Overview of non-innovator biological products in India

Published in: Volume 9 / Year 2020 / Issue 1
Category: Opinion
Author(s):
Visits: 1485 total, 6 today
Keywords: biosimilar, CDSCO, Innovator Reference Biological Product, Non-innovator Biological Product, RCGM

Author byline as per print journal: GR Soni, PhD

Abstract:
As per regulatory requirements, biosimilar drugs must show high similarity to their reference product in quality, preclinical and clinical tests. It is by these means that biosimilars are considered to be safe and efficacious. In India, any major deviation(s) from science-based principles in the manufacturing of a recombinant DNA-derived therapeutic biological product leads to its classification as a ‘non-innovator’ biological, which are approved as ‘New Drugs’. According to the World Health Organization (WHO), these biological products have uncertain safety and efficacy when compared to the reference biological and are therefore not recommended for use. However, these so-called non-innovator biological products continue to be developed in India, for reasons including brief and poorly implemented guidelines on biologicals, a lack of expertise on biosimilars amongst drug regulatory committees, lack of coordination among government departments working on biosimilars, poor quality accreditation in testing laboratories, and a lack of patent protection for innovator drugs. There is an urgent need to identify deficiencies in the ministries responsible for biosimilars in India, which could be through a scientific audit. Compliance with such an audit could strengthen the Indian regulatory system and thus increase the provision of affordable, high quality biosimilars in India.

Submitted: 23 May 2019; Revised: 14 October 2019; Accepted: 19 October 2019; Published online first: 1 November 2019

Introduction

A significant portion of the 1.3 billion Indian population suffers from chronic diseases including cancer, diabetes and autoimmune disorders. Generally, people belonging to lower- and middle-income groups are the worst affected as they cannot afford expensive recombinant DNA (rDNA)-derived innovator reference biological products (IRBPs). Although efficacious and widely used in developed countries, IRBPs are inaccessible to a large portion of the Indian population due to their cost. Examples of globally available IRBPs include insulin, epoetin, granulocyte colony-stimulating factor (G-CSF) and monoclonal antibodies such as the anticancer treatments rituximab and trastuzumab. At the time of writing, 26 biosimilars have been approved in the US while the EU has approved 66 biosimilars. India, meanwhile, has approved 83 rDNA-derived non-innovator biological products (NIBPs) (CDSCO, 2019), but no such product has been approved as a similar biologic [1].

Of these NIBPs, 14 were approved before the adoption of the Indian guidelines for biosimilar evaluation in 2012. The regulatory framework for these products is unclear, leading to concerns about their safety. The World Health Organization (WHO) guidelines for similar biotherapeutic products [2] state that biotherapeutics that have not shown similarity to a reference biotherapeutic product through head-to-head demonstration should not be described as similar or named a biosimilar. Indian regulation, however, allows NIBPs approved prior to the release of the 2012 guidelines to be classified as similar biologics. These products should be re-assessed by regulatory authorities and, until biosimilarity with the reference drug product has been shown, should not be classified as biosimilars. Even therapeutic products approved after 2012 have major regulatory lapses, and it is important that these products be reviewed also.

India is however highly capable in the formulation of active pharmaceutical ingredients (APIs) and has a high export rate for its APIs due to regular good manufacturing practice (GMP) inspections of its manufacturing premises by US and EU regulators. Nevertheless, the Indian pharmaceutical industry does not produce equivalent amounts of rDNA-derived biosimilar products, which are of higher value than generic, chemical drugs. The country is therefore highly dependent on the import of rDNA clones (cells which secrete therapeutic protein). In many instances, the manufacture of complex biologicals from these imported clones is non-scientific in nature. Often, the test drug product is improperly compared with the respective IRBP to establish biosimilarity without establishing a goal post/range of critical quality attributes. For this reason, international regulators are uncertain of the quality of Indian NIBPs and these drugs cannot be exported to more developed countries, such as the US and EU Member States. So, although the Government of India (particularly the Ministries of Health, Pharmaceuticals and Science and Technology) is providing support to various organizations (including the Central Drugs Standard Control Organisation (CDSCO), Department of Biotechnology (DBT), Indian Council of Medical Research (ICMR) and the clinical and pharmacology department of the All India Institute of Medical Science (AIIMS)) to develop affordable and accessible biosimilars, so far the results are not encouraging.

WHO has issued several guidelines on similar biotherapeutic products [3-6] and the EU [7] and US [8] both have statutory or notified guidelines for biosimilars. The Indian similar biologic guidelines however, first published in 2012 and subsequently revised in 2016, are non-statutory and non-notified in the Gazette of India (an authorized legal document of the Indian Government). Further, the Indian guidelines are general in nature and lack clarity on many important issues, including classification and assessment of critical quality attributes [9]. Even the manufacturer’s checklist issued by the Review Committee on Genetic Manipulation (RCGM) of the DBT in August 2018 is brief and ambiguous in nature [10]. Partial compliance with the guidelines by inter-ministerial committees (RCGM of DBT and CDSCO of Ministry of Health & Family Welfare) have resulted in the generation of a large number of NIBPs which are approved as ‘New Drugs’. This review will address the issues responsible for the generation of NIBPs of unreliable quality and discuss measures to correct these issues, including scientific audits and training for regulators, which would support the provision of safe and efficacious biosimilars in India.

Global requirements for development of biosimilars

rDNA-derived IRBPs have achieved significant success in treating life-threatening and chronic diseases. Since IRBPs are costly and therefore not easily accessible to the majority of patients in India, manufacturers aim to develop more affordable biosimilar versions. A biosimilar product which has been shown to be highly similar to the reference drug in quality, preclinical and clinical testing can be marketed at reduced cost, without com- promising efficacy. The benefit of the reduced cost is transferred to the patients. High similarity at the quality level is regarded as a prerequisite for licensing the drug. Accordingly, a stepwise approach is applied to evaluate the similarity of biosimilar with the IRBP [3-8]. Biosimilar manufacturers are required to regularly interact with regulators, from the initial stages to the final stage of issuing marketing authorization.

In India, the pathway for similar biologic production (as per the 2016 Indian similar biologic guidelines) has been followed only partially and NIBPs can be approved using abbreviated pack- ages, often with limited data. The safety, efficacy and potency of biosimilars is highly similar to the reference biological, while NIBPs offer uncertain safety and efficacy. Since NIBPs and biosimilars have important differences, NIBPs should not be approved via the biosimilars pathway. NIBPs should undergo complete testing, rather than using the abbreviated pathway of clinical testing that is applied to biosimilars. Following is a brief description of the procedure used for manufacturing biosimilars.

The first and most important step for manufacturing of any biosimilar against an already licensed and marketed reference biological is to thoroughly understand the IRBP and establish a goal post/range of critical quality attributes such as biopotency, receptor binding, high molecular weight impurities, charge variants, glycans [4, 9, 11, 12]. These, along with amino acid sequencing and determination of secondary and tertiary structure should be performed, with as many IRBP batches (possibly covering their entire life cycle) as scientifically possible, as per the US Food and Drug Administration (FDA), WHO and EU guidelines, preferably from the host country. If obtained from abroad, bridging studies should be performed. Various validated orthogonal assays are required for determination of the structure and function of the IRBP as well as for establishing goal post/range of critical attributes. Then, out of several clones generated by the manufacturer, the clone which is stable and meets the predefined goal post/range of quality attributes of IRBP is selected. The development of a goal post/range of critical tests and a suitable cell clone are essential because of the proprietary nature of the IRBP and its clone as well as the non-availability of clinical and other confidential data.

The thorough characterization of the selected clone and having suitably sized master and working cell banks are essential for the preparation of any rDNA-derived biological product. The working cell bank is important for manufacturing a consistent product. The therapeutic protein should be checked during the manufacturing process against predetermined ranges (based on the reference biological). Finally, 10 or more batches of the reference and newly produced drug should be compared head-to-head to establish biosimilarity [13]. Even if the analytical comparability results of a biosimilar product satisfy the acceptable limits, additional analyses might be required if the test results show a trend that differs from that of the IRBP.

Once biosimilarity has been established at the physicochemical and biological level, pharmacokinetic and pharmacodynamic assays should be performed on several batches of the test product, along with toxicity tests in suitable animals. Finally, the same batch of test product should undergo comparative abbreviated clinical testing in humans to establish the non-inferiority (and non-superiority) of the test drug relative to the IRBP at a suitable confidence interval. Once the rDNA-derived therapeutic biological is approved and given MA it is the responsibility of the manufacturer to ensure that the drug specifications are well within the range of critical results from the biosimilar. Drug specifications are different and more precise than the critical range of quality attributes. The manufacturer should have suit- able infrastructure and competence to consistently provide the approved biological drug [11, 12, 14-16]. This well-established procedure for manufacturing biosimilars is generally not followed in India, as outlined below.

General overview of non-innovator biological products (NIBPs) in India

Indian regulators of NIBPs
The Institutional Biosafety Committee (IBSC) has one representative from the Department of Biotechnology, but the majority of members lack expertise on biosimilars. The Department of Biotechnology in India, through the RCGM, is responsible for research and development as well as initial pilot manufacturing of rDNA-derived therapeutic biological products, including biosimilars. The RCGM committee comprises more than 20 members, mostly drawn from fields other than biosimilars, including more than 10 members from the agriculture industry (including specialists in genetically modified crops, environment, animals and toxicology) and others from molecular biology, cell fermentation, pharmacology, immunology and clinical medicine. Even the CDSCO, a national regulatory authority, and its rDNA-derived biological products committee and Drug Technical Advisory Board (DTAB), which deals with all chemical and biological drugs, lack experts in the field of biosimilars. An article by Ms Amy Duval, Senior Director of Biosimilars at healthcare research organization Decision Resources Group highlighted various issues in the Indian pharmaceutical market, including the use of non-originator biologicals, poor IP protection and improperly conducted clinical trials. Overall, she suggested price, not clinical data, is the key driver in the Indian market [17]. In this same article, a number of scientists discussed weaknesses in the composition of RCGM and CDSCO regulatory boards [17], although the RCGM committee is overdue for reconstitution. RCGM committee members, after examination of a dossier, meet every 45 days and only interact with the sponsor for approximately half an hour. This consists of a presentation on physicochemical and bioassay results, followed by presentation of toxicological data. Recently, many of the members of newly reconstituted RCGM do not have regulatory and biosimilar expertise and the committee now meets monthly. Overall, the casual approach taken by non-subject experts in committees that approve NIBPs is a major cause of concern in India.

The biosafety of genetically modified plants crops and the development of biosimilars are two vastly different subjects which I believe should be regulated by separate expert committees, although this is not the case at present in India. The Genetic Engineering Appraisal Committee (GEAC), under the Ministry of Environment, assesses the risk to the environment of imported rDNA biological products, but does not have any experts on biosimilars. Furthermore, a conflict of interest can be seen in some members who have ties with firms developing biosimilars. Other issues include a lack of pre-meeting with manufacturers to help them solve their technical problems, limited interaction between committees of different ministries and delays in the production of suitable biological products. In India, multiple different ministries deal with rDNA-derived therapeutic biological products. In contrast, the US and EU provide several pre- and post-drug application submission meetings. Furthermore, drug applications in the US and EU are submitted through a single window system and the proposal is examined by a large number of subject experts in a time-bound manner.

Violation of Indian guidelines on ‘similar biologic’
There are several major violations of the official biosimilar guidelines by Indian manufacturers and regulators. These include the use of only three lots of test drug and a single lot of reference biological (three or more lots recommended by RCGM after 31 August 2018) sourced from India, or if from abroad then without performing bridging studies. This is in opposition to the required 10 or more batches each of the reference biological and test drug [13]. Another common violation is the failure to properly establish biosimilarity, i.e. not checking whether critical test results fall into a predetermined goal post/range based on results from the IRBP. These issues are linked, as the required range of critical tests cannot be performed on a single lot of reference biological.

Determination of molecular mass by peptide sequencing and molecular weight by SDS-PAGE, non-specific western blot, impurity testing by SDS-PAGE and size exclusion chromatography (without validation) are commonly performed to assess molecular similarity. Improper performance of functional bioassays and binding assays for establishing biosimilarity, as well as misunderstanding of the term reference standard, by the RCGM committee show a lack of basic expertise. For more reading on this, the differences in reference biological and reference standard are well highlighted by the work of Drs Robin Thorpe and Meenu Wadhwa [18]. Further, drugs showing only partial biosimilarity at the quality level are frequently (and improperly) recommended for pharmacological and toxicological studies in animals.

The committee of clinical trials (part of CDSCO) is of the nature that, without verifying the results of quality and pre- clinical testing, the clinical trial of a proposed test drug can be conducted without using a sufficient number of patients and without statistical equivalence margin testing [9]. Non-inferiority tests may be performed, but tests are not performed to rule out the superiority of a biological test product with the IRBP at a suitable confidence interval. Furthermore, clinical trials have been conducted with inappropriate reference biologicals. For example, Actorise (darbepoetin alfa, Hetero) was compared wrongly to epoetin alfa, and not with the required biological Aranesp (originator darbepoetin alfa, Amgen) during the clinical trial CTRI/2012/07/002853. Similarly, pegylated filgrastim GCS-F (Wockhardt Ltd) was inappropriately compared with non- pegylated GCS-F Neupogen (Roche) (CTRI/2009/091/001016). Further, Dr Reddy’s Reditux has not been subjected to head-to- head comparison with the originator rituximab in clinical trials.

Double standards of Indian manufacturers on biosimilars and NIBPs
Often, the same companies make substandard quality NIBPs for India and high quality biosimilars for export. In 2014, Mylan (USA) and Biocon (India) launched Hertraz and CANMab, two biosimilars of trastuzumab, in India, without adhering to the Indian biosimilar guidelines. The companies could not obtain US approval for their products because of stringent regulation, leading them to anticipate rejection of their application. Instead, they gained approval for a new biosimilar (MYL-1401O Ogivri of trastuzumab-dkst) fulfilling the regulatory requirements of FDA. Referring to the FDA briefing document (Oncologic Drugs Advisory Committee Meeting 13 July 2017), it is possible to understand the difference in the quality of the product launched in India and the same drug approved in the US [19]. In India, the established procedure for developing biosimilars, e.g. establishing required critical attributes range, performing complete orthogonal bioassays and binding assays, was not followed.

Similarly, Apotex (via its European market arm, Accord Health- care) gained market access in the EU to a biosimilar filgrastim, manufactured by Intas Pharmaceutical Limited (India). The biosimilar supplied in the EU is likely to be of higher quality than that approved and marketed in India because of the requirements of EMA, which, for example, requires sufficient numbers of test and reference biological lots, i.e. 10 or more, and the performance of validated biological and binding assays. Such requirements are missing in India.

Lack of transparency in approval of Indian NIBPs
There is high transparency in the approval procedure followed for licensing and marketing of innovator biological drugs or their biosimilars by the FDA and EMA. Moreover, technical assessment reports of approved complex biological products are scientific in nature and shared by these experienced and globally recognized agencies through their websites, which are available in the public domain. In contrast, there is a total lack of transparency of such technical information in India. Even approved lists of IRBPs or NIBPs are unavailable. Similarly, other scientific information used for the approval of biological products is not shared. Many of the innovator companies of blockbuster (sales of more than US$1 billion per year) biological products have not filed patent applications in India, leading Indian regulators to permit the marketing of domestically developed copies. Of course, this policy is in the public interest (as it reduces cost) but can compromise the quality and efficacy of biosimilar products. Under the TRIPS Agreement [20], pre-1995 product patents do not apply in India. Furthermore, because innovators have not sought patent protection for some drugs in India, there is an opportunity for Indian companies to supply other countries where these IRBPs have not been patented. Indian companies are therefore often more interested in the development of NIBPs than biosimilars as they can be sold domestically and exported to unregulated/semi-regulated countries.

Policies for approval of domestic and imported rDNA- derived therapeutic biological products
Biological products developed in India from imported rDNA clones are regulated by the RCGM (until the preclinical testing stage, with the exception of rDNA-derived coagulation factors VIII and IX, which are regulated by CDSCO as a conventional blood product), whereas imported biosimilars and IRBPs are regulated by the CDSCO. In the US and EU, manufacturers must conduct exhaustive characterization and biosimilar assessments as part of the information submitted to support their marketing authorization/licensing application. In India, however, biosimilarity is taken for granted by the CDSCO. In fact, there is no government-approved and notified laboratory which can verify the biosimilarity of a biosimilar made by any manufacturer in India. Rather, such biological products are tested as per drug product specifications. An rDNA-derived product expert committee of the Indian Pharmacopoeia Commission (IPC), India is intended to make suitable standards, but so far, no progress has been made on developing reference standards for complex biologicals, such as therapeutic antibodies. Problematically, these bodies work independently and lack experts on biosimilars. Major scientific and regulatory gaps among the various committees coupled with a lack of professionalism and expertise have resulted in the approval of a large number NIBPs with uncertain safety and efficacy, and therefore associated with patient risk.

Indian non-innovator biological products (NIBPs) in the global regulatory context Views of global institutions on Indian NIBPs

Medicines regulatory authorities such as the EMA, FDA and WHO lack confidence concerning the quality of rDNA-derived biological products manufactured by Indian companies, based on what had been approved in India previously [17, 21-24]. Studies conducted on Indian NIBPs of erythropoietin (Wockhardt), Etanercept-etacept (Cipla), Intacept (Intas), Rituximab (Dr Reddy’s) and insulin (Marvel Science Pvt Ltd) for example, have shown significant differences in critical attributes when compared to their respective reference biological [21, 22]. The case of chronic kidney disease patients treated with an erythropoietin NIBP in 2007–08 developing pure red cell aplasia is a well reported example of adverse effects being caused by such drugs [21]. These incidences hint to the poor quality and questionable safety of NIBPs approved in India. There are many similar reports highlighting the non-scientific approval of NIBPs in India [23-26].

This point has further been emphasized by the Generics & Biosimilars Initiatives (GaBI), an authoritative resource on global developments in the field of generics and biosimilar, which states when a new Indian NIBP is approved that: ‘It should be noted that Similar Biologics approved in India might not have been authorized to as strict a regulatory process as is required for approval of biosimilars in the European Union. The European Medical Agency (EMA) regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biological, and also include a rigorous comparability exercise with the reference product’ [27].

Further, the Indian Chronicle Pharmabiz, a pharmaceutical newsletter, reported in 2017 that Indian regulations for biosimilars are not as demanding as FDA or EMA regulations [26]. There is less emphasis on the demonstration of biosimilarity during preclinical development and during clinical trials and sample size is often not driven by statistical considerations [9]. Consequently, Indian pharmaceuticals cannot be approved as biosimilars in developed countries, as they have not undergone the strict development process required for an FDA or EMA marketing authorization application. Therefore, Indian NIBPs have limited export potential. Moreover, India has been producing ‘intended copies’ of already licensed biological products since 2007 under an abbreviated approval process that relies on limited efficacy data, thus allowing local biopharmaceutical manufacturers to keep production costs low. These intended copies do not meet the strict criteria for demonstration of biosimilarity that regulatory bodies such as EMA and FDA require for review and approval of biosimilars. As a result, the Indian company Marvel Life Sciences officially notified the EMA Committee for Medicinal Products for Human Use (CHMP) in December 2007 that it would withdraw its application for MA for their biosimilar human insulin as they were unable to meet the standards for comparability [22].

In 2018, a study of rituximab samples from five different Indian manufacturers revealed failings in all or some comparability tests including peptide sequencing, antibody dependent cell Cytotoxicity (ADCC), purity, charge variant and glycan testing, when compared with the reference biological [23]. Similar findings have been reported on several occasions, including by the CII-Sathguru Biosimilar report of 2018, which showed that NIBPs manufactured in India are of uncertain quality and cannot be exported to more developed and highly regulated countries [25].

WHO guidelines for assessment of risk-benefit of NIBPs already in the Indian market
In recognition that certain WHO Member States have registered NIBPs using regulatory pathways that are inconsistent with the WHO guidelines for biosimilars, in 2016 WHO developed guidelines that provide a roadmap for regulatory assessment of NIBPs [28]. The guidelines clearly state that biologicals registered without a comprehensive head-to-head comparison with an IRBP should not be classified as biosimilars, because little is known about the safety or efficacy of such products. The guidelines recommend a stepwise approach for regulatory assessment of such bio-therapeutic products taking into consideration the risk: benefit ratio of keeping the products on the market, missing elements from the original dossier and the procedure for obtaining additional data from the sponsor [28]. This WHO recommendation is currently not complied with in India and NIBPs remain in use. The majority of IRBPs provide 60%–85% more benefit than risk. NIBPs developed without following the guidelines on biosimilars are likely to have a much lower benefit to risk ratio.

Confusing nomenclature and substitution of NIBPs
Each biological product has an international nonproprietary name (INN) which reflects scientific characteristics such as chemical structure and pharmacological properties. This name differs from the proprietary name, which is generally a trade- mark and registered for private use and may change over time. In the US, FDA has introduced the addition of a distinct four-letter suffix to the non-proprietary name of a biological. This helps the prescriber to differentiate between the biosimilar and its respective IRBP in the event of adverse reactions occurring during pharmacovigilance. This raises the question of whether such nomenclature could be applied to NIBPs, in order to help track these products in the market. Most importantly, the nomenclature on the label should be clear and easily identify the rDNA-derived therapeutic biological product.
Related issues include substitution, switching and interchangeability, both among biosimilars and between biosimilars and reference products, which have not been fully addressed by the latest iteration of the Indian biosimilar guidelines (2016). These practices should not be adopted by physicians until these issues are resolved. In the EU, the decision of interchangeability is left to individual Member States. On the other hand, in the US there remains regulatory uncertainty regarding biosimilar substitution. This has long been a market access concern for manufacturers because, although an interchangeable biosimilar product can be substituted for reference product without provider intervention, no approved biosimilars have so far been deemed interchange- able by FDA. As mentioned, India’s policy on substitution, switching and interchangeability is yet to be established.

WHO pilot prequalification programme for rituximab and trastuzumab
WHO has recently initiated a pilot prequalification (PQ) programme to increase the affordability and accessibility of essential biological anticancer drugs (rituximab and trastuzumab) in low- and middle-income countries. Indian manufacturers of these biologicals can in theory qualify for the WHO programme for the development of affordable and quality biosimilars (for domestic use as well as export). However, because Indian regulators do not follow WHO guidelines on biosimilars, the CDSCO and NIB may struggle to comply with the programme. It is recommended however that manufacturers intending to comply with WHO’s biosimilar guidelines should participate in the PQ programme in order to provide affordable biosimilars, and therefore assist patients in low- and middle-income countries like India.

Copycat versions of patented drugs from Bangladesh
Another important issue to address is the fact that India is flooded with NIBPs of patented cancer drugs from Bangladesh [29]. These drugs are supplied to Indian importers using a loophole in the Intellectual Property Right (Imported goods) Enforcement Rules (2007) [30]. According to these rules, no action can be taken against goods of a non-commercial nature contained in personal baggage or sent in small consignments intended for personal use of the importer. Taking advantage of these rules, certain suppliers obtain copycat versions of patented drugs. Such drugs can be imported into India for personal consumption, avoiding the scrutiny of custom authorities, and then sold through illegal channels. As per the Drugs and Cosmetic Act 1940 [31], any drug which is not licensed by Drug Controller General India (DCGI) cannot be sold in the country, but copycat versions of patented drugs not licensed in India are slipping through the net [27]. There is therefore an urgent need to check entry of such suspicious biological products in India by making a suitable amendment to the Drugs & Cosmetic Rules 1945 [31].

Conclusion

Biosimilars produced using established, science-based principles are desirable for their reasonable prices as well as safety and efficacy which is comparable to the reference product. This requires step-by-step characterization of the biological product using validated and highly sensitive orthogonal assays including physicochemical assays, bioassays and binding assays, which are able to detect even minor differences between the biosimilar and reference biological, followed by preclinical and clinical testing. Establishment of biosimilarity of the test product with the reference biological is even more important than molecular identity. However, it is evident that there are major lapses in the manufacturing of rDNA-derived therapeutic biological products in India, approved as ‘New Drugs’ (as per Drugs & Cosmetic Rules 122 E, Government of India) in violation of the Indian similar biologic guidelines 2016.

There is a lack of expertise in the development of biosimilars in India, evident from the use of non-validated bioassays and binding assays, for example. Simply comparing the test results of the proposed biosimilar with results from a single lot of reference biological yields NIBPs of either inferior or superior quality, which could have unknown consequences in patients and are not permitted as per global biosimilar guidelines. Other issues include the failure to perform proper pharmacokinetic and pharmacodynamic studies in suitable animal models and, more seriously, the failure to follow biosimilar guidelines and conduct clinical studies in humans. There is a misconception that few major differences in critical quality attributes at quality level can be resolved during the clinical trials. This practice is not permissible by any biosimilar guidelines. In fact, clinical data cannot be used to justify substantial differences in quality attributes [32]. Despite revisions to the Indian Similar Biologic Guidelines in 2016, there remains no significant improvement in the quality of rDNA-derived therapeutic biological products in India. The guidelines are brief, vague and only partially complied with. These major scientific deficiencies and a lack of interaction between various governmental organizations, e.g. CDSCO, RCGM, ICMR, AIIMS, IPC, NIB, have derailed India’s attempt to provide quality biosimilars to low-and middle-income patients.

It is known that testing based on pharmacopoeia specifications alone cannot ensure the safety and efficacy of rDNA-derived biological products [33]. Thus, rDNA-derived products must be tested using biosimilar principles, not only on the basis of conventional pharmacopeia specifications. Information available on the website of the Indian drug regulator CDSCO [1] suggests that not a single batch of rDNA-derived therapeutic proteins has been found to be of substandard quality by the NIB. However, I assert that this is due to a lack of subject expertise within the NIB, meaning testing of such products is done based only on specifications given in pharmacopoeia or provided by sponsors. There was an opportunity to obtain scientific benefit when a Memorandum of Understanding (MoU) was signed between the Medicines Healthcare Products Regulatory Agency (MHRA) and CDSCO on ‘Regulatory cooperation’ on 5 October 2015, but it seems Indian regulators (CDSCO, RCGM, NIB, IPC) have not benefited from this. I believe that if the MoU had been properly utilized by Indian regulators, there would have been a greater chance of improving the quality of Indian biosimilars.

Although the cost of a limited number of NIBPs, e.g. rituximab, trastuzumab and bevacizumab, can be controlled by the government, the quality of these and other critical drugs seem to be compromised. The non-reimbursement of expenses for costly NIBPs by insurance companies and their limited availability in the Jan Aushadhi and Ayushman Bharat Programmes (to treat low-income patients) are a cause of concern and must be addressed as a priority.

Quality concerns over NIBPs manufactured in India have been raised on many occasions, including as mentioned above and also by Professor Malhotra of SMS Hospital, Jaipur, India in 2011 [24] and Neher Nupur et al. of Indian Institute of Technology, New Delhi, India in 2018 [23]. The potential for low quality NIBPs to generate unanticipated clinical outcomes should not be overlooked. There is a need to identify the major scientific gaps in the manufacturing process through a technical audit conducted by biosimilar subject experts, from institutions such as WHO, EMA and FDA. There is precedent for this in India, where WHO National Regulatory Authority (NRA) inspections are carried out for the Indian regulator CDSCO and their Central Research Institute (CRI) in Kasauli, Himachal Pradesh, which is responsible for manufacturing human vaccines. WHO NRA inspection periodically assesses the quality control system, the experience of laboratory personnel involved in certifying the quality of vaccines and documentation of manufacturing facilities by assigning a suitable grading percentage (25%, 50%, 75%, 100%). Assignment of a grade of below 75% means improvement is required. CDSCO and CRI are qualified by WHO for the inspection of facilities that manufacture immune sera and vaccines.

The recommendations of such a scientific audit could include increased interaction between different ministries, provision of biosimilar experts in government committees, provision of training for regulators and laboratory personnel and their regular participation in various biosimilar workshops. Such recommendations, along with strengthening of the accreditation system, pharmacovigilance, post-marketing surveillance and protection of IP rights could certainly help the Government of India in significantly improving their technical committees and guidelines for producing rDNA-derived therapeutic biological products. Necessary help should be obtained from domestic or overseas companies with expertise in supplying biosimilars to developed countries and the government should involve their own or other well-regarded experts in various committees. Even a one-time audit exercise could help to restore the confidence of foreign prescribers in Indian biosimilar products.

Finally, it is reiterated that the Government of India, which recently initiated universal healthcare coverage with the Ayushman Bharat Programme, should consider the inclusion of as many biosimilars as possible in its public health schemes. The vision of the Indian drug regulator, CDSCO, to protect and pro- mote the health of its citizens can be achieved by protecting the supply of domestically produced, high quality biosimilars and phasing out NIBPs of uncertain quality which are currently being used in the country.

Competing interests: The author declares no conflict of interest.

Provenance and peer review: Not commissioned; externally peer reviewed.

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