In the pharmaceutical industry, clinical trials play a crucial role in securing approval from regulatory agencies since these tests attest to the safety of use for humans and the efficacy of the pharmaceutical products. But these studies can be quite expensive. Global spending on clinical trials was estimated to be $48.4 bn in 2020, a whopping 24.2% of the total pharmaceutical development spending of $200 bn that year
i. It is estimated that these costs, which are rising faster than any other aspect of drug development ii, will continue to rise to $68.9 bn by 2025 iii and $84.44 bn by 2030 iv.
Rise of the CROs
Controlling drug development costs without sacrificing rigour is important to lower the prices of products, while maintaining the companies’ return on investment. So, drug companies, be it from the West or within India, have been approaching Indian CROs (Clinical Research Organizations or Contract Research Organizations)
v for their help since 2005 (when the country started to comply with the Agreement on Trade-Related Aspects of Intellectual Property Rights or TRIPS). Due to their access to highly qualified scientists, doctors, and research professionals, low recruitment cost of volunteers, and the lesser rate of compensation for an injury sustained or death during clinical research, over time, nearly a fifth of all trials globally has come to be hosted by India vi.
However, with rising manpower costs, the window of India’s operating cost advantage is fast narrowing even as the ambitions of the Indian CROs are soaring. So, to maintain their hold on their drug industry customers, India’s CROs are trying to establish themselves as less of an outsourced assistant for research and more of a partner who can offer globally recognized processes and quality standards while completing these studies as quickly as possible.
Quality & Speed - Keys to CROs’ Reputation
Being fast to market with a product is a huge advantage for any new pharma product. And it is especially important for generic drugs which are plagued by the phenomenon of dramatic price erosion
vii with each new entrant. So, in addition to the cost of service, client companies select CROs after carefully examining several factors, including the CRO’s service portfolio, expertise, clinical knowledge, access to patients, ready availability of adequate study slots, workforce skills, facilities and even financial strength. This is to ensure that their study will be conducted with excellent rigour and alacrity.
Excellence in rigour ensures minimal or no observations and deviations generated during the studies. Higher the number of observations/deviations, the more the chances of regulatory queries, which can eventually expand lead times for approvals. Alacrity ensures that processes, though rigorous, are executed in the shortest possible time. As a result, the final reports from CROs can be delivered quickly after clinical trials. This helps companies decide on the future of the concerned product early. If this clinical trial process gets delayed, the company’s plans are jeopardized.
Challenges for CROs
On their part, the CROs would like nothing better than to offer their clients the seamless service they expect, viz. quicker response to initial client enquiries related to study feasibility, faster protocol creation, faster study approvals from regulatory bodies, improved access to required volunteers for studies and hospital slots for trials, availability of well-trained staff who can flawlessly conduct the studies with minimal observations/ deviations. Last but not the least, they would like to ensure that these capabilities culminate in a final report delivered in good time to the sponsor! However, these steps do not happen like clockwork due to the intrinsic challenges posed by the nature of work involved in every stage of the process:
Delays in responding to initial client enquiries
Clients/Sponsors reach out to CROs when their internal product development/ optimization is about to get over. The objective is to quickly get the CROs’ inputs on the feasibility of conducting the study in their respective facilities, and suggest innovations if any. Feasibility reports that have to be sent in as a response to these sponsor enquiries require the CRO sales team to coordinate with multiple stakeholders in the Clinical Research Department (CRD) - PIs (Principal Investigators, i.e., doctors), Bio Analytics department and Statistics team. However, most of these responders are either busy with currently running studies or reports of recently concluded studies. As a result, this coordination with stakeholders and creating the report takes a lot of time. During this time, clients may choose to move on to other CROs.
When an attempt is made to meet deadlines (usually one week) for submission in this environment, the pressure of time leads to certain compromises - the rigour is missed. For instance, some aspects of the report may be repetitions of previous studies, and may not be relevant to the current study. This can lead to gaps related to the scope, and, consequently, budget issues later.
Issue with quality and timeliness of protocols
Even after the contract has been signed with sponsors, protocol creation faces delays. This time, the medical writers need to coordinate with the CRD, especially the PIs, who have to contribute and eventually sign off on the protocol document.
Eventually, when there is a pressure of time on the Medical Writers to submit the protocol as per the set deadline, this often leads to mistakes or miss-outs. Case report forms or CRFs may not be made properly or thoughtfully; Informed Consent Documents or ICDs may have errors, etc. Redundancies in CRFs have the potential to generate observations during the trials. When these mistakes are discovered just before the study start date, they require additional cycles of approvals from regulatory agencies, leading to anxious moments for the CROs, and, in the worst cases, delaying the study schedules.
After required approvals, the clinical trials are held at the facilities or hospitals of the CROs, where, multiple studies are conducted daily. The study facility itself is a high-pressure environment where every activity (from dosage to drawing blood samples, to providing food) has to happen at a precise time and manner, as described in the protocol.
The CRD (doctors, nurses, and phlebotomists) is always in the thick of things while conducting these studies in these facilities. However, as mentioned earlier, while conducting these precisely timed studies, different members of the CRD have to support other functions in the following ways:
The PIs have to support the protocol making & feasibility of future studies while conducting the current ones.
The PIs, nurses, and phlebotomists have to close out their activities and respond to observations/ deviations raised from concluded studies while working on ongoing studies.
CRD members are, in effect, always pulled in different directions, and keep moving between the past (the final reports of completed studies), present (current study) and future (feasibility reports, the protocols)! In this melee, since they cannot ignore the ongoing study activities, what gets compromised are the support activities — feasibility studies and the post-study activities (review of CRFs, reports by PIs, resolution of observations/ deviations raised by Quality Assurance, etc.). These lead to high elapsed times, errors and miss-outs.
Lack of rigour in training
One of the compromises made is often in the rigour of training needed by the clinical team (nurses, phlebotomists and custodians) before an upcoming new clinical trial starts. This is because, in this chaotic environment, trainers (PIs/doctors) and trainees associated with the execution of an impending study are caught in a conflict between executing the current studies they are already part of, and preparing for the future study that they will have to undertake soon. After struggling to get everyone together in one room, these training sessions are often conducted without a full quorum. The expectation is that this training will be passed on to other members by the members who are already trained. But this often results in inadequate awareness about critical aspects of the study protocol. This lack of awareness results in a higher number of observations, and worse still, deviations, all of which impact the lead times and quality of report-making. As mentioned earlier, higher observations made during a study can result in increased regulatory queries after the submission of the dossiers by the sponsor.
Struggle in Quality Control
All of the above lead to a high number of avoidable observations/deviations raised during the trials by the Quality Control (QC) Department. Resolution of all these issues will now require the intervention of the CRD team, who have to explain the observations/deviations, and mitigate their effect on the study outcome. But when QC raises these observations, the response from CRD teams is often sluggish because they are always busy with ongoing studies.
Start-stop report writing
In addition to the difficulty of completing QC in a timely fashion, another challenge of this environment is that post-study, the reports of each study from the Bio Analytics and Pharmacokinetics & Biostatistical departments need to be integrated with the CR report. When multiple study reports are open in the system, it is difficult to ensure that all information of one study arrives together from the three departments. This delays the final integration of reports from CRD, BA and BPD. As a result, the final submission of the report to the sponsor gets delayed.
A close examination of the environment makes it clear that CRD is the most critical resource in the system. It is seen very clearly that the availability of the CRD makes or mars the flow of multiple activities in the system. Without proper alignment of CRD members with the rest of the functions, the progress of almost all tasks gets delayed. The delays ultimately lead to compromises and more delays. It is a vicious loop which is difficult to get out of.
Resolving the Dilemma
Once it is recognized that the critical factor to make CRO activities flow seamlessly is to ensure that CRD capacity aligns with the rest of the functions, the steps to do so seem rather apparent.
Step1: Remove the CRD from the conflict between the present study, potential future study (protocol making) and past studies (report making)
A big portion of time of CRD resources is spent on current studies. This cannot be avoided. However, with the separation of responsibilities within CRD, dedicated teams can spend quality time either taking care of feasibility responses or in protocol preparation as required. This can eliminate the delay in customer response, and reduce the compromises/ errors/ misses during protocol making. Further, the concerned CRD can focus on ensuring the smooth execution of current studies without being pulled into other activities.
Step 2: Put in place WIP control in CRD teams for pending reports of completed studies
A clear and simple priority system and restriction on the number of completed studies being worked upon at a time can ensure that CRD spends their limited time (left after ongoing studies) focusing on closures of the more urgent reports, and that they do not spread their capacity across too many projects.
Step 3: Ensure subordination of all other function capacities to limited CRD availability
All resources have to subordinate to the limited pockets of capacity available with the CRD (just like a pit stop in F1 racing, where the driver has limited time available before he returns to the race track). Processes have to be set up to ensure that time available for nurses, phlebotomists, and PIs in between their regular rounds of current studies is optimally used to close open observations from previously concluded studies that need their input.
Another step to improve the efficiency of the use of CR resource time is to put in processes for real-time Quality Control of data, i.e., checking subject data entered into the recording systems (CRFs) as soon as it gets generated during a study. Currently, information moves in a batch to QC – after a batch of one study period. Larger the batch of data arriving at QC, more is the time taken for review by QC, and more is the time elapsed between the end of the study and the flow back of observations. This time gap creates context switching for the CR resource, and increases the time needed to resolve the issues.
Step 4: Decouple PI from having to train everyone (PI only trains the trainers)
To ensure that tasks are executed without error, it is necessary for protocol training to be effective. But for this, it is assumed that PIs and trainees busy executing their current studies must successfully sync time with each other. However, if one examines the training requirements, it is clear that the training content is not necessarily common for all groups. Moreover, if the PI trains the group leads, these group leads can, in turn, train others. This means that different groups can be trained at different times on only their respective tasks. This reduces the challenge for sync and ensures better, more focused training.
Step 5: Use a priority system to ensure sync between departments
Processes can also be put in place to align priorities between the different departments, which sometimes work in parallel on the same study. This is especially important for report writers working on study data, BA & BPD on blood samples. With a clearly defined global priority system, there will be improved synchronization, and all inputs will be available faster for report completion.
Step 6: Ensure that people start work only with all inputs
Even if there is a global priority system, some inputs may still lag. In this situation, if people start work, it will lead to future interruptions and rework. So, people should start work only when all necessary inputs – documentation, corrections, material, etc., are at hand. Routine full kit readiness meetings can be held at various levels to arrange for the missing material/ information.
Step 7: Do away with date-driven execution and initiate high-frequency management instead (in feasibility report making, protocol preparation and report preparation)
Pre-defined date commitments on every project are not in sync with the principles of the WIP rule and a common global sequenced priority of projects. Delays in such deadlines eventually lead to everything becoming urgent. This can again trigger bad multi-tasking in the system and more delays. Hence one needs a process of daily management and pre-defined issue resolution frequency rather than the usual process of intervention close to committed deadlines. During these meetings, experts can look at issues together, understand each other’s views, and work towards solving them.
Step 8: Improve the visibility of individual studies
Every study is like a project, comprising hundreds of activities to be conducted before, during and after the trials. The project begins with preparatory activities (such as procurement of stickers, buffers, preparation of blood collection vials, etc.) required for a study, and ends with the final integration of CR, BA and BPD reports. All preparatory activities for a study have to be completed in time before the study schedule. Likewise, all post-study report creation and analytical activities should be executed as fast as possible for submissions to be fast. A project management software system for monitoring the progress of individual tasks in a study, and providing the expected time of completion (ETC) of all reports, goes a long way in providing visibility into the status of a study. This is particularly important in an environment where many projects are in different phases of their trials (pre-study, during the study and post-study). So, providing this visibility is essential to indicate to the management where and when to intervene.
When all the above steps are in place, one can ensure that studies are conducted smoothly. The number of observations and deviations observed during the studies is low (40%-50% reduction), and the final integrated report gets generated in the least possible time after the study schedule (25%-35% faster). This will not only enable CROs to complete more studies with the same resources, but the fast turnaround of studies will also make the sponsors happy (customer satisfaction in the high 90s). Moreover, as the quality of reports will improve significantly, the chances of queries from regulatory authorities post submission, can go down. With such a reputation for quality and speed of execution, CROs can establish lasting partnerships with pharmaceutical giants across the globe.
v) CROs are companies that provide clinical trial management services for these pharmaceutical, biotech, herbal/nutraceuticals and medical device companies. Although there are different types of CROs, typically, the major role of the CRO is to plan, coordinate, execute, and supervise the processes involved in the development of a clinical trial and to be the central contact point between the sponsor and other clinical trial stakeholders (e.g. ethics committees, regulatory agencies, vendors, volunteer recruiters and hospitals).
vii) More suppliers enter as the market for generics mature, leading to lower prices and lesser margins for all players.
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