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Petitioner: M/s Alfalah Medicos and another VS Respondent: Government of Punjab and others
Court Name: Lahore High Court Judge(s): Shams Mehmood Mirza Title: M/s Alfalah Medicos and another vs Government of Punjab and others Case No.: W.P. No.10045 of 2016 Date of Judgment:2016-05-05 Reported As: 2016 LHC 2136 Result: Appeal Dismissed
Judgment Shams Mehmood Mirza, J:- By this writ petition filed under Article 199 of the Constitution of the Islamic Republic of Pakistan, 1973, the petitioners seek to challenge the decision of the Grievance Committee rendered on 24.03.2016 dismissing the representation of petitioner No.2. 2.Petitioner No.2 (Getz) is a drug manufacturing company and petitioner No.1 (Alfalah) is its authorized distributor. Getz imports and markets a drug called Uni peg-V (Unipeg) in Pakistan, which is statedly used primarily for the treatment of Hepatitis C. The Director General, Health Services through advertisement in the newspaper invited bids for procurement of a number of drugs/medicines, which included "Injection Peglated Interferon 180 mcg Alpha2a/120mcg Alpha 2b" (hereinafter referred to as Interferon). The procurement of the Interferon was sought in connection with the prevention and control of Hepatitis Control Program initiated by the Government of Punjab. Getz claims that Unipeg is biosimilar to Interferon in dosage form, strength, quality, performance characteristics and intended use. Clause 12 of the bidding documents required Bio equivalence/Bio Similarity study from World Health Organization (WHO) audited laboratory/DRAP authorized laboratory/ICH certified/audited laboratories (hereinafter referred to as the prescribed laboratories). It is an admitted position that Unipeg has not yet been certified by any of the prescribed laboratories and, therefore, does not fulfill the criteria mentioned in the bidding document. Alfalah applied for the bidding documents and feeling dissatisfied by insertion of clause 12 contained therein filed a suit for declaration and permanent injunction before the civil court at Lahore. The trial court on 15.12.2015 suspended the operation of clause 12 of the bidding document. On 07.01.2016, the Director General, Health Services again advertised for procurement of Interferon but this time it required prequalification of suppliers. In the second round, Getz obtained the bidding documents for prequalification instead of Alfalah. Clauses 10 and 11 of the bidding documents again required Bio equivalence/Bio Similarity study from World Health Organization audited laboratory/DRAP authorized laboratory/ICH certified/audited laboratories. Getz, it is claimed, tendered the prequalification documents on
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22.01.2016 under protest. There were four other bidders in addition to Getz. The prequalification applications of Getz and another were, however, rejected on 17.03.2016 on the ground that their drugs did not meet the criteria mentioned in clauses 10 and 11 of the bidding documents whereupon a grievance application was moved by Getz on 18.03.2016 before the Grievance Committee, prequalification Hepatitis Control Program. On 19.03.2016, Alfalah, although not an applicant in the second procurement process, moved a stay application before the trial court in the suit earlier filed by it whereupon the trial court directed the respondents to comply with its earlier stay order dated 15.12.2015 and operation of order dated 17.03.2016 was suspended. The petition filed by Getz before the Grievance Committee was dismissed on 24.03.2016 on the ground that it had failed to comply with clauses No.10 & 11 of the bidding document, hence this writ petition. 3.During the pendency of this writ petition, CM No.1295 of 2016 was filed by intervener, Roche Pakistan Limited (Roche), which was pre-qualified in the second round of procurement and was later declared the successful bidder. This application was contested by the petitioners by filing their written reply. The said application was allowed on 14.04.2016 by this Court and the petitioners were directed to file the amended memo of parties reflecting the name of Roche as respondent No.5. 4.The respondents have filed their reply and parawise comments to the writ petition in which the stance of the petitioners has been controverted. 5.Learned counsel for the petitioners made the following submissions: a.Alfalah being a distributor of the medicines manufactured by Getz can maintain this writ petition even though it did not apply for and participate in the pre-qualification of bidding advertised by the respondents in the second round. b.The advertisement for prequalification of tenders for supply of Interferon was in violation of stay order dated 15.12.2015 passed by the trial court in the suit initiated by Alfalah. It was further submitted that this Court can take notice of the disobedience by the respondents of the order of the civil court. c.Unipeg is registered with Drug Regulatory Authority of Pakistan (DRAP) since 2010 and is being sold throughout Pakistan. DRAP gave two years time to Getz for carrying out Bio-similarity Studies as per the guidelines of WHO on 20.10.2015 and as such the petitioner still has time available to it for complying with clauses No.10 & 11 of the biding documents. d.Clauses 10 & 11 of the bidding document violate Article 148 of the Constitution of Islamic Republic of Pakistan, 1973 as the said clauses deviate from the Federal standards, which is not conducive for the inter- provincial trade. e.Clauses 10 & 11 impede free competition as Roche has a monopoly over the medicine to be supplied to the respondents. 6.Learned counsel for the respondents, on the other hand,submitted that clauses 10 & 11 were not only not inconsistent with the Drug Regulatory Authority of Pakistan Act, 2012 (DRAP Act) rather they complied with the Federal standards provided therein. It was further stated that free competition was not stifled on account of inclusion of clauses 10 & 11 as five bidders participated in the prequalification process out of which two bidders were selected. Learned Assistant Advocate General submitted that drug manufactured by Getz did not comply with the Federal Standards contained in the DRAP Act. It was also alleged that the Government of Punjab included clauses 10 and 11 for pre-qualification of the contractors as it wanted to provide the best medicine for Hepatitis C, which disease was endemic in the province of Punjab. 7.Learned counsel for the intervener submitted that Roche applied for registration of its drug "Pegasys" which is the trade name of Pegylated Interferon and is approved by FDA, EMA and Swiss medic for treatment of Hepatitis B and C, which application was granted approval by the Ministry of Health. On account of disputes between Roche and Ministry of Health, Roche introduced "Ropegra" in Pakistan at a much more reduced price. Ropegra, it is claimed, is exactly the same substance as Pegasys and is imported from the same manufacturer, the only difference being that Ropegra is sold in vial form at a much lower price. A number of serious objections were raised on Unipeg with regard to its quality, safety and efficacy. 8.Arguments heard and record perused.
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9.The primary question requiring determination is whether the terms contained in the bidding documents requiring Bio equivalence/Bio Similarity study of the drugs from the prescribed laboratories violated the federal standards and stifled free competition. In order to resolve the controversy, it is imperative to look at the various provisions of DRAP Act to ascertain whether the enhanced requirement in the bidding document violated its provisions. Section 32 of the DRAP Act clearly states that its provisions shall not be in derogation to the provisions of Drug Act, 1976 rather they will be in addition to them. Section 4 of the Act deals with the composition of DRAP and one of its directors namely "Director Biological Drugs" is incharge of a Division of Biological Evaluation and Research which is responsible, inter alia, for the evaluation, assessment, registration and licensing of Biologicals and shall perform other functions connected therewith including all the functions of National Control Authority for Biologicals as required for the pre-qualification by WHO of locally manufactured human biological drugs. One of the core functions of DRAP is to implement the internationally recognized standards such as good laboratory practices, current good manufacturing practices, bioequivalence studies, clinical trials, biosimilar evaluations, and endorsement and systematic implementation of World Health Organization Guidelines etc [see section 7 (ix) of the DRAP Act]. 10.The definition of "Biologicals" in terms of section 2 (v) read with Schedule 1 of the DRAP Act, insofar as it is relevant, reads as under BIOLOGICALS includes,- (1) Biological drugs produced by biological systems and which require standardization by biological assays according to the relevant and updated recommendations of the World Health Organization published in Technical Report Series and Biological Standardization report and includes: (a)Blood products including Plasma, Albumin, Clotting Factors, Factors VIII, IX, Mixed Clothing Factors Tractions, Fibrinogens, Immunoglobulins: (b) (c) (i) human interferons, natural hormones, recombinant antibodies, monocolonal antibodies and derivatives gene therapy products; Similarly the definition of biosimilar drugs is contained in clause 6 of the Act, which reads as under: (6) Originators Biological Drugs means a biological drug which has been licensed by the national regulatory authority on the basis of a full registration dossier i.e. the approved indication(s) for the use were granted on the basis of full quality, efficacy and safety data: (a)reference biotherapeutic product (RBP) means an originator biological drug product that was licensed on the basis of a full registration dossier. It does not refer to measurement standards such as international, pharmacopoeia, or national standards or reference standards: (b)biosimilar biologicaldrugsmeanSimilar Biotherapeutic Product (SBP) which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product; (c)Similarity means absence of relevant difference in the parameters of interest. 11. The above definition of "Biologicals" makes it clear that these are generally made from human or animal materials (or both), as against the most traditional prescription drugs made through chemical processes i.e. generic drugs. Biologicals are 200 to 1,000 times the size of a small molecule (generic) drug, and far more structurally complex. Additionally, biologicals and biosimilars are manufactured in living cells, then extracted and purified, whereas small molecule drugs and generics are manufactured purely via chemical synthesis. A biosimilar product is similar to an existing biological product meaning thereby subject to slight variations there must be clinically no meaningful differences in terms of safety, efficacy, purity, and potency between them. 12. Roche with its parawise comments has appended the copy of the "Guidelines on Evaluation of Similar Biotherapeutic Products (SBP's)" issued by the WHO, which were adopted by the 60th meeting of the WHO Expert Committee on Biological Standardization, Geneva, 19-23, October 2009. WHO as part of its mission in setting standards for biological products provides guidelines and recommendations for manufacturing and evaluating biologicals. The scientific principles outlined in the WHO Guidelines for evaluation of SBPs serve as
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a benchmark for global acceptability of these products. In its introduction, the WHO Guidelines refer to the rationale of launching of Biosimilar Products and SBP's in various countries and provide the difference between SBP and generic drugs. The relevant portions read as under: Introduction Biotherapeutic products (biotherapeutics) have a successful record in treating many life threatening and chronic diseases. However, their cost has often been high, thereby limiting their access to patients, particularly in developing countries. Recently, the expiration of patents and/or data protection for the first major group of originator's biotherapeutics has ushered in an era of products that are designed to be 'similar' to a licensed originator product. These products rely, in part, for their licensing on prior information regarding safety and efficacy obtained with the originator products. The clinical experience and established safety profile of the originator products should contribute to the development of similar biotherapeutic products (SBPs). A variety of terms, such as 'biosimilar products', 'follow-on protein products' and 'subsequent-entry biologics' have been coined by different jurisdictions to describe these products. The term 'generic' medicine is used to describe chemical, small molecule medicinal products that are structurally and therapeutically equivalent to an originator product whose patent and/or data protection period has expired. The demonstration of bioequivalence of the generic medicine with a reference product is usually appropriate and sufficient to infer therapeutic equivalence between the generic medicine and the reference product. However, the approach established for generic medicines is not suitable for development, evaluation and licensing of SBPs since biotherapeutics consist of relatively large, and complex proteins that are difficult to characterize. The clinical performance of biotherapeutics can also be much influenced by the manufacturing process and some clinical studies will also be required to support the safety and efficacy of a SBP. Similarly, the reference biotherapeutic product is defined in the WHO Guidelines as under: Reference biotherapeutic product (RBP) A reference biotherapeutic product is used as the comparator for head-to-head comparability studies with the similar biotherapeutic product in order to show similarity in terms of quality, safety and efficacy. Only an originator product that was licensed on the basis of a full registration dossier can serve as a RBP. It does not refer to measurement standards such as international, pharmacopoeial, or national standards or reference standards. A reading of the WHO Guidelines shows that the DRAP Act closely follows it insofar as the definitions of Biologicals, biosimilars and Reference biotherapeutic product are concerned. 13.It is an undisputed fact that the regulatory authorities all over the world have outlined robust data requirements to demonstrate bio-similarity of a drug. Biosimilar manufacturers will generally need to generate data from lab testing, non-clinical testing and clinical testing to show that the bio-similar drug they have developed will provide the same therapeutic benefit and risks to patients as the Reference biotherapeutic product. 14.Having gone through the definitions, it becomes essential to look at the documents available on the record relating to the respective drugs of Getz and Roche. Roche has appended a plethora of documents including the Certificate of Medicinal Product issued by the European Medicine Agency and the summary of its product's (Ropegra) characteristics. The registration certificates issued by the DRAP to the drugs of both Getz and Roche are quite instructive and clearly show that the Roche's drug (Ropegra) was registered with DRAP as "biological" and is, therefore, the Reference biotherapeutic product whereas Getz applied for registration of Unipeg as biosimilar to the reference drug. Accordingly, condition (xvii) contained in petitioner's drug registration letter dated 20.10.2015 was inserted, which reads as under The claim to declare Unipeg-V as biosimilar is not authoirized by drug Registration Board. As per decision of meeting of 246th, firm shall conduct parallel biosimilarity study as per WHO guidelines immediately after grant of registration and shall submit complete studies within two years in any case. Manufacture will provide progress report to this effect to Director of Biological Division on quarterly basis. Regular monitoring through pharmacovigilance system shall be observed
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through pharmacovigilance cell unit of the manufacturer and report be furnished be pharmacovigilance centre, Pharmacy Services and Biological Division. In case of any severe adverse event, immediate mandatory reporting procedure shall be followed if any of the condition is not suited or public health risk reported at any stage during registration shall stand cancelled with immediate effect. From the reading of the above, it becomes apparent that Unipeg was not declared biosimilar drug by DRAP and accordingly the petitioner was required to conduct biosimilarity study along the WHO Guidelines and submit the report within two years. Exactly how this condition was incorporated in the petitioner's drug registration letter also requires to be highlighted. Drug Registration Board in its 244th meeting, amongst others, decided the case of Getz with regard to Unipeg. The relevant extracts of the said meeting reads as under: Final Decision of the Drug Registration Board in its 244th Meeting: - a) Biosimiliarity is the principal requirement for the registration of biological drugs, as it is part of requirements of DRAP Act, 2012 mainly focusing on patient safety and also to promote biological production and availability of biological products. b) All those manufacturing units which have been approved by Central Licensing Board for manufacturing of biological drugs and also had qualified product specific inspection by panel of Registration Board, are allowed registrations of applied biological drugs for local manufacturing on case to case basis. Item for which product specific inspection is required, then it will be conducted by already constituted panel of Registration Board. c) Local manufacturer will provide legalized documents from concerned regulatory body confirming the status of licensed manufacturer of concentrate/bulk source in its country of origin. Moreover manufacturer will provide legalized documents for confirmation that finished product is also available in market from the same biological material. Case will be processed for issuance of registration letter after fulfillment of above mentioned requirements, with following conditions: i. Registration is exclusively for trial manufacturing of the drug and manufacturer shall not be allowed in any way to sale/utilize these trial manufactured drugs. Manufacturer will perform biosimilarity studies as per WHO guidelines confirming the biosimilarity of applied product to original innovator product. ii)Manufacturer will submit actual result of conducted biosimilarity studies to the Biological Division for its scientific evaluation through Expert Committee on Biological Drugs (ECBD). Moreover manufacturer will also provide sufficient quantity of these trial manufactured drugs to Biological Division for testing by National Control Laboratory for Biological (NCLLB) as per WHO guidelines. iii) Recommendation of ECBD and report of NCLB will be submitted to Registration Board for permission of commercial manufacturing of the product or otherwise. d) This decision supersedes all the already taken decisions so far in the earlier meetings of Registration Board on the subject cases. (Emphasis supplied) It is clear from the decisions taken by Drug Registration Board in its 244th meeting that the manufacturer of the biosimilar drug was not allowed its sale rather the registration was meant for manufacturing and for performing biosimilarity studies as per WHO guidelines. It appears that one of the drug companies (M/s Macter International) approached the Ombudsman concerning its drugs whereafter certain recommendations were made by the Ombudsman. In terms of the recommendations of the Ombudsman, the matter was again taken up by the Drug Registration Board. As is apparent from the minutes of the 246th Meeting of the Registration Board, the drug firms which included Getz made the following demands The firms unanimously presented/argued that Registration Board previously did not implement/ demand CoPP/Free sale certificate from local manufacturer of biological drugs. But now only GMP certificate of the foreign manufacturer can be provided which should be accepted by the Drug Registration Board. Moreover, the condition of providing biosimilarity data should not be imposed as per previous practice of Registration Board for already registered locally manufactured drugs as this condition will result in further delay which can be very damaging to new biopharmaceutical units. Condition of clinical studies should not be imposed. The manufacturer shall ensure the quality, safety and efficacy of locally manufactured biological drugs by them. The following decision of the Drug Registration Board in its 246th meeting shows that the Board agreed to issue
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the registration certificate subject to certain conditions. It is, however, important to note that the waiver of biosimilarity studies as demanded by the firms was not accorded approval by the Drug Registration Board. 1. As the Registration Board in 244th meeting has already approved registration of biological drugs for four manufacturers (M/s. Macter International Karachi, M/s. Getz Pharma Karachi, M/s. Nextar Pharma, Karachi and M/s. Hilton Pharma, Karachi) for local manufacturing. In order to issue registration letter, the Board advised these manufacturers to provide following document as discussed and agreed during the deliberations with manufacturers: a. The firms shall provide legalized GMP certificate of biological drug manufacturer abroad (who will provide concentrate / ready to fill bulk of biological drug to Pakistani manufacturers for further processing) as an evidence that the manufacturer is an authorized manufacturer of that particular biological drug in its country of origin. b.The firm shall provide studies conducted by manufacturer abroad (dully verified with statement for correctness / genuineness of data) regarding structural similarity of subject biological drug product (concentrate/ ready to fill bulk for further processing) with reference biological product (innovator). c.The local manufacturer shall be authorized to manufacture the finished biological product and then perform bio-comparability studies including identity testing to parent molecule, purity testing, in vitro biological activity, potency and toxicity with support of iso-electro focusing data, gel electrophoresis, Western-Blot and other analytical techniques) and stability studies of finished biological product. Data provided by the local manufacturer shall be evaluated by the Expert Committee on Biological Drugs. Recommendation of the committee shall be considered by the Registration Board for issuance of registration letter. d.The firms shall conduct parallel bio-similarity studies as per WHO guidelines immediately after grant of registration and shall submit complete studies with in two (2) years in any case. Manufacturer will provide progress report to this effect to Directorate of Biological Drugs on quarterly basis. e.Regular monitoring through pharmacovigilance reporting system shall be observed through proper pharmacovigilance cell of the manufacturer and report will be forwarded to the National Pharmacovigilance Centre, Division of Pharmacy Services and Biological Division of DRAP. In case of any severe adverse event, immediate mandatory reporting procedure shall be followed. f.If any of the conditions is not fulfilled or public health risk reported at any stage, the drug registration shall stand cancelled with immediate effect. g.All the provisions as contained in the Drugs Act, 1976 and rules made there under including provisions of Lot Release certification from National Control Laboratory for Biologicals shall be strictly adhered to. (Emphasis supplied) The terms and conditions mentioned in the decision taken by the Drug Registration Board were then incorporated in registration letter dated 20.10.2015 issued to the petitioner. 15. A reading of various provisions of DRAP Act shows that it has adopted the standards/protocols prescribed by WHO in its Guidelines for licensing of a bio-similar drugs. After the promulgation of DRAP Act, all applications for seeking authorization for manufacturing and marketing of biosimilar drugs in Pakistan are required to be evaluated on the basis of the standards set out in the WHO Guidelines regarding licensing of biosimilar drugs. These Guidelines, therefore, by reference have a statutory force. The scientific principles outlined in the WHO Guidelines for evaluation of SBPs serve as a benchmark for global acceptability of these products. These WHO Guidelines stipulate as mandatory requirement that adequate tests are conducted prior to the approval of biosimilars. The WHO Guidelines also provide…
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