Scope for review of Teriparatide submissions

Details of the Reviewers

The names of reviewers have been withheld, consistent with PBAC procedures

Timing of review

The principal reviewer commenced the assessment on May 25, 2006. The secondary reviewer was contracted on June 2, 2006 to assist with the evaluation of the matter related to the health utilities. The final report was supplied to the Office of the Convenor on September 8, 2006 in both paper and electronic copy.

Matters for review

The sponsor nominated the following issues upon which review is sought:

1. PBAC concern that the indirect data comparison and subgroup analysis does not support the claim of superiority-paragraph 4 of PBAC minutes.
2. PBAC claim that the submission provides no evidence to suggest any biological plausible reason to explain the claimed difference between teriparatide and the comparator-paragraph 9 of PBAC minutes.
3. PBAC concern with regard to continuing use of the same utility values in spite of the sponsor’s efforts to address these concerns in its responses-paragraph 4 of PBAC minutes.

Top of page
The following extract from the March 2006 PBAC short minutes provides the context in which the sponsor’s request for review has arisen. “The PBAC accepted there is a strong clinical need for an effective treatment for patients with osteoporosis who continue to have symptomatic vertebral fractures whilst receiving a bisphosphonate, with calcium and vitamin D supplementation. The PBAC noted that this re-submission had addressed a number of outstanding issues, including the requested restriction, the appropriate comparator, the toxicity of teriparatide and the uncertainty over the predicted usage. However, some issues remained outstanding, including (a) the reliance on an indirect comparison across placebo-controlled trials to infer the superiority claim for teriparatide over alendronate rather than a head-to-head randomised trial; (b) use of the results of the post hoc sub-group analysis in place of the overall ITT results for teriparatide in the clinical conclusions and the economic model; and (c) the continuing use of the same utilities and disutilities, as previously, in the model where the sensitivity analyses indicate the model is sensitive to the assumptions used to derive the incremental utility estimates from the trial-based outcomes measures.

Furthermore, no evidence was submitted to suggest any biologically plausible reason that teriparatide is more effective in the high risk sub-group than in the overall trial population… As noted previously, the submission again sought to base its biological plausibility arguments on the different mechanisms of action of the two alternative drugs. The PBAC concluded that although this might be relevant to the question of differential treatment effects across the drugs, it is irrelevant to the question here of the biological plausibility of the one drug (teriparatide) having an increasing relative treatment effect as baseline fracture severity worsens. The PBAC thus considered that the re-submission therefore provides no new basis that could change the PBAC’s previous view concerning the invalidity of adopting the results of this group analysis rather than the results of the overall ITT analysis as the basis for deriving an estimate of the effectiveness of teriparatide to compare with alendronate.”

Materials considered

The sponsor indicated (via the office of the Convenor for PBS Independent Review) that the review should consider the material provided at the March 2006 and July 2005 meetings of the Pharmaceutical Benefits Advisory Committee (PBAC).

The Convenor provided the following list of documents. The documents contain material provided by the sponsor, the material provided to PBAC, and the PBAC records.

March 2006 PBAC Meeting (labelled by sponsor as November 2005 submission)

Sponsor Submission

1. Cover letter
2. PB 11
3. TGA approval product information
4. Extract from PBAC Minutes July 2005
5. Answers to Key Questions
6. Executive Summary
7. Regulatory Documents
   7.1.1 TGA – Clinical Evaluation Report
   7.1.2 TGA – Request for pre-ADEC response and Delegates “Request for ADEC Advice”
   7.1.3 Eli Lilly – pre-ADEC Response
   7.1.4 ADEC Resolution
   7.1.5 Eli Lilly letter of 7 March 2003, responding to ADEC resolution
   7.1.6 Periodic Safety Update (provided in hard and electronic copy)
8. Main Body of Submission (labelled Volume 4 by sponsor)
9. Appendix to Submission (labelled Volume 4 by sponsor) (provided in hard copy and electronic copy)
   Top of page
10. References (labelled Volumes 5a and 5b by sponsor)
11. Teriparatide Study Reports (provided in electronic copy only except for GHAC)
    11.1.1 GHAC
    11.1.2 GHBJ
    11.1.3 GHAJ
    11.1.4 GHAH
    11.1.5 GHBM
    11.1.6 GHBQ
    11.1.7 GHBU
12. Models and spreadsheets used in the submission – (provided in electronic copy only)
13. Previous sponsor submissions to PBAC (Note: did not form part of the March 2006 evaluation by PBAC) (provided in electronic copy only)
    13.1.1 Sponsor submission March 2003 (considered by PBAC June 2003)
    13.1.2 Sponsor submission December 2003 (considered by PBAC March 2004)
    13.1.3 Sponsor submission March 2005 (considered by PBAC July 2005)
    
    PBAC Agenda Papers: Teriparatide – March 2006
14. Secretariat overview and attachments (white pages)
15. Pharmaceutical Evaluation Section (PES) commentary (pink pages)
16. Pre-Subcommittee response (blue pages)
17. Economics Subcommittee (ESC) Advice to PBAC (green pages)
18. Restrictions Working Group (RWG) Advice to PBAC (purple pages)
19. Pre-PBAC response (yellow pages)
20. July 2005 PES Commentary (routinely provided to PBAC Chair and discussants only, available to other members on request).
    (There was no Drug Utilization Subcommittee (DUSC) commentary or advice for this item).
    PBAC Minutes
21. Relevant Extract of March 2006 Short Minutes
22. Relevant Extract of ratified PBAC Minutes of March 2006
    July 2005 PBAC Meeting (labelled by sponsor as March 2005 submission)
    Sponsor Submission
23. Cover letter
24. PB11
25. Answers to Key Questions
26. TGA product information
27. Preface
28. Executive Summary
29. Main Body of Submission (labeled Volume 4 by sponsor)
30. Appendix to Submission (labeled Volume 4 by sponsor) (provided in hard copy and electronic copy)
31. References (labelled Volume 6 by sponsor)
32. Models and spreadsheets used in the submission (provided in electronic copy only)
    PBAC Agenda Papers: Teriparatide – July 2005
33. Secretariat overview and attachments (white pages)
34. Pharmaceutical Evaluation Section (PES) commentary
35. Drug Utilization Subcommittee (DUSC) secretariat commentary
36. Pre-Subcommittee response
37. Economics Subcommittee response
38. DUSC Advice to PBAC
39. Restrictions Working Group (RWG) Advice to PBAC
40. Pre-PBAC response
41. March 2004 PES Commentary (routinely provided to PBAC Chair and discussants only, available to other members on request).
    PBAC Minutes
42. Relevant Extract of July 2005 Short Minutes
43. Relevant Extract of ratified PBAC Minutes July 2005

Sponsor’s nomination of priority of material

The Convenor advised that the sponsor requested that the GHAC clinical study be considered essential and that the other clinical studies should be considered as necessary. Similarly, the sponsor advises that the references in the fourth submission (i.e. the March 2006 PBAC submission) are essential, and that the references in the July 2005 PBAC submission should be reviewed as necessary.