Platelet Response as the Basis for Approval in Chronic Immune(Idiopathic) Thrombocytopenic Purpura (ITP): A Regulatory Perspective

Francesco Pignatti,1* Beatriz Flores,2 and Bertil Jonsson3

The assessment of the benefit-risk balance of drugs intherapeutic areas where drug development has beensparse over the last decades can be challenging for regula-tors due to the lack of established regulatory guidelinesand experience. There is a need to carefully consider whichtype 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 throm-

bopoietin receptor (TPO-R) agonists intended for the treat-ment of patients with chronic immune (idiopathic) thrombo-cytopenia (ITP), also called chronic primary ITP. Prior regu-latory experience with new drug applications in this clinicalsetting was mainly based on immunoglobulin therapyfor which, considering the wide clinical use, only limitedclinical data had previously been required for marketingauthorization.Romiplostim (Nplate1) and eltrombopag (Revolade1),

have been approved in Europe for the treatment of sple-nectomized patients with chronic refractory ITP or as sec-ond-line therapy for non-splenectomized patients in whomsurgery is contraindicated. In the United States, the indica-tion has been broadened to the treatment of patients withchronic ITP who have had an insufficient response to corti-costeroids, immunoglobulins, or splenectomy.The precise role of TPO-R agonists in the treatment of

chronic primary ITP is still debated. Part of the debatestems from the fact that the demonstration of efficacy forthese approvals was based on platelet counts rather thanevents of bleeding, the latter (together with mortality) beingconsidered the most important clinical efficacy endpoint.Although positive effects have been described, no strongclaims have been made in the product labeling aboutreducing events of bleeding.In a critical review in this issue of the American Journal

of Hematology, Altomare et al. underline the difficulties ofmeasuring the efficacy of these agents on clinically signifi-cant bleeding and mortality risk, partly due to ethical studydesign considerations and the use of concomitant and res-cue ITP medication [1]. This review should be read in con-junction with a meta-analysis performed by the Cochranecollaboration, which concluded there was no evidence tosuggest that TPO receptor agonists improve significantbleeding events in chronic ITP while the adverse effectsare similar to placebo or standard of care [2].This conclusion raises the important question about whatclinical efficacy endpoint data should be available to allowa proper benefit-risk evaluation at the time of marketingauthorization.We agree that the therapeutic goal for treatment in

chronic ITP is to provide a safe platelet count to preventbleeding rather than correcting it to a normal level. Theassociation between platelet count and major bleeding/mor-tality risk in the absence of treatment is well established,and it is widely recognized that a platelet count below 30 3109 L21 is especially associated with an increased inci-dence of bleeding complication. An adequate platelet countcan also avoid or defer the risks of more toxic treatments

(e.g., splenectomy and immunosuppression) and reducecorticosteroid exposure. Thus, a response based on adurable platelet count increase has been accepted by regu-lators as a relevant clinical efficacy endpoint to assess theclinical benefit of these products.However, there may be room for improvement in the defi-

nition of this primary endpoint for which no uniqueapproach exists. For example, in the case of eltrombopag,the primary efficacy endpoint in the RAISE study wasspecified as the probability of achieving a platelet countwithin a specified range (�50 3 109 L21 and �400 3 109

L21) during the 6 month treatment period, while for theTRA100773B study it included the proportion of patientswith a platelet count increase above a specified level (�503 109 L21) at Day 43. For romiplostim, the primary efficacyendpoint in the pivotal studies was the incidence of a dura-ble platelet response defined as achieving at least 6 weeklyplatelet responses (platelet count �50 3 109 L21) duringthe last 8 weeks of treatment, with no rescue medicationadministered at any time during the treatment period. In arecent publication by the International Working Group(IWG), Rodeghiero et al. [3] propose criteria for assessingresponse to ITP treatments where response is describedas a platelet count increase �30 3 109 L21 and at least atwofold increase of the baseline and the absence of bleed-ing [3]. This endpoint definition seems to be preferable tothose considered above, since it allows a more balancedevaluation of the effect in patients with different baselinevalues and incorporates the clinically relevant variable ofbleeding. Furthermore, the use of concomitant treatmentmay also be considered for inclusion in the definition oftreatment response, depending on the specific objectives ofthe 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 majorityof bleeding events in ITP are relatively minor, with a verylow incidence of serious and life-threatening complications,such as intracranial hemorrhage. An objective measure-ment of bleeding is also difficult to make, due to the lack ofa validated scale in this disease. Additional factors can alsoaffect the risk of bleeding (e.g., lifestyle, age, concomitantdiseases, and prior steroid use), which may be difficult toassess in a clinical trial.

Conflicts of interest: Nothing to report

*Correspondence to: Francesco Pignatti, European Medicines Agency, 7Westferry Circus, London E14 4HB, United Kingdom.E-mail: francesco.pignatti@ema.europa.eu

1The European Medicines Agency, London, United Kingdom; 2Medicinesand Healthcare Products Regulatory Agency, London, United Kingdom;3Medical Products Agency, Uppsala, Sweden

Received for publication 18 June 2012; Accepted 19 June 2012

Am. J. Hematol. 00:000–000, 2012.

Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.23300

Commentary

VVC 2012 Wiley Periodicals, Inc.

American Journal of Hematology 1 http://wileyonlinelibrary.com/cgi-bin/jhome/35105

The mortality risk in chronic ITP is not only associatedwith the low risk of severe bleeding but also with the risk ofinfection or malignancies secondary to immunosuppressivetreatments. Chronic ITP is a rare condition and this limitsthe size of clinical studies. Therefore, the statistical powerto detect differences in mortality risk and severe bleedingevents in a clinical study is expected to be very low.The EMA is currently drafting new guidelines on the clini-

cal development of medicinal products intended for thetreatment of chronic primary ITP. Key aspects will includethe relevant target population, the definition of the thera-peutic goal, identification of an optimal dose, relevant pointsfor consideration in the design of confirmatory studies, andrequirements for pediatric development. The guideline isintended to reflect regulatory experience and recently pub-lished literature on chronic ITP, including the recommenda-tions proposed by the IWG [3]. A draft is expected to beavailable 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 managementof this condition change in the absence of solid evidence ofan effect on significant bleeding events or mortality?Patients and physicians are in the best position to makeinformed decisions about individual situations. Other stake-holders such as hematologists, health technology assess-

ment bodies, health economists, and third-party payers willneed to determine the relative effectiveness and cost-effec-tiveness, and ultimately, the place in the therapeutic arma-mentarium of TPO-R agonists in chronic ITP. Regulatoryagencies will continue to collect and assess the post-mar-keting data of TPO-R agonists to further inform future ben-efit-risk decisions.

Publication DisclaimerThe views expressed in this article are the personal

views of the author(s) and may not be understood orquoted as being made on behalf of or reflecting the positionof the European Medicines Agency (EMA) or one of itscommittees or working parties.

References1. Altomare I, Wasser J, Pullarkat V. Bleeding and mortality outcomes in ITP clinical

trials: An analysis or thrombopoietin mimetics data. Am J Hematol 2012.2. Zeng Y, Duan X, Xu J, et al. TPO receptor agonist for chronic idiopathic throm-

bocytopenic purpura. Cochrane Database Syst Rev 2011 Jul 6;(7):CD008235.3. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology,

definitions and outcome criteria in immune thrombocytopenic purpura of adultsand children: Report from an international working group. Blood 2009;113:2386–2393.

2 American Journal of Hematology

commentary