Replagal (agalsidase alfa) - Notice of Compliance with Conditions - Qualifying Notice

2005-12-16

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Contact: Regulatory Affairs Division

Biologics and Genetic Therapies
Directorate
Tunney's Pasture
Address Locator #0601E3
Ottawa, Ontario
KlA 0L2

File #: 9427-T0773-21
Control #: 068304

October 30, 2003

[employee name removed]
Head of Regulatory Affairs
Transkaryotic Therapies Inc.
700 Main Street
Cambridge, MA
U.S.A. 02139
Fax: (617) 613-4444

Dear [employee name removed]

Your New Drug Submission for Replagal™ (Agalsidase alfa, α-Galactosidase-A), Control # 068304, submitted on September 15, 2000 has been reviewed and is judged to qualify for a Notice of Compliance (NOC) under Health Canada's Notice of Compliance with Conditions (NOC/c) policy.

Please refer to the Health Canada documents entitled Guidance for Industry: Notice of Compliance with Conditions (NOC/c) and Notice of Compliance with Conditions (NOC/c) Policy, both dated November 6, 2002, for detailed information on requirements for consideration under this policy. These documents should be read in their entirety, however particular attention should be paid to Section 3.3: "Issuance and Response: NOC/c Qualifying Notice (NOC/c-QN)" of the Guidance. These two documents may be found at the following locations on the Health Canada website:

http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/nocc_guidance_e.html; and

http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/nocc_policy2002-eng.php.

It is noted that Section 5.2.1: "Product Monographs" of the Guidance for Industry: Notice of Compliance with Conditions (NOC/c) is based on the new format for Products Monographs as per the new Guidance for Industry: Product Monograph, dated September 22, 2003. Therefore, the Product Monograph sections described therein will not be entirely applicable to the Replagal Product Monograph. In light of this, please note the recommendations below when reviewing this section.

1. The "boxed text" should be on the cover page of the Product Monograph, as well as at the start of the body of the Product Monograph, before any other text. The boxed text should contain the following wording:
   
   "Replagal shows promising preliminary evidence of efficacy for treatment of patients with Fabry's Disease; however, the optimal dose requires further investigation. A study is underway to further evaluate different doses of Replagal therapy to further assess and determine what the ideal dose and schedule should be."
2. The "symbolic identifier" described in Section 5.2.1 should be included in the following 3 specific sections of the Product Monograph:
   Dosage and Administration;
   Clinical Trials; and
   Insert for Patients.

In preparing your response to this Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), please also note the clinical comments in the following paragraphs, provided for your consideration.

The overall clinical development plan for Agalsidase has focussed upon the single dose regimen of 0.2 mg/kg, IV, every two weeks. No other doses have been evaluated on a sustained basis, precluding any assessment of dose-response relationships of clinical safety, bioactivity or efficacy.

Selecting the clinical dose based upon "saturating" the liver with enzyme activity assumes liver "saturation" may be a logical approach to selecting the minimum dosage to make the enzyme available to other tissues. However, it is conceivable that impacting the clinical disease may require dosages considerably in excess of those required for liver "saturation."

The Fabry's disease knockout mouse studies are notable for suggesting that the 1 mg/kg dose Agalsidase exhibited more complete resolution of lipid storage than the lower dose.

Replagal does have merits that render it a potentially viable treatment. It meets the necessary criteria for recommending clearance under the NOC/c policy in that:

1. Replagal is intended for use in Fabry's disease which is a serious, life-threatening, severely debilitating condition for which there is no existing therapy available on the Canadian market.
2. Replagal does show promising evidence of clinical effectiveness as demonstrated by a reduction of CTH levels in both urine and plasma for patients receiving active treatment in trials TKT003 and TKT005.
3. By replacing the deficient enzyme effectively, Replagal has the potential to prevent many of the serious manifestations of the condition.
4. Replagal has an acceptable safety profile from the clinical evidence to date.
5. Replagal is found to be of high quality.

You have proposed (in an email dated July 2, 2003 and further discussed by phone) a draft protocol titled "A Phase IV Protocol Short Term Alternative Dosing Study of Replagal Enzyme Replacement in Patients with Fabry's Disease". This pharmacodynamic study is designed to assess the effects of alternative dose regimes on reduction of plasma Gb3 and to help to select a dose/regimen for a long-term study utilizing clinical endpoints, against the current dose / regimen of Replagal (0.2mg/kg bi-weekly). The maximum dose in this study proposal is 0.4 mg/kg/week. This is equivalent to 4 times the dose proposed in the NDS without a strong rationale for the proposed dose range for the above noted "Short Term Alternative Dosing Study".

Thus there remains a concern that the 0.2 mg/kg/2weeks dose may be inadequate for control of symptoms and that some patients will be receiving a dose that is not optimal. Therefore you should consider a proposal that would be adequate to address the concern, in respect of optimizing therapy of patients with Fabry's disease and, ensuring the policy requirements are met for a confirmatory study. This proposal should include measures regarding these dosage concerns for all the Canadian patients who are currently being treated or will be treated with Replagal therapy so as to best ensure dosage optimization in Canada.

Your response to this Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) should reference the submission control number and should be sent to the following address, within 30 calendar days of the date of receipt of this letter:

Submission and Information Policy Division
Bureau of Operational Services
Therapeutic Products Directorate
Finance Building, Tunney's Pasture
1st Floor, A..L. 0201A1
Ottawa, Ontario
K1A 1B6

Yours sincerely,

Original signed by

Dixon M. Ho, B.Sc.
A/Unit Head, Biotherapeutics and
Radiopharmaceuticals
Submission Management Division
Centre for Policy and Regulatory Affairs
Tel: 613-957-0361
Fax: 613-957-0364