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With many new therapeutics approved annually, the demand for biologics has seen exponential growth in the pharmaceutical market.

In the bioanalytical community, the study of large molecules is now a hot topic of discussion.

The snowballing importance of peptides and proteins as therapeutic agents, combined with the colossal opportunities offered by new MS-based technology, has unlocked a new world for bioanalytical scientists.

Ligand-binding assays (LBAs) such as enzyme-linked immunosorbent assays (ELISA) or UV identification of individual peptides using high-performance liquid chromatography (HPLC) are the standard methods for the quantification of biologic drugs.

However, these methods are typically expensive, are time-consuming to develop, and have limited selectivity and antibody cross-reactivity.

This results in a lack of interference specificity and high background levels that are not appropriate for fulfilling the specifications of the biopharmaceutical industry to identify different proteins and peptides with increasing sensitivity and reproducibility.

Liquid chromatography combined with tandem mass spectrometry (LC-MS-MS) has been widely used for small molecule bioanalysis in pharmaceutical laboratories since the 1980s.

Like smaller molecules, LC-MS-MS also carry advantages for biologics:

• It is not susceptible to cross-reactivity of the antibody because LC-MS-MS involves direct assessment of the analyte’s chemical properties.
• It provides excellent selectivity, being able to discern and quantify extremely homologous isoforms with precision and accuracy over a large linear dynamic range, even at low levels.
• Due to its high analytical sensitivity and selectivity, in addition to its high-throughput capability, LC-MS/MS has been considered the primary technique to measure the concentrations of first-generation and second-generation antipsychotics in schizophrenia patients.

Mass spectroscopy has gained increased interest for peptide and protein analysis over LBA because:

• LBA detects molecules based on binding affinity and 3D conformational structure, but it may not be able to distinguish between a protein and its metabolites.
• In contrast with LBA, MS-based approaches have the potential and would be able to produce more precise data on unchanged peptide/protein levels in situations where metabolism hampers reliable LBA data.
• MS techniques usually offer absolute concentrations of medications. This can depend on the form of an assay for LBA methods, and they may provide either an absolute or free concentration of drugs.

However, LC-MS-MS-based bioanalysis for large molecule drugs poses a range of new obstacles, like difficulties in sample processing and extraction measures for the quantification of large molecules.

The reasons include the following:

• The background peptides and proteins in the biological matrices compete with the biotherapeutic molecule of interest, creating interference problems and impacting accuracy.
• The lack of significant evidence during quantification arises from being unable to catch free drugs that may circulate in serum.

Recently, many LC-MS-MS technological advancements have been made that can help solve all of these concerns.

In particular, the increase of ionization efficiency and ion transmission in recent triple quadrupole instruments has greatly enhanced sensitivity, allowing biologics to be detected at picogram or sub-femtogram levels.

Advances in technologies inside the LC-MS-MS include improved ion collision focusing, which brings more ions to the detector, as well as upgrades to the dynamic range of the detector to increase bioanalysis sensitivity and efficiency.

Recently, there has been a growing interest in integrating LBA immunoaffinity enrichment with LC-MS-MS quantification to integrate LBAs with the sensitivity and selectivity of LC-MS-MS technologies with greater precision and wider immune capture capabilities.

Automated Column-switching LC–MS/MS, Microextraction packed sorbent (MEPS)/LC-MS/MS, and Disposable Pipette extraction (DPX)/LC-MS/MS are some of the recent techniques that have been used to quantify large molecules.

Two major methods are widely used when using LC-MS/MS-based technologies for the bioanalysis of large molecules:

1. Intact analyte LC–MS(/MS) approach

This approach is predominantly used for peptides, small proteins, and oligonucleotides with a molecular weight typically below 4–8 kDa.

2. LC–MS/MS approach using a digestion step

This approach is more complex and mainly used for proteins or larger peptides.

This approach involves an (enzymatic) digestion step in addition to the intact analyte approach, where the protein/peptide is digested into smaller peptides.

Today, it is most common to use traditional LC-MS/MS triple quadrupole instruments for quantification for both the intact and the digested analyte approaches.

According to the existing standards, 4-6-15 (four out of six QC samples should be within 15% of the nominal value) is used as an approval criterion for large molecular LC-MS/MS assays. 4-6-20 approval requirements are proposed for larger intact analytes, in particular, if a hybrid LC-MS/MS approach is used.

A labeled peptide for peptide analysis or either a labeled intact protein or a labeled signature peptide can be used as an Internal Standard (IS) to establish a successful LC-MS/MS method.

Several guideline documents have been issued by the ICH and FDA to help standardize large-molecule bioanalysis studies. These recommendations can be found on the website of the appropriate regulatory agency.

While LC-MS-MS technologies have progressed to be more appropriate for biological bioanalysis, for non-experts who need to create and measure new biologics, the variety of mass spectrometry technologies and techniques, sample preparation methods, and reagents could be overwhelming.

The new advances in instrumentation and software will bring substantial changes in the consistency and efficiency of bioanalysis tests, providing more accurate and compliant results with significant patient safety consequences.

REFERENCES

1. Suma Ramagiri, Trends in Bioanalysis Using LC–MS–MS. The Column, The Column-12-07-2015, Volume 11, Issue 22.
2. Magnus Knutsson, Ronald Schmidt & Philip Timmerman, LC–MS/MS of large molecules in a regulated bioanalytical environment – which acceptance criteria to apply? Future Science, BIOANALYSIS VOL. 5, NO. 18, https://doi.org/10.4155/bio.13.193

 

Advancement in medical sciences has benefited humanity in many ways. However, in the process of conducting clinical trials, incidences of scientific, moral, and ethical misconduct have been unearthed that have shaken up the scientific community and public. This led to the formation of a formal organization in 1979 by the United States (US) namely the “International Ethical Guidelines for Biomedical Research Involving Human Subjects” to protect and safeguard the interests of trial subjects. Following this, many countries drafted their own guidelines for Good Clinical Practices (GCP). However, with increasing number of clinical trials being conducted at sites in multiple countries, it was necessary to have a uniform guideline for conducting clinical trials. This gave rise to the International Conference on Harmonization (ICH)-GCP guidelines in 1996 with the objective of providing a uniform standard that facilitates the acceptance of clinical trial data by the regulatory authorities of the respective countries. Over the course of time, many countries adapted the ICH-GCP guidelines to frame their own guidelines. India too followed suit with the Indian Council of Medical Research (ICMR) introducing the “Ethical Guidelines for Biomedical Research on Human Subjects” that is continuously revised and amended to ensure that clinical trials are conducted with utmost quality, giving priority to the welfare of the subjects involved.1

India – A global destination

India is emerging to be a favorite destination for clinical trials for many international companies due to several factors:

☉  Conducive Regulatory Environment: Internationally harmonized and favorable regulatory processes such as fast track approval of investigational new drugs making the Indian clinical research environment more amenable to conducting clinical trial. Market trends show a compound annual growth rate (CAGR) of approximately 12% (US dollars 987 million) in the Indian clinical trials industry from US dollars 500 million in 2017.1,2,3,4,5

☉  Trained Manpower: Availability of skilled healthcare professionals who are specialists in different therapy areas, well-versed in the English language and who ensure compliance to ICH-GCP guidelines.1,2,3

☉  Technology Infrastructure: World-class technologies in data management and information technology and related services.1,2,3

☉  Patient Pool: Large population who are treatment naïve and have a diverse genetic and ethnic makeup. With India becoming increasingly urbanized and with greater connectivity between the urban and rural areas, it becomes convenient to recruit patients from different geographical areas. In addition, there is a high incidence and prevalence of acute and chronic diseases due to lifestyle changes leading to diseases such as diabetes, cancer, and so on. Such lifestyle-related disorders open up the possibility of conducting more clinical trials in these disease areas.1,2,3,6

☉  Ease of recruitment: In countries such as the US, approximately 86% of the clinical trials fail to recruit the required number of subjects leading to delay of almost a year. This delay costs the sponsor company several million dollars. Some of the reasons for delayed recruitment are unwillingness of patient to participate, stringent safety requirements, and hefty compensation packages. India provides the possibility of recruitment of patients with relative ease with due to increased trial compliance and transparency especially with the recent release of the New Drugs and Clinical Trial Rules 2019 that consists of updated rules and regulations for fast tracking approval of clinical trials. Among countries with fast growing economies, it has been noted that India has a growth rate in recruitment sites of approximately 22.6% with the highest growth rate seen in China (≈36%).1,2,7,8

☉  Competitive costs – Cost effectiveness is a pushing factor for many trials being shifted to India. The cost to develop a new drug is estimated to be almost 50% less than what would be required in the US or in the European Union. 1,2,3

Future of clinical research in India

Specific guidelines are being worked upon by the Central Drugs Standard Control Organization (CDSCO) for stem cell research, biosimilars, and medical devices to protect patients as well as to encourage clinical research and development in the country. After a lull period in the Indian clinical industry before 2015 due to ethical and quality concerns, open communication between sponsor representatives and the regulatory team of CDSCO has helped in reconsidering India once again as a potential global destination for enrolling a diverse population in clinical trials that adhere strictly to ICH-GCP guidelines.6

Sources

1. Das NK and Sil A. Evolution of Ethics in Clinical Research and Ethics Committee. Indian Journal of Dermatology. 2017 Jul-Aug;62(4):373-9

2.Burt T, Sharma P, Dhillon S et al. Clinical Research Environment in India: Challenges and Proposed Solutions. Journal of Clinical Research and Bioethics. 2014;5(6):1-8.

3.Bajpai V. Rise of Clinical Trials Industry in India: An Analysis. Hindawi Publishing Corporation. Review Article. ISRN Public Health. 2013:http://dx.doi.org/10.1155/2013/167059

4.Melissa Fassbender. India poised to become ‘one of the largest clinical trial hub’ says CRO. (2018). https://www.outsourcing-pharma.com/Article/2018/08/13/India-poised-to-become-one-of-the-largest-clinical-trial-hubs-says-CRO?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright Accessed on May 12, 2015.

5.https://www.medgadget.com/2019/01/india-cro-market-growing-at-an-impressive-cagr-of-12-by-2023-says-recent-study.html Accessed on May 12, 2015.

6.Reconsidering India as a Clinical Trial Location. Pharm-Olam. https://cdn2.hubspot.net/hubfs/4238150/PharmOlam_March2018/PDF/pharm-olam_india_clinical_trials_white_paper_1.pdf?t=1524594556831 Accessed on May 14, 2019.

7.Pathan IK, Nuthakki S, Chandu B et al. Present Scenario Of Clinical Trials In India. International Journal Of Research In Pharmacy And Chemistry. 2012;2(2):ISSN: 2231-2781

8.Luo J, Wu M, & Chen W. Geographical Distribution and Trends of Clinical Trial Recruitment Sites in Developing and Developed Countries. Journal of Health Informatics in Developing Countries. 2017;11(1). http://www.jhidc.org/index.php/jhidc/article/download/157/211

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Veeda through its V-Konnect series interacted with Dr. Susobhan Das and discussed about “Current outlook of Biosimilar Development”

About the V- Konnect

V-Konnect interview series, is a program to get in touch with specialized industry experts to know their views on opinions on current relevant subject matters.

About Dr Susobhan Das – Founder & CEO at Amthera Life Sciences

Dr. Das is a Founder & CEO of Amthera Life Sciences Pvt. Ltd which is a preclinical stage Biosimilar Drug development company based at Bangalore.
Dr. Das has extensive techno-commercial experiences in early stage Biologics Development. He has 20 years of experience in advanced biotechnology research and Biopharmaceuticals development. He has served as a member of USP Biologics and Biotechnology Expert Panel and also worked as a Director at United States Pharmacopeia, India site.
Dr. Das has also worked at senior management level at Intas Pharmaceuticals developing Biosimilar for global markets.
Dr. Das has worked as member of Expert committee on Biologicals and rDNA Products: Indian Pharmacopeia Commission (IPC); Govt. of India. He has authored research papers which are published in peer-reviewed National and International journals

Transcript.

1. What are the key international developments with respect to EU and
USFDA biosimilar requirements?
A: One key development towards biosimilar acceptance has been the issuance of guidance on “interchangeability” by US-FDA in May this year. This will pave the way for the substitution of one product for the other without a prescriber’s involvement, as is the case for generic small molecule pharmaceuticals. This I believe, is a significant action and will promote competition in the biologic market in the US.
Another development is the issuance of a revised guidance by FDA titled “Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality Considerations” also in May this year. This is the revised version of an earlier guidance titled “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” published on April 30, 2015. FDA says this revision is to reflect on agency’s recommendations on the design and evaluation of comparative analytical studies intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product and in anticipation that this will provide additional clarity and flexibility for product developers on analytical approaches to evaluating product structure and function.
For Europe, although approval rate of Biosimilars are much higher that the US, uptake of biosimilars are somewhat country specific, with the large EU5 countries still do not have interchangeability options. However, payers have significantly employing various tools which may lead to higher biosimilar uptake. For example introduction of prescribing target i.e. prescribing biosimilars to a predetermined percentage of patients. NHS of UK introduced biosimilar adoption framework with the idea that switching of patients to a biosimilar may be inserted into clinical practice with incentive offerings for staff to offset switching costs. This year in May, NHS has published a document titled “what is a biosimilar medicine” for clinical and nonclinical stakeholders about the role of biosimilars in the healthcare system. The document explains among many others aspects, on the overall savings from Biosimilars as well as suggest that a prescriber can switch from a reference to a biosimilar product. However, switching at the pharmacy level is still not permitted without the consent of the prescriber as of now.

2. What are the main attributes for higher market approvals of Biosimilars in Europe compared to the US?
A:The first biosimilar, Zarxio, approved in the United States only in 2015 whereas Omnitrope, another biosimilar was approved by the European Medicines Agency (EMA) way back in 2006. Since then, the EMA has approved more than 40 biosimilars as of 2019. Essentially this shows that EMA as the pioneering agency to advance biosimilars approval and uptake for the world. To understand this one may refer the concept paper on the development of a guideline on the comparability of biotechnology-derived products published in 1998 which led to the introduction of a directive in EU legislation with the idea of “similar biological medicinal product” in 2001. Therefore, definition and a legal framework for market authorization for Biosimilars was first introduced in the world by the EU and is monitored and updated on an ongoing basis which is key for larger market approval rate of biosimilars in the EU. By now the EU has already an experience of over a decade of Biosimilar use and established the fact that biosimilars have similar efficacy and safety concerns as that of the reference products and can save a significant portion of healthcare costs. Only three official biosimilars is in the market in the US, although around 15 are approved and their uptake has been slower than anticipated. For example less than 15% for filgrastim biosimilar and 3% for the infliximab biosimilar holds as market share. This is partly due to the lack of pricing incentives from biosimilars as well as more attractive contract offers from the innovator product. A host of other reasons for this slow approvals and uptake could be considerations on overall quality, safety, and clinical efficacy of the biosimilar plus manufacturer reliability (supply without disruptions), reimbursement rates set by insurance companies or commercial payers, and support services for health care professionals and patients. In other words, assurance on the efficacy and safety from the providers as well as less out-of-pocket expenses is key to most US patients. Currently this is yet to happen in the US, although progress has been made to achieve these goals. On the contrary, a range of different policies to generate pricing pressure, drive adoption, and ultimately yield cost-savings for their healthcare systems have been implemented in the EU countries which somewhat led to higher uptake rate for the biosimilars.

3. What is the scenario of prescribers’ acceptance of biosimilars over the
innovator biological products?
A: In the beginning of biosimilar era, it was the differences between lots in quality characteristics were cited to be reason enough for great concerns on efficacy and safety of the product. From this we have come to a stage where regulatory agencies have formalized acceptable changes of quality characteristics in the “innovator products” with no impact on efficacy and safety. We also have for more than a decade of real world experiences of biosimilar use with comparable efficacy and safety concerns in the EU. Moreover, we now have the outcome of NOR-SWITCH trial which demonstrated that “switching from infliximab originator to CT-P13 [a biosimilar] was not inferior to continued treatment with infliximab originator”. All of these experiences I believe, has led to higher prescribers’ acceptance of biosimilars over the innovator product given there is incentives attached all through the stakeholders chain (for example for the provider, prescriber, payer and insurer). The EU is clearly way ahead in implementing policies with the above considerations and will reap benefits hugely in the healthcare cost savings. Although slow, the US has finally initiated action that may eventually allow biosimilars to be interchangeable with the innovator product. First to this idea was the finalization of the guidelines on interchangeability this year in May.

4. What is your opinion on Indian biosimilar industry, whether it attained its
potential or this just the beginning of the journey?
A:Indian biosimilar industry has now been very firmly established with defined
regulatory path and a number of large and medium manufacturers with more than 70 biosimilars approved. India is also the first country to approve a biosimilar monoclonal antibody to Rituximab in 2007 and interestingly without having a published guideline which first appear in the year 2012 and in a revised form in 2016. This approval has tremendously helped the patients to have access to the product with almost half the cost of the innovator product. Interestingly, another mAb, Trastuzumab indicated for HER2 positive breast cancer is now available at almost 65% less than the innovator price, due to the launch of an Indian biosimilar. Moreover, 3 companies from India has biosimilar products registered in the US, the EU and Japan. This shows the maturation of Indian biosimilar industry as a global player. These facts although very positive, India still has huge gaps in filling up the affordability factor with its very low per capita income populace. On the contrary, India has very high number of incidences and disease burden in most therapeutic segments such as Cancer, Diabetes, Infections, Arthritis, Blood factor disorders etc. Therefore, affordable and quality biosimilars is a big opportunity for India. However, what is critically needed is a policy framework somewhat similar to that is being followed in the EU which incentivizes all the stakeholders involved with biosimilar use including the insurance sector. Unfortunately, medicine costs in India is largely an out-of pocket expense and this needs to change very rapidly. Given these policies are
implemented, Indian biosimilar industry has tremendous potential to impact healthcare in a significant way.

5. Where does China stand with biosimilar approvals and the regulatory
requirements?
A: This year in February Chinese regulators approved their first biosimilar. A biosimilar Rituximab indicated for non-Hodgkin’s Lymphoma. Although biotherapeutics development in China continue to grow exponentially over the past decade, no biosimilar drug however was approved until 2019. This is primarily because of lack of a national regulatory guidance which was first published in February 2015. This guidance document followed the same principles and requirements consistent to that as formalized by FDA and EMA. Some other changes also happened simultaneously to foster pharmaceutical approvals and market authorizations such as China Food and Drug Administration (CFDA) is now National Medical Product Administration (NMPA) which falls under the State Administration for Market Regulation (SAMR). The Centre for Drug Evaluation (CDE) which reviews applications under NMPA remains without change in function. China currently has more than 200 biosimilars under clinical development. Interestingly two key recent development in policy setting by NMPA can be seen either as a barrier to biosimilar growth or bring serious competition : One is listing of foreign made drugs for urgent unmet medical needs which can be approved for registration without any clinical trials being conducted in China. 48 such drugs have been listed for public review, out of which 11 are biologic drugs. The second one is reduced or no import cost of new cancer drugs or drugs for hard to treat cancer. Another very interesting development is the Market Authorization Holder [MAH] program implemented by the Chinese regulatory agency as a pilot program which allows holders of a NMPA biologics approval will have an option to manufacture the drugs on their own or use any contract manufacturer. This policy has given significant boost to the CMO industry inside China and will surely foster growth in the Chinese Biosimilar industry along with new drug development.

6. How switching and interchangeability affect biosimilars access and its
market size?
A:EMA and EU commission defines 3 terms related to biosimilar switching:
interchangeability, switching and automatic substitution. Interchangeability is a general term which includes both switching, when the prescriber decides to use one over another and substitution when this exchange happens at the pharmacy level without the consultation of the prescriber. In the US though FDA designated interchangeability may refer to automatic substitution at the pharmacy. Europe has been at the fore front in terms of interchangeability and currently allow physician guided transitions of biosimilars restricting pharmacy level substitution and this is without any separate or additional
regulatory guideline or drug development criteria. As a result we see a very high uptake of Biosimilars in some select EU countries. Therefore, we may envisage that interchangeability or substitution will surely bring competition as well as uptake and cost savings. Indeed a follow-on-biologic to Lantus like Basaglar has gained a market share of around 30 percent and the Neupogen market share is down by 20 percent from the competition of Zarxio a biosimilar.

Disclaimer:
The opinions expressed in this publication are those of the Interviewee and are not intended to malign any ethic group, club, organization, company, individual or anyone or anything. Examples of analysis performed within this publication are only examples. They should not be utilized in real-world analytic products as they are based only on personal views of the Interviewee. They do not purport to reflect the opinions or views of the VEEDA CRO or its management. Veeda CRO does not guarantee the accuracy or reliability of the information provided herein.

Veeda through its V-Konnect series interacted with Dr. Ashok Kumar and discussed about “Current Outlook of Indian Pharmaceutical industry”

About the V- Konnect

V-Konnect interview series, is a program to get in touch with specialized industry experts to know their views on opinions on current relevant subject matters.

About Dr. Ashok Kumar – President, Centre for Research & development at Ipca Laboratories Limited

Dr. Ashok Kumar carried out his Ph.D. work at CDRI, Lucknow under the supervision of Padmashree Dr.Nitya Nand. This was followed by Post-Doctoral studies with Prof. Sir John Cornforth CBE, FRS a Chemistry Nobel Laureate, at the University of Sussex, England from 1981-1984.

He started his carrier with Alchemie Research Centre at ICI, Bombay in 1985 and served Lupin Laboratories before taking up the job with Ipca Laboratories Mumbai, a leading Pharma Company in the year 2000 and is presently heading the Centre for Research & Development of Ipca in the capacity of President.

He is a co-author in more than three dozen papers published in peer reviewed International Journals, co-inventor in more than 150 patent applications filed, has presented scientific papers and keynotes in many National / International Conferences in addition to delivering invited talks on R&D Management, Idea Management, Innovations, Role of Common Sense and Philosophy in Discovery / Research and many more such topics.

Interview Transcript.

1. What are the immediate key priorities for the Indian pharmaceutical industry?
A1: To remain competitive Indian Pharma’s Key priorities should consider the followings:

GMP Regulatory Issues: Strengthening of the regulatory framework and involvement of the relevant automation to at least avoid, if not completely eliminate human errors. Updating the systems may turn out to be costly, but certainly would help in increasing compliance & qualifying US FDA’s needs and expectations.

API Manufacturing: Technological interventions in manufacturing of APIs supported by PAT is likely to make production easy, environmental friendly and cost effective, however, would require development of expertise & mindset. These changes will obviously make API manufacturing more competitive and will also help in reducing our dependence on China to a great extent.

Innovations in API development using intelligent chemistry approach and manufacturing with the help of emerging technologies leading to cost competitiveness is more easy for Indian Pharma companies because it is going to be a mere extension of what we have been doing since long.

2. Is there any one area where you would anticipate growth? How do you see India developing in that area in the coming years?
A2. Though we are yet to discover the way to do something which qualifies under the head ‘Made in India’, India has done reasonably well in providing quality services. Providing economical services to IT sector and being 3rd largest producer & supplier of finished dosage formulations of generic formulations / drugs, across the globe for quite some time, can definitely be considered good examples where India has fared well.

Following service areas, which warrant more skill than creativity, are likely to see reasonable growth in India:

a. Contract & Custom Research and Development.

The global pharmaceutical Contract & Custom Research and Development/Manufacturing market is poised to post a CAGR of >9% during the next four years i.e. 2019-2023. India is contributing to its growth in a big way via significant technological advances in healthcare infrastructure and scientific innovations in drug development pursuit, owing to which MNC giants are outsourcing the Contract & Custom Research and Development and manufacturing operations to the service providers based at India. Skilled labor at economical price, state of art infrastructure along with relative ease of doing business in India is amongst the very many reasons for the growing popularity of outsourcing these activities.

b. Clinical Research

The latest revision of clinical trial rules by DCGI is indeed a boon for the Clinical Research industry in India. Fast-tracked clearance of proposals coupled with incentive will surely boost Clinical Research sector growth.

c. Medical Tourism

India is fast emerging as the preferred Medical Tourism Destination. While the Global Medical Tourism Market is anticipated to grow at a CAGR of 16.1% during next five years i.e. 2019-2025, the Indian medical tourism industry is way ahead at 18% CAGR YOY and is expected to be worth USD 9 billion by 2020 and USD13.3 billion by 2022. 4.95 lakh foreign tourists visited India for medical purposes in 2017, a significant increase from 2.33 lakh in 2015. Currently, India holds close to 18% of the global medical tourism market share and this is expected to increase to 20% by 2020.

d. Assisted Reproductive Technology (ART) for in-vitro fertilization.

The global ART market size was estimated to be around USD 21 billion in 2017. This has now been anticipated to reach USD 50.71 Billion by 2026. In line with the global growth statistics, ART industry in India is expected to grow by a compounded annual growth rate of 10%. Contributing factors to this growth are the increasing number of infertility cases due to lifestyle diseases, growing mental stress and pollution, fertility threatening treatments such as anti-cancer therapy, social stigma of being childless, lengthy adoption processes and favorable regulatory framework.

3. Does the future of Indian Pharma lies beyond generic if yes where we stand today?
A3: New Drug Discovery:
If Indian Pharma wants to make its future secured and sustainable, it will be possible only if India decides to put sincere efforts in New Drug Discovery.

Few companies have seriously attempted and are continuing investment in NCE / NBE development leading to out-licensing or furthering into clinical studies, but to increase the success rate we have to accept few hard facts:

• Blindly synthesizing & testing molecules in search for new drugs is an outdated model & is very unlikely to give anything worthwhile.

• Drug Discovery is no more about developing me-too kind of products but developing the products addressing the unmet medical need.

• In the era, when drug discovery is directed towards the dev. of personalized treatments, the most important thing is to find a new target based on Omics (Genomics, Proteomics, Metabolomics etc.) by investing in the research in basic Biological Sciences. India is somehow not very active in this area & therefore requires a serious / sincere beginning, if we want to remain relevant throughout.

• The cost of drug discovery and development as we all know, is exorbitant with very poor success rate and therefore many drugs these days are developed in collaboration by a no. of Multi-National Companies to share the risk and development cost. The question always comes to my mind is, why Indian Pharma Companies cannot join hands and feel proud for developing new drugs!

• For Indian companies, the easiest and perhaps most rewarding approach to start with for developing and getting US FDA approvals is by repositioning improving the approved drugs with known toxicity profiles and data, which can reduce the time for development with limited resources through 505(b)(2) pathway. It’s not as inexpensive as ANDA but it gives approval as NDA and can get relevant exclusivity & tag of new drugs.•

The only two things which are critical to travel on this path is to be honest & have long term goals supported by serious assessment of the progress. Instead of results, learning should be the aim of this activity. The philosophy from being ‘fast & first’ to ‘creative & innovative’ will be a game changer.

4. Do you think Quality has been a significant challenge for the Indian drug makers over the last few years? If yes then do you think that may improve soon?
A4: To the best of my understanding it’s not about quality, but rather compliance. The reasons for FDA’s observations and warnings are due to the most prevalent practice followed by most of the people in India, called Juggad – taking short-cuts – in qualifying products without following SOPs.

Since it is more to do with attitudes/mind-sets this problem can partly be addressed by making the doers understand the significance of following systems for securing their jobs. People are likely to be more compliant in future as they are aware of the enmass removal of employees by most of the Pharma Companies and non-availability of (repetitive) jobs in future, if the performance of Pharma Industry does not improve.

5. The industry seems to be moving towards heavy automation and electronic data records. Is that a solution?
A5: AI, automation and digitization is likely to have great impact on the compliance & regulatory controls for two main reasons. First, implementation of these emerging technologies will help keeping a track and controlling the process to reduce or completely eliminate compliance related issues and second, by giving a message of ‘perform or perish’. And since availability of jobs is already on decline it will act as a deterrent for employees to take short-cuts.

6. What kind of strategies must be implemented in order to enhance the acceptability of Indian advantages that steroids bring drugs, drug products and related services across the globe?
A6: Simply by ensuring regulatory compliance and this can be achieved by implementing automation & digitization, wherever possible, and continuously working on job specific skill development program for employees.

A change in Philosophy from being ‘fast’ to ‘flawless’ will possibly help companies in changing attitudes of their work force and the outcome.

7. Where India Pharmaceuticals Industry stands Vis-a-Vis to China?
A7. India v/s China
 ⇒ NDDDR: Though both India & China have not created much visible impact on New Drug Discovery and Development but China is way ahead of India on this front. The reason for this difference is due to China’s thrust and progress in the research, mainly biological sciences, including Genomics and Proteomics, key to find and validate new targets & also developing new drugs which are becoming increasingly personalized with time

⇒ Generics / Branded Generics: The 1970 Patent Act was the turning point but given the availability of science graduates, with chemistry and pharmaceutical sciences background, India could take an early lead in Pharma Research creating base for developing and supplying generic &/or branded yet cheaper generic drugs to the whole world

China on the other hand developed strong hold in chemicals and intermediates, key to APIs and are the world leaders in this segment. More than 70% of APIs / intermediates required to manufacture finished products by Indian Pharma companies are sourced from China. Chinese though little late in developing capabilities to meet regulatory requirement of Western World, however, are now catching up fast & quite a good number of Chinese companies have successfully got approvals of large number of ANDAs from USFDA in recent past. As far as the development of Biosimilars/ ‘Follow-on Biologics’ are concerned both the countries are almost at par, at present.

⇒ Industrial Infrastructure: If we compare India with China, the latter possess far better industrial infrastructure. And ‘Made-in-China 2025’, the mission with which China is building up its Modern Chemical Industry, with reforms ensuring greater Safety & Environment, development of Green Industrial Parks & the Eco-Systems having in built controls on emissions, waste disposal, waste water treatment, it will be one of the best in the world. Unfortunately Indian Govt., has not yet given much serious thought towards strengthening our Pharma Industry, which may lead to serious repercussions.

8. What do you consider are the main issues for the generic, bio similar and value-added medicines industries over the next 2-5 years?
A8: Generics are going to face increased challenges mainly due to the non-availability of Block-Busters to copy in the future and increased market competition leading to further price erosions in India as well as in the US. Indian Pharma regaining the growth obtained in past is highly improbable in (near) future. Decline of Para 4 opportunities in the US market also reduces the opportunity of developing Value Added Products.

In the light of the above mentioned facts, leading Indian Pharma companies have already plunged into either Biosimilars or Complex Generics development or are planning to do so.

Developing Biosimilars, though appear to be generic version of biologics but in true sense are not. It is a different ball game all together, and requires huge investment, longer time from Lab to Market (minimum 8 years) with no guarantee of return on investment in short to mid-term. This is important because many companies are focusing their development efforts on few selected molecules without investigating the kind of market competition they may have to face by the time their molecules reach the market.

As evident from the information available in public domain, many generic companies have either suffered heavy losses in the Biosimilars venture or have shut down their development program midway due to predictable non-viability and same may turn out to be true for more players in future, unless they move with caution and awareness.

Development of ‘Complex Generics’ or ‘Hybrid Medicines’, as defined by EMA (because their authorization depends partly on the results of the tests on the reference medicine and partly on new data from clinical trials), have their own challenges because of the lack of guidelines for regulatory approvals. If developed by hit and trial to replicate the innovator’s product, it will be treated as pure generic, and will lack market exclusivity. And if developed through 505(b)(2), the most ideal approach, the product will qualify as new drug and would need to be marketed through sales / market forces by promotion and most generic companies may not be able to do so. IP related issues due to existing patents from innovator companies and the funding required to develop product through US FDA, may cost somewhere between USD 10-20 million / molecule, and thus needs diligent evaluation before venturing into.

Disclaimer:

The opinions expressed in this publication are those of the Interviewee and are not intended to malign any ethic group, club, organization, company, individual or anyone or anything. Examples of analysis performed within this publication are only examples. They should not be utilized in real-world analytic products as they are based only on personal views of the Interviewee. They do not purport to reflect the opinions or views of the VEEDA Clinical Research or its management. Veeda Clinical Research does not guarantee the accuracy or reliability of the information provided herein.