Sponsor's response to Independent Review Report for Teriparatide
The following page outlines the sponsor response to the Independent Review Report for Teriparatide
Page last updated: 02 March 2007
Response to the Independent Review
Item 9.1. Teriparatide- FORTEO – Lilly
The sponsor acknowledges the following outcomes of the independent review:
Indirect comparison and subgroup analysis
The gold standard for demonstrating superiority is the conduct of a head-to-head randomised
controlled trial, however, in the absence of these data the sponsor undertook appropriate
statistical measurements to optimize the validity of the indirect comparison. While
the design of the GHAC and FIT trials are similar, the validity of the indirect comparison
is compromised by the early termination of the GHAC and the subsequent loss to follow-up
of patients.
The post-hoc subgroup analysis of the SQ3 patient group is the major deficiency of
the submission and as such cannot adequately support the claim of superiority of teriparatide
over the comparator in this severe patient group.
Sponsor’s response
As stated in the PBAC submissions, there are no clinical trials to exactly match the
requested listing. The proposed listing was developed over the course of the submissions
in consultation with the scientific and medical community in an effort to make teriparatide
available in a cost-effective manner to patients at most need for this therapy. The
available clinical data demonstrates that teriparatide is a potent and effective treatment
for osteoporosis. However, the cost-effectiveness of this product as a first line
treatment cannot be demonstrated at the proposed price. Furthermore, the TGA-approved
indication for teripartide stipulates that this product should only be used where
other agents are considered unsuitable, that is, alternative should be considered
for first-line management of osteoporotic fracture.
Therefore, while the clinical trial was designed for a broader patient group, the
sponsor has worked with the clinical community to determine those patients where other
agents would be considered unsuitable and where teriparatide would offer the most
benefit. The SQ3 fracture group is a small but significant subgroup of patients with
osteoporotic fracture. PBAC has previously acknowledged this is a group with a significant
clinical need. No clinical trial of any available agent has been conducted specifically
in this patient sub-group, all analyses published to date have been post-hoc analyses
of existing datasets. These analyses have been conducted by Eli Lilly and Company
using both the raloxifene and teriparatide fracture outcomes trials.
The ideal trial for the proposed listing is unlikely to occur for the following reasons:
- The TGA approved indication limiting teriparatide to second-line use is unique to Australia, thus in all other countries where teriparatide is registered this product is available as a first line treatment and this continues to be the case;
- The FDA and other regulatory agents do not require head-to-head comparisons of new bone agents. Therefore, the main objective has been to demonstrate anti-fracture efficacy over “no therapy”. Once efficacy was established, head-to-head comparisons have been limited to markers of efficacy – namely bone turnover, BMD etc. These trials have been conducted for teriparatide with and alendronate comparator. The results for BMD are consistent with the results for BMD reported in the GHAC and FIT-VFA trials;
- The clinical trials program for teriparatide has moved into other areas of clinical need including glucocortocoid induced osteoporosis, pain management and fracture healing;
Furthermore, a head-to-head RCT in the SQ3 patient subgroup is technically difficult
and has a low probability of being completed in a timely manner at sufficient power.
The characteristics of the patient group included under the proposed listing means
it would be difficult to recruit required numbers and retain them in study, due to
age and increasing co morbidities. The recruitment of patients to fracture endpoint
studies is generally slow at best, and in the case of studies involving older age
group participants, the disposition from the trial can exceed recruitment. This was
the case reported for the study of hip fractures using risedronate. The sponsor is
fully supportive of demonstrating the efficacy and safety of a product in head to
head clinical trials, however, from a pragmatic and feasibility standpoint, this remains
a patient group who are unlikely to be studied in a prospective randomised controlled
trial.
2. Biological plausibility of difference between teriparatide and alendronate
The Independent Reviewer has concluded that there is sufficient evidence to support
the claim that there is a biologically plausible argument that teriparatide’s anabolic
mechanism of action could result in a superior therapeutic action in a severe patient
subgroup compared with antiresorptive therapies. However, this claim is theoretical
and is not adequately supported by the available clinical evidence.
Sponsor’s response
Eli Lilly accepts the Independent Reviewer’s evaluation of the biological plausibility
of the difference between teriparatide and alendronate. This area of research continues
to be studied in the scientific literature, mostly in preclinical studies and using
surrogate markers. However, for reasons stated above, we are unlikely to be able to
confirm this biological hypothesis with a prospective RCt conducted in an SQ3 patient
subgroup.
Utility values
The principal criticisms of the utility study raised in the PBAC minutes related to
the method used to derive the utility weights and the application of these weights
in the base case CUA. The Independent Reviewer notes “…the sensitivity analysis, which
does allow for the proportion of symptomatic and asymptomatic fractures and the disutility
associated with symptomatic fractures, is plausible” (page 6). These sensitivity analyses
were described by the reviewer as clinically plausible and reflecting the uncertainty
surrounding the method used to derive the utility weights and the final weights themselves.
The Independent Reviewer further notes the lack of explicit guidance on the steps
required for deriving utilities for CUA analysis.
Sponsor’s response
The base case CUA reported in the submission was in the range of $15,000 - $45,000.
Under a scenario where the vertebral fracture utilities were adjusted such that 70%
of patients have 1/3 the disutility the ICER increases to be in the range of $45,000
- $75,000. In the case where the vertebral fracture utilities are adjusted so that
70% have no disutility (zero disutility if asymptomatic) the ICER increases to be
in the range of $75,000 - $105,000. Thus, the ICER is sensitive to the utility values
included in the modelled evaluation but our interpretation of the reviewer’s comments
is that the likely range lies somewhere between $45,000 and $105,000.
In conducting the utility study, we contacted medical specialists treating patients
with severe (SQ3 grade) osteoporosis. These practitioners were not asked to determine
whether the patients were symptomatic or asymptomatic. The response from specialists
has been that these patients with low BMD and multiple fractures would experience
symptoms of pain and other functional measures. The clinical trials demonstrated that
at least 80% of patients with SQ3 grade fractures report pain associated with the
fracture. While pain is a contributory factor to this disutility score, other functions
of daily living, physical function, emotional status, and symptoms scores are affected
by SQ3 fractures. Furthermore, prospective data collected during most osteoporosis
trials have demonstrated that both symptomatic and asymptomatic vertebral fractures
are associated with a reduction in QoL. ¹ ²
The sponsor accepts the Independent Reviewer’s comments relating to guidance on the
measurement of utilities. We have, through various submissions, sought to provide
utility values using appropriate methods for deriving utilities and we note the extensive
measures that have been taken in the current draft guidelines to address the measurement
of utilities. The pivotal trials for both teriparatide and alendronate were conducted
during the later half of the 1990’s, thus the inclusion of specific measures for derivation
of utilities that would be required for a PBAC submission under the draft guidelines
are lacking from these trials.
¹. OLEKSIK A, LIPS P, DAWSON A, MINSHALL ME, SHEN W, COOPER C, KANIS J. Health-Related Quality of Life in Postmenopausal Women With Low BMD With or Without Prevalent Vertebral Fractures J Bone Miner Res 2000;15:1384–1392)
². Oglesby AK. Minshall ME. Shen W. Xie S. Silverman SL. The impact of incident vertebral and non-vertebral fragility fractures on health-related quality of life in established postmenopausal osteoporosis: results from the teriparatide randomized, placebo-controlled trial in postmenopausal women. Journal of Rheumatology. 30(7):1579-83, 2003 Jul.
Concluding remarks
Eli Lilly Australia accepts the outcomes of the Independent Review and was aware of
the limitations of a sub-group analysis and indirect comparison when the re-submission
was lodged and at the time of the request for the independent review. We believe that
the approach taken in the submission was valid given the requested positioning for
listing and the limitations of the clinical data available. We are encouraged by the
confirmation of the claims relating to the biological plausibility of teriparatide
superiority, but accept the limitations of the data to support this claim. We concur
with the comments made in relation to the utilities and the lack of explicit guidance
for measurement of utilities in the PBAC guidelines and advice.
We respectfully request, however, that in considering the outcomes of this independent
review on the listing of teriparatide on the PBS, the PBAC provide some guidance on
the positioning of products on the PBS for the following areas:
- where the TGA approved indication is not consistent with the clinical data package;
- for high-risk patient sub-groups unlikely to be studied under prospective RCT conditions;
- where clinical practice has advanced since the conduct of the pivotal trial.
We will continue to assess any other options that may lead to subsidised availability of teriparatide in Australia. Should any options appear to have sufficient merit these will be provided in the pre-PBAC response due on October 25th.
