Regulatory Decision Summary for Vablys

Vablys (dequalinium chloride 10 mg intravaginal tablet) is a new-to-Canada proposed treatment of bacterial vaginosis in adult women, using a known quaternary ammonium active with known low target site specificity. There is a need for alternative therapeutic products for the treatment of bacterial vaginosis in Canada due to the disadvantages associated with the potential for development of resistance to antibiotics. Antiseptic agents such as Vablys represent a viable alternative to traditional antibiotics to treat this disease.

During the review of the original NDS, the Non-Clinical portion of the review was completed and considered acceptable. Overall, the non-clinical data suggested that dequalinium chloride exerts its antimicrobial activity against a wide range of pathogens locally after vaginal application. Also, it appeared to be well tolerated following vaginal administration (no systemic or toxicologically relevant side effects were reported), and vaginal absorption was deemed likely low based on available data. The non-clinical data did not raise any safety issues that would preclude approval of Vablys for the proposed indication. The Product Monograph (PM) was revised during review at this time to ensure the accuracy of information reported and to capture the limitations of the data.

The Clinical Pharmacology section was also reviewed and generally considered acceptable. There was some indication of systemic distribution (albeit limited), which was in contrast to non-clinical findings. These discrepancies have since been addressed through revisions to the PM.

However, as mentioned previously, a few major submission deficiencies and omissions were identified during the Clinical Safety and Efficacy review. These deficiencies included, for example, unsubmitted clinical study reports deemed relevant to the safety and efficacy assessment. Also, a biostatistical consult found that the sponsors pre-specified and post-hoc analyses results were insufficient to confirm Vablys efficacy compared to the active comparator, and that an adequate justification for the selection of the 15% non-inferiority margin was not provided. As such, an NOD was issued April 29, 2020 as per Health Canadas Management of Drug Submissions Guidance Document (July 2019).

In August 2020, the Sponsor provided a response to the NOD (R-NOD). Based on a re-review of the one pivotal study 380104, it was deemed acceptable that one well-conducted pivotal study was sufficient to establish safety and efficacy given the post-hoc analyses showing assay sensitivity and robustness. The two supportive clinical studies, long-standing safety profile of the drug, history of clinical use, and the type of the drug (i.e., antiseptic agent) were sufficient to establish safety.

Vablys was shown in the pivotal study to be non-inferior (NI) compared with clindamycin vaginal cream for the primary efficacy variable, the clinical cure rate 3 - 14 days after the end of treatment. In terms of the durability of the effect, cure rates 2 - 6 weeks after the end of treatment achieved with Vablys were at least as high as those achieved with Clindamycin, again indicating non-inferiority of Vablys to Clindamycin. Most of the secondary efficacy variables were also supportive for the primary variable with no apparent differences between treatment groups. The post-hoc analyses indicated that Vablys was non-inferior to Clindamycin at NI margin of 15% in term of the total non-failure rate. It was also concluded that the 15% NI margin was adequately justified and statistically valid. Therefore, the evidence from the post-hoc analyses was robustly supportive of the conclusion that Vablys was non-inferior to Clindamycin.

In regards to safety findings, Vablys is well tolerated in clinical studies. The overall incidences of adverse events and of drug related adverse events were lower for Vablys as compared to Clindamycin. Evaluation of spontaneous reports from extensive post-marketing experience confirms that most events currently reported with Vablys use are minor, local signs and symptoms. The only notable risk that has been identified with Vablys use is the potential for vaginal ulceration/maceration, particularly with higher doses and longer duration of treatment. This was resolved by reducing the recommended dose and limiting the treatment duration to that currently proposed and as used in the pivotal study. The risk is further mitigated by the Product Monograph contraindication of pre-existing ulceration of the vaginal epithelium and the vaginal portion of the cervix.

Ulcerations of the vaginal epithelium may occur in patients in whom the vaginal epithelium is pre-damaged, for example, as a consequence of oestrogen deficit. No data are available to Health Canada to consider that the safety of Vablys in women over 55 years of age has been established. Therefore, Health Canada has not authorized an indication for use in women over 55 years of age.

Regarding post-market safety, dequalinium chloride vaginal tablet (Fluomizin) has been marketed in Europe since 1993 and, to date, over 30 million patients have been exposed. The reporting rate of systemic serious adverse events (dyspnea, hypertensive crisis) is very rare. The Marketed Health Products Directorate (MHPD) reviewed the Periodic Safety Update Reports (PSURs) provided in this NDS, covering 12 years of recent post-market safety data. No new safety information on dequalinium for vaginal use was identified from these reviews. Pyrexia, cystitis, hypersensitivity reactions such as allergic reactions with symptoms like urticaria, erythema, exanthema, swelling, rash or pruritus are labelled in the post-marketing adverse reaction section of the Canadian PM. Based on the safety profile of the drug, MHPD did not recommend that the sponsor submit a Risk Management Plan (RMP).

Based on the overall safety and efficacy assessment of information submitted, the benefit-harm-uncertainty profile of Vablys is considered to be favourable when the drug is administered to patients under the conditions specified in the labeling. Vablys is an effective and well-tolerated medication for the treatment of bacterial vaginosis in adult women, which would otherwise be treated with traditional antibiotics.

Regarding the Quality and Labelling assessments, the sponsor addressed all of the issues raised throughout review. The final New Drug Quality Division recommendation for a Notice of Compliance (NOC) was issued on July 5th, 2021. The final approved Product Monograph after Clinical, Quality, and Labelling Review is dated July 15, 2021.