Platelet response as the basis for approval in chronic immune (idiopathic) thrombocytopenic purpura (ITP): A regulatory perspective
Authors: Francesco Pignatti, Beatriz Flores, Bertil Jonsson
Journal: American Journal of Hematology (2012)

The assessment of the benefit-risk balance of drugs in therapeutic areas where drug development has been sparse over the last decades can be challenging for regulators due to the lack of established regulatory guidelines and experience. There is a need to carefully consider which type of clinical data, in terms of both safety and efficacy, should be required to allow a proper benefit-risk evaluation. Between 2007 and 2010, the EMA assessed two thrombopoietin receptor (TPO-R) agonists intended for the treatment of patients with chronic immune (idiopathic) thrombocytopenia (ITP), also called chronic primary ITP. Prior regulatory experience with new drug applications in this clinical setting was mainly based on immunoglobulin therapy for which, considering the wide clinical use, only limited clinical data had previously been required for marketing authorization. Romiplostim (Nplate®) and eltrombopag (Revolade®), have been approved in Europe for the treatment of splenectomized patients with chronic refractory ITP or as second-line therapy for non-splenectomized patients in whom surgery is contraindicated. In the United States, the indication has been broadened to the treatment of patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The precise role of TPO-R agonists in the treatment of chronic primary ITP is still debated. Part of the debate stems from the fact that the demonstration of efficacy for these approvals was based on platelet counts rather than events of bleeding, the latter (together with mortality) being considered the most important clinical efficacy endpoint. Although positive effects have been described, no strong claims have been made in the product labeling about reducing events of bleeding. In a critical review in this issue of the American Journal of Hematology, Altomare et al. underline the difficulties of measuring the efficacy of these agents on clinically significant bleeding and mortality risk, partly due to ethical study design considerations and the use of concomitant and rescue ITP medication [1]. This review should be read in conjunction with a meta-analysis performed by the Cochrane collaboration, which concluded there was no evidence to suggest that TPO receptor agonists improve significant bleeding events in chronic ITP while the adverse effects are similar to placebo or standard of care [2]. This conclusion raises the important question about what clinical efficacy endpoint data should be available to allow a proper benefit-risk evaluation at the time of marketing authorization. We agree that the therapeutic goal for treatment in chronic ITP is to provide a safe platelet count to prevent bleeding rather than correcting it to a normal level. The association between platelet count and major bleeding/mortality risk in the absence of treatment is well established, and it is widely recognized that a platelet count below 30 × 109 L−1 is especially associated with an increased incidence of bleeding complication. An adequate platelet count can also avoid or defer the risks of more toxic treatments (e.g., splenectomy and immunosuppression) and reduce corticosteroid exposure. Thus, a response based on a durable platelet count increase has been accepted by regulators as a relevant clinical efficacy endpoint to assess the clinical benefit of these products. However, there may be room for improvement in the definition of this primary endpoint for which no unique approach exists. For example, in the case of eltrombopag, the primary efficacy endpoint in the RAISE study was specified as the probability of achieving a platelet count within a specified range (≥50 × 109 L−1 and ≤400 × 109 L−1) during the 6 month treatment period, while for the TRA100773B study it included the proportion of patients with a platelet count increase above a specified level (≥50 × 109 L−1) at Day 43. For romiplostim, the primary efficacy endpoint in the pivotal studies was the incidence of a durable platelet response defined as achieving at least 6 weekly platelet responses (platelet count ≥50 × 109 L−1) during the last 8 weeks of treatment, with no rescue medication administered at any time during the treatment period. In a recent publication by the International Working Group (IWG), Rodeghiero et al. [3] propose criteria for assessing response to ITP treatments where response is described as a platelet count increase ≥30 × 109 L−1 and at least a twofold increase of the baseline and the absence of bleeding [3]. This endpoint definition seems to be preferable to those considered above, since it allows a more balanced evaluation of the effect in patients with different baseline values and incorporates the clinically relevant variable of bleeding. Furthermore, the use of concomitant treatment may also be considered for inclusion in the definition of treatment response, depending on the specific objectives of the trial. In the past, the EMA has recommended the inclusion of bleeding as a key secondary endpoint since it is a well-known complication of the disease. However, the majority of bleeding events in ITP are relatively minor, with a very low incidence of serious and life-threatening complications, such as intracranial hemorrhage. An objective measurement of bleeding is also difficult to make, due to the lack of a validated scale in this disease. Additional factors can also affect the risk of bleeding (e.g., lifestyle, age, concomitant diseases, and prior steroid use), which may be difficult to assess in a clinical trial. The mortality risk in chronic ITP is not only associated with the low risk of severe bleeding but also with the risk of infection or malignancies secondary to immunosuppressive treatments. Chronic ITP is a rare condition and this limits the size of clinical studies. Therefore, the statistical power to detect differences in mortality risk and severe bleeding events in a clinical study is expected to be very low. The EMA is currently drafting new guidelines on the clinical development of medicinal products intended for the treatment of chronic primary ITP. Key aspects will include the relevant target population, the definition of the therapeutic goal, identification of an optimal dose, relevant points for consideration in the design of confirmatory studies, and requirements for pediatric development. The guideline is intended to reflect regulatory experience and recently published literature on chronic ITP, including the recommendations proposed by the IWG [3]. A draft is expected to be available for public consultation in the second half of 2012. There is currently no clear consensus on treatment for patients with chronic ITP. Should the clinical management of this condition change in the absence of solid evidence of an effect on significant bleeding events or mortality? Patients and physicians are in the best position to make informed decisions about individual situations. Other stakeholders such as hematologists, health technology assessment bodies, health economists, and third-party payers will need to determine the relative effectiveness and cost-effectiveness, and ultimately, the place in the therapeutic armamentarium of TPO-R agonists in chronic ITP. Regulatory agencies will continue to collect and assess the post-marketing data of TPO-R agonists to further inform future benefit-risk decisions. The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency (EMA) or one of its committees or working parties.