Medicine research and clinical trials are crucial to the success and growth of the 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 working 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 in the 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 industry’s performance in a big way. Hence, it is imperative to work on cost-control strategies for clinical trials.

Factors to Be Considered:

• Stretching 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 the trial. It also emphasizes on the importance of site selection.

• Logistics Decisions

Most of the clinical trials in phase 3 or 4 are conducted on a large scale at a global level. And hence logistics cost comes into the picture. More often than not, 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 the clinical site directly or make sense to have a local depot there.

Prior studies may be factored in, although they 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 and the risks of stock outages and aids in supply management.

IRT systems can be programmed to monitor depot inventories and 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 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 keys to the 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 improving the worth of the drug in the investigation.

Contract Research Organization (CRO) plays a vital role as a service provider for the pharmaceutical industries.

The market size of the global contract research organization (CRO) services was estimated at USD 38,396.4 million in 2018. By the end of 2026, it is expected to hit USD 90,926.3 million.

It should be noted that in terms of the number of generic drugs, 20% of global exports are from India. This makes India the biggest global supplier of generic medicines.

It is very much obvious that to get marketing approval for generic drugs on foreign soil, manufacturers from India have to clear all the regulatory parameters.

Thus BA/BE studies are of great importance, and conducting them needs due planning and experience. Generic companies have the R&D for product development, manufacturing, and its quality testing.

Many of the bigger pharmaceutical firms have their own clinical and bioanalytical units. They are capable of carrying out Phase 1 and BA/BE studies.

However, because of the desire to produce more compounds in shorter time periods, there comes the point when the internal resources become saturated.

Often several smaller firms, virtual companies, and generic companies do not have the privilege of performing BA/BE trials with their own dedicated clinical unit or full in-house capability.

They may not have the clinical and bio-analytical capability. Thus the role of CRO or outsourcing of BA/BE studies comes into the picture. They reduce the cost of BA/BE study, help pharmaceutical companies to file ANDA applications, and bring new medicines to market quickly.

The typical services outsourced for BA/ BE studies from a pharmaceutical company to a CRO may include Bioanalytical Analysis, Bioanalytical Site Selection and Qualification, Clinical Study Design, Clinical Protocol Development, Clinical Site Selection and Qualification, Clinical Conduct, Clinical Monitoring, Data Management, Pharmacokinetic Analyses, Statistical Analyses, Pharmacokinetic Report Writing, Integrated ICH Report Writing, Project Management, and FDA/Regulatory Consultation.

How to Select a CRO?

The first step before outsourcing a study to a CRO is to develop a list of potential CROs that are involved in conducting BA/BE studies. CROs that have good experience in conducting BA/BE studies and can meet the sponsor’s timeline should be given first preference.

The list should include the CROs that provide all services and also the ones that provide only clinical or analytical services.

CROs that have a proven record of carrying out BA/BE studies with appropriate clinical conduct, laboratory analysis, data management, biostatistics, pharmacokinetics, and medical writing should be given priority.

They should be in compliance with Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and other applicable regulatory practices and guidelines.

How to Assess the Qualification of a CRO?

The sponsor company should assess a CRO on different parameters before finalizing to outsource the project. The parameters include Clinical Capabilities, Bioanalytical Capabilities, Pharmacokinetic capabilities, and quality deliverables on time.

The sponsor should obtain copies of past FDA inspection reports (483s and Establishment Inspection Reports {EIRs}) through the Freedom of Information (FOI). The client should also request any FDA warning letters (if any) that have been issued against the CRO.

The ability to recruit volunteers for both small and large sample studies is a major assessment criterion for the qualification of any CRO. The CRO should be able to recruit the entire study population at a single center, preferably as a single group.

The client should make sure that the Bioanalytical team is well-experienced in analyzing the analyte or metabolite of the drug as appropriate.

The client should also check that the facility follows cGLPs and have clean inspection history from regulatory bodies. The Bioanalytical team of the CRO should be able to provide a written validation report.

The CRO should have validated pharmacokinetic and statistical programs in place and should be compliant with 21 CFR Part 11 (especially concerning change control).

The CRO should also provide performance metrics used for monitoring the timelines and financial metrics. The client should request ‘‘references’’ that include those companies which outsourced studies and, in return, had successful ANDA or NDA approvals.

After evaluating the credentials and performance metrics of each CRO, the sponsor should physically visit the site and audit the clinical, bioanalytical, and pharmacokinetic capabilities of the CRO.

The audit should include the evaluation of the:

• Procedure for the CRO to handle an unexpected and serious adverse event (AE) investigation.
• Training records for the clinical team
• CRO’s capability to synchronize plasma urine deliveries to different bioanalytical facilities
• CRO’s ability to coordinate functional handoffs
• CRO’s clinical project management capabilities
• Validation of the data collection system
• SOPs, CRF and database correction, change control
• Deliverables like CRFs (CRO or sponsor format), transport procedures to the bioanalytical unit, Content of the written clinical report

The client should also asses the capability of the laboratory project management with regard to their coordination with the clinic, pharmacokineticist, and the sponsor during the study.

Finally, to support the BA/BE study, the CRO should provide written documentation of the final analytical report that should contain supplementary project-specific validation data.

Thus, in a nutshell, it can be said that factors like the number of years in the business, qualified team of scientific, medical, and statistical experts, the ability of CRO to recruit volunteers, a sufficient number of beds for in-housing, calibrated laboratory equipment with suitable SOPs, location of the CRO, duration of getting IEC/IRB approval, employee training on SOPs, adherence to GCP and GLP, correct volunteer database, appropriate ambulatory service, clean kitchen facilities with maintained hygiene, recreation rooms for volunteers, working QAU system, facility management, and accurately designed scientific organization charts assess the qualification of a CRO to conduct BA/BE studies.

Conclusion

A generic manufacturer outsources a BA/BE study so that their product can be proved bioequivalent with that of a Reference Listed Drug (RLD).

The key elements for the success of the BA/BE study between the client and the CRO are transparent Communication at all levels, Sensitivity to the requirement of the project, the Timelines, and Flexibility to recognize and adjust to unexpected events throughout the project timeline.

Work culture compatibility between a sponsor and CRO is also a substantial merit, as it leads to a more aligned relationship in the future.

REFERENCE

1. Outsourcing Bioavailability and Bioequivalence Studies to Contract Research Organizations, Patrick K. Noonan. Generic Drug Product Development Solid Oral Dosage Forms Chapter 13, Pg. No. 299-321.

When it comes to developing nations, there is a greater preference among the populace for generic pharmaceutical drugs as opposed to branded ones. In India, generic drugs comprise of 71% of the pharmaceuticals market. The reason for this is not hard to guess – a large proportion of population having low income level means the market is bound to be highly price sensitive.

Generic drugs & healthy human volunteers

Generic drugs may not have to go through the full gamut of clinical trials from Phase 1 to Phase 3, but they do have to pass the Bio-Availability and Bio-Equivalence (BA/BE) tests in order to earn the marketing license. Healthy volunteers have an important role to play in enabling the BA/BE testing of such drugs. Through BA/BE testing, a pharmaceutical company can determine if the molecule that they have developed has a similar response to the branded drug that it seeks to compete with. Another reason BA/BE testing is important is to identify if there is a possibility of any side-effects occurring as a result of being exposed to the generic drug molecule.

How healthy volunteers contribute in BA/BE testing of Generic Drugs

Because the drug is only being tested for bioavailability and bioequivalence with a previously known drug, the testing can be performed on healthy volunteers and need not necessarily involve patient volunteers. Pharmaceutical companies would find it easier to recruit healthy volunteers as the number of patient volunteers would be comparatively lesser, and not all of them would be willing to subject themselves to a clinical test. Thus, healthy volunteers play an important role in enabling the market introduction of generic drugs, which have a key role to play in making healthcare affordable in India and other developing countries.

Reviewing the role of healthy volunteers in testing of Investigational Drugs

In addition to this, First-In-Human (FIH) Phase 1 clinical studies for investigational drugs are also preferably performed on healthy volunteers. The key goal that is sought to be achieved through healthy volunteer studies is to determine the pharmacokinetics and pharmacodynamics of a novel drug that is sought to be introduced, as also to determine the right level of dosage and its safety and tolerability. Typically, this involves a total of 20-80 healthy volunteers divided into groups of 3-6 each, who are administered escalating doses of the investigational drug. Through these studies, a pharmaceutical company attempts to identify the bodily mechanisms involved in absorption, metabolism, and excretion of the drug, its pharmacokinetic profile, and the safety and tolerability of the drug at different dosage levels. By conducting trials on healthy volunteers, a pharmaceutical company gets to understand the body response to a drug as well as its safety profile in the absence of any pre-existing pathological conditions influencing the response.

Thus, healthy volunteers play a key role in the journey of pharmaceutical drugs, both branded and generic, from the laboratory to the market. Not only do pharmaceutical companies benefit by being able to reduce the time taken between the drug research and commercialization, the fact that the drug can be introduced early means it can also be sold at lower prices, thus benefiting the patients who would depend on the drug for treatment.

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 conduction of clinical trials to a Contract Research Organization (CRO) for the following reasons:

The Core Competency

A pharmaceutical company have its energies dedicated towards 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 of which they attain vast experience and expertise in conducting clinical trials. CROs guarantee the technical expertise required in clinical studies, corroborate the quality of the research and results.

Expertise of working with different regulatory bodies

Working with multiple national international Pharmaceutical companies have enabled CROs have of obtaining 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 add on. Because of such experiences, a CRO is capable of guiding a pharmaceutical company with regards 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 pharma company can comfortably rely on the CRO when it comes to ensuring that the clinical trials are executed in the best way possible.

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.

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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 purpose

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 would prefer having virtual tours, since they help in cutting down traveling 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 future:

– The complexity of clinical development requirements is constantly increasing, and consequently, the need is increasingly being felt for specialized expertise for taking 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 the smaller ones, do not have the internal infrastructure to conduct studies on their own. The fully loaded costs for every successful molecule have now grown to $2 billion+ on average, and therefore, the importance of therapeutic expertise and scalability to reduce costs and time-to-market for new drugs is being acknowledged across the pharma industry.

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 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’ view 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 are accessible to professionals and non-professionals implies the Sponsor’s efforts in promoting transparency and building trust with the public.

Patient engagement initiatives

Conclusion

Patient centricity is gaining prominence as access to healthcare increases. This inevitably puts the clinical research industry in 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