Legal analytics

<p> <strong>Introduction</strong> </p> <p> Today most European countries prohibit automatic substitution of biologic drugs. However, it seems not to be the case in Russia. High-cost breakthrough biological drugs are still procured by the state at public auctions under their INNs and not their trade names, which in most of the cases makes biologic drugs of different manufacturers automatically interchangeable. Furthermore, the HCPs in Russia must prescribe the drugs under their INN, unless a healthcare commission decides that no alternative therapy exists for a particular patient (then the necessary drug may be prescribed under its trade name). </p> <p> <strong>Current regulatory framework</strong> </p> <p> Currently Russian legislation lacks a definition and clear criteria of interchangeability of drugs on the level of federal law. However, the practical need to determine interchangeability (e.g. during state procurement auctions or during antimonopoly proceedings) has resulted in the development of <em>ad-hoc</em> practices of the Federal Antimonopoly Service (the <strong>FAS</strong>) and the courts determining interchangeability of certain drugs on a case-by-case basis. </p> <p> For example, in the Letter No. АЦ/19080 dated October 16, 2007 the FAS confirmed that different trade names of INN "<em>insulin</em>" and INN "<em>cyclosporine</em>" are not comparable and not interchangeable. </p> <p> However, in its Letter dated September 17, 2009 the FAS confirmed that certain drugs having the same active ingridient "<em>Epoetinum alfa</em>" are interchangeable according to their indications, therapeutic and clinical effect as well as due to the fact that there are no clinical data on adverse reactions caused by replacement of therapy options in Russia. </p> <p> Unfortunately, in its decisions the FAS does not rely on internationally accepted approaches to determining drug interchangeability. Instead, the FAS develops its own approach on the basis of formal criteria used for the state procurement purposes. In particular, this concerns the same treatment of biologic and chemical drugs by the FAS. However, the approach of the FAS is often reversed by the Russian courts and the most recent court practice (on both chemical and biologic drugs) is quite illustrative. </p> <p> For instance, in the Decision of the Federal Arbitration Court of the Central Region on case No. А08-8134/2012 dated May 26, 2014 the court expressly refused to apply the Letter of the FAS No. АК/11528 dated April 22, 2009 where drugs having the same INN "Octreotidum" with different pharmaceutical forms were found by the FAS to be interchangeable.<a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftn1" title="_ftnref1" style="color: #215083;">[1]</a> Instead, the court studied interchangeability interpretations of FIP and IFPMA. Based on these interpretations, the court decided that drugs with the same active ingredient may not necessarily be therapeutically equivalent, which means that they also cannot be considered automatically interchangeable. The court directly stated that therapeutic equivalence should be confirmed for each particular drug on an individual basis and based on scientific evidence. </p> <p> The necessity to prove interchangeability of drugs with relevant scientific evidence was also confirmed in the Decision of the Federal Arbitration Court of the East-Siberian Region on case No. А74-4879/2013 dated June 9, 2014. Here the court rejected the FAS's reasoning that two drugs with INN "Piperacillin + [Tazobactam]" in different pharmaceutical forms are interchangeable. The court based its analysis on the registered instructions for use of the relevant drugs and concluded that a drug in the form of lyophilisate may be not automatically interchangeable with a drug in the form of powder. </p> <p> <strong>Regulatory trends</strong> </p> <p> On June 27, 2014 the Draft Law No. 555485-6 amending the Federal Law on Drug Circulation (the <strong>Draft Law</strong>) was submitted by the Russian Government to the State Duma. The Draft Law proposes significant regulatory reform in the pharmaceutical sector. As a part of this reform, the Draft Law introduces a definition of drug interchangeability and sets forth unified criteria for chemical and biologic drugs, which should be used to determine whether certain drugs may be substituted. </p> <p> According to the Draft Law, interchangeable drugs are drugs which may be compared by their therapeutic equivalence or bioequivalence, quality and quantity of the active substance, pharmaceutical form, dosage, administration method, and manufacturing conditions, to a reference drug. </p> <p> The Draft Law further incorporates the following interchangeability criteria: </p> <p> a) equivalence of quantitative and qualitative characteristics of pharmaceutical substances; </p> <p> b) equivalence of dosage forms; </p> <p> c) equivalence of composition of excipients; </p> <p> d) equivalence of administration method; </p> <p> e) the absence of differences in bioavailability during bioequivalence studies or absence of differences in safety and effectiveness characteristics during therapeutic equivalence studies;<a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftn2" title="_ftnref2" style="color: #215083;">[2]</a> </p> <p> f) the absence of publicly available clinical studies which confirm that substitution of an innovative drug by its generic or biosimilar may cause unforeseeable and adverse reactions.<a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftn3" title="_ftnref3" style="color: #215083;">[3]</a> </p> <p> Please note however, that according to the Draft Law usage of different salts, ethers, complexes, isomers, crystalline forms and other derivatives of the same active ingredient; as well as difference in dosage forms and difference in composition of excipients do not prevent interchangeability if bioequivalence studies or therapeutic equivalence studies prove that such differences do not influence pharmacokinetics and/or safety and effectiveness of the relevant drug. </p> <p> On the one hand, these amendments may create a unique pathway for biologic drugs in Russia. On the other hand, a number of legal risks are currently associated with the above interchangeability concept (e.g. unified approach to interchangeability of chemical drugs and various types of biologic drugs, including drugs for gene therapy). </p> <p> <strong>Conclusions</strong> </p> <p> The outlined amendments have a good chance of becoming law by the end of 2014. It means that Russia may become one of the headliners of legislative trends, which may in the future affect other countries (including members of the Customs Union). Therefore, the manufacturers of biologic drugs (including drugs for gene therapy) must pay attention to what is going on within the regulatory landscape in this field. </p> <p> <strong>Author's bio</strong> </p> <p> Maria Borzova is a senior associate and manager of life-sciences projects at VEGAS LEX (local Russian law firm having substantial experience in the pharmaceutical sector). Her experience is focused on advising pharmaceutical companies and manufacturers of medical devices on various aspects of commercial law, competition law, state procurement and sector-specific regulations. Maria also advises on regulatory affairs and is often involved in elaboration of defense strategies during antimonopoly proceedings. Maria is a member of FAS expert boards and active advisor of professional pharmaceutical and medical associations. She is an author of various publications on life-sciences issues in medical journals. </p> <p style="background-image: initial;"> <a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftnref1" style="color: #215083;"><span style="color: #365f91;">[1]</span></a> In the mentioned letter the FAS stated that two drugs with INN "Octreotide" having different pharmaceutical forms (microspheres for preparation of suspension and lyophilisate for preparation of suspension) are interchangeable. </p> <p style="background-image: initial;"> <a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftnref2" style="color: #215083;"><span style="color: #365f91;">[2]</span></a> Please note however, that no guidelines are approved yet in relation to the procedure for confirmation of equivalence in quality and quantity of pharmaceutical substances, pharmacokinetics and pharmacodynamics, safety and effectiveness of biologic drugs. </p> <p style="background-image: initial;"> <a href="file:///C:/Users/kirilichevaa/Desktop/%D0%91%D0%BE%D1%80%D0%B7%D0%BE%D0%B2%D0%B0_Corporate%20LiveWire_07%202014.doc#_ftnref3" style="color: #215083;"><span style="color: #215083;">[3]</span></a> If such data are available, the Draft Law requires conducting randomized clinical trials to prove that such risks are not applicable to a particular generic or biosimilar drug. Unfortunately, the issue of whether such studies confirm to ethical principles of conducting clinical trials is not resolved. </p>