Generics in chronic myeloid leukemia: current arguments for and against and the established evidence

Abstract

Tyrosine kinase inhibitors became the mainstay of management in patients with chronic myeloid leukemia. The substantially high treatment cost has unfortunately been a major issue. Recent market entry of the imatinib generics are expected to lower the price and increase the availability of the drug worldwide. However, concerns about their efficacy and safety seem to slacken the approval of the generics in many countries. In this editorial, we discuss the current evidence on imatinib generics based mainly on Turkish experience and other limited data available.

Keywords::

• chronic myeloid leukemia
• generic
• imatinib
• tyrosine kinase inhibitor

There has been a dramatic change in the management and prognosis of the chronic myeloid leukemia (CML) with the introduction of imatinib mesylate (IM) (Glivec; Novartis, Basel, Switzerland), the first tyrosine kinase inhibitor (TKI) [1], specifically designed to target the BCR/ABL mutated clone. Since then, TKIs have become the mainstay of treatment in CML, leading to a decline in the annual mortality rates from 10–20 to 2% and have improved the estimated 10-year survival from less than 20% to more than 80% [2]. But there is no rose without a thorn, as the saying goes. The improved outcome achieved with imatinib resulted in a substantial increase of the therapeutic expenses. The annual cost of IM treatment has been reported to vary between US $24,000 and US $92,000 among countries in different regions of the world, depending on the geopolitical and socioeconomic conditions [3]. The original IM was priced at nearly US $30,000/year when it was first released in 2001, which then increased to US $92,000 in 2012 [4]. The high long-run cost of the IM therapy has raised growing concern about issues such as limited access to treatment and sustainability of the national health care systems [5]. Since the health care systems and the reimbursement authorities most probably could not afford the expenses of the original TKIs in the near future even in developed countries, IM generics at a lower price could improve the treatment penetration and increase accessibility to treatment, thus expanding the population of CML patients who live longer on TKI therapy [4]. However, the great enthusiasm caused by the entry of the long-awaited IM generics into the market is rapidly marred by questions regarding their efficacy and tolerability.

Active pharmaceutical ingredient of the IM can be found in three polymorphic forms (α, β or γ) [6]. The innovator molecule is in the β-crystal form, while the majority of generics have the α-form. Initial evidence suggested that the β-crystal form was superior in terms of efficacy and pharmacologic properties. However, this was later disproved by studies showing no difference in efficacy, water solubility and absorption between α and β forms [6]. Parrillo-Campiglia et al. tested a generic formulation on healthy, fasting, male volunteers against the original IM in a randomized, open-label study and found that the generic drug met the regulatory criteria for bioequivalence with regard to the rate and extent of absorption [7]. Both formulations have been reported to be well tolerated by the study population.

Current literature includes a number of case reports on the efficacy and safety of IM generics with contradictory results [8–10], which deserve a cautious evaluation, since case reports stand at the lowest level of evidence when it comes to making clinical decisions. Another issue is that IM generics are not all the same. Making a generalization based on the evidence obtained from one generic molecule is not always justified as generics may vary in their formulation and production quality, leading to potential differences in their efficacy and safety. However, no significant difference between the original molecule and the generics in terms of efficacy and safety has been reported from India, where these molecules have been in use since 2006. [6].

Generics of IM have been approved in many countries including Canada, India, Iraq, Colombia and Turkey [3,6,11,12]. The entry of the IM generics into the Turkish drug market has resulted in substantial price reductions since August 2012. Each box of generic IM (400 mg/day, 30 tablets) is approximately US $150 cheaper than the original molecule in Turkey, which corresponds to a cost saving of approximately US $18,000,000 per 10,000 patients per year [13]. Since there are limited data and some concerns about the efficacy of generics in the clinical setting, some of Turkish CML patients who still prefer to use the original molecule have to pay the price difference out of their own pocket, since it is not reimbursed.

To evaluate the outcome of CML patients on generics and to answer questions raised on the efficacy and tolerability of the generic molecules, we, retrospectively, conducted two studies in our CML cohort that primarily consisted of patients who had been diagnosed and have been strictly followed according to the European LeukemiaNet criteria at our center [14]. In the first study, we compared patients receiving original imatinib to those who started with the original drug but then had to switch to one of the generics due to reimbursement policy after August 2012 when IM generics became available in Turkey. A total of 145 patients with chronic phase CML (CP-CML) who were diagnosed and followed between 2000 and 2013 entered the study. The hematologic response (HR), cytogenetic and molecular response (MR) rates, as well as the tolerability data at 6 months after the switch have been found to be comparable, at least non-inferior, to those of the original drug [3]. The switch did not lead to any significant loss of MR. However, this should be interpreted with reservation, since one can rightly say that a follow-up period of 6 months is too short to draw firm conclusions. The persisting MR to generics could readily be explained by the continuing inhibition that had been achieved earlier by the original molecule, as there are studies showing durable MRs after discontinuation of Glivec [15,16]. To disprove our hypothesis, we conducted a second study, where we compared patients who were started and continued with the original imatinib to those who have been using generics from the very beginning on. There as well, we could not demonstrate any significant difference in terms of efficacy (HR, cytogenetic, MR) and tolerability between these two groups that were well balanced regarding the age, gender and risk scores [17]. Thus, early evidence provided by our two retrospective studies suggests that the IM generics in Turkey are not only effective in the upfront setting but may also replace the drug in patients on original IM without causing any loss of MR on short notice.

Alwan et al. [11] evaluated the HRs in patients with chronic phase-CML in a prospective study setting where patients had to switch from the original molecule to a generic IM (Imatib, Cipla) for at least 9 months and then switch back to the original IM. Dose escalations to 600 or 800 mg original IM once daily or changing to nilotinib 400 mg twice daily were allowed if patients failed to show optimal response to 400 mg IM after switching from the generic drug. The authors claim that the majority of patients lost HR and experienced intolerance on generic drug, which then all improved upon retreatment with the original molecule.

In another study, Saavedra et al. [12] discussed the outcome of 12 chronic phase-CML patients on generic IM (eight switched to a generic IM, four used generic IM upfront). They report treatment failure and severe adverse events in 63 and 75% of the patients, respectively, who switched to a generic IM. Resistance or suboptimal response with an intolerance rate of 75% was observed in all of the four upfront generic users.

There are other reports showing comparable or inferior results with the generic molecules [18,19]. Malhotra and colleagues [20] analyzed the plasma levels of original and generic IM molecules to test whether there was a correlation between plasma levels and response in CML patients. They could show no difference between the generic and the original molecule.

There are different formulations of generic IM in different countries, whereas the original IM is the same worldwide; this may be one of the reasons for the contradictory results [3,11,12]. On the other hand, authors might have a tendency to report patients with inferior efficacy and/or intolerability on generics. Furthermore, standards of diagnosis and follow-up might differ among centers from which the publications were made and the follow-up duration in the studies, on which the evidence was based, is usually short. In conclusion, with the conflicting limited data at hand, it is difficult to make decisive statements about the efficacy and safety of the imatinib generics [21].

Considering all the aforementioned limitations of the retrospective studies, the most appropriate way to get reliable information on the efficacy and safety of IM generics would be comparing the generic molecules with the original drug in a Phase IV study. However, it is obvious that such a study is very difficult to perform since it would hardly be supported by the pharmaceutical companies. We, therefore, have to depend on well-designed large-scale retrospective studies including patients diagnosed and followed with standard care of practice, until long-term solid prospective data are available.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.