There is always a gap between research and application, and the function of clinical trials is to bridge it. By allowing researchers to determine a drug or medical device’s impact on real people, trials demonstrate how medical science can align theory with practice. Otherwise, there would be no telling whether an intervention is successful, much less safe.
Bringing medical interventions to the market involves numerous stages. Typically, years pass before a treatment enters clinical trials, where it spends many more years advancing through phases. The exact length of the process varies based on the researchers’ abilities to control variables that can shift the time frame.
In particular, a clinical trial’s success depends largely on mitigating the tension between attrition and retention. Per Desai, more than half of all terminated trials ended because of low participant accrual, 80% are delayed or require additional study sites because of slow enrollment, and “insufficient retention” leads to a failure to “answer the original research questions appropriately.”1 As the BDO’s 2022/2023 Clinical Research Organization Insights Report reveals, the problem extends to the operational side, with the turnover rate among clinical research associates in the United States at 28% in 2021.2
People, including patients and staff, are essential to both starting and completing a clinical trial, and a full appreciation of the importance of retention requires examining the nuanced range of activities that clinical trials entail and the impacts of dropouts at every point in the process.
What are the main stages of the development process?
To begin, it is essential to acknowledge the precise steps involved in bringing a medical intervention to market and what each step broadly entails. The process, which can take up to 15 years to complete, encompasses five primary stages:
- Discovery and Development
- Preclinical Research
- Clinical Research
- Regulatory Review
- Post-Approval: Marketing and Post-Market Safety Monitoring
The following sections examine the activities associated with each stage and the personnel and attrition-related concerns that may arise.
1. Discovery and Development
Discovery recognizes the potential for a new medical intervention. It begins with testing molecular compounds, researching a disease process, and identifying any unintended effects caused by existing treatments. Development then occurs after researchers select a subject that they consider promising. They execute laboratory experiments to understand its mechanism of action, potential benefits, ideal dosage and delivery, side effects, variable interactions, contraindications, and efficacy compared to similar interventions.
Early on, researchers may encounter hundreds to thousands of potential interventions, but testing whittles the candidates down to those that demand additional study. The key activities and milestones include the following:
- Target identification and validation: Identifying a target means pinpointing where, in the pathogenesis of a disease, a therapeutic molecule binds to effect a change in biological activity. Validation is conducting experiments to confirm the therapeutic effect of the molecule.
- Hit identification: “Hit” is the term for the specific therapeutic molecule that can interact with the target to produce a desired effect. Researchers can identify a hit through a diverse range of screening methods.
- Assay development and screening: An assay is a test to analyze the effects of a therapeutic molecule, allowing researchers to determine how it operates at the cellular and biochemical levels.
- High-throughput screening: Researchers use rapid, automated methods to test multiple molecules that can interact with the specified biological target. The idea is to identify molecular candidates that modify the target in the desired manner.
- Hit to lead (H2L): The H2L process evaluates molecule hits to narrow down the candidates. The likeliest molecules to develop into clinically active drugs proceed to lead optimization.
- Lead optimization: Researchers synthesize and modify the lead candidate molecules to optimize their efficacy.
Key roles during early drug discovery include biologists, chemists, pharmacologists, toxicologists, and other scientists. Aside from the academic and professional credentials required to conduct scientific studies, researchers must demonstrate attention to detail and cognitive stamina.
Because discovery sets the foundation for the subsequent stages of drug development, attrition among the scientific staff at this point would not only portend difficulties but also cause delays as the coordinators try to recruit replacements with comparable expertise.
Example
Studying a clinical condition that currently lacks an effective treatment, a team of academic researchers identifies a signaling pathway whose activation may cause a therapeutic effect in the target disease state. Using phenotypic screening, they identify and validate a target whose deactivation appears to trigger the therapeutic reaction. The researchers also identify tens of thousands of compounds that could potentially interact with the target to achieve the response. Via high-throughput screening and the H2L process, they can narrow down the potential hits to a single candidate after three years.
2. Preclinical Research
At the preclinical research stage, the intervention in development undergoes in vitro (laboratory) and in vivo (animal) testing to examine its potential to cause harm. In the case of a drug, for example, the studies necessitate revealing salient details about its toxicity and appropriate dosing levels.
During preclinical research, researchers must comply with Food and Drug Administration (FDA) requirements concerning good laboratory practices (GLP), as defined in the Code of Federal Regulations Title 21, Part 58, which outlines the minimum requirements concerning how the study is conducted, the facility and equipment used for the study, its written protocols and operating procedures, and its system of quality assurance oversight. Importantly, GLP also covers personnel requirements, specifying that there “shall be a sufficient number of personnel for the timely and proper conduct of the study” and that the staff must have the “education, training, and experience” necessary to perform their functions.3
The important preclinical stage is when researchers begin to connect the study to real-world applications. Closely examining how a therapeutic candidate behaves in controlled environments and animal systems can reveal whether it is viable for clinical trials. Indeed, at the end of preclinicals, the researchers determine whether to advance the research to the next stage.
As with discovery and development, the attrition of preclinical scientific staff may cause major delays in a study. Possibly more concerning is the loss of institutional knowledge, as preclinical research produces substantial data about drug viability in a biological system. Every instance of staff dropout represents a loss of understanding about a treatment’s potential benefits and dangers, requiring significant time and money toward rehiring equivalent talent and recovering usable intelligence.
Example
In the laboratory, the academic researchers perform additional screening tests to confirm whether there is pharmacodynamic activity between the target and the hit compound. They then test the compound on isolated cultures to find that it has the intended effect.
Next, they test on animal models, namely rats due to their genetic similarity to humans. The researchers induce the target disease state in the rats and then treat them with the hit compound. Additional confirmatory tests show that the therapeutic activity is valid and that the compound also has an anti-inflammatory effect.
After four years of study, the researchers determine the compound’s mechanism of action and find that it may have adverse effects on the kidneys in high doses, but quantitative tests have indicated the ideal dose for maximum effect and minimal adversity. They have also performed toxicity testing in both rats and dogs and confirmed the safe use of the compound in both species.
3. Clinical Research
The clinical research stage is when trials take place. As the most time-consuming and cost-intensive part of a research study, this stage may last upwards of a decade.
It also requires the submission of essential documentation to the FDA: the investigational new drug (IND) application or, in the case of medical devices, the investigational device exemption (IDE). These important applications are formal requests that a drug’s developer or sponsor makes to use a candidate intervention on human subjects in a clinical trial.
Thus authorized, the researchers can begin the trials, which consist of three primary phases:
Phase One
In phase one, which normally lasts a few months, the researchers typically recruit up to 100 volunteers, either healthy people or those who have the disease or condition that the candidate drug is meant to treat. The purpose is to determine safety and dosage. Based on the animal data from preclinicals, the researchers adjust the drug doses in human subjects to determine the amount that is tolerable and the acute side effects it produces. With the information gathered here, they gain valuable insights into how to administer the drug, optimize its use, and minimize its risks.
Phase Two
Starting with phase two, the trials begin to center entirely on volunteers with the target disease or condition. The number of participants may increase now to several hundred. That is insufficient to determine for certain whether the drug is beneficial, but it does provide further data about its efficacy and safety, which researchers put toward refining their research methods, questions, and protocols. The total length of phase two trials can be anywhere from a few months to two years.
Phase Three
In phase three, the trials become both larger and longer. Working with several hundred to several thousand volunteers, researchers monitor adverse reactions caused by the candidate drug. Incorporating more participants can improve age, gender, or ethnic diversity, thereby improving the general understanding of the trial’s results. Also, the longer-form nature of the trials allows researchers to identify the long-term or less prevalent side effects that may have gone unnoticed in the previous two phases. As a result, much of the safety data for the drug arises from the third phase.
In any of these phases, staff or participant turnover may introduce tremendous knowledge gaps and costly timeline disruptions. Ideally, to achieve a smooth and efficient clinical research process, it is important for the staff who participated in the IND/IDE application to continue their involvement until the end of the trials. This is because the trial design and its protocols are articulated early in the clinical research phase, and acclimating substitutes to the procedure—not to mention recruiting them in the first place—requires additional time and money for training.
If a research study cannot find equivalent replacements for staff dropouts, it must proceed with either inexperienced members or an understaffed team. Either case raises concerns about poor data quality, procedural inconsistencies leading to data loss, and regulatory noncompliance stemming from their unfamiliarity.
Staff turnover, in turn, can beget patient turnover. Often, what fosters ongoing patient participation in a clinical trial is the rapport they have with the CRAs and coordinators, but that rapport dissipates when members leave. High staff turnover commonly correlates with poor patient retention, and a trial cannot continue, especially in the latter phases, unless it has enough volunteers. This challenge may be even more difficult for candidate drugs for medical conditions such as multiple sclerosis and certain rare cancers, for which the participant pools are smaller.4
Example
Given the promising findings during preclinical research, the researchers deem the hit compound to be a candidate for clinical research. They design a study for humans, defining the following parameters:
- Selection criteria
- Drug-administration protocol
- The number of participants
- The length of the study
- The assessments to be used
- Strategies for minimizing research bias
- Data review and analysis protocols
As part of their selection criteria, the researchers decide to recruit participants ranging from 30 to 55 years old, as the target condition is most prevalent in this age range.
Next, they submit an IND application to the FDA. The application includes data about their animal studies, the compound’s toxicity, and the protocols for the clinical trials they wish to conduct, as well as details about the investigators’ qualifications and how they develop the treatment. The FDA determines that the application sufficiently minimizes risk to potential volunteers and approves the application.
For phase one, the researchers work with 80 participants with the target condition. Based on their preclinical safety data, they increase dosing in the participants to gauge potential adverse effects and the expected side effects of using the treatment. Thus, over six months, the researchers can acquire a better sense of the appropriate dosage.
Phase two increases the number of participants to 500. Continuing to monitor safety, the researchers also begin to recognize common responses to the treatment that help pinpoint additional side effects and therapeutic uses. The total length of the phase is 1.5 years.
In phase three, the participants number 3,000. Administering the treatment to this larger group of patients over three years confirms that it has the intended effect and only minimal side effects on most users. Because it is the longest phase, it reveals longer-term side effects in a fraction of users that arise after one year of regular treatment.
4. Regulatory Review
At the regulatory review stage, a drug’s developer applies to the FDA for authorization to market their product. The application in question is the new drug application (NDA), whose purpose is to establish that a candidate drug is both effective and safe to use in its target population.
Along with the NDA, the developer includes all the evidence for the drug’s efficacy and safety gathered from preclinical and clinical trials. In addition, they provide information about the drug’s patent, its recommended labeling and directions for use, potential abuse concerns, safety updates, review board compliance, and any studies conducted overseas.
For developers of medical devices, the application depends on the device’s regulatory class. A 510(k) application, for example, is for demonstrating that a Class 2 device is like other devices currently on the market, while a premarket approval (PMA) application is for Class 3 devices. As with NDAs, the developer provides evidence supporting their claim. PMAs must include data from all the clinical and nonclinical studies conducted on the device, and the FDA visits the manufacturing facilities to confirm compliance with good manufacturing processes.
On the FDA’s side, a review team receives and evaluates the application. If the review team determines the application is complete, it has six to 10 months to approve it. In this process, each team member comprehensively reviews a portion of the application, and FDA inspectors visit the clinical study sites to validate the data presented. Upon approval, the FDA works with the developer to refine the product’s labeling. Sometimes, the administration delays approval to clarify issues or request additional data.
Should the review team decide the application is incomplete, it will decline to file. If the application contains insufficient supporting data, the FDA may assemble an advisory committee to get input from experts and the public.
Even in the latter half of the development process, with the intervention on the cusp of approval, staffing problems can hamper progress. Besides the possibility that earlier delays may have postponed regulatory review by months to years, any previous inconsistencies in data integrity, analysis, or interpretation may produce insufficient reportage in the view of the FDA, which could result in denial or at least deferment of an application.
Example
Convinced of the treatment’s efficacy and safety, the researchers submit an NDA to the FDA, including reports on all the studies they have conducted and the data they have gathered. In addition, they provide recommended labeling details, directions for use, proof of regulatory compliance, updates about the drug’s safety, and information about its patent.
The FDA receives the application. Over eight months, the review team—which includes a pharmacologist, a medical officer, and a statistics expert—determines the application is complete. The individual members of the team review the portions of the application that relate to their expertise (for example, the pharmacologist examines the animal study data). The agency sends inspectors to the clinical study sites; they confirm there is no evidence of data manipulation or omission. The review team then recommends approval of the drug to an FDA official, who agrees with the recommendation.
5. Post-Approval: Marketing and Post-Market Drug Safety Monitoring
Developing a drug or medical device does not end with FDA approval. First, there are the commercialization processes. Once it is approved, the product undergoes manufacturing to produce it en masse and marketing to bring it into public awareness. Then come the post-marketing surveillance and pharmacovigilance, which refer to the ongoing process of monitoring product safety and taking measures to minimize newly recognized risks.
Post-marketing surveillance is vital because preclinicals and clinical trials are not foolproof mechanisms for ensuring efficacy or safety. When the public starts using a medical intervention, a more complete understanding of its effects comes into view. The FDA reviews reports about potential issues that arise post-approval and informs consumers via cautions and other labeling modifications, noting that users have the information they need to preserve their well-being. In addition, the FDA conducts regular inspections of manufacturing facilities to ensure compliance with best practices and oversees advertising to ensure truthfulness.
Though it may seem that the FDA, consumers, and health providers are responsible for much of the post-market safety monitoring, the developer also possesses a great deal of responsibility. This necessitates staff to enter data about adverse events (AEs), conduct quality control of AEs, update MedDRA coding, execute pharmacovigilance audits, and manage vendors, to name a few. Without sufficient staff, developers can easily find themselves struggling to manage the myriad activities required to maintain their products’ safety, usability, and reputation.
Example
A new drug is on the market. The FDA passively monitors the drug’s safety concerns via MedWatch, a gateway through which consumers report problems with medical interventions. As many MedWatch submissions mention side effects not listed on the labeling, the FDA determines that the drug needs new caution labeling to ensure safe use. On the developer’s side, the staff updates databases with new adverse events. Also, third-party pharmacovigilance audits keep both the developer and the FDA apprised of potential safety issues.
Leveraging a Life Sciences Staffing Partner for Clinical Trial Success
The activities and objectives of clinical research fluctuate from stage to stage. Starting in the lab and ongoing after FDA approval, the process requires scientific expertise to begin, the coordinative talents of the clinical trial staff to resume, and the vigilance of the post-market personnel to ensure continuing relevance. Throughout, shifting arrangements of teams work hard to maintain data integrity, patient safety, and regulatory compliance, but attrition can compromise these at any step. Retention is crucial for taking new drugs and devices from conception to market as efficiently as possible.
While you cannot guarantee a smooth ride in any clinical study, working with a specialized staffing partner can help make it happen. An agency experienced in the life sciences not only understands what a trial needs to run smoothly but also has access to a vast pool of talent to fulfill the study’s requirements. With a partner undertaking the responsibility of staffing a clinical trial, you can prevent delays, minimize losses, find experienced and specialized talent, and more quickly bring life-changing interventions to the people who need them.
References
- Mira Desai, “Recruitment and Retention of Participants in Clinical Studies: Critical Issues and Challenges,” Perspectives in Clinical Research 11, no. 2 (May 6, 2020): 51-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342339.
- BDO, 2022/2023 Clinical Research Organization Insights Report: Managing Talent and Pay in a Competitive Market and Volatile Economy (BDO USA, LLP, 2023), https://www.bdo.com/getmedia/a6fb62d9-36f2-46d9-a053-deeffc84ca30/TAX_GES_2022-2023-BDO-CRO-Insights-Report.pdf.
- United States Food & Drug Administration, Code of Federal Regulations Title 21 (FDA, 2023), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=58.29.
- Aylin Sertkaya et al., Examination of Clinical Trial Costs and Barriers for Drug Development (Office of the Assistant Secretary of Planning and Evaluation, July 24, 2014), https://aspe.hhs.gov/reports/examination-clinical-trial-costs-barriers-drug-development-0.
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