alexa Implementation of a Robust Pharmacovigilance Method for Filgrastim Non-Innovator Products in Cancer Patients in Routine Clinical Practice Complying With Mexican Regulations for Biocomparables | Open Access Journals
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Journal of Pharmacovigilance
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Implementation of a Robust Pharmacovigilance Method for Filgrastim Non-Innovator Products in Cancer Patients in Routine Clinical Practice Complying With Mexican Regulations for Biocomparables

Huerta-Sanchez Olivid Marisol1, Aguilar-Ponce José Luis2, Meneses-García Abelardo2, Herrera-Gómez Ángel2, Herrera-Hernández Ricardo2, Monroy-Cruz María Teresa2, Burgeño-Ferreira Juan Andrés3, Castañeda-Hernández Gilberto1 and López-Gamboa Mireya1,2,4*
1Departamento de Farmacología, Cinvestav, IPN, Mexico City, Mexico
2Instituto Nacional de Cancerología, Mexico City, Mexico
3Biometriccs and Statistics Unit Centro Internacional de Mejoramiento del Maíz y Trigo INT, México
4Pro Pharma Research Organization S.A. de C.V., Mexico City, Mexico
Corresponding Author : Mireya López-Gamboa
Prol. Emperadores #298, Col. Emperadores
Del. Benito Juárez
México City, Mexico, CP 03320
Tel: 52 55 63 07 97
E-mail: [email protected] propharmaresearch.com
Received: July 31, 2015 Accepted: August 07, 2015 Published: August 10, 2015
Citation: Marisol HSO, Luis APJ, Abelardo MG, Ángel HG, Ricardo HH, et al. (2015) Implementation of a Robust Pharmacovigilance Method for Filgrastim Non-Innovator Products in Cancer Patients in Routine Clinical Practice Complying With Mexican Regulations for Biocomparables. J Pharmacovigilance 3:174. doi:10.4172/2329-6887.1000174
Copyright: © 2015 Marisol HSO, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Background and aim: Mexico, as other countries, has recently changed regulatory requirements for noninnovator biopharmaceuticals (biocomparables); a suitable pharmacovigilance program being now mandatory. Hence, our aim was to implement a robust pharmacovigilance method for filgrastim products of different brands used in routine clinical practice in Mexico.

Method: Prospective, phase IV, non-interventional study performed at the Instituto Nacional de Cancerología (National Institute of Cancerology) of Mexico. All pharmacy dispensations of filgrastim products were reviewed and recorded during four months. Patients received a diary for voluntary notation of adverse drug reactions (ADR) every time they were dispensed filgrastim. Additionally, medical records were consulted and contrasted with patientgenerated information. ADR analysis was performed according to the Mexican official norm on pharmacovigilance NOM-220-SSA1-2012.

Results: The procedure allowed to trace which filgrastim brand was administered to every patient. 373 patients received diaries. 214 patients returned diaries with information suitable for further analysis. Very common ADRs were musculoskeletal pain and headache. Common ADR were pain in extremities, asthenia, general body pain, nausea, pain in site of injection, vomit, paresthesia, abdominal discomfort, decreased appetite and diarrhoea. All ADRs were probably or possibly related to filgrastim and corresponded to previously reported ADRs. No new ADRs were detected.

Conclusion: The used methodology was robust enough to identify and characterize ADRs for each filgrastim brand product directly from patient information. It thus allows performing pharmacovigilance studies for biopharmaceuticals, both innovator and non-innovator, guaranteeing traceability and complying with current Mexican regulations for biocomparables.

Abstract

Background and aim: Mexico, as other countries, has recently changed regulatory requirements for non-innovator biopharmaceuticals (biocomparables); a suitable pharmacovigilance program being now mandatory. Hence, our aim was to implement a robust pharmacovigilance method for filgrastim products of different brands used in routine clinical practice in Mexico.

Method: Prospective, phase IV, non-interventional study performed at the Instituto Nacional de Cancerología (National Institute of Cancerology) of Mexico. All pharmacy dispensations of filgrastim products were reviewed and recorded during four months. Patients received a diary for voluntary notation of adverse drug reactions (ADR) every time they were dispensed filgrastim. Additionally, medical records were consulted and contrasted with patient-generated information. ADR analysis was performed according to the Mexican official norm on pharmacovigilance NOM-220-SSA1-2012.

Results: The procedure allowed to trace which filgrastim brand was administered to every patient. 373 patients received diaries. 214 patients returned diaries with information suitable for further analysis. Very common ADRs were musculoskeletal pain and headache. Common ADR were pain in extremities, asthenia, general body pain, nausea, pain in site of injection, vomit, paresthesia, abdominal discomfort, decreased appetite and diarrhoea. All ADRs were probably or possibly related to filgrastim and corresponded to previously reported ADRs. No new ADRs were detected.

Conclusion: The used methodology was robust enough to identify and characterize ADRs for each filgrastim brand product directly from patient information. It thus allows performing pharmacovigilance studies for biopharmaceuticals, both innovator and non-innovator, guaranteeing traceability and complying with current Mexican regulations for biocomparables.
Keywords

Filgrastim; Biocomparables; Adverse reaction; Pharmacovigilance
Introduction

Granulocyte colony-stimulating factor (G-CSF) is a naturally occurring cytokine that stimulates the proliferation and differentiation of hematopoietic stem and progenitor cells committed to the neutrophil and granulocyte lineages. Fully differentiated neutrophilic granulocytes are functionally activated by G-CSF [1,2]. Due to its hematopoietic activity, recombinant G-CSF (filgrastim) is used as an integral part of supportive therapy across multiple indications. Filgrastim is a biopharmaceutical. Biopharmaceuticals are medical products whose active drug substance are made by living organisms, exhibiting high molecular complexity and are sensitive to changes in the manufacturing processes [3,4].

In recent years, the patents of several biopharmaceuticals, including filgrastim, have expired, allowing the commercialization of non-innovator products [3,5]. Non-innovator biopharmaceuticals cannot be considered as generics, since they are not identical to the corresponding reference product. Differences in the manufacturing process, such as cell line origin, can induce subtle differences in molecular structure that may have a significant impact in clinical efficacy and safety [3,4].

Therefore, the World Health Organization (WHO) has recommended the creation of a new category of drugs for non-innovator biopharmaceuticals coined similar biotherapeutic products [6], also known as biosimilars [3-5]. Biosimilars must show a highly similar molecular structure as well as equivalent efficacy and safety with regard to the reference medication. Additionally, a suitable pharmacovigilance program should be implemented [6]. Following WHO guidelines, an important number of countries have modified their regulatory requirements to accommodate biosimilars [4].

Mexico has been one of the world leaders in biopharmaceutical regulation [7], the General Health Law being modified as early as 2009 [8]. Legislative changes are consistent with WHO guidelines, although the Mexican authorities preferred the designation biocomparable instead of biosimilar for non-innovator biopharmaceuticals [7,8]. Further legislative actions were subsequently implemented; in a way that Mexico presently has a solid regulatory environment for biocomparable evaluation and commercialization [7-10].

As it is the case in many other parts of the world, Mexico had to deal with the presence in non-innovator biopharmaceuticals that came onto market before biocomparable regulation was put in place [7]. To address this situation, the Mexican regulatory agency, also known as COFEPRIS (Comisión Federal para la Protección de Registros Sanitarios or Federal Commission for the Protection against Sanitary Risks in English) has allowed time for the manufacturers of such products to carry out the necessary biocomparability assays to meet the new regulatory standards.

Hence, the present challenge for a non-innovator biopharmaceutical in Mexico is to carry out the required tests to become a true biocomparable. COFEPRIS has issued guidelines on the analytical, preclinical and clinical tests required for a series of candidates [9,10]. Moreover, other regulatory agencies, such as the European Medicines Agency (EMA), have also issued guidelines in this sense [3,4]. One subject that remains pending, however, is pharmacovigilance. There is a consensus that a stringent pharmacovigilance program is necessary for biosimilars/biocomparables [3,4,6,8,10]. Notwithstanding, the issue of traceability has not yet been fully solved.

The Food and Drug Administration (FDA) of the United States has recently approved a filgrastim biosimilar that is identified by a suffix [11]. In Mexico, COFEPRIS approved the biosimilar filgrastin with the distinctive denomination (brand name) ZARZIO. No suffix was added by the Mexican regulatory authority. Moreover, under the present regulation, medicines provided by the social Mexican security system are identified by codes.

Each code is attributed according to the international non-proprietary names (INN), in a manner that innovators and non-innovators of a given medicine exhibit the same code [12,13]. Furthermore, products manufactured by different companies, but sharing a same code, can be interchanged. Evidently, pharmacovigilance studies of biopharmaceuticals must be adapted to this situation, as it is not likely that the code system will be changed in the near future.

Filgrastim is widely used in Mexico [14,15], as it is in other countries [2,3,5]. Hence, several products, from different manufacturers are commercially available. This complicates pharmacovigilance studies, particularly due to the code system by which medicinal products are identified, prescribed and dispensed in social security institutions.

The decision of which product is actually administrated to a given patient is taken at the pharmacy level, in a manner that the treating physician frequently ignores which brand is his/her patient receiving. We therefore decided to directly collect information from patients, requesting them to fill a diary. Diaries have been demonstrated to be a useful tool for collection of adverse reactions [16-18]. In the oncology setting, diaries have demonstrated to be a useful tool for recording efficacy and safety data for antiemetic drugs [19,20].

Here we describe the use of diaries to collect direct patient information on adverse drug reactions (ADR) to perform a pharmacovigilance study of different filgrastim products commercialized in Mexico and dispensed at the Instituto Nacional de Cancerología (INCan, National Institute of Cancerology), a national reference oncology hospital in Mexico City. Information provided by patients, however, was also confronted by dispensing information provided by the pharmacy and with medical files to avoid biases. We were able to demonstrate the robustness of this methodology for ADR evaluation of filgrastim containing products complying with present Mexican regulations for biocomparables.
Methods

Study design

This was a prospective, no interventional, Phase IV, transversal, descriptive, monocentric study carried out at INCan. According to Mexican official normativity the study protocol was approved by the National Center of Pharmacovigilance of the Federal Commission for the Protection Against Sanitary Risks (Centro Nacional de Farmacovigilancia de COFEPRIS) with the number “CNFV/FI/0042/2013”.
Patient population

Patients from INCan, either males or females, older than 18 years of age who were prescribed filgrastim were eligible for participation. Patients were offered to voluntary fill a diary on filgrastim ADR at the moment of drug dispensation at the pharmacy. Those patients accepting to fill the diary were included in the study. Diaries were returned during the next follow-up visits.
Study variables

The variables considered in the study were: (a) Number of filgrastim prescriptions. (b) Product data (INN and brand name, commercializing and manufacturing companies, units dispensed, batch number and expiration date). (c) Prescription instructions (dose, route of administration, dosing frequency). (d) Patient clinical data on medical record. (e) Therapeutic drug history (concomitant medication, including chemotherapy), (f) Reported ADRs (type of reaction, start and end dates, consequence, outcome, impact). Patient identification data were managed as no nominal. Information was coded in order to maintain patient confidentiality.
Data collection

All prescriptions including filgrastim were reviewed and recorded during four months. Study medication data were collected at the moment of dispensation. Patients received a diary for adverse drug reaction (ADR) reporting every time they were dispensed filgrastim. This diary was returned voluntarily by the patient in their next visit to the hospital. Demographic and relevant medical record variables, as well as the therapeutic drug history, were obtained from medical records.

Reported ADRs were classified following the criteria of the NOM-220-SSA1-2012 [21]. Seriousness was reported as serious or non-serious and severity as mild, moderate and severe. Information quality was classified as grade 0, 1, 2 or 3. Causality assessment was performed using the Naranjo Algorithm [22]. All ADRs were notified to the National Center of Pharmacovigilance by the available forms according to NOM-220-SSA1-2012 [21].
Bias risk reduction

In order to decrease the risk of bias, data were obtained in three different formats and times. (a) Drug data at the moment of dispensation. (b) ADRs reported in the patients diaries. (c) Data reported in institutional medical files by treating physicians in medical. All data recorded were confronted and those showing inconsistencies were not included for further analysis.
Statistical methods

A descriptive statistic of the study variables was performed.
Results

Six hundred diaries were handed to 373 patients who accepted to participate in the study. Some patients received more than one diary, as diaries were handed every time filgrastim was dispensed. Three hundred and sixty-eight diaries were returned by 221 patients. Hence the diary recovery rate was 61%. The proportion of the patients returning the diaries was 59%.

The diaries from seven patients were not included for further analysis, as they contained ambiguous information. Hence, data for 214 patients were considered for the purposes of this study. Table 1 shows the demographic and clinical data of patients (classification for type of neoplasia) receiving filgrastim who were included in the study.

During the four months of data collection 673 prescription containing filgrastim were identified. In 93% of the cases it was possible to trace INN, expiration date, brand name, batch number and manufacturing and commercializing companies. Filgrastim was mainly dispensed as three non-innovator products as follows: 1628 vials of Biocilin® (Rimsa, Mexico, D.F.), 319 vials of Dextrifyl® (Pisa, Guadalajara, Jal.), 230 vials of Inmunef® (Teva, Mexico, D.F.) and less frequently (146 viales) as the innovator product Neupogen® manufactured by Amgen (Mexico, D.F.) and commercialized by Roche (Mexico, D.F.) at the time of the study.

Ninety-eight (71 females and 27 males) of the 214 patients considered in this study reported at least one ADR. That is, ADRs were experienced in only 45% of the patients receiving filgrastim, 55% being free of ADRs. Information derived from patient diaries was of good quality, being of grade 2 and 3. In order to limit the risk of bias, information from the diaries was confronted with that derived from clinical files. No discrepancies were detected when these comparisons were performed.

Table 2 describes the reported ADRs as well as causality relationships with filgrastim according to the Naranjo’s algorithm. Musculoeskeletal pain was the most frequent ADR, followed by headache, which was also very common. All other reactions were common or not very common. No new ADRs were observed. All the collected ADRs had been previously reported to be associated with filgrastim [23-26].

It was possible to clearly distinguish which brand of filgrastim product was been administrated to each patient, as it can be seen in Table 3.

No attempt was made to compare the tolerability of the used medications, as the study was not powered for these purposes. An unexpected finding, however, was the fact that 28 patients received more than one brand of filgrastim during their treatment.
Discussion

Patent expiry of many biopharmaceuticals has prompted the appearance of biosimilars/biocomparables [3,4]. Biosimilars/biocomparables are indeed welcome. Experience in Europe with filgrastim has shown that prices actually go down once biosimilars are commercialized. As high prices are the most frequent limitation to the therapeutic use of biopharmaceuticals, biosimilars have importantly increased access of filgrastim in those countries where such products are available [3]. Notwithstanding, a sine-qua-non condition for biosimilars/biocomparables to accomplish their objective is to guarantee their equivalent quality, efficacy and safety with regard to their corresponding innovators [27]. For this, it is necessary to create and adequate regulatory environment. WHO hence provided guidelines to allow member countries to adapt their regulations to the new realities [6].

Following WHO guidelines, many countries have modified their regulatory requirements to accommodate for biosimilars/biocomparables. However changes in clinical and commercial settings have occurred faster than legislative actions [7]. Therefore, several non-innovator biopharmaceuticals hit the market in several countries before biosimilar/biocomparable legislation was put in place [4,7]. In the meantime, their commercialization is allowed. This situation allows implementing methodologies for the pharmacovigilance of these products according with the new regulations in the routine clinical setting.

We therefore decided to implement the patient diary approach to perform a pharmacovigilance study of filgrastim products dispensed at the INCan. This approach has been previously used and has shown to be successful not only for collecting data on ADR [16-20] and it is compatible with the Mexican normativity on pharmacovigilance [21]. Indeed, our approach was approved by the Nation Center for Pharmacovigilance. Filgrastim safety has previously been reported Mexican patients, the results being quite consistent with our study [15]. This report, however, presents the limitations of a retrospective study and therefore does not comply with the recommendations of WHO guidelines on similar biotherapeutic products [6]. Local pharmacovigilance studies for biopharmaceuticals are necessary, as data cannot always be directly extrapolated form one population to another. There evidence that the effects of infliximab show dissimilarities between Japanese and Caucasian [28]. Moreover, although information is scarce, there is evidence that the Mexican population has a more favorable tolerability towards rituximab compared to Caucasian patients [29]. Notwithstanding, it has been reported that switching from innovator rituximab to a non-innovator product which did not fully document its biocomparability resulted in anaphylactic reactions [30]. Hence, a stringent pharmacovigilance program for biosimilars/biocomparables is absolutely required to ensure patient safety in each partocular country. It should be bear in mind that safety data of an innovator biopharmaceutical cannot be directly extrapolated to a non-innovator that is similar, but not identical [3].

Our approach allowed obtaining good quality information about filgrastim ADR. No new ADRs were identified. In fact, the ADR profile observed in our study is consistent with previous reports on both innovator and biosimilar filgrastim in routine clinical practice [5,31,32]. Our results also allowed to trace the brand and batch number of the filgrastim product administered to each patients and thus to derive reliable pharmacovigilance data. Data derived from the present study were no further analyzed, as this was an exploratory study, which purpose was to show that ADR collection and traceability are possible. Hence, it was not powered for comparisons between products. We detected that, in few cases, an individual patient received more than one brand of filgrastim. At present, it is not recommended to switch brands of a given biopharmaceutical product [3]. Hence, our approach is also useful to detect, and thus to correct, deviations from current prescribing guidelines.

The present study shows that a pharmacovigilance study can be performed in Mexico for filgrastim products using the diary approach, which can also be useful for the evaluation of other biopharmaceuticals. This strategy allows collecting good quality information on ADR directly from patients, while confrontation with clinical files reduces the risk of bias by subjective patient perception. With this approach, it was possible to unequivocally distinguish which filgrastim brand was administered to a given patient at a given time, and hence to trace the effects of a given product even in a setting where various brands are used simultaneously. Furthermore, the diary strategy allows distinguishing deviations from guidelines, as cases where more than one brand is administered to an individual patient [3].

In conclusion, the present study demonstrates that it is possible to perform pharmacovigilance studies for biopharmaceuticals in Mexico under the conditions of drug identification and dispensation prevailing in the social security system, complying with the new regulations for biocomparables.
Acknowledgement

The authors of this study wish to thank to Dr. Apodaca Cruz Ángel, Lic. Enf. Caballero Tinoco Maria del Rosario, Dávalos Fiesco Martha, García González Victoria Julisa, Sanchez Naranjo Mario, Ventura Felipe Raul, for helping to bring the their participation on the logistic, data acquisition and executon of the study.

Financial support: Huerta-Sanchez Olivid Marisol and López-Gamboa Mireya are grateful for the financial support of Consejo Nacional de Ciencia y Tecnologia with scholarship number 295160 and post- doctoral grant, respectively.
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