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Regulatory and clinical aspects of psychotropic medicinal products bioequivalence Ewa Bałkowiec-Iskraa,b,n,1, Grzegorz Cessaka,b,1, Olga Kuzawińskaa,b, Katarzyna Sejbuk-Rozbickaa, Konrad Rokitac, Dagmara Mirowska-Guzela,d a

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Poland The Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Poland c Nowowiejski City Hospital, Poland d 2nd Department of Neurology, Institute of Psychiatry and Neurology, Poland b

Received 24 August 2014; accepted 22 March 2015

KEYWORDS

Abstract

Bioequivalence; Generic medicinal products; Psychotropic medicinal products; Registration

Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost, leading to containment of public expenditures on medicinal products reimbursement. The critical assessment of bioequivalence of any reference medicinal product and its counterpart is based on comparison of their rate and extent of absorption. It is assumed that two medicinal products are bioequivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. Bioequivalent medicinal products are declared to be also therapeutically equivalent and can be used interchangeably. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of this article is to provide a description of rules that guide registration of generic medicinal products in the European Union and to analyze specific examples from the scientific literature concerning therapeutic equivalence of reference and generic antidepressant and antipsychotic medicinal products. & 2015 Elsevier B.V. and ECNP. All rights reserved.

n Corresponding author at: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Banacha 1b, 02-091 Warsaw, Poland. Tel./fax: +48 22 1166160. E-mail address: [email protected] (E. Bałkowiec-Iskra). 1 These authors contributed equally to this work and are listed alphabetically.

1.

Introduction

According to the definition provided in the Directive 2001/ 83/EC of the European Parliament and of the Council of

http://dx.doi.org/10.1016/j.euroneuro.2015.03.008 0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

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E. Bałkowiec-Iskra et al.

November 6th 2001 on the Community code relating to medicinal products for human use (Consolidated version: 16/11/2012), a generic medicinal product is “a medicinal product which has the same qualitative and quantitative composition of active substances as the reference medicinal product, the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by means of appropriate bioavailability studies” (Directive 2001/83/EC). It boils down to the fact that both a reference medicinal product and its generic counterpart contain the same active substance in equal amounts. These products however, can differ in the content of certain excipients. The latter may have an impact on the release of active substance, thereby changing the bioavailability of the medicinal product. That is why it is also required to show that the dissolution profiles of the generic and the reference medicinal product are similar, before the product can be granted its marketing authorization. Factors that can also determine identity of the reference and generic medicinal product are the physicochemical properties of the active substance (e.g., solubility and microionization) as well as the manufacturing process (e.g., granulation and strength of compression during tableting). Equivalence with respect to the above-mentioned characteristics is verified via dissolution tests of the active substance in vitro. Generic medicinal products must meet the same quality, efficacy and safety criteria as a brand name counterparts (Ford and t' Hoen, 2002). They must be manufactured according to the Good Manufacturing Practice (EMA CHMP Guideline, 2010).

2. Methods of assessing drug bioequivalence and bioavailability Bioequivalence trials are obligatory for the authorization of every generic medicinal products. All generic medicines currently in the market have been shown to be bioequivalent with their reference (also called “innovator”) medicines, according to the accepted criteria, described in relevant documents and prepared by European or national drug agencies (e.g. European Medicines Agency (EMA), Food and Drug Administration (FDA), Health Canada). According to Article 10 (1) of the Directive 2001/83/EC, it is not required to provide the results of pre-clinical and clinical trials in order to authorise a generic medicine. Application refers to the information that is contained in the dossier of the authorization for the reference medicinal product, that has been authorized under Article 6 of the Directive 2001/ 83/EC for at least 8 years. A generic medicinal product can be placed in the market 10 or 11 years after the authorization of the reference medicinal product, contingent on the exclusivity period applicable to the reference product (European Commission Notice to Applicants, 2013). Medicinal products are considered bioequivalent, if there are no clinically significant differences in bioavailability between generic and reference medicines. Bioavailability is a term commonly used in the field of pharmacokinetics that refers both to the percentage of the drug dose that enters the systemic circulation following extravascular administration and to the rate of that process. Most of the medicines

that are taken orally reach their site of action via the systemic circulation. Consequently measurements of blood concentration of the active substance or its active metabolite serve as markers of the concentration at the site of action. Thus, bioavailability can be considered a surrogate marker for the clinical effectiveness and safety of the medicinal product. Bioavailability is assessed using three main pharmacokinetic parameters: the area under the concentration time curve (AUC), the maximum plasma concentration (Cmax) and the time to maximum plasma concentration (Tmax). These parameters refer respectively to the extent (AUC) and the rate (Cmax, Tmax) of absorption of the active substance. Absorption is the first phase of transformations that a medicinal product undergoes in the organism. It is however characterized by a potentially high variability, which is to a significant extent dependent on the drug itself. It would explain why it has been assumed and commonly accepted that a similarity in the extent of absorption defines medicinal product bioequivalence. There are two consistent factors that determine drug absorption from the alimentary tract: the properties of the pharmaceutical form of the drug and the grade of its ionization. Other factors vary from individual to individual and include pH of the gastrointestinal tract environment, activity of the digestive enzymes, presence of the food in the stomach, gastrointestinal tract blood supply, diseases of the digestive tract, etc. Other phases of the medicinal product trafficking through the organism, that are described by other pharmacokinetic parameters depend to a much greater extent on the individual characteristics of the patient. Therefore, the analysis of subsequent phases that the medicinal product undergoes in the body seem unjustified. This is because potential differences in the subsequent phases would only be due to inter-individual differences and would not reflect systematic differences between generic and reference products. It has been assumed, that the serum concentration of the active substance denotes its clinical effects, both therapeutic as well as toxic. It has been established that two medicinal products can be regarded as therapeutically equivalent, if the profile of changes in the active substance concentration of the generic and the reference product, remains within defined and accepted limits of bioequivalence (Garcia-Arieta and Gordon, 2012). Two medicinal products are regarded as bioequivalent if the ratio of the logarithmic values of the AUC and Cmax parameters are within the acceptance interval of 80–125% based upon a 90% confidence interval (Nuss et al., 2004). In case of drugs with a narrow therapeutic index the interval is 90–111% (EMA CHMP Guideline, 2010). It should be emphasized that the accepted limits of tolerable differences between the parameters include these results from personal changes in patient's metabolic status and physical activity (EMA CHMP Guideline, 2010). Differences in bioavailability may occur inter alia as a result of several factors, including a partial release of a drug from the pharmaceutical formulation, incomplete absorption from the site of administration and first-pass metabolism. The objective of bioequivalence studies is to show the lack of significant differences in the absorption profiles between reference and generic medicinal products. It has been proven by long-term studies and published observations that medicines containing the same active substance in equal amounts

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

Regulatory and clinical aspects of psychotropic medicinal products and showing no significant differences in the absorption rate, have essentially the same therapeutic effects. The extent of similarity of the dissolution profiles between the reference and generic products has been precisely defined, along with the methodology of the bioequivalence trials, that are required in order to guarantee therapeutic equivalence. The latter is understood as the nature of the clinical effect (EMA CHMP Guideline, 2010).

3.

Bioequivalence trials

Design of the trials has been defined by the EMA in the document titled: “Guideline on the investigation of bioequivalence” prepared by the Committee for Medicinal Products for Human Use (CHMP) (EMA CHMP Guideline, 2010). Moreover, bioequivalence trials on the immediate release medicinal products must be conducted according to other CHMP guidelines, including: “General Considerations for Clinical Trials”, “Guideline for Good Clinical Practice”, “Statistical Principles for Clinical Trials”, “Structure and Content of Clinical Study Reports” and “Pharmacokinetic studies in man”. Bioequivalence studies of modified release, transdermal and orally inhaled products are carried on according to separate guidelines (EMA CHMP Guideline, 2010). Requirements and limits of the bioequivalence studies apply both to test product and participants. According to the cited above “Guideline on the investigation of bioequivalence”: “the test product should usually originate from the batch of at least 1/10 of production scale or 100, 00 units” and “the production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale”. Moreover, comparative dissolution profile testing between samples from additional pilot or full scale production batches and the clinical batch for which bioequivalence has been demonstrated should be established. In accordance with EMA requirements, usually a bioequivalence study is carried out with the participation of a minimum of 12 healthy volunteers (if a greater variability of pharmacokinetic parameter is expected the number of participants is increased). Exceptions to this rule include situations when due to safety concerns administration of the drug to healthy volunteers would be unethical (for example cytotoxic anticancer drugs). In such cases, it is mandatory to perform studies with patients, while ensuring proper supervision. Inclusion criteria for the volunteers are always defined in detail and pertain to several factors, such as age (above 18 years), body mass index (in the range of 18.5–30), sex (either, with consideration of the risk to women of childbearing potential), smoking (preferably non-smokers), a history of drugs or alcohol abuse (preferably none). For each participant physical examination, medical history and necessary laboratory tests should be carried out before, during and after the completion of the study. In order to minimize variability of the drug absorption among participants diet, fluid intake and physical activity is standardised.

4.

Study design

In the most frequent single-dose design that compares two medicinal products, a cross-over with multiple (two) doses is

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used, for the reference and generic products, respectively. Each of the volunteers receives a single dose of one of the evaluated medicines, while the administration of the other one is preceded by a wash-out period (this ensures elimination of the first drug from the system, which equates to 5 half-life periods of the drug). Both the number and the time of plasma or urine samples collection should be chosen to sufficiently describe the plasma concentration-time profile. For an immediate release formulation a sampling period longer than 72 h is not considered necessary. Bioequivalence is assessed upon 90% confidence intervals for the ratio of the participants geometric means of test (generic) to reference drug for the AUC and Cmax. Detailed requirements for the study design are described in: “Guideline on the investigation of bioequivalence” (EMA CHMP Guideline, 2010).

5. Possible exemptions from bioequivalence trials Situations in which bioequivalence trials may be waived have been defined by EMA in the “Guideline on the investigation of bioequivalence” (EMA CHMP Guideline, 2010). They pertain to generic products for oral administration in oral immediate release dosage formed with systemic action (such as tablets, capsules, oral suspensions), with reference to which the rules can be applied based on a biopharmaceutics classification system (BCS) (World Health Organization General notes, 2011). According to this system there are four classes of substances depending on their solubility and permeability through biological membranes. Classes: I. II. III. IV.

High solubility and high permeability. Low solubility and high permeability. High solubility and low permeability. Low solubility and low permeability.

The use of the BCS system allows to wave the obligation to carry out bioequivalence studies in vivo only if the active substance is characterized by high solubility, known absorption in vitro and is considered not to have a narrow therapeutic index. In case of unmodified release forms, waiver from bioequivalence trials is possible in the following situations: 1. a. The drug substance is BCS class I (high solubility, complete absorption). b. Permeability in vitro485% within 15 min or 85% within 30 min. c. The same qualitative and quantitative composition of excipients that might affect bioavailability (e.g. sorbitol, mannitol, sodium lauryl sulfate). 2. a. The drug substance is BCS class III (high solubility, low permeability). b. Solubility in vitro485% within 15 min. c. The same qualitative and quantitative composition of excipients that might affect bioavailability. The same

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

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E. Bałkowiec-Iskra et al. qualitative and similar quantitative composition of any other excipients.

If the above-mentioned requirements are fulfilled, it is sufficient to provide a dissolution test in vitro to demonstrate equivalence of the reference and test product. Identity of the dissolution profiles at three pH values may confirm equivalence of the generic and original medicinal products. It is possible to waive the obligation to carry out bioequivalence tests if the test and reference product contain different salts of the same active substance, and both have BCS class I. However it should be highlighted that, if the test contains ester, ether, isomer, a mixture of isomers, complex or derivative of an active moiety different than the one contained in the reference product, it is necessary to perform bioequivalence tests. Bio-waivers on the basis of the BCS classification can be used with regard to immediate (unmodified) release, solid pharmaceutical products for oral administration and systemic action. The rules described above do not apply to products administered sublingually, via the buccal mucosa and in modified release forms. In case of orodispersible tablets, BCS-based waiver can be applied only if absorption from the oral cavity is excluded. In case of oral solutions (and under the condition that they are aqueous solutions), suppositories and topical products (eye drops, nasal sprays or cutaneous solutions) a waiver of the need to provide equivalence data may be acceptable, if the test product contains the same concentration of the same active substance as the original product, and excipients do not affect the pharmacokinetic parameters of the active substance. Bioequivalence studies are not required, if the product is a gas for inhalation.

6. Registration requirements for different strengths of a test product There is a possibility of obtaining a bio-waiver for several strengths of the same product if the following criteria are fulfilled: 1. All strengths of the product are manufactured by the same manufacturing process. 2. All strengths of the product have the same qualitative composition. 3. The composition of the individual strengths is quantitatively proportional. 4. In vitro solubility criteria have been met, confirming the adequacy of waiving additional in vivo bioequivalence testing.

If the above described conditions are met, it is acceptable to extrapolate the results obtained with a single strength to the remaining ones. It should be emphasized that a full bioequivalence study – (e.g. in case of application for registration of several strengths) – should be conducted for the drug of maximum

strength. However, this rule does not apply if the active substance is characterized by high solubility. In case of an exemption from in vivo testing, bioequivalence is demonstrated on the basis of physico-chemical/ dissolution tests, as well as knowledge about the substance's absorption from the pharmaceutical form in question in vivo, that is dependent on its solubility, polarity and dissociation. (EMA CHMP Guideline, 2010).

7.

Benefits from marketing of generics

Among European countries Poland is in the lead when it comes to the consumption of medicines (in quantities), additionally the domestic pharmaceutical market is characterized by a high generic market share (there too Poland stands out among other European countries). The selected 19 antipsychotic and antidepressant drugs have 209 equivalents in total (Table 1). In 2010, their share amounted to 66% in sales for the domestic pharmaceutical market as a whole (including prescription and over-the-counter medication; PWC Report, 2011). In the majority of cases a generic medicinal products entry to the market results in a price decrease of the reference product. It is also natural for the sales of the reference medicinal product to fall for the benefit of the generic. It has been shown that the difference in the price of the reference drug between the period when it had been under registration data protection and after the protection has expired is proportional to the number of generic drugs that entered the market (Lexchin, 2004). The reason why the price of the reference drug is much higher than the price of the generic drug is different registration requirements posed to the products. Authorization of a new active substance for human use requires phase I (on healthy volunteers in order to evaluate the active substance's effect on human organism, determine drug pharmacokinetics and tolerable dose, etc.), phase II (with the participation of a small group of patients – in order to evaluate the efficacy, safety and pharmacokinetic changes) and phase III (in a large group of patients in order to compare the investigated drug with the standard therapy) clinical trials. Other expensive steps include: synthesis of the active ingredient and pre-clinical trials. That is why the development of new medicinal products requires time and extensive financial investments on the part of the drug maker. The post-registration period is when the expenses made to introduce the medicinal product to the market are supposed to give return on the investment. However, it should be emphasized that phase IV trials are not conducted until far more patients than in phase III trials are receiving the drug. The differences in prices between the reference and corresponding generic products are therefore only due to the lack of obligation to perform biochemical, pre-clinical and clinical trials. All these steps constitute a significant financial burden on the marketing authorization holder of the reference medicine. Notably it would be unjustified to re-perform a full series of clinical trials for an active substance, the efficacy of which is already well known. According to the estimations of the reference products manufacturers, the costs incurred from the moment of the active ingredient synthesis until marketing authorization of the product are fully recovered only in 3 out 10 medicinal products (Grabowski and Vernon, 1990). Therefore from the economic point of view it is unsurprising that these manufacturers are reluctant to accept the presence of

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

Regulatory and clinical aspects of psychotropic medicinal products

Table 1

5

Generics of selected psychotropic medicinal products available in Poland.

Active substance Pharmaceutical form

Reference product registration year

Number of generics (for a single dose )

Year of registration of the currently available generic

Amisulpride Chlorpromazine Citalopram Clozapine Escitalopram

2000 1952 1998 1993 2007 2010 1989

2 1 9 1 22 7 9

2010–2012 1957 2001–2012 1995 2009–2014 2013–2014 1995–2012

NA

3

1988–2002

1983 1987 1999

1 2 8

2011 1998–2013 2005–2009

1994 1996

1 29

2002 2002–2012

2007 1995 1999 2009

18 7 25 7

2008–2014 2003–2010 2005–2013 2011–2013

1996 1999 1998 1995 2000

10 2 15 7 20

2003–2010 2008–2009 2002–2014 2011–2012 2006–2013

2003

3

2009–2012

Tablets Solution for injection Coated tablets Tablets Coated tablets Orodispersible tablets Fluoxetine Tablets, coated tablets, hard capsules Haloperidol Tablets, solution for injection, oral drops Levomepromazine Coated tablets Mianserine Coated tablets Mirtazapine Coated tablets, orodispersible tablets Moclobemide Coated tablets Olanzapine Tablets, coated tablets, hard capsules Orodispersible tablets Paroxetine Tablets, coated tablets Quetiapine Coated tablets Prolonged-release Tablets Risperidone Coated tablets Oral solution Sertraline Coated tablets Tianeptine Coated tablets Venlafaxine Prolonged-release capsules Ziprasidone Capsules

NA – not available. References: The Office for Registration of Medicinal Products, Medical Devices and Biocidal Products List 2014. Available at: http:// www.urpl.gov.pl/urzedowy-wykaz-produktow-leczniczych-2014 (date of access: 11/07/2014).

generic medicines on the market. On the other hand, it should be noted that in many cases the same entity holds marketing authorization for the reference, as well as the generic product.

8. Therapeutic equivalence of antidepressant and antipsychotic drugs As it has been described above that, according to the current state of knowledge, demonstration of bioequivalence of a generic medicinal product in accordance with the well-defined legal requirements of an application is sufficient for obtaining a marketing authorization. However, generic medicinal products are subject to postmarketing safety and efficacy monitoring in accordance with the relevant legal requirements. Such proceedings have proven effective, and resulted in, for example postmarketing withdrawal from the United States (US) market of one of the generic products containing bupropion due to the lack of its therapeutic equivalence (Woodcock et al., 2012). Cases of worsening of the clinical status after switching to a different medicinal product containing the same active

substance are being reported to relevant authorities and published. As a result, isolated case studies reporting such incidents can be found in medical databases. Among case studies concerning bioequivalence of psychotropic drugs, the majority refers to antipsychotic products that contain (inter alia) olanzapine, risperidone or clozapine. Noteworthy, currently in Poland there is only one generic clozapine available in the market. The situation is analogous in Spain and Czech Republic. In France, Great Britain and Sweden there are two generic olanzapines whereas in the Netherlands and Germany as many as 11 are available in the market. In contrast risperidone and olanzapine generics are very well represented in European markets (Table 2). Despite a number of generic drugs available throughout the European Union, only single case reports that describe clinical state deterioration or adverse effects can be found in medical research databases. Moreover, these publications, come not only from European Union countries but also from the US and Canada and include case and study reports on the action of generic olanzapine, risperidone and clozapine. A nearly seven-year long observation of the mental status of 85 patients treated on an outpatient basis has not revealed

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

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E. Bałkowiec-Iskra et al.

Table 2 Number of risperidone and olanzapine generics available on the market of selected European Union countries.a Country

Risperidone

Olanzapine

Czech Republic France Germany Great Britain Netherlands Spain Sweden

11 20 45 7 14 38 19

26 28 71 6 30 51 25

a References: Spain: www.aemps.gob.es, Czech Republic: www.sukl.cz/modules/medication, France: agence-prd.ansm. sante.fr, Great Britain: www.medicines.org.uk/emc, Sweden: www.lakemedelsverket.se/LMF/, Netherlands: www.cbg-meb. nl, Germany: www.pharmnet-bund.de, Date of access: 11.08. 2014.

statistically significant differences in dosing, number of relapses and frequency of visits between the groups treated with the reference versus generic olanzapine, as well as the group which switched from the reference to generic medicinal product (Araszkiewicz et al., 2008). However, we have found two case studies of mental status worsening (Ruzic et al., 2010a; Samuel et al., 2013) and adverse events occurrence, including acathisia (Goldberg, 2012), teeth staining (Galarneau, 2013), as results of taking the generic olanzapine. There are also 3 case studies that describe symptom exacerbation after switching to the generic risperidone (Hardan et al., 2010; Ruzic et al., 2010b). A majority of studies concerning safety and efficacy of generic medicinal products have been conducted on clozapine, which is considered the most effective antipsychotic drug to date and indicated for treatment-resistant schizophrenia. According to the analysis published in the Br J Psych no changes in the clinical status have been identified in a group of 337 patients in the 3 months since switching from a reference to a generic product, while 193 patients have actually experienced an improvement (Paton, 2006). Similarly, in two years of observation of 108 patients there were no differences in the duration of hospitalizations, the number of outpatient visits and median clozapine serum concentration between patients treated with the reference and generic drug. Moreover, in patients treated with the generic there have been statistically fewer emergency room admissions (Healy et al., 2005). In addition, there have been no observations of any significant clinical status worsening after introduction of a generic clozapine (Oluboka et al., 2010; Makela et al., 2003). Moreover, Stoner et al. (2003) have reported a significant improvement in the clinical status as measured by the BPRS (Brief Psychiatric Rating Scale) in three months since switching from the reference to generic clozapine in 58% of patients. Differences in the clinical effectiveness of a drug can also be evaluated by the need for dose modification. In a retrospective study of 58 patients only 2, 1 and 3 required a dose adjustment, after respectively, 2, 4 and 6 months

since the replacement of the reference product with its generic (Alessi-Severini et al., 2006). There were also no differences in compliance during therapy with the reference and the generic drug and not a single case of treatment discontinuation during the 6 months of observation. On the other hand, Mofsen and Balter (2001) have reported seven cases of clinical status worsening (i.e. exacerbation of both positive and negative symptoms) after the introduction of a generic clozapine. In addition, Kluzik et al. (2001) have observed a significantly worse performance in BRPS and CGI-I (Clinical Global Impressions Improvement) tests. It should however be emphasized that the above-mentioned US reports of clinical state deterioration refer only to the first clozapine generic that was registered by the FDA in 1999 (Ereshefsky and Glazer, 2001). In a study summing up all primary research published between 1995 and 2008, including cases of 966 patients who switched from reference clozapine to one of its 4 generics available on the American market, no symptoms of clinical status worsening, changes in clozapine serum concentration nor incidences of reduced treatment tolerability have been observed after switching from reference to generic treatment in the majority of the analyzed studies (Bobo et al., 2010). Literature review summarizing all case studies referenced in the PubMed between 1974 and 2010 and concerning therapeutic differences between psychotropic reference and generic drugs indicates that the total number of cases characterized by ineffectiveness or adverse effect was 16 for antidepressants (e.g. an increase of depression symptoms, signs of drug intoxication, anxiety and allergic reaction) and 13 for antipsychotic drugs (Desmarais et al., 2011).

9. Factors affecting therapeutic equivalence of bioequivalent drugs A thorough review of the selected publications shows that changes in therapeutic equivalence of bioequivalent antipsychotic and antidepressant drugs occur very rarely. However, as a recently published study showed, psychiatrists report a relatively low willingness to use the generic drugs (Hamann et al., 2013). Potential causes for impairments in generic drugs efficacy and safety include: a lack of compliance resulting from a poor doctor-patients cooperation, the nocebo effect and manufacturing drug defects. A low compliance and resulting difficulties with continuation of treatment are, as the CATIE1 study has shown, the main obstacles to an effective treatment of psychotic disorders (Lieberman et al., 2005). An impaired cooperation between the doctor and the patient when it comes to the treatment modification may be due to a lack of acceptance and trust in the novel therapy. This fact may be followed by: an increased risk of occurrence of acute symptoms of clinical state deterioration, a relapse or a need for rehospitalization (Ayuso-Gutierrez and del Rio, 1997). Thus a candid consultation concerning the prescribed new, generic drugs is necessary and may be a critical factor that determines treatment effectiveness. Also the importance of the placebo effect in psychotropic drug treatment should be noted. It is considered to play an important role in the

Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

Regulatory and clinical aspects of psychotropic medicinal products clinical effectiveness of antidepressants and analgesics. The placebo effect depends on several factors, including: the type of treatment used (tablet, injection, medical procedure), but also the size, shape and even the color of the tablet (Benedetti, 2008). An unexpected change in the presentation of the prescribed drug may cause anxiety in patients and thus decrease its clinical effectiveness or even lead to appearance of adverse effects. It has been demonstrated that the placebo effect decreases when more affordable drugs are used. When the patient is informed about receiving a less expensive generic it may cause nocebo effect, and thereby reduced clinical effectiveness of the treatment. Also, the sole expectation of improvement, often combined with the use of known treatment, has a significant impact on the occurrence of the desired placebo effect (Pacheco-Lopez et al., 2006). There is a study describing a case of the lack of treatment effectiveness due to a reluctance to use a generic product by a patient treated with venlafaxine (Cai et al., 2013). That is why, in order to secure treatment effectiveness, it is crucial to explain to the patient the reasons for the change and to reassure him/her about the similarity in action of different products containing the same active substance. A possible reason for the decreased treatment effectiveness may also lie in manufacturing defects of certain batches of drugs. This happens on very rare occasions, but such possibility should always be considered and in case of doubts it should be reported to the relevant authorities.

10.

Conclusions

Introduction of a specific set of rules that enabled registration of generic medicinal products constituted one of the major breakthroughs in pharmacotherapy. Generic drugs currently available in the market meet the criteria of bioequivalence, that have been agreed upon by registration agencies all over the world. They allow treatment that is as effective and safe as the one achieved with reference products. Lower prices of generic medicinal products are due only to the reduced costs of obtaining the marketing authorization; and these drugs meet the same quality requirements as the reference products. Similar to reference products, they are a subject to postmarketing surveillance of adverse drug reactions.

Role of the funding source No external funding was used in preparation of this report.

Contributors Ewa Bałkowiec-Iskra and Grzegorz Cessak contributed equally to this work and are listed alphabetically. They wrote the following parts of the article: “Introduction”, “Methods of assessing drugs BE”, “BE trials”, “Study design”,“Therapeutic equivalence of antidepressants and antipsychotic drugs”, “Factors affecting therapeutic equivalence”, “Conclusions”. Olga Kuzawinska wrote: “Possible exemptions from BE trials” and “Registration requirements for different strengths of test product”. Katarzyna Sejbuk-Rozbicka wrote : “Benefits from marketing of generics”. Konrad Rokita co-wrote: “Factors affecting therapeutic

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equivalence”. Dagmara Mirowska-Guzel co-wrote: “Bioequivalence trials”. All the authors contributed to and have approved the final manuscript.

Conflict of interest The authors declare no conflict of interest. Grzegorz Cessak is the President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (National Competent Authority) and member of the EMA Management Board, Ewa BałkowiecIskra, M.D., Ph.D, D.Sc. is an EMA Expert.

Acknowledgment The Authors would like to express their gratitude to Dr. Agnieszka Balkowiec for critical reviewing of the manuscript and Ms. Karolina Lenczewska-Samotyja and Ms. Anna Zaremba for English editing. This project has been supported by the Polish National Science Center, based on the Decision no. DEC-2012/05/B/NZ4/02385. This project has been realized with the use of the CePT infrastructure that had been financed from the European Union funds – European Regional Development Fund, Innovative Economy Programme 2007–2013.

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Please cite this article as: Bałkowiec-Iskra, E., et al., Regulatory and clinical aspects of psychotropic medicinal products bioequivalence. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.008

Regulatory and clinical aspects of psychotropic medicinal products bioequivalence.

Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost...
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