Three ways to reduce cost and complexity in Clinical Trials

December 31, 2019

Posted in - Veeda

Medicine research and clinical trials are crucial to the success and growth of healthcare industry. However, it is also the segment that faces varied economic challenges and fluctuations. Furthermore, the looming expiry of their products’ patents keeps the industry constantly on its toes and work on its operational efficiency to survive and grow.

Clinical Trials – The Cost Factor!

Clinical trials are one of the largest cost drivers in the healthcare industry. These trials are sponsored by healthcare and/ or biotech companies. According to an article published on clinical trials arena in 2018, “the average cost of moving from phase 1 to phase 3 is over $79.1 million and is as high as $52.9 million for single phase 3.” This cost may go up anytime due to various factors and it impacts the performance of the industry in a big way. Hence, it is imperative to work on cost control strategies for clinical trials.

Factors to be considered:

Streching timeline

Delays affect clinical trial budgets to a great extend and can be financially damaging too. One of the most common reasons for delays in clinical trials is patient recruitment and retention, which is quite a complicated and tough aspect of the trial. A research claims, “69% of patients final pre-screening, 58% decline consent and 8% drop out after the enrolment.” Researchers are adopting a patient-centric approach, wherein, patients’ point of view is considered. The approach would aid in patient recruitment and retention and control the delays in trial. It also emphasizes on the importance of site selection.

Logistics Decisions

Most of the clinical trials in phase 3or 4 are conducted on a large scale at a global level. And hence logistics cost comes into the picture. More often than not, the product shipment decisions are based more on previous experiences and less on the feasibility of the site. It is best to take a pragmatic approach to it and analyze if it would be feasible to ship the product to clinical site directly or make sense to have a local depot there. Prior study may be factored in, although may have less or zero relevance to a new trial. Instead, a study must be conducted on demand and supply for the site and the logistics and operational costs must be evaluated before deciding.

Interactive Response Technology (IRT)

Automating the processes through IRT can bring down the costs significantly. It reduces manual oversights, the risks of stock outages and aids in supply management. IRT systems can be programmed types of muscle pumping to monitor depot inventories, batch expiries and keep supply managers updated about the it through alerts. IRTs can be custom-built to provide real-time feed on varied aspects of operations in clinical trials including stocks, supply-chain, shipment, etc. This small investment can optimize the operations greatly and aid in cost control. It also simplifies the entire complexity of the tedious processes.
Cost control and increasing operational efficacies are the key to profitability of any clinical trial. And there are several opportunities to pursue this goal. A tactical approach and its successful execution would mean saving millions of dollars and improved worth of the drug in investigation.

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.

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

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

Onboarding Patients with Technology

Eliminating Distance Issues

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