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Petitioner: ROCHE PAKISTAN LIMITED through Authorized Attorney VS Respondent: PAKISTAN through Secretary and 3 others
Court Name: Sindh High Court Judge(s): Muhammad Ali Mazhar Title:ROCHE PAKISTAN LIMITED through Authorized Attorney vs PAKISTAN through
Secretary and 3 others Case No.: Suit No,2161 and C.M.A. No,14255 of 2016 Date of Judgment:2017-10-12 Reported As: PLD 2018 Sindh 222 Result: Application dismissed. Judgment ORDER MUHAMMAD ALI MAZHAR, J.---By means of this suit for declaration and permanent injunction, the plaintiff has entreated for the declaration that decision of the defendant Nos,2 and 3 to register Reditux injection as a Similar Biotherapeutic Product is ultra vires the WHO Guidelines and the Drug Regulatory Authority of Pakistan Act, 2012; what's more the plaintiff has wished for the quashment of the decision of the defendants Nos,2 and 3 with permanent injunction prohibiting the defendant Nos,2 and 3 not to issue Letter of Registration nor permit the defendant No,4 to market and sell the aforesaid injection. 2. The epigrammatic facts put forward in the plaint are that the plaintiff is engaged in the import, marketing, sale and distribution of pharmaceutical products, diagnostic reagents, chemicals and equipment. At some point, the plaintiff applied to the competent authority for registration of its drug "Mabthera", which is trade name for Rituximab, a genetically engineered chemical chimeric monoclonal antibody approved by the United States a Food and Drugs Administration (FDA) for treatment of non-Hodgkin's lymphoma. However vide letter dated 28.02.2013 the brand name of the plaintiff's drug was changed from Mabthera to Ristova. The defendant No,2 was established pursuant to the provisions of Section 3 of the Drug Regulatory Authority of Pakistan Act, 2012 for effective coordination and enforcement of the Drugs Act, 1976 and to develop, issue, adopt and enforce standards and guidelines to ensure quality, efficacy and safety of therapeutic goods. The cause of distress to the plaintiff is the application moved by the defendant No,4 on 28.01.2011 for registration of its drugs Reditux Injection 500 mg/50mL and Reditux Injection 100mg/10mL (Reditux) which it claimed Similar Biotherapeutic Products of Rituximab (Mabthera/Ristova). Since the
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defendant No,4 claims Reditux to be a Similar Biotherapeutic Product of Rituximab so it is under obligation to strictly comply with the WHO Guidelines. 3. The learned counsel for the plaintiff argued that the clinical trials submitted by the defendant No,4 were retrospective whereas the defendant No,4 quoted Mabthera/Ristova as Reference Biotherapeutic Product without conducting any prospective studies. The application failed to accomplish the requirements of the WHO Guidelines and DRAP Act therefore Reditux was not fit to be registered as a Similar Biotherapeutic Product. It was further contended that the DRAP Act especially describes Biological and lays out mechanisms for their licensing and registration. The obligation of fulfilling the requirement of the WHO Guidelines is to merely ensure the quality, efficacy and safety of Similar Biotherapeutic Products. No clinical trials for proving ' biosimilarity of Reditux have been conducted in accordance with WHO Guidelines. In this regard a recent study comparing the efficacy and safety of Mabthera and Reditux has been submitted by a number of pharmaceutical companies for registration of their socalled bio similar in various jurisdictions but the said study is a retrospective analysis and not in compliance with the prerequisites of the WHO Guidelines. 4. The learned counsel further argued that in the 256th meeting of the Registration Board held on 03.4.2016, the defendant No,4's case was deferred for expert opinion however, in 260th meeting convened on 29th June, 2016 the experts stated that the defendant No,4 submitted bio similarity studies and they recommended Reditux for registration. 5. It was further averred that the plaintiff wrote a letter to the Chairman of Registration Board with the request to revisit its approval as the defendant No,4 failed to provide head-to-head trials and quality, safety and efficacy data as per the WHO Guidelines nor provided full registration dossier but the plaintiff's efforts have been in vain. The learned counsel referred to the case of M/s.Alfalah Medicos and another vs. Government of Punjab and others, reported in PLD 2017 Lahore 124 in which learned Lahore High Court laid down that WHO Guidelines have statutory importance and unless their requirements are fully complied with, a Similar Biotherapeutic Product may not be licensed under the DRAP Act. 6. The learned counsel for the defendant No,4 argued that the only question involved in this case is whether the WHO Guidelines on evaluation of similar biotherapeutic products are mandatory for registration of the defendant No,4's drug "Reditux" under the Drug Regulatory Authority of Pakistan Act, 2012, Drugs Act, 1976 and under the Rules and Regulations made under these Acts. The drug Reditux to be imported by the defendant No,4 has been granted registration letter which will only be issued after a further inspection of the facilities of Dr.Redy's Laboratories, India, by the Drug Regulatory Authority of Pakistan. 7. He further contended that the plaintiff has neither alleged nor questioned the defendant No,4's drug 'Reditux' for any patent violations, trademark or copyright nor any unfair competition involving the competition laws nor alleged that it is not safe. The three experts opinions certifying the defendant No,4's drug as safe and efficacious which is being sold in 15 countries including India, Russia, Ukraine etc. The bio-equivalence studies/trials have been conducted on the drug Reditux. The DRAP has taken nearly 06 years to register the defendant No,4's drug Reditux and the Registration Board granted the registration in its meeting held on 29.6.2016. The WHO Guidelines on evaluation of similar Bio-therapeutic products are not mandatory for registration because there is no express provision in any of the drug laws which states that the WHO Guidelines are mandatory for registration of biological drugs. 8. He further argued that Drug Regulatory Authority of Pakistan Act, 2012 has not repealed the Drugs Act, 1976. This Act creates a Central Authority known as the Drug Regulatory Authority of Pakistan whose function is to implement the Drugs Act, 1976, and the Rules made thereunder. The only provision of DRAP Act, 2012, which makes reference to registration of non-originator drugs is
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Schedule-I. The plaintiff ignored that the above provisions made reference of three provisions i.e Section 7(ix) of the Act, 2012, Schedule-I, Para 1 and Schedule-I, Para 6, if it is accepted that the above provisions are relevant then two principles of interpretation of statutes will prove that they are not applicable to the registration of drugs. Firstly, it is well settled that if there are special provisions dealing with a particular issue e.g. registration of drug like Section 7, Drugs Act, 1976 and the Drugs (Licensing, Registering and Advertising) Rules, 1976 then these provisions will prevail over general provisions contained in the statute. He further argued that the judgment rendered by the Lahore High Court in the case of M/s. Alfalah Medicos and another v. Government of Punjab and others is distinguishable and has no binding force on this court primarily for the reason that in the said case registration of any drug was not involved but the case pertained to the tender process. Judicial precedents cited by the Counsel for the defendant No,4 (1) 1993 SCMR 1635 (Golden Oraphies (Pvt.) Ltd. and others v. Director of Vigilance, Central Excise, Customs and Sales Tax and others). Interpretation of statute. Where a special provision had been made on a subject add there was also a general provision susceptible of covering the same field, presumption would be that the general provision is not intended to interfere with the operation of the special provision. (2) 2000 SCMR 1305 (Maulana Nur-ul-Haq v. Ibrahim Khalil). Interpretation of statutes. Mandatory or directory nature of a statute. Where the consequence of failure to comply with the provision is not mentioned the provision is directory and where the consequence is expressly mentioned the provision is mandatory. (3) PLD 1986 SC 14 (Ihsan-ur-Rehman v. Mst. Najma Parveen). Precedent. Two different views expressed by separate High Courts. Such views although have persuasive value for each other but were not as such binding on each other. (4) F. Hoffmann-La Roche Ltd. and another v Cipla Limited on 19 March, 2008) [Equivalent citations: 148 (2008) DLT 598, MIPR 2008 (2) 35]. The crucial aspect here is whether refusal of injunction would cause such irreparable hardship to the plaintiff as cannot be later compensated in mandatory terms, this Court is of the opinion that as between the two competing public interests, that is, the public interest in granting an injunction to affirm a patent during the pendency of an infringement action, as opposed to the public interest in access for the people to a life saving drug, the balance has to be tilted in favour of the latter. (5) Brawn Laboratories Ltd. v Rhone Poulenc Rorer S.A. and another (on 1 May, 1999) [Equivalent citations: 1999 IIIAD Delhi 849, 79 (1999) DLT 507, 1999 (49) DRJ 630]. Grant of injunction would not be in larger public interest as the same may result in denial of life saving drug to heart patients resulting in grave and irreparable loss, injury and consequences to patients. (6) 2017 MLD 785 (Al-Tamash Medical Society v. Dr. Anwar Ye Bin Ju and others). The phrase prima facie case in its plain language signifies a triable case where some substantial question is to be investigated or some serious questions are to be tried and this phrase 'prima facie' need not to be confused with 'prima facie title'. 9. The learned Additional Attorney General argued that pursuant to Section 7 of the DRAP Act, 2012 the DRAP is empowered to issue guidelines and monitor enforcement in respect of inter alia; the licensing of the manufacture of therapeutic goods, as well as the registration thereof; and the implementation of internationally recognized standards such as good laboratory practices, current good manufacturing practices, bioequivalence studies, clinical trials, bio similar evaluations and endorsement and systemic implementation of World Health Organization, International Conference on Harmonization and Food and Drug Administration guidelines. Clause 1(6) of Schedule I to the 2012 Act defines the term "Originator Biological Drugs" to mean those biological drugs that are licensed by national regulatory authorities on the basis of full registration dossier. Similar Biotherapeutic Products are defined in Schedule I to mean biological drugs that are similar
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in terms of quality, safety and efficacy to licensed reference Biotherapeutic product. The parameters referred to in the said clause are "quality, safety and efficacy", which are measured against the profile of the originator Biological Drug. 10. It was further contended that the Guidelines on Evaluation of Similar Biotherapeutic Products adopted at the 60th meeting of the WHO Expert Committee on Biological Standardization (the WHO Guidelines), stipulates an obligation to provide all information to NRA as is required for the purpose of licensing on SBP, is that of the manufacturer of the SBP. No such obligation is imposed on the importer. The WHO Guidelines are intended only to be used as a basis for NRAs to establish their own regulatory frameworks, hence the WHO Guidelines are by their own terms, directory rather than mandatory in nature. While DRAP endeavors to implement the WHO Guidelines, which is a function that DRAP has the requisite authority to perform, there is no express obligation under the applicable law requiring it to ensure that the guidelines are implemented either at all or in their entirety. 11. He further argued that key considerations for the selection of RBPs with which to compare the proposed SBP, include that the RBP should inter alia (i) have been marketed for a considerable duration and (ii) have a volume of marked use. The Drug substance of the RBP and the proposed SBP should also be similar and the dosage from and route of administration of both drugs should be the same. 12. While referring to the Alfalah Medicos case, he argued that the learned Single Judge held that the principles set out in the WHO Guidelines serve as a benchmark for global acceptability of SBP and a step-wise approach is therefore, recommended, while this case is distinguishable on the facts and issues to be decided. 13. He further argued that in the 256th Meeting, the Registration Board considered the data provided by the defendant No,4 for the licensing Reditux. Amongst the factors considered by the experts, is the fact that compliance certificate for Reditux has been issued by both the Food and Drug Administration of the United State Department of Health and Human Services (USFDA) as well as the Medicines and Healthcare Products Regulatory Agency of the Department of Health of the United Kingdom (MHRA). The registration dossier supplied for the purpose has also been evaluated in detail and the experts have observed that Reditux is highly comparable to its RBP in terms of quality, efficacy and safety and they noted that the manufacturer of Reditux is certified by international regulatory agencies in various countries. 14. Much emphasis were made by the learned Additional Attorney General that DRAP will take certain additional steps in order to ensure the quality, safety and efficacy of a drug that is considered for registration as SBP which includes inspection of the laboratories of the manufacturer as well as of the method of transportation and facilities used for the purpose thereof. Upon arrival of the relevant product in Pakistan, DRAP carries out further testing to satisfy itself that the product that has been imported may be authorized for marketing in Pakistan, i,e, that the quality, safety and efficacy of the product has not been compromised. 15. Heard the arguments. First of all I would like to focus on the Drugs Act, 1976 in which Section 4 is relevant to the regulation and prohibition of import of drugs, while Section 5 germane to regulation of manufacture of drugs, whereas Section 7 alluded to registration of drugs which postulates that the Federal Government shall cause all drugs to be registered in accordance with such conditions and procedure as may be prescribed. For the ease of reference, Section 7 of the Drugs Act 1976 is reproduced as under:- "7. Registration of drugs: (1) The Federal Government shall cause all drugs to be registered in accordance with such conditions and procedure as may be prescribed and for that purpose set up a Registration Board, consisting of such number of persons, possessing such qualifications, as may be prescribed.
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Explanation: In this section, "drugs" means drugs which are in the finished form ready for use. (2) The members of the Registration Board shall exercise such powers, including the powers of an Inspector, as may be prescribed. (3) The Registration Board shall, [with the approval of the Federal Government and, by notification in the official gazette,] make regulations to regulate the conduct of its business. (4) Any member of the Registration Board may, at any time, by writing under his hand addressed to the Federal Government, resign his office or shall vacate his office if the Federal Government, being of opinion that in the public interest it is necessary so to do, so directs. (5) Subject to subsection (4), the members of the Registration Board shall hold office for the prescribed period. (6) The Federal Government shall, by notification in the official Gazette, fix the date after which no drug which is not registered shall be allowed to be exported, imported, manufactured, stored, distributed or sold. (7) A person applying for the registration of a drug shall furnish such information in respect of the drug as may be prescribed, including information relating to its efficacy, safety and quality, or as may be required by the Registration Board for the purpose of the evaluation of the drug. (8) Single-ingredient drugs shall be registered generally by their generic names while compound drugs shall be registered generally by their proprietary names. Explanation: In this subsection,-- (a) "single-ingredient drugs" means drugs containing one active ingredient; (b) "compound drugs" means drugs containing more than one active ingredient. (9) The registration of a drug shall be subject to such conditions, as may be prescribed. (10) Where the Registration Board registers a drug, it shall inform the person applying for its registration and the Provincial Governments of its having done so and of the conditions subject to which it has been registered. (11) If the Registration Board, on the basis of information received or an inquiry conducted by it, is of opinion that:- (a) the registration of a drug was procured by fraud or misrepresentation; or (b) the circumstances in which a drug was registered no longer exist; or (c) there has been a violation of the conditions subject to which a drug was registered; or (d) it is necessary in the public interest so to do; the Registration Board may, after affording to the person on whose application the drug was registered an opportunity of showing cause against the action proposed to be taken, cancel or suspend the registration or specify any further conditions to which the registration shall be subject and inform such person and the Provincial Governments accordingly. (12) The Provincial Governments shall take all such steps as may be necessary to ensure compliance with the conditions subject to which a drug is registered and to prevent the manufacture or sale of a drug:-. (a) which has not been registered; or (b) the registration of which has been cancelled or stands suspended." 16. However Rule 29 of the Drugs (Licensing, Registering and Advertising) Rules, 1976 is somewhat relevant which elucidates that the Registration Board may, if it considers necessary in case of a new drug molecule, cause the application for registration and the information and material supplied to it under Rule 26 to be evaluated by a Committee on Drugs Evaluation, whereas Rule 26 makes reference of an application for registration of a drug for the local manufacture of a drug substance having the same active ingredient or salt thereof, therapeutic use, dosage form and route of administration that has already been approved by the Registration Board and has not been withdrawn from the sale for the reasons of safety or effectiveness. In sub-rule (2) of Rule 29
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the Registration Board may before issuing a certificate of registration cause the premises in which the manufacture is proposed to be conducted to be inspected by itself or by its sub-committee or by a panel of Inspectors or experts appointed by it, for the purpose. In sub-rule 6 it is further provided that Registration Board shall, before registering a new drug or molecule for which the research work has been conducted in other countries and its efficacy, safety and quality has been established therein, requires the investigation on such pharmaceutical, pharmacological and other aspects, to be conducted and clinical trials to be made as are necessary to establish its quality and where applicable, the biological availability, and its safety and efficacy to be established under local conditions. However, it is provided under the same sub-rule that for the special circumstances to be recorded in writing, the Registration Board may register a drug and require such investigations and clinical trial to be conducted after its registration. 17. By virtue of the Drug Regulatory Authority of Pakistan Act, 2012, the Drug Regulatory Authority of Pakistan (DRAP) was established to provide for effective coordination and enforcement of the Drugs Act, 1976 and to bring harmony in inter-provincial trade and commerce of therapeutic goods. The provincial assemblies of Khyber Pakhtunkhwa, Punjab and Sindh have passed resolution under Article 144 of the Constitution of the Islamic Republic of Pakistan to the effect that Majlis-e-Shoora (Parliament) may by law regulate the issue. In this Act "Biological" means biological drugs as defined in Schedule-I, while "Pharmaceutical dossier" means a set of documents, as specified in Schedule-I whereas "Therapeutic goods" includes drugs or alternative medicine or medical devices or biological or other related products as may be notified by the Authority. Under Section 3 the Authority has been established and its composition is provided under Section 4, whereas under Section 7 certain powers and functions have been conferred upon the authority. For the ease of reference, relevant provision of Section 7 of DRAP Act, 2012 and the Schedule-I relied upon by the plaintiff's counsel is reproduced as under:- "7. Powers and functions of the Authority.- The powers and functions of the Authority shall be to:- (a) (c) issue guidelines and monitor the enforcement of,- (i) (ix) implementation of internationally recognized standards such as good laboratory practices, current good manufacturing practices, good distribution practices, cold chain management, bioequivalence studies, stability studies, anti-spurious codes, clinical trials, biosimilar evaluations, and endorsement and systematic implementation of World Health Organization, International Conference on Harmonizations and Food and Drug Administration guidelines etc.; "SCHEDULE-I [see section 2 (v, xii, xviii, xix, & xxviii)] 1. 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 Clotting Factors Tractions, Fibrinogens, Immunoglobulins; (b) immunological products including Antisera, Antitoxins, specific Immunoglobulins; (c) in vivo diagnostics including Tuberculins, Lepronin, Histoplasmin, Coccidioidin, Allergens, Allergens Extracts, Antibodies conjugated with isotopes for imaging studies; (d) antigens, cytokines/antibodies/cells injected to elicit a biological response; (e) vaccines, including:--
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(i) bacterial vaccines including live, killed whole cell, protein sub-unit, polysacchride or glyco- conjugate, toxin derivatives, and rDNA biotechnology developed; (ii) viral vaccines including live, inactivated, sub-unit, rDNA, conjugated; (iii) polyvalent combinations of vaccines containing combination of vaccines defined in e (i) and d(ii). (f) toxins and venoms including snake venoms, scorpion venoms etc; (g) immunostimulants of biological origin including BCG vaccine for immunotherapy; (h) biotechnology products which are primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology or other processes involving site specific genetic manipulation techniques. (i) human interferons, natural hormones, recombinant antibodies, monoclonal antibodies and derivatives gene therapy products; (2) "Biological Drugs (Finished form)", are Biological Drugs that are defined in subsection (1) above and are manufactured, packed by the manufacturer under his responsibility of quality assurance and is further released by the National Control Authority or the National Control Laboratory of the country of origin under the World Health Organization's Lot Release system of evaluation. (3) "Biological Drugs (Ready-to-fill form)", are Biological Drugs that are defined in subsection (1) above but are manufactu.-ed at one site in the form of a "Ready-to-fill Bulk" but are transferred to another site for final filling, labeling, packaging and quality control of the finished form. No further formulation or dilution of the Ready-to-fill bulk is allowed in this case of manufacture. The final product is released by the Pakistan's National Control Laboratory for Biologicals under the World Health Organization's Lot Release system of evaluation. (4) "Biological Drugs (Concentrated form)", are Biological Drugs that are defined in subsection (1) above that are manufactured at one site but are stored in the form of Concentrated-Bulk of the active ingredient at controlled temperatures. Such Concentrated-Bulk may be transferred to any other site under temperature controlled conditions for further dilution, stabilization, filling and packaging. The diluted and stabilized bulk requires its own set of quality control test and the final finished form of such Biological Drugs under go another set of complete quality…
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