).

Patients treated with Rekovelle received an individualized dosing regimen based on their serum anti-Müllerian hormone level and body weight. The daily Rekovelle dose was fixed throughout the stimulation period. Women could be treated with Rekovelle for a maximum of 20 days, and coasting was not allowed. The Gonal-F dosing regimen was administered in accordance with its labelling, with a starting dose of 150 IU during the first five stimulation days, followed by possible dose adjustments based on the follicular development. The maximum daily Gonal-F dose allowed was 450 IU. Women could be treated with Gonal-F for a maximum of 20 days, and coasting was not allowed.

The ongoing pregnancy rate was 30.7% in patients treated with Rekovelle and 31.6% in patients treated with Gonal-F (difference = -0.9%; 95% confidence interval [CI]: -5.9% to 4.1%). Hence, the study demonstrated that Rekovelle was non-inferior to Gonal-F in terms of ongoing pregnancy rate since the lower limit of the 95% CI of the estimated difference in ongoing pregnancy rate between Rekovelle and Gonal-F was above the preplanned non-inferiority margin of -8.0%.

The overall average number of oocytes retrieved among the women who underwent triggering of final follicular maturation was 9.6 for patients treated with Rekovelle and 10.1 for patients treated with Gonal-F.

The proportion of patients with 8 to14 oocytes retrieved was 41.7% in patients treated with Rekovelle and 37.4% in patients treated with Gonal-F.

ESTHER-2 trial

ESTHER-2 trial was a controlled, assessor-blind, parallel-group, multicentre, multinational trial that evaluated the immunogenicity of Rekovelle in repeated cycles of controlled ovarian stimulation in women undergoing an assisted reproductive technology program. Efficacy was evaluated as a secondary objective in an exploratory manner.

In ESTHER-2, a total of 513 patients started treatment in controlled ovarian stimulation cycle 2 and 188 patients started treatment in controlled ovarian stimulation cycle 3. The daily dose of Rekovelle was modified according to the patient's ovarian response in the previous cycle. In patients with adequate ovarian response in the previous cycle who did not develop ovarian hyperstimulation syndrome, the same daily dose of Rekovelle was used. In patients who demonstrated ovarian hypo-response in the previous cycle, the daily dose of Rekovelle in the subsequent cycle could be increased by 25% or 50%. The maximum daily dose studied was 24 µg of Rekovelle in controlled ovarian stimulation cycle 3.

The primary endpoint of the trial was the proportion of subjects with treatment-induced anti-FSH antibodies after up to two repeated controlled ovarian stimulation cycles.

Anti-FSH antibodies were measured before and after dosing in patients undergoing up to three repeated treatment cycles with Rekovelle. Before exposure to Rekovelle, the incidence of anti-FSH antibodies was 1.4%. After treatment, the incidence was 1.1% in controlled ovarian stimulation cycle 1, 0.8% in controlled ovarian stimulation cycle 2 and 1.1% in controlled ovarian stimulation cycle 3. None of the anti-FSH antibodies had neutralizing capacity.

For more information, refer to the Rekovelle Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Rekovelle was evaluated on the basis of data derived from two Phase III clinical trials, ESTHER-1 and ESTHER-2 (described in the Clinical Efficacy section).

In ESTHER-1, among 665 patients treated with Rekovelle and 661 patients treated with Gonal-F, adverse events were reported by 54.6% and 50.8% of patients, respectively. The most frequently reported adverse events, grouped by Medical dictionary for regulatory activities (MedDRA) system organ classes (SOC), were reproductive system and breast disorders (20.6% for Rekovelle and 21.5% for Gonal-F) and pregnancy, puerperium and perinatal conditions (15.3% for Rekovelle and 16.9% for Gonal-F).

Serious adverse events occurred in 16 patients (2.4%) in the Rekovelle group and in 10 patients (1.5%) in the Gonal-F group.

A total of 19 patients discontinued treatment due to an adverse event: 9 patients (1.4%) in the Rekovelle group and 10 patients (1.5%) in the Gonal-F group.

Ovarian hyperstimulation syndrome was experienced by 55 patients in the trial: 23 patients (3.5%) in the Rekovelle group and 32 patients (4.8%) in the Gonal-F group.

In ESTHER-2, among 252 patients treated with Rekovelle and 261 patients treated with Gonal-F in controlled ovarian stimulation cycle 2, adverse events were reported in 119 (47.2%) and in 124 (47.5%) patients, respectively. Among 95 patients treated with Rekovelle and 93 patients treated with Gonal-F in controlled ovarian stimulation cycle 3, adverse events were reported in 46/95 (48.4%) and in 42/93 (45.2%) patients, respectively.

In controlled ovarian stimulation cycle 2, ovarian hyperstimulation syndrome was experienced by 3 patients (1.2%) in the Rekovelle group and by 8 patients (3.1%) in the Gonal-F group. In controlled ovarian stimulation cycle 3, ovarian hyperstimulation syndrome was experienced by 2 patients (2.1%) in the Rekovelle group and by 1 patient (1.1%) in the Gonal-F group.

Serious adverse events occurred in 4 (1.6%) patients in each treatment group during controlled ovarian stimulation cycle 2. There was only 1 serious adverse event in controlled ovarian stimulation cycle 3, which was a case of ovarian hyperstimulation syndrome in the Gonal-F group. Adverse events led to discontinuation for 3 patients (1.2%) in the Rekovelle group and 4 patients (1.5%) in the Gonal-F group. In controlled ovarian stimulation cycle 3, adverse events led to discontinuation for 3 patients (3.2%) in the Rekovelle group with no discontinuations reported in the Gonal-F group

In the post-marketing setting, ovarian torsion has been reported in connection with ovarian hyperstimulation syndrome.

Overall, Rekovelle has an acceptable safety profile for the controlled ovarian stimulation in women undergoing assisted reproductive technologies such as an in vitro fertilization or intracytoplasmic sperm injection cycle.

Appropriate warnings and precautions are in place in the approved Rekovelle Product Monograph to address the identified safety concerns.

For more information, refer to the Rekovelle Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical data for follitropin delta, the medicinal ingredient in Rekovelle, included conventional studies of safety pharmacology, repeated dose toxicity and local tolerance. The studies demonstrated no unexpected hazards for humans when follitropin delta was used at appropriate doses. The overdose of follitropin delta resulted in exaggerated pharmacological actions. When administered in doses above the recommended maximal dose in humans (≥0.8 µg/kg/day), follitropin delta had negative effects on fertility and early embryonic development in rats. As highlighted in its Product Monograph, Rekovelle is contraindicated for use during pregnancy and lactation.

No genotoxicity and carcinogenicity studies have been conducted, since follicle-stimulating hormone (FSH) is an endogenous protein hormone.

In view of the intended use of Rekovelle, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

Appropriate warnings and precautionary measures are in place in the Rekovelle Product Monograph to address the identified safety concerns.

For more information, refer to the Rekovelle Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The medicinal ingredient in Rekovelle, follitropin delta, is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line by recombinant deoxyribonucleic acid (DNA) technology. The amino acid sequences of the two FSH subunits in follitropin delta are identical to the endogenous human FSH sequences. The expressing cell line can influence the characteristics of the recombinant FSH, and differences in glycosylation profile, sialic acid pattern and isoform profile have been documented between follitropin delta and recombinant FSH products such as follitropin alfa and follitropin beta produced in Chinese hamster ovary (CHO) cell lines.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that follitropin delta consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Follitropin delta is produced in a human cell line by recombinant DNA technology. The drug substance manufacturing process is comprised of several steps divided into upstream and downstream operations. The steps include: thawing of a working cell bank vial; propagation of the inoculum and seeding into bioreactors; FSH production and collection into harvest bags; pooling of harvests; purification of FSH; and nanofiltration and filling into bags. The sponsor has demonstrated that the proposed drug substance manufacturing facility is able to consistently manufacture follitropin delta of an acceptable quality.

The drug product manufacturing process consists of formulation, sterile filtration, and aseptic filling into sterile pyrogen-free glass cartridges. The sponsor has demonstrated that the proposed drug product manufacturing facility is able to consistently manufacture Rekovelle cartridges of an acceptable quality.

Rekovelle is available as a sterile aqueous solution intended for subcutaneous administration in a 3 mL cartridge (Type I glass) with a plunger (halobutyl rubber) and an aluminium crimp cap with a rubber inlay. Cartridges are available in three strengths with label claims of 12 µg, 36 µg and 72 µg of follitropin delta in 0.36 mL, 1.08 mL and 2.16 mL, respectively. Cartridges are designed to be used in conjunction with the Rekovelle injection pen.

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 the follitropin delta with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, three consecutively manufactured final product lots were tested using a subset of release methods. The results obtained were similar to those reported by the sponsor and within the sponsor's specifications.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life for Rekovelle is considered acceptable, when stored at 2ºC to 8ºC and protected from light.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug product was not warranted since the facility was recently evaluated and obtained a satisfactory rating.

The sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The follitropin delta manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The expressing cell line is of human origin and contains no endogenous retrovirus-like particles. The adventitious agent safety studies suggest that the host cell system does not pose an unusual risk and the purification system is capable of inactivating/removing potential viral contamination to acceptable levels.

Date modified: