Category: Blog

Every new drug or molecule that is developed in the laboratory needs to undergo extensive trials before it could be marketed.

And with a growing number of innovative molecules and drugs that are being developed by pharmaceutical companies, the role of Contract Research Organizations (CROs) in aiding clinical trials is set to grow in prominence.

According to a report by Frost & Sullivan, the global CRO market, which was valued at $45.8 billion in 2018, is set to grow at a CAGR of 7.9% and reach a total size of $71.7 billion by 2024.

The key driver behind this growth is the increasing requirement for novel therapies to meet precision medicine needs.

While a pharmaceutical company could certainly develop in-house capabilities to conduct those trials, better sense would dictate outsourcing the conduct of clinical trials to a Contract Research Organization (CRO) for the following reasons:

The Core Competency

A pharmaceutical company has its energies dedicated to developing new drugs and managing commercially viable mass production of drugs.

However, between the two aspects, there is a crucial step of conducting clinical trials and obtaining regulatory clearances.

And that requires specialized expertise of its own.

CROs have professional teams working, with their core competency concentrated in the area of conducting clinical trials.

CRO generally work with multiple pharmaceutical companies, and as a result which they attain vast experience and expertise in conducting clinical trials.

CROs guarantee the technical expertise required in clinical studies and corroborate the quality of the research and results.

Expertise of Working With Different Regulatory Bodies

Working with multiple national and international Pharmaceutical companies has enabled CROs to obtain clearances from various regulatory bodies.

Having a vast experience of working with regulatory bodies such as DCGI (India), FDA (United States), ANVISA (Brazil), MHRA (United Kingdom), AGES (European Union), MCC (South Africa), NPRA (Malaysia), as well as WHO, is an added on.

Because of such experiences, a CRO is capable of guiding a pharmaceutical company with regard to the right ways of filing for regulatory clearances in different countries, thus making the process of new market entry smoother.

Comprehensive Portfolio of Clinical Research Services

Setting up an entirely new testing facility and procuring the necessary special-purpose equipment to conduct a certain type of drug testing might be unviable for a pharmaceutical company from a cost-effectiveness perspective.

This is because such capabilities that would be built to serve specific purposes would be sub-optimally utilized.

However, because a CRO helps multiple pharma clients with conducting clinical research, it is commercially more viable for a CRO to create facilities for conducting diverse clinical studies.

Effective Project Management and Quality Assurance

By employing a CRO, a pharmaceutical company would be able to obtain the services of dedicated project managers who can support the company throughout the lifecycle of clinical studies.

Also, a competent CRO would have a robust quality assurance policy in place.

Because of this, a pharmaceutical company can comfortably rely on the CRO when it comes to ensuring that clinical trials are executed in the best possible way.

Time and Cost Savings

By focusing only on its own areas of domain expertise and outsourcing clinical trials and regulatory filings to a CRO, a pharmaceutical company could achieve major cost savings due to the following reasons:

• Elimination of the need to spend capital on procuring equipment for clinical trials.
• Elimination of the need to recruit human resources with the required set of special skills, who would also have to be paid high salaries.

Based on the above-mentioned factors, it is easy to see why, for a pharmaceutical company, it makes great sense to recruit the services of a CRO.

Also, read our article on how to select a CRO.

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.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

As per Global Data, around 69.9% of global clinical trials since April 2020 suffered disruption due to the suspension of enrolment, whereas 12.8% are due to delayed initiation, and 17.3% are due to slow enrolment.

Moreover, among the trials affected by slow enrolment, around 15.4% (of the 17.3%) have been due to reduced availability of sites and investigators.

Given the situation that the pharmaceuticals sector finds itself in, there are bound to be significant changes in clinical research practices.

Some of these trends have been listed below:

1. Virtual Tour of Facility for Audit Purposes

With in-person visits to a CRO office for inspection of facility infrastructure no longer possible due to the pandemic, there is a growing demand for virtual tours of the facility for conducting audits.

Once CROs create these virtual tours, even in the post-COVID era, most pharma companies will prefer having virtual tours, as they help reduce travel costs and time.

2. Pharmaceutical Companies to Have Greater Reliance on CROs

There are a couple of factors due to which pharmaceutical companies are bound to have a much greater reliance on CROs in the future: – The complexity of clinical development requirements is constantly increasing, and consequently, the need is increasingly being felt for specialized expertise to take care of the requirements.

This is on account of pharma companies having to address multiple therapeutic areas, such as in-orphan diseases, oncology, CNS, diabetes, cardiovascular diseases, and internal medicine.

Often, biopharmaceutical companies, especially smaller ones, lack the internal infrastructure to conduct their own studies.

The fully loaded costs for every successful molecule have now grown to over $2 billion on average, and therefore, the importance of therapeutic expertise and scalability in reducing costs and time-to-market for new drugs is being acknowledged across the pharmaceutical industry.

One aspect where data-driven approaches can prove immensely beneficial is in conducting Real World Evidence (RWE) studies, where the economic value of a new drug or therapy can be ascertained.

RWE studies are occupying a place of increasing importance in the pharmaceutical industry because developmental and regulatory costs are increasing, and therefore, it is necessary to be reasonably assured of the commercial success of a new drug that is sought to be introduced in the market.

As such, CROs would strive to develop in-house data analytics capabilities, and pharmaceutical companies would come to rely on CROs to a great extent for commercial advice.

‘Necessity is the mother of invention,’ goes an old proverb.

The necessity to innovate upon the way clinical research has been traditionally conducted might bring about a complete transformation with regard to trial processes and efficiency.

We can confidently say that in the post-COVID era, clinical research is poised to witness exciting times.

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.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

Shift in Focus

The clinical research industry has come a long way from viewing patients as mere “subjects” to playing an integral part in the success of clinical trials.

Pharmaceutical and biotechnology industries are consciously making changes in the conduct of clinical trials by designing patient-centric trials.

With access to technology, many of the patients are well-informed, making it important for sponsor companies to encourage quality patient-physician interactions even before enrollment into a trial.

This approach is a win-win situation for the Sponsor and patient, with the patient made aware of the trial design and expected outcomes, while the Sponsor finds cost-effective solutions even before patient enrollment.

Multi-dimensional Approach to Transparent Communication

Sponsor companies are seen engaging in innovative ways of gathering patient feedback, such as contests or competitions, to gauge patients’ views on varied aspects of the trials, be it design, perceived effectiveness, patient needs, or even on different regulatory documents.

For instance, patient feedback on informed consent forms (ICFs) can help simplify language so that the form easily conveys trial rules, procedures involved, and/or the expected/unexpected risks of participation.

By promoting open communication between companies, doctors, and patients using technology and social media platforms, the chances of patient retention and satisfaction are higher, thereby leading to improved clinical outcomes.

Encouraging hospitals and clinics to maintain centralized electronic medical records can also contribute to accurate, timely, and seamless storage of patient data.

This, in turn, reduces errors in data handling with easier access to full patient history while conducting clinical trials.

In addition, publishing clinical trial documents such as protocols and study reports on a centralized repository that is accessible to professionals and non-professionals implies the Sponsor’s efforts in promoting transparency and building trust with the public.

Patient Engagement Initiatives

Pharmaceutical industries, stakeholders, regulatory bodies, and healthcare providers understand the need to have a patient engagement model built on mutual trust, transparency, accountability, inclusiveness, and effective communication and partnership.

Research studies are being carried out to examine the implementation of patient-centric activities in contract research organizations and in pharmaceutical/biotechnology companies.

These studies suggest that each company has its own way of implementing patient centricity, with many factors influencing their decision, such as organizational hierarchy, investment, and availability of resources.

Although patient engagement initiatives have gained momentum in the past decade, there is an urgent need to standardize these initiatives across pharmaceutical/biotechnological sectors and regulatory bodies to maintain ethical clinical practices as well as to measure performance using operational metrics.

Conclusion

Patient centricity is gaining prominence as access to healthcare increases.

This inevitably puts the clinical research industry in the spotlight to adapt and adopt technologies to build a mutually beneficial partnership.

This helps in keeping a check on the quality and ethical aspects of the clinical trial with better research outcomes and healthcare, as well as improved return on investments.

Sources

• Sharma NS. Patient-centric approach for clinical trials: Current trend and new opportunities. Prespect Clin Res. 2015;6(3):134-138.
• Pushparajah DS. Making Patient Engagement a Reality. The Patient – Patient-Centered Outcomes Research. 2018 Feb;11(1):1-8.
• Yeoman G, Furlong P, Seres M et al. Defining patient centricity with patients for patients and caregivers: a collaborative endeavor. BMJ Innov. 2017 Apr;3(2):76-83.
• Lamberti MJ and Awatin J. Mapping the Landscape of Patient-centric Activities Within Clinical Research. Clinical Therapeutics. 2017 Nov;39(11):2196-2202

The last two decades have witnessed many businesses capitalize on technological solutions to improve their processes and profitability, and the healthcare industry is no different.

Technological solutions have added a great deal of value to the healthcare industry.

Their application in clinical trials has 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 trials and drug outcomes.

However, factors such as patients’ data confidentiality, regulations and compliance issues, and 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 with information that is simple, to the point, and easy to understand.

Here, using the 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, enabling patients to fill out 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 reduce informed consent errors.

Eliminating Distance Issues

Technology has eliminated the distance issues and is aiding clinical researchers in finding and reaching out to patients worldwide.

For a successful patient-centric clinical trial, finding the right quality and number of patients is a must.

With mobile technology and IOT, the location of the patient is becoming immaterial.

Technology has made it possible to connect with global patients in eloquent ways and collect larger volumes 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.

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 pharmacokinetic 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 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 populations 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.

Pharmacokinetics deals with the change in concentration of a drug over time within 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 various formulations, including creams, foams, gels, lotions, and ointments.

The ability to enhance cutaneous drug distribution of both lipophilic and hydrophilic products has been demonstrated by new vesicular formulations, including microemulsions, 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:

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

Absorption and Distribution

After administration of a topical drug, the first layer to be absorbed is the drug, and then it is distributed throughout the tissue.

The concentration of a drug that reaches the target site from a topically administered medicine is highly dependent on these three characteristics:

1. Drug
2. Its formulation
3. 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 effective barrier by allowing only a few percent of a topically applied dose to be absorbed.

The absorption of topical drugs into the skin depends on various factors, including molecular size, lipophilicity, pH of the formulation, penetrant concentration, chemical enhancers, skin hydration, skin enzymes, temperature, and formulation composition.

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

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

Also, the FDA has proposed that all skin samples 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 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 produce a concentration profile after 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 closely related to clearance, as they are the first permeable sections of circulation encountered 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 interesting to know that the skin contains all the major enzymes responsible for metabolism, which are found 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 Food and Drug Administration (FDA), are investing time and money in developing various 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

1. 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.
2. WJ McAuley, L Kravitz. Pharmacokinetics of topical products. Dermatological Nursing, 2012, Vol 11, No 2.

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 be suitable for all clinical trials, particularly in cases involving trials that use orphan drugs, patients with terminal illnesses, epidemiological studies, and others.

Factors That Plague Clinical Trials

It has been reported that approximately 50% of Phase III clinical trials do not achieve their objectives 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 a larger 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 it 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, quality control, and current risk management plan, to name some of them.

Also, read How to select a CRO?

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 are 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.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information in this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness, or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability, and fitness for a particular purpose.

Nothing herein shall, to any extent, substitute for the independent investigations and the sound technical and business judgment of the reader. In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

For information, contact us at:

Veeda Clinical Research Limited

Vedant Complex, Beside YMCA Club, S. G. Highway,
Vejalpur, Ahmedabad – 380 051,
Gujarat India.
Phone: +91-79-3001-3000
Fax: +91-79-3001-3010
Email: info@veedalifesciences.com

Veeda, through its V-Konnect series, interacted with Dr. Arun Bhatt and discussed “Clinical Trials in India and its regulatory perspective with New CT rules.”

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. Arun Bhatt – Consultant – Clinical Research & Development

Dr. Bhatt is currently working as a consultant in pharmaceutical medicine and clinical pharmacology.

He is the Editor-in-Chief of the ISCR journal- Perspectives in Clinical Research. Dr. Bhatt has extensive experience in the Indian pharmaceutical industry in clinical research, drug development, and regulatory affairs.

He was the former President of ISCR, President at Clininvent, CEO of CMI (India experience), and Medical Director at Novartis.

He was awarded the ISCR Special Award in 2017 for his contribution to the Research Fraternity, the Outstanding Service award by the Drug Information Association in 2012, and the Honorary Fellowship by Clinical Research UK in 2009.

He is also a qualified assessor of NABH Accreditation for Clinical Trials sites and has more than 150 publications in national and international journals.

Transcript.

1. What are the challenges you see in the Indian clinical trial sector today? Can you please mention how to overcome these challenges?

A:

• Quality of trial conduct.
• Gaps in Knowledge of Regulations, Ethics, and Science.
• Challenges can be tackled if all stakeholders participate passionately in the training and development of their teams and strive for quality in the conduct of clinical trials. Some of the actions are discussed below.

2. Despite professional competence and a large patient pool availability, India is yet to reach its potential in clinical trials. How this can be improved?

A:

• Professional competence is not in clinical research but in clinical diagnosis. We need investigators who are trained and passionate about academic clinical research, and who are willing to get trained in clinical trial regulations, ethics, and science, and who are willing to devote time to conduct good clinical research of internationally accepted standards. This is essential to build quality in clinical trials.
• Large patient pool is not organized or classified. The sites should develop a detailed database of patients, including demography, disease, and drug information. This would help in quick screening and fast recruitment of subjects.
• The government should create awareness about 1) the need for new drug development and clinical trials, and 2) regulatory efforts to ensure the protection of the rights, safety, and well-being of patients.
• Ethics committees should receive support, guidance, and training from government bodies – ICMR – and hospital administration to ensure that they can fulfill their primary responsibility of protecting the rights, safety, and well-being of patients.
• Industry sponsors should invest in supporting all the above efforts and encouraging academic investigator-initiated trials.

3. With the recent changes in new CT rules, what can be the benefits and shortcomings for clinical trials conducted in India?

A:

Benefits

• Time-bound approvals for clinical trials in 90 working days
• Advantages of Indian R&D discovery for the initiation of Phase I in 30 working days
• Accelerated approval/trial waivers for serious and rare diseases

 Challenges:

• Investigators: Academic trials to comply with ICMR guidelines  , Ethics committees (EC):
• Dual registration from the DCGI office and the Department of Health Research  Composition: 50% non-affiliated members
• Short comings
• Independent Non-institutional ECs, which may not be competent in ethical oversight, are permitted to oversee clinical trials
• Sponsor is concerned about delays in approval because of irrelevant queries
• Lack of clarity/transparency in the regulatory inspection process
• No change/improvement in the SEC review process
• Approval requirements for non-interventional Phase IV studies
• Some of the criteria for accelerated approval/waivers are unclear and are at the discretion of regulatory authorities

4. What are the industry expectations from Indian regulatory going forward?

A:

• Transparency and clarity in accelerated/waiver criteria/pathways
• Professional regulatory inspection with graded regulatory actions along the lines of the FDA and EMA

5. Where do you see the Indian Clinical trials industry in the next 5 years?

A:

• Depends on how the new regulations improve the quality and conduct of Indian trials and how the society and media react to the favorable regulatory environment for new drugs and clinical trials
• All stakeholders should learn from past deviations and watchfully conduct clinical trials in compliance with regulations.
• Over the next 5 years, all stakeholders should strive for ensuring human protection and data integrity and to establish an image of India as a quality innovation R&D hub.
• Focus should be on quality, and Quantity will follow.

6. What are the current issues surrounding clinical trial data integrity, and what can be done to improve it?

A:

• Attitudinal shift by sponsors to reject data whose integrity is suspect
• Strengthen the QA and monitoring process
• Reward sponsor team members who discover data integrity issues and whistleblowers
• Action – suspension of the contract, blacklisting, regulatory notification, information sharing with industry – against responsible parties – in-house staff, CROs, investigator sites
• Training in documentation, monitoring, and QA for the sponsor and investigator site staff
• Training of ECs in oversight and monitoring to detect data integrity issues and to take appropriate actions

7. What measures should the industry take to ensure clinical trials are carried out safely?

A:

• Training of in-house staff – monitors, project managers, medical monitors, auditors, and site staff in pharmacovigilance, assessment of causality and clinical trial relationship of SAE, regulatory reporting, and compensation
• Train the site personnel thoroughly in protocol procedures, especially selection criteria, follow-ups, and safety assessments
• The project team should promptly detect important protocol deviations, which can impact the safety of subjects, and take appropriate actions, e.g., exclude patients, stop recruitment, and inform EC, etc.
• Medical monitor and the project team should verify the assessment of causality and clinical trial relationship of SAE by the investigator, considering company safety information and medical condition
• Ensure that the investigator complies with the regulatory requirements of free medical management

8. How do you position Indian ethics committees with respect to functioning and competence in the current global scenario? What are your views on the steps to be taken to further improve the functions of the ethics committee?

A:

• Barring a few empowered ECs in major academic institutions, most ECs lack competence in fulfilling their vital responsibility of ensuring the protection of rights, safety, and well-being of clinical trial participants.
• Department of Health Research should provide training and conduct ongoing monitor/review of the functioning of ECs.

On a closing remark, Dr. Arun Bhatt mentioned that “As a country, we should remember those who forget history are condemned to repeat it, and conduct clinical trials balancing the twin requirements of human protection and data integrity. We should comply with regulations and guidelines both in letter and spirit!”

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 the 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.

Many respiratory diseases have been historically treated using inhalation drugs, as this route of administration allows for a higher drug concentration to reach the target organ, thereby reducing systemic effects.

Apart from respiratory disorders, trials are ongoing to determine the efficacy of inhaled insulin in diabetes management. ^{1, 2}

Although pulmonary delivery of insulin is a valuable option with the advantage of ease of administration compared to injections, further research is ongoing to study its safety through the oral route. ^{1, 2}

An ideal inhalation device is one that delivers a reproducible and fixed dose of the drug to the lung, is patient-friendly, and is not cumbersome.

The commonly prescribed inhalation devices are pressurized metered-dose inhalers (MDIs), nebulizers, and dry-powder inhalers.

All inhalation devices undergo stringent in vivo and in vitro testing to determine the safety and efficacy of the drug through these devices. ³

However, inhalation clinical trials bring forth a number of challenges.

Device-drug Compatibility

There are hiccups that investigators and sponsors face while conducting inhalation trials, such as the need to use cumbersome and costly devices as well as the probability of bronchospasm due to the drug or non-drug component(s).

In addition, some inhalation drugs can cause withdrawal symptoms.

Other factors that influence the trial results are the difference in drug bioavailability in each patient due to varied breathing patterns or the presence of a comorbidity that affects drug absorption.

For instance, epoprostenol has a short half-life of 3 to 5 minutes, requiring continuous nebulization for long periods, making it difficult to administer or prescribe on a long-term basis.³

Safety Issues

A number of inhalation trials were terminated in the initial phases due to issues such as poor drug solubility and bioavailability, leading to dangerous levels of undissolved drug in the systemic circulation. ⁴

Patient Training and Adaptability

For effective therapy, the patient should be able to use the device correctly.

Inhalation drugs and devices are often viewed as complex by many patients, and thus require practical demonstration as well as repeated follow-up by medical staff to ensure that the patient is using the device as intended for optimal drug delivery.

The patient should also be encouraged to use e-technologies that help in self-monitoring to look out for symptoms that may require medical intervention and help raise awareness about the respiratory disease. ⁵

Many studies have observed that the inappropriate use of inhalers is a cause for improper management of respiratory diseases.

A study in a university hospital in Northwest Ethiopia by Mebrahtom Metal demonstrated that approximately 71% of the subjects were handling inhalation devices incorrectly due to a lack of awareness about MDIs, consequently leading to poor asthma control. ⁶

Another study by Arora Petal reported approximately 95% error in subjects using MDI and approximately 82% error in subjects using dry powder inhalers. ⁷

Regulatory Laws in India

There are no specific regulatory guidelines laid down by the legislative body, Central Drugs Standard Control Organization (CDSCO), and the Drug Controller General of India (DCGI), for inhaled products.

As applicable to all trials in India, inhalation clinical trials should also adhere to Schedule Y and Rules 122A to E of the Drugs and Cosmetics Act, 1945, as well as Good Clinical Practices (GCP) and ethical guidelines for biomedical research on human subjects.

The guidelines followed for bioavailability and bioequivalence studies are also applied to inhalation trials.

However, bioequivalence studies for inhaled drugs are still in their nascent stages in India.

Although pharmacokinetic (PK) bioequivalence studies alone are being accepted worldwide to establish equivalence of inhalation products, India is yet to approve second entry orally inhaled drugs with data from PK bioequivalence studies alone. ⁸

Creating a Conducive Environment for Inhalation Clinical Trials

To build India’s competence in inhalation trials, the recruited staff should have expertise in handling phase I/bioequivalence studies.

The DCGI and CDSCO can also come up with specific study timelines as well as suggest appropriate study designs for inhalation trials in consultation with the technical committee.

As the comparison of clinical efficacy endpoints between two orally inhaled products provides shallow dose response curves, equal weightage should be given to in vitro bioequivalence assessments. ⁸

Emphasis cannot be laid enough on the need for the investigator to share all medical decisions with the patient to improve patient compliance rates in clinical trials. ⁵

Human factor (HF) studies can be designed to include strategies that mitigate errors caused by improper device use.

HF studies also help in understanding the effect of the interaction between the patient and device on the safety and efficacy of the inhalation drug.

HF studies are gradually showing their presence globally, especially in clinical trials that involve the use of devices. ⁹

With companies increasingly seeking alternative solutions, the route of inhalation delivery will continue to grow.

This makes it critical for the scientific community to fill the existing gaps for conducting successful inhalation trials.

Sources

1. Cavaiola TS and Edelman S. Inhaled Insulin: A Breath of Fresh Air? A Review of Inhaled Insulin. Clinical Therapeutics. 2014;36(8):1275-89.
2. Oleck J, Kassam S, and Goldman JD. Commentary: Why Was Inhaled Insulin a Failure in the Market. Diabetes Spectrum. American Diabetes Association. 2016;29(3):180-4. https://doi.org/10.2337/diaspect.29.3.180
3. Holgate ST, Bousquet J, Chung KF et al. Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma. Respiratory Medicine, 2004;98(6):479–487.
4. Forbes B, O’Lone R, Allen PP et al. Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses. Advanced Drug Delivery Reviews. 2014;71:15-33.
5. Shakshuki A and Agu RU. Improving the Efficiency of Respiratory Drug Delivery: A Review of Current Treatment Trends and Future Strategies for Asthma and Chronic Obstructive Pulmonary Disease. Pulmonary therapy. 2017;3:267-81.
6. Mebrahtom M, Mesfin N, Gebreyesus H et al. Status of metered dose inhaler technique among patients with asthma and its effect on asthma control in Northwest Ethiopia. BMC research notes. 2019;12:15.
7. Arora P, Kumar L, Vohra V et al. Evaluating the technique of using inhalation device in COPD and bronchial asthma patients. Respiratory Medicine. 2014;108(7):992-8.
8. Lee SL, Saluja B, Garcia-Arieta A et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. AAPS Journal. 2015;17(5):1285-1304.
9. Vaidya A. Learnings and Challenges of Conducting Human Factors Studies on Inhaler Devices. Clinical Trials Arena. 2017. https://www.clinicaltrialsarena.com/news/case-study-learnings-and-challenges-of-conducting-human-factor-studies-on-inhaler-devices-5852797-2/ Accessed on June 21st, 2019.

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.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

In the clinical research industry, safety norms and processes should be applied to every aspect, starting from drug development to post-marketing use of approved drugs, keeping in mind patient safety and data credibility at every stage of clinical development.

Patient safety requires the collaborative effort of the regulatory system, the healthcare system, and the sponsor.

Equally important is the need for effective communication with patients by the regulatory bodies and health care systems to maintain transparency.

Such communication also helps in instilling confidence in patients about the scientific credibility of the trial.

For instance, the Central Drugs Standard Control Organization (CDSCO) in India utilizes information technology to keep the public informed about ongoing and completed trials.

All data, starting from the filing of an application to the trial results, is available on the website.

Sponsors, clinical research organizations, as well as ethics committees are required to furnish their details on the website.

Data safety and monitoring boards (DSMB) are also formed to monitor trials, especially large trials, for safety and reliability of data.

DSMBs play a significant role in letting the public know if the investigational drug poses any threat, as well as to ensure that the sponsor does not purport the results to be unbelievably beneficial to the targeted patient population.

Emphasis should also be laid on novel and practical-oriented training programs for students in the health care profession to expose them to real-world situations.

Students should understand the importance of having risk assessment, risk management, and risk mitigation plans in place to improve patient safety.

Periodic assessment and continuing medical education programs for medical professionals are also pivotal in ensuring that they remain competent in their respective fields and prioritize patient safety and moral ethics in their profession.

The successful implementation of patient safety and data integrity is a multidisciplinary approach that requires sincere and diligent effort of each individual and organization involved in the conduct of clinical trials.

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.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained on this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions, or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information on this article or for any consequential, special or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

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