How technology is helping to put patients at the center of Clinical Trials

December 23, 2019

Posted in - Veeda

How technology is helping to put patients at the center of Clinical Trials

Last two decades has witnessed many businesses capitalize on technological solutions to improve their processes and profitability; and healthcare industry is no different. Technological solutions have added a great deal of value to the healthcare industry. Their application in clinical trials have not only boosted the operational efficacies but also aided in patient centricity.

Patient centricity ensures factoring patients’ point of view and puts them at the center of the trial. Patient-experience is very crucial for better clinical trial and drug outcome. However, factors such as patients’ data confidentiality, regulations and compliance issues, inaccessibility of patients at the required time have posed a challenge to this novel approach. IOT driven technology has come to offer a solution and is helping more and more researchers adopt the approach and improve their processes.

Information Sharing

Patient recruitment is a tasking process and researchers have to put in lot of efforts in order to provide important information about the trial. Lack of clarity in this communication can make it leave the patients in ambiguity and make the recruitment process more challenging. Patients need to be provided information, which is simple, to the point and easy to understand. Here, using digital medium eases things out for them. A short audio-visual presentation on the matter with necessary details would certainly improve the patient experience; it enables them to comprehend every aspect of the trial and facilitates their decision-making process.

Onboarding Patients with Technology

Use of technology in clinical trials for onboarding certainly alleviates the experience for patients. Onboarding requires patients to sign a consent form. In the past, these were required at multiple stages and considering everything was manual, a lot of paperwork was involved, making it quite taxing. Technology has taken the entire consent process digital. The advanced Electronic Content Systems (ECS) for clinical trials are patient-friendly and regulatory compliant that enables patients to fill their consent forms online, automating the process of patient enrollment and making it faster and efficient. Such systems lessen the administrative workload via improved consent tracking management and reducing informed consent errors.

Eliminating Distance Issues

Technology has eliminated the distance issues and is aiding clinical researchers find and reach out to the patients world-wide. For a successful patient-centric clinical trial, finding the right quality and number of patients is must. With mobile technology and IOT, location of the patient is becoming immaterial. Technology has made it possible to connect with global patients in eloquent ways and collect larger volume and better-quality data through virtual trials.

While more advanced technological applications are still needed, technology has certainly aided patient centricity in clinical trials, enabling better quality studies and results. It has had a positive and encouraging impact on the patients’ experience.

V-Konnect- Dr Susobhan Das

October 1, 2019

Posted in - Veeda

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.

Types of Glucose Clamps and Their Advantages

September 25, 2019

Posted in - Veeda

Introduced in the 1970s by Ralph A De Fronzo, Jordan Tobin, and Reubin Andres to quantify insulin secretion and resistance, glucose clamp studies are now considered the “gold standard” for studying pharmacodynamic and pharmacokinetics effects of different formulations of insulin.

There are many variants of the glucose clamps, such as hyperinsulinemic-euglycemic, hypoglycemic, and hyperglycemic glucose clamps.

Hyperglycemic glucose clamps are used for quantifying the sensitivity of beta cells to glucose by maintaining a steady hyperglycemic state through the infusion of variable concentrations of glucose.

Hypoglycemic clamps have been used to study iatrogenic hypoglycemia and the effect of hypoglycemic agents on hepatic glucose production, while hyperinsulinemic-euglycemic clamps are used for their ability to detect subtle differences in insulin preparations.

For hyperinsulinemic-euglycemic pumps, the plasma insulin concentration is raised to a pre-determined level by priming and continuous infusion of insulin. In addition, the plasma glucose concentration is maintained by exogenous glucose infusion to induce a steady state of hyperglycemia.

This helps in measuring the whole-body sensitivity to insulin, wherein the concentration of infused exogenous glucose must be equal to the amount of glucose used by the body in response to the induced hyperglycemic state.

Similarly, hyperglycemic pumps function by keeping a constant plasma glucose concentration with the desired hyperglycemic plateau and are helpful in assessing an individual’s insulin secretion capacity.

In hypoglycemic clamp studies, a pre-defined blood glucose concentration is maintained for a specified period by separate intravenous infusion of insulin and glucose.

Blood samples are then collected at the glucose plateau phase for the further biochemical study of counter-regulatory hormonal responses.

This may help in identifying any glycemic threshold that can be correlated to the onset of hypoglycemic symptoms.

Advantages of Glucose Clamps

 Reproducible results with accurate measurement of insulin action
 Hyperinsulinemic-euglycemic pumps are safe for use in elderly patients as well as in special population such as individuals with renal or hepatic disorders.
 Hypoglycemic clamp is the best method to understand and study counter-reactions to hypoglycemic conditions.
 The perfect apparatus for assessing preparations of insulin or insulin analogs
 Clamp studies do not interfere with the results of other test techniques and can be used in combination with them. For example, the determination of hepatic function.

To validate the outcome of glucose clamp studies, it is necessary to ensure the good quality of glucose clamps along with improved computer algorithms to obtain optimal glucose infusion rates and sound blood glucose data.

Eventually, such standardized results will be beneficial in research studies on diabetes and its management.

Pharmacokinetic Considerations for Topical Drugs

September 25, 2019

Posted in - Veeda

Introduction

Pharmacokinetics deals with the change of concentration of a drug with respect to time inside the human body. Absorption, distribution, metabolism, and excretion are the four main phases of a pharmacokinetic study. Pharmacokinetic studies of drug molecules provide insight into how to minimize the need for clinical studies.

They also reduce the costs of generic product development by simplifying bioequivalence testing. Topical medication is defined as pharmaceutical products that are applied to a particular place on or in the body, like the skin or mucous membranes.

Local Anaesthetics, Corticosteroids, Retinoids, NSAIDs, Antivirals, Vitamin D3 derivatives, and Immunomodulators are some classes of topical drugs. Topical drugs are also available in different formulations like creams, foams, gels, lotions, and ointments.

The ability to increase cutaneous drug distribution of both lipophilic and hydrophilic products has been shown by new vesicular formulations such as micro-emulsions, liposomes, and nanoparticles.

The evaluation of pharmacokinetic studies for topical drugs is carried out according to the stratum corneum (SC) concentration-time curve. This curve was generated after assessing the concentration of the drug in the outermost layers of the skin (SC) with respect to time. The curves provide information on drug absorption, steady-state, and drug elimination.

For assessing the bioequivalence of a topical drug product, the following parameters are considered to be the major criteria:

The maximum concentration of active drug molecules in the SC (Cmax)
The time to achieve the maximum concentration (Tmax)
The area under the curve in the SC versus the time curve (AUC)

Absorption and Distribution

After administration of a topical drug, the first absorbed is a drug and then distributed through the tissue. The concentration of a drug that reaches the target site from a topically administered medicine is highly dependent on these three characteristics:

Drug
Its formulation
Properties of the skin to which it is applied.

The stratum corneum plays a significant role in the permeation of topical drug products. It acts as an effectual barrier by allowing only a few percent of a topically applied dose to get absorbed.

The absorption of topical drugs into the skin depends on factors like molecular size, lipophilicity, pH of the formulation, penetrant concentration, chemical enhancers, skin hydration, skin enzymes, temperature, formulation compositions, etc.

To provide a reasonable approximation of the concentration of drugs in the skin as a function of time and to derive the dermatokinetics parameters (Cmax, Tmax, and AUC) of definite importance, frequent measurement of drug levels in the skin is vital.

Therefore the FDA’s draught guidelines for DPK states that, at the minimum, eight separate locations must be evaluated for drug levels: from which four of the sites are examined during uptake (e.g., 0.25, 0.5, 1, and 3 hours post-application), four sites during clearance (e.g., 4, 6, 8, and 24 hours post-application).

Also, the FDA has proposed that all skin samples to be taken on a single day to prevent inter-day variability, which is of considerable concern because of the restricted supply of skin in a given subject.

The success of the skin kinetic analysis depends similarly on the development of sensitive analytical methods to measure the drug quantity. Tape Stripping, Micro dialysis, and In-vitro percutaneous tests such as Flux assessment and concentration of skin tissue are the feasible approaches for pharmacokinetic examination of topical formulations.

These pharmacokinetic skin sampling experiments are used mainly to assess topical product bioequivalence. Another important instrument for evaluating dermatokinetic parameters is confocal laser scanning microscopy.

For fluorescent drugs or probes, confocal images are feasible and do not require the skin to prepare optical sections. This method helps an investigator to produce a profile of concentration after the topical application of the drug product.

Clearance and Metabolism

Most of the dermatokinetics studies revolve around the absorption phase of a topical drug. However, clearance of a topical drug is equally important in assessing the bioavailability of the topical formulations. Following skin permeation, the key process involved in post-absorption is clearance.

Continuous, fenestrated, and discontinuous are the three types of capillaries found in the human body. The capillaries are very much related to clearance since they are the first permeable sections of circulation experienced by a permeate that has been added topically.

Parameters that alter the drug clearance of topical products include the thickness of the blood vessel, the area, the distance between blood vessels, and the blood flow rate.

It is very much interesting to know that the skin contains all the major enzymes responsible for the metabolism found is in the liver and other tissues. These enzymes possess the ability to catalyze several metabolic reactions.

Evaluating the metabolism of topical formulations through in-vivo experiments is difficult since biological specimens can often contain metabolites from other tissues.

In-vitro permeation studies and measuring the metabolite in skin homogenate or the receptor fluid are the methods through which the metabolism of topical drugs is assessed.

Conclusion

Evaluating the dermatokinetic parameters is of paramount importance to assess the safety and efficacy of topical formulations. Numerous approaches are used to determine the real-time measurement of molecules in the skin layers.

Regulatory bodies, such as the US FDA, are investing time and money to develop different techniques for characterizing the pharmacokinetics of topical drugs.

The maximal concentration of the active drug molecule in the SC (Cmax), the time to achieve the maximum concentration (Tmax), and the area under the curve (AUC) are the most commonly assessed parameters in dermatokinetic studies.

Different methods are reported for assessing the pharmacokinetic profile of topically applied drug molecules, as discussed above. Clearance and Metabolism of topical drugs are also essential to consider the pharmacokinetics of topical formulations.

Finally, one should know that most of the topical drug molecules entering the dermis are quickly cleared by the microvascular system. However, few drug molecules get retained in the skin leading to the depot effect.

REFERENCE

Nair, S. Jacob, B. Al-Dhubiab, M. Attimarad, S. Harsha. Basic considerations in the dermatokinetics of topical formulations. Brazilian Journal of Pharmaceutical Sciences vol. 49, n. 3, jul./sep., 2013.

WJ McAuley, L Kravitz. Pharmacokinetics of topical products. Dermatological Nursing, 2012, Vol 11, No 2

V-Konnect – Dr. Ashok Kumar

August 9, 2019

Posted in - Veeda

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.

Approach for Rescue Trials

July 30, 2019

Posted in - Veeda

Conducting a clinical trial is a complex and challenging task and involves robust scientific understanding and logistics planning. Although there are international guidelines for good clinical practices, the standard approach may not work for all clinical trials, especially in the case of trials that use orphan drugs, terminally ill patients, epidemiological trials, and so on.

Factors That Plague Clinical Trials

It has been reported that approximately 50% of phase III clinical trials do not achieve their objective or fail to demonstrate the desired results.

Some of the major issues that pharmaceutical companies face while conducting large-scale trials are:

Meeting regulatory deadlines: Inadequate or poor patient recruitment, poor execution, or complicated study design are some reasons that contribute to the inability of a company to meet timelines. Approximately 80% of trials are behind schedule. Analysis shows patient recruitment to be one of the prime reasons for the study delay.

Data quality: A flawed study design and complacency in following the patient eligibility criteria required for enrolment also affect the data quality and ethics of a trial. In addition, lack of patient informed consent or breach of confidentiality are other serious unethical practices that affect final data quality.

Infrastructure and resources: While accounting for infrastructure and resources, sponsor companies sometimes underestimate the requirement of trained staff at each step of a trial. A sponsor may need to recruit more number of clinical trial associates, study coordinators as well as other trained personnel depending on the number of trial sites and targeted cohort size.

At times, the importance of site inspection is also overlooked. Site inspections help in evaluating the technical capability of the staff and confirm if the site is well equipped to handle additional responsibilities.

Unexpected challenges: Sponsor companies are sometimes caught unaware by challenges that crop up during the execution of a trial. Without a risk management plan (RMP), it is impossible to identify warning signs and can also bring the trial to an abrupt halt.

All the above factors require the sponsor to look for remediation measures, and this is where rescue trials come into the picture.

Rescue Trials

There are different approaches that pharmaceutical companies employ for rescue support. For specific issues, the company may choose to bring on board a third party with expertise in a specific function or completely outsource study management and control to a contract research organization (CRO).

Integrating into an ongoing study requires the onboarding team to have the flexibility as well as the insight to identify problem areas that have led to the failure of the Sponsor’s trial.

Therefore, it is necessary for the CRO to have demonstrated expertise in handling a particular therapeutic area or to have the technical know-how of running rescue studies. This will help in seamless knowledge transition and identification of bottlenecks that have caused the trial to fail.

In case the trial is being transferred from another CRO, there should be a clear communication and handover plan from the outgoing CRO to the onboarding CRO and the Sponsor Company.

This communication should include strategic details such as current study status, vendors involved, database migration, documentation, and quality control, current risk management plan, to name some of them.

Key Takeaway

For a successful rescue study, there should be documented compliance and effective documented communication between the sponsor and CRO.

Corrective action and preventive action (CAPA) at each stage of the trial is necessary, especially in the case of rescue studies, to meet study milestones and to avoid any further delay in trial execution.

Disclaimer:

The information contained in this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use. Accordingly, the information in this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services.

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