Participant recruitment is one of the biggest bottlenecks in clinical research today. 

In early drug development, effective volunteer recruitment is critical for building a robust package of clinic trial data, ensuring scientific validity, containing study costs, and maintaining timelines. In studies that require specific types of volunteer populations, it’s important to develop a focused plan for recruitment.           

Different populations may demonstrate widely varying responses to drug therapies due to physiological, lifestyle, or other disparities. To safeguard those for whom standard requirements may not offer sufficient protection, special populations provide an evaluation of factors such as dosage or dose interval modifications to address these differences.

For example, individuals over the age of 65 are more likely than younger individuals to take multiple drugs concurrently, making drug interactions of particular concern. Because older populations respond differently than younger patients to drug therapy, obtaining clinical efficacy and safety data for these populations is critical in early drug development.

Furthermore, growth in global pharmaceutical markets is driving drug development in Europe and Asia. Multi-ethnic approaches to clinical trial programs, such as ethnobridging for native Asian populations living in other countries, must account for cultural differences to satisfy international regulatory authorities.

If you’re a sponsor, it will be of utmost importance to work with a trusted contract research organization (CRO) that is transparent about timelines and can guide your expectations. 

An experienced partner can effectively target hard-to-recruit populations such as the elderly, post-menopausal, hypertensive, and healthy smokers, to name a few.

An organization that has completed multiple studies with similar types of populations will have a baseline understanding of recruitment challenges and can provide an honest assessment of the time expected to recruit the full cohort. When studies have stricter criteria or more screening procedures for qualification, recruitment will require more time. It’s important to find a partner that provides a realistic, trust-based approach to recruitment rather than one that promises to quickly recruit every participant.

In addition to identifying appropriate study participants, the right partner can help minimize screen failures due to multiple exclusion/inclusion criteria. 

Such a partner will demonstrate a successful track record with metrics including:

• Number of studies completed
• Database size and number of active healthy volunteers
• Recruitment timelines and strategies for special subject populations
• Communicate effectively

Sponsors may consider the following five tips when it comes to interviewing and partnering with a CRO for their early drug development needs.

Inquire about the volunteer database

When rapid study startup is critical, a robust database provides an immediate starting point for recruitment. A large database demonstrates that the CRO has access to an adequate population of volunteers who understand clinical research and are amenable to participating. Consistent recruitment activities and a database of multiple trials also can help keep volunteers active.

Consider your CRO's location

Whether your trial must be conducted at a single site or multiple sites, you may want to consider the location of the sites available and their advantages and disadvantages. Facilities in larger cities tend to recruit from more ethnically diverse populations or those with better access to public transportation options. The longer the facility has been in existence, the more established relationships it will have with the local community and population.

Know what questions to ask your CRO's

To determine how the CRO will prioritize your study, ask whether it is recruiting for multiple studies of the same kind concurrently. If so, your study would compete with others for the same volunteers and consequently have access to a smaller pool of potential participants, which could delay your recruitment completion. Ask about recruitment and screening timelines, because extended timelines could indicate difficulty recruiting that population. Determine if full trial cohorts can be enrolled at one time or if there is a need to divide them into sub-cohorts for admission, which could be another indicator that the site has difficulty enrolling a specific population.

Employ best practices regarding patient safety

If you have concerns about volunteers participating in overlapping studies, work with a partner who uses a registry that tracks volunteers and their participation in trials, including the date of the last dose of a study drug. This information will help establish a sufficient wash-out period, during which the participant receives no active medication. Such registries are confidential and established through fingerprinting, and they enhance patient safety as well as facilitate data integrity.

Find a CRO that can integrate services

Look beyond the CRO’s ability to recruit large cohorts of volunteers and examine its track record of complete study delivery, including the expertise of its team of medical directors and project managers, as well as other capabilities. The right partner can also guide protocol development and study design to maximize your clinical data output, and rapidly deliver data and insights quickly to move you to the next milestone.

When you are looking for a partner who is dedicated to Phase I trials and early development, choose Quotient Sciences. 

To find out more about our clinical pharmacology capabilities, get in touch with us today.

As Sr. Director of Operations at Quotient Sciences, Miami, Harpreet is responsible for the day-to-day running of the clinical pharmacology unit. She oversees an experienced team of nurses, clinical, and laboratory staff to deliver healthy volunteer studies successfully, on time, and to the highest quality standards.

You mentioned that you started off in nursing, so why did you pursue a career progress into the pharmaceutical industry?

Early in my career as a dialysis nurse, I took care of patients with major health problems. I saw firsthand the benefits they received from newly marketed treatments and this made me determined to develop my career in clinical research. I earned a Master of Science degree in Nursing with a specialty in Clinical Research Management from Duke University and my role at Quotient allowed me to use my clinical background and education to set up and run early-phase studies.

I am passionate about using new technologies in drug development and have spearheaded our transition from paper to electronic source documentation and managed the start-up of an on-site laboratory within our Miami clinic.

Have you always worked in the Clinical Pharmacology space?

After working as an acute dialysis nurse, I moved into early-phase clinical research and have worked in the clinical pharmacology space for the last 21 years.  I love working in the early phase as it’s fast-paced, the projects move quickly, and customers are always keen to see the clinical data.   

As the Senior Director of Operations, what does your day-to-day look like?

No two days are the same and with a global client base, I have to work flexibly to provide support across different time zones.  A typical workday may include making rounds in the clinic, reviewing new protocols with our Sr. Medical Director, and discussing continuous improvement plans with operational colleagues. The one constant, however, is working side by side with my team, to overcome any challenges in the delivery of projects for our customers.

What do you enjoy most about your role and why?

Knowing that we are helping to develop new medicines and get them to patients faster is exciting and very rewarding. What better mission can one have?

How do you see your role evolving over time as the business grows?

In recent years I have been working with Quotient’s senior leadership to strengthen and expand the capabilities in Miami.  For example, we have just finished a huge project to build a new industry-leading compounding pharmacy, capable of preparing a broad range of dosage forms for first-in-human and early-phase clinical studies.  This project took nearly 9 months to complete and was a considerable investment for our organization.  We now have state-of-the-art cleanroom suites meeting USP 797 and USP 800 standards to prepare sterile and non-sterile dosage forms and handle both hazardous and non-hazardous compounds.

As the company grows, my role will continue to evolve as we broaden our service offerings to support our client’s needs in the drug development process.

Tell us about the Miami facility and what role it plays within Quotient’s early development network

The Miami site specializes in clinical pharmacology studies with a proven track record of almost a thousand studies over the past 25 years. With 144 beds and a large recruitment database of 20,000 healthy volunteers, we’re known for being able to rapidly start up new studies in record time and complete studies quickly with full cohorts of subjects.

We also work closely with our Quotient teams in Philadelphia (US), Nottingham, Reading, and Edinburgh (UK) to deliver highly bespoke programs of work that save clients considerable time and money. Translational Pharmaceutics® is our unique platform which integrates formulation development, manufacturing, and clinical testing to deliver exceptional benefits to clients. A recent white paper from Tufts CSDD concludes that Translational Pharmaceutics® reduces development times by 12 months on average and creates significant financial gains ($ multi-million) for biotech/pharma companies.

What benefits do clients receive by working with a development and manufacturing organization that also has clinical pharmacology expertise?

Quotient Sciences has development, manufacturing, and clinical pharmacology expertise across multiple sites in the US and UK.  Our clients are therefore able to place projects at any of our sites and Quotient can integrate different activities to accelerate their drug development plan. For example, our Philadelphia team can develop and manufacture new drug products (e.g. tablets or capsules) which can then be rapidly tested in clinical studies at our Miami clinic. This tight integration helps us get new medicines to patients faster.

Since Quotient Sciences acquired the Miami facility back in 2017, what additions and improvements have been made to better support our client’s needs?

Until the recent addition of our new pharmacy, a lot of our focus has been on strengthening our Project Management and Data Sciences functions and adopting a multidisciplinary team structure for project delivery.  We have also recruited and trained many new employees to increase our overall capability and capacity and laid the framework for continued growth and development. Feedback from client questionnaires indicates that these changes have made a really positive impact on their programs, especially with enhanced levels of project communications.

With all this expansion in facilities comes a need to continually increase headcount.  How much has changed in terms of the number of employees at the Miami location since you started up until now?

I have seen Quotient Sciences Miami grow significantly during my tenure. We have dedicated a lot of time towards becoming efficient and ensuring that our new employees become capable and experienced in supporting our existing team.  We also have great employee engagement and retention, and as such, I am surrounded by many dedicated and long-serving team members, many of whom have been with us for over 10 years. 

For any qualified candidates looking for a position at Quotient Sciences Miami, what can they look forward to?

Teamwork. Joining a great company like Quotient Sciences is a competitive effort on the part of new hires and we select only the top candidates to join our team.  Team members can expect a collaborative and hands-on approach to delivering projects and a leadership team that encourages working together, driving for results, and operational excellence.

Can you tell us about the new pharmacy capabilities? How does this help customers who want to start clinical studies quickly?

Quotient Sciences is the only drug development provider that can offer pharmacy compounding, GMP drug product manufacturing, and clinical testing all under the same organization.  Our experienced pharmacy team and new cleanrooms enable us to prepare low, medium, and high-risk compounded products for dosing in the Miami clinic. Using the formulation and manufacturing capabilities across the Quotient Sciences network, we can then help our clients seamlessly transition from simple first-in-human pharmacy formulations to a robust solid oral product for their downstream patient trials.  By simplifying the supply chain with an integrated project team and a single development partner this offering enables our clients to achieve proof-of-concept up to 15 months faster.

Tell us how the Miami facility can support our client’s clinical pharmacology needs and deliver studies with quality service and speed.

Our clinical pharmacology expertise encompasses first-in-human (SAD/MAD), DDI, food effect, TQT, and BA/BE studies. Our experienced and dedicated project managers work closely with the IRB and screening team to ensure timely enrollment. We are accustomed to helping clients with rapid study start-ups and with an on-site CLIA-certified laboratory for fast turnaround times, we work to get clinical data to our clients quickly – but not at the expense of quality. Our excellent regulatory inspection history speaks to the high-quality delivery by our project and clinical teams.

What else do you think differentiates Quotient from other drug development organizations?

Our clients rely on the expertise of Quotient Sciences to accelerate their drug development programs in a variety of ways. Uniquely, Quotient provides both clinical pharmacology/research (CRO services) and pharmaceutical development & manufacturing (CDMO services) to the pharmaceutical and biotech industry. These services can be provided individually, or as an integrated service which has been shown to dramatically shorten development times, reduce outsourcing costs, and significantly simplify supply chains for customers.

The ability to move quickly and cost-effectively from candidate selection to first-in-human clinical trials is a theme that comes up often from clients. One way which we strive to do this is through services offered from our compounding pharmacy in Miami, FL.  

The compounding pharmacy is part of our clinical pharmacology services in Miami, FL, where we conduct Phase I trials with healthy volunteers.  

In this article, learn about the capabilities of our Miami, FL on-site compounding pharmacy, and ideal uses for pharmacy compounding to accelerate FIH to POC trials.

What are the advantages of choosing pharmacy compounding for FIH trials?

Quotient Sciences simplifies the drug development supply chain, acting as a single partner with integrated project team and services. We can help through all stages of development.  

At our Miami site, fit-for-purpose pharmacy preparation can be used to quickly start FIH trials. In this approach, a FIH trial using a simple and cost-effective dosage form, such as powder- in-capsule or bottle (also called PIC or PIB, or drug in capsule/bottle), solution or suspension, has the benefit of improving timelines to the clinic while still providing maximum dose flexibility to achieve Phase I objectives of obtaining PK and safety data.  

Emerging clinical data within the FIH study itself can be used to inform formulation technologies (such as solubility enhancement) enabling selection of a technology and/or drug product to move forward with. This means that simultaneously, we can develop and manufacture solid oral drug product, like a tablet, for Phase 2 patient trials within the same program. This allows for POC patient trials to begin with immediate GMP clinical trial material supply.  

The ability to manufacture and dose multiple formulation types in real-time, coupled with the ability to use smaller batch sizes and abbreviated data packages, ensures that we can carefully manage CMC investments and minimize API usage.  

Are there certain programs that benefit from choosing pharmacy compounding?

We have used compounding for a range of drug candidates including small molecules, peptides, fusion proteins, and monoclonal antibodies. These have been across oral and intravenous dosage forms, and for a range of therapeutic areas.  

As discussed, compounding delivers significant benefits for accelerating to FIH programs and when transitioning from FIH to POC. A simple drug in capsule or drug in bottle for reconstitution at bedside is the quickest route to clinic with compounding and dosing occurring within 24 hours.  

Compounding is beneficial on any early clinical program where there is a desire to get data rapidly and keep dose flexibility throughout the trial. In addition to FIH single and multiple ascending dose (SAD/MAD) studies, pharmacy compounding has used in other study types, including:

• Absolute Bioavailability and Relative Bioavailability studies
• Drug Drug Interaction (DDI) studies
• TQT studies
• Food Effect and PK studies
• Studies in special populations (e.g. Elderly)
• Device trials
• Formulation screening studies

Sterile compounding with sterilization by aseptic filtration is another quick route to clinic as proof of concept especially for chronic indications such as HIV infections, CNS indications, oncology, viral infections, certain rare diseases, and metabolic conditions.  

Another advantage of pharmacy compounding is its adaptability in dose-finding studies for combination therapies, where precise modulation of each active pharmaceutical ingredient (API) is essential. This approach is well suited to drug delivery systems requiring an initial burst release followed by sustained drug exposure. By systematically varying the proportions of immediate-release and modified-release components, the optimal formulation for therapeutic efficacy can be efficiently identified.  

In molecules with limited stability, compounding allows for early assessment of their potential for further development.

For small molecules that have solubility and bioavailability challenges, we help clients select the right formulation technology for their poorly soluble molecules. We apply a data-driven process based on the physicochemical and biopharmaceutic properties of the API with a full range of solubility enhancement technologies including lipidic systems, micronization, spray drying, and hot melt extrusion.

Finally, the best formulation, with accompanying formulation technology, can be selected and a new solid oral dosage form manufactured, ready for packaging and shipment for patient trials.

When was the compounding pharmacy at Quotient Sciences – Miami last renovated?  

In 2020, we upgraded the Miami compounding pharmacy to add more IP storage space, including refrigerated storage space at 2 to 8°C and freezer storage at -20°C.  

Clean rooms in the facility were built to ISO Class 7 air quality standards with ISO Class 5 Primary Engineering Controls (PEC), which include laminar airflow workbenches (LAFWs) and biological safety cabinets (BSCs), allowing us to handle potent APIs and Hazardous investigational products  

The laboratory space also expanded to support our new pharmacy and provide efficient processing of higher volumes of biological samples.  

What dosage forms can be handled at Quotient Sciences – Miami?

Within the pharmacy and clinic, we can handle a variety of dosage forms including active pharmaceutical ingredients (APIs) or processed intermediates in oral solutions, suspensions, powder-in-capsule (PIC) or powder-in-bottle (PIB), and sterile preparations for parenteral delivery.  

More about Quotient Sciences – Miami pharmacy compounding and clinical pharmacology  

Learn more about our pharmacy compounding capabilities in our info sheet and see a preview of the Miami pharmacy in this video. 

In this interview, we speak with Clare Preskey about her day-to-day in the Nottingham clinic. 

Clare Preskey is Executive Director of Clinical Operations, responsible for the oversight of day-to-day activities that take place in our Nottingham Phase I clinic. This includes volunteer screening and management, oversight of our clinical laboratory and pharmacy teams to ensure on-time project delivery, and driving continuous improvement and innovation initiatives.

Looking back to when you were first starting your career, was your goal to be where you are now?

I have always held a passion for science and the study of physiology and pharmacology. I started my career at Quotient Sciences in 2010 fresh out of university as a Clinical Scientist. My key responsibilities were ensuring the well-being of our volunteers and the collection of clinical data.

Later, I moved into Project Management, where I gained valuable experience in customer management and developed a broader understanding of our business. I held several roles within Project Management, last as a Team Lead prior to moving into a clinical operations role. I have always held a passion for clinical sciences and operational excellence, so my current role is a great fit. 

What are some of the biggest changes and improvements that you have seen over the years at Quotient Sciences?

When I first joined the company, we were a much smaller business: one building containing a 30-bed clinical unit, a GMP suite, and approximately 100 employees. The people at Quotient Sciences are at the heart of the business; we have a great culture and tight-knit teams. Close teamwork is imperative when managing complex and integrated projects in short timeframes for our customers. 

Quotient Sciences has always had a focus on continuous improvement and high-quality standards. The biggest change has been the expansion in facilities and capacity, including the evolution of our Translational Pharmaceutics platform, over the last 10 years. Despite our growth, the ethos of who we are and what we do has not changed. We’ve been able to retain our core values, agility, and integrated processes.

We never stand still; we are always pushing boundaries, trying to do things better and more efficiently! I am privileged to work with such committed, talented teams. 

How do the different functions work together to deliver Translational Pharmaceutics programs?

Teamwork is key to any Translational Pharmaceutics program and establishing cohesive communication channels across departments. Our processes have been built over many years, with SOPs and protocols geared to be adaptive. Planning is also an essential practice that is embedded in our operational processes (e.g. kick-off meetings) to ensure the highest quality project delivery that is the right first time.

What do you enjoy most about your role and why?  How do you see your role evolving as the business grows?

The environment at Quotient Sciences is dynamic and fast-paced. Every day brings different challenges and opportunities! 

We work with so many different customers, molecules, and study designs. My colleagues are incredibly passionate and dedicated to every one of our projects and customers. We learn and grow together, expanding our knowledge and gaining new skills. Getting things right the first time is very important to me.

I love what we do and I always feel energized to come to work, ready to learn and take on the next challenge. 

Data integrity is crucial when developing new medicines to ensure their safety and effectiveness for patients.

Data integrity is central to our operations. Our rigorous quality systems across all our facilities ensure the accuracy and consistency of data collected from our formulation development, drug product manufacturing, and clinical programs. This commitment safeguards volunteer and patient safety and ensures compliance with regulatory requirements. 

In this article, learn about data integrity in pharma and clinical trial data integrity from our team.

What is data integrity in drug development?

Data integrity is the maintenance and assurance of data accuracy and consistency over the lifecycle of a drug product/study. It is a critical aspect of the design, implementation, and usage of any system that stores, processes, or retrieves data.

Data integrity must follow global mandatory requirements for regulated healthcare industries for developing and bringing a new medical product to market. In addition, data integrity must comply with Good Manufacturing Practices (GMP), Good Clinical Practices (GCP), and Good Laboratory Practices (GLP), often collectively termed GxP.

Why is data integrity so important in drug development and clinical trials?

Data integrity and clinical trial data integrity is essential because it ensures that the raw data collected is valid, complete, and well-documented.

The goal of data integrity is to ensure that all data—original records, observations, and other documented activity— required to reconstruct the clinical study is available, complete, accurate, and authentic. This is to assure the safety, efficacy, and quality of the trial as well as the product being evaluated.

How does data integrity differ from data security in drug development?

Data integrity and data security are related terms, each playing an important role in the successful achievement of the other.

Data security is the protection of data against unauthorized access or corruption and is necessary to ensure data integrity. It is extremely important, as unauthorized access to sensitive data can lead to the changing of records and data loss.

Data integrity is a desired result of data security, but the term data integrity refers only to the validity and accuracy of data rather than the act of protecting data. 

How is raw data defined and how does it relate directly to data integrity?

Raw data is the original and first documentation of the captured data. It is essential that the integrity of raw data be maintained. The documentation of raw data can be done in different formats: electronic data entered in software and computerized systems, data entered exclusively on paper sources, and hybrid systems which have both paper and electronic data entry.

Data integrity requirements apply to each of these formats.

What does ALCOA stand for and how does that relate to data integrity?

Regulators wanted to make certain that the integrity of data is preserved during the drug development lifecycle and through commercialization, so they established the ALCOA principle (later revised to include the “plus").

ALCOA ++ stands for Attributable, Legible, Contemporaneous, Original, and Accurate:
•    Attributable data collection—including the place of origin and the date of data collection. Any alterations to the data should be noted, and clear identification of the person making the correction should be available.
•    Legible—data should be easily read
•    Contemporaneous—time and date of data collection should correspond accurately with the time and date of data recording.
•    Original—original data should be preserved and maintained. In case of duplications/copies of the original data, the creator of the copy should confirm the authenticity of the copies (True Copy).
•    Accurate—data should be error-free, and in case of any updates or corrections, a clear note/comment should be noted to support such change.

The Plus (+) in ALCOA ++:
•    Complete—data should be complete in nature (no omissions), including any changes that have been made during the life of the data.
•    Consistent—data should be chronologically arranged, with an audit trail available for any updates or changes to the data.
•    Enduring—the manner used to record the data should be one that will last a long time without losing readability.
•    Available—data should be accessible whenever needed, over the life of the data, and after study/protocol completion as per regulatory requirements.
•    Integrity—emphasizes honesty and ethical behavior in data handling, encourages a culture of transparency and accountability.
•    Transparency—all data processes should be open to scrutiny, encourages audit readiness and traceability.

How is ALCOA++ applied to GxP?

GxP is a collection of quality guidelines and regulations established to ensure the safety and efficacy of drug products.  Collectively these define the Good Practices, where “x” may stand for laboratory, clinical, manufacturing, or distribution.

Independent of the environment, all regulatory agencies have a statutory obligation to ensure that the drugs available in their specific country fulfill the necessary requirements for safety, quality, and efficacy. They are responsible for effectively reviewing all documents containing both clinical and non-clinical data before giving permission for the marketing of a new drug to ensure the efficacy, quality, and safety of the drug in humans.

Additionally, regulatory agencies encourage manufacturers, clinical sites, and sponsors to implement effective and robust strategies to ensure that accurate and secure data management systems are in place and routinely monitored by the quality unit.

What types of data integrity violations do regulatory agencies monitor? What are the consequences of data integrity violations?

All regulatory authorities have similar expectations on data integrity and clinical trial data integrity. Some examples of violations that have been reported by the FDA, include:
•    Deletion or manipulation of data
•    Aborted sample analysis without justification
•    Invalidated results without justification
•    Destruction or loss of data
•    Failure to document work contemporaneously
•    Uncontrolled documentation
Consequences of poor data integrity and data security can be severe. They can include harm to the company’s reputation, financial losses, vulnerability to hacking or other cyberattacks, fines, legal action, and risks to patient safety. 

What are the benefits of Good Documentation Practices?

Good Documentation Practices (GDP) are part of data integrity and clinical trial data integrity to help ensure that the recording of raw data meets ALCOA++ principles.
Some benefits of Good Documentation Practices include:
•    The creation of legal evidence
•    The determination of responsibility
•    The conservation of acquired skills
•    The facilitation of communication and the ability to provide a story of the events
•    The establishment of an audit trail for clear visibility
•    The accurate reconstruction of events
An inspector or auditor must be able to reconstruct the series of a product’s or project’s events and confirm the integrity of the related data using paper or electronic documents.

What are audit trails and why are they important?

Per FDA, audit trail means a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record.  Audit trails include those that track the creation, modification, or deletion of data (such as processing parameters and results) and those that track actions at the record or system level (such as attempts to access the system or rename or delete a file).

Audit trails are important because they provide a means of verifying the data's accuracy and completeness by, providing a chronological sequence of events via a clear view of the documentation and record updates to confirm data integrity.  

Ultimately, in any regulatory environment, audit trails are crucial to show record compliance and data integrity. If a task or event is not documented, it does not happen.

In a pharmaceutical manufacturing or clinical setting, data integrity is everyone's responsibility. Best practice is to document tasks immediately and follow established procedures or protocols to avoid risks of miscommunication, assumptions, or worse: the appearance of fraud. It only takes a few seconds to review work to ensure the document complies with ALCOA ++ and maintains data integrity. 

At the International Society for the Study of Xenobiotics (ISSX) conference in September 2021, Quotient Sciences [1] and ObsEva [2] presented a scientific poster describing a ¹⁴C open-label, two-part radiolabeled study in female subjects to assess the absorption and disposition of nolasiban after oral and intravenous (IV) administrations and to determine the mass balance, routes and rates of metabolism and excretion, and absolute bioavailability.

Nolasiban is an orally active oxytocin receptor antagonist being developed by ObsEva to enhance the receptivity of the endometrium to embryo implantation.

The radiolabeled drug product was manufactured in a GMP (Good Manufacturing Practice) suite co-located with the clinical pharmacology unit. Cohort 1 received a single oral dose of ¹⁴C-nolasiban. Total radioactivity analysis was performed on blood, plasma, urine, and feces samples. Plasma samples were analyzed for nolasiban. Cohort 2 received a single oral dose of nolasiban followed by an IV infusion of ¹⁴C-nolasiban. Plasma samples were analyzed for nolasiban and ¹⁴C-nolasiban.

Mass balance data showed that a mean of 94% of the administered radioactivity was recovered over the 240-hour sampling period. Renal elimination was found to be the main route of elimination. The absolute bioavailability of nolasiban was evaluated to be 77.4%. The proposed metabolic pathway for nolasiban was characterized by oxidation (hydroxylation) and conjugation with glucuronic acid.

Overall, the integration of the radiolabeled human IV microtracer, mass balance, and metabolism study was an efficient and effective method to understand the human drug disposition of nolasiban.

Access the poster

Poster authors:

1. Quotient Sciences: I Shaw, S Sidhu

2. ObsEva: L Marchand, J-P Gotteland

3. Ex-ObsEva: O Pohl

4. Pharmaron-UK: R Cooke

The role of clinical operations is key in the delivery of successful clinical trials and plays an important part in the overall drug development process. 

Core responsibilities for clinical operations include ensuring volunteer safety, smooth delivery of clinical trials in accordance with the protocol, and adherence to Good Clinical Practice (GCP) guidelines at all times.

We have a proven track record in clinical pharmacology spanning over three decades and over 1,300 Phase I studies completed. With expertise in first-in-human studies, our industry-leading medical directors are able to rapidly recruit large groups of healthy volunteers.

In this article, Ian Nisbet shares more about our approach clinical operations.

Where do you conduct clinical studies at Quotient Sciences?

We are a world leader in the delivery of clinical pharmacology studies. Our Phase I studies are run at our clinical unit in Miami, FL (144 beds and integrated pharmacy compounding capabilities included), and from our clinical unit in Nottingham, UK, where we have 85 beds available.

We have highly experienced medical/clinical teams on both sides of the Atlantic that includes Principal Investigators and Sub-Investigators. Across our clinical teams, we have colleagues dedicated to volunteer safety and the successful delivery of clinical studies.

Each of our clinics can be fully integrated with our global formulation development and manufacturing capabilities, through our unique Translational Pharmaceutics® platform.

What types of clinical studies are conducted at Quotient Sciences, and what is the purpose of each study type?

We conduct a range of Phase 1 studies, including:

• Translation Pharmaceutics programs, which integrate drug substance, drug product manufacturing, and clinical testing activities to accelerate development timelines
   
• First-in-human studies (FIH studies), which evaluate the safety, tolerability, and pharmacokinetics (PK) of a new drug in healthy volunteers
   
• Drug-drug interaction studies (DDI studies), which assess if the safety and efficacy of a drug are altered when it is taken alongside other drugs
   
• Food effect studies, which investigate the effects of food on the rate and extent of absorption of a drug when it is taken shortly after a meal (fed conditions) compared to when it is taken under fasting conditions
   
• Thorough QT studies (TQT studies), which test the cardiac safety of a drug
   
• Bioavailability studies, which determine whether a drug can reach the systemic circulation and its intended site of action while minimizing undesired side effects
   
• Bioequivalence studies, which compare two drugs, or two sets of formulations of the same drug, to show that they have equal bioavailability, either for generic drugs or when a formulation of a drug is changed during development
   
• 14C human ADME mass balance studies, which obtain a comprehensive picture of the absorption, distribution, metabolism, and excretion of a drug in the body using radiolabeling
   
• Japanese bridging studies, which compare the safety and efficacy of a drug in different ethnic groups

When conducting FIH studies, what types of samples are usually collected and how is this done?

Typically, safety and tolerability are the primary objectives for FIH studies, where we capture safety data including vital signs, electrocardiograms (ECGs), blood parameters, and adverse events across a wide range of single and multiple doses. Often, we may also collect additional cardiac data via telemetry or Holter monitoring.

Our clinical units have all the necessary clinical equipment available to perform safety monitoring and data collection in accordance with the clinical protocol.

We also collect blood and/or urine and fecal samples for analysis, so that PK or pharmacodynamic (PD) profiles can be generated to provide an understanding of how the drug is processed by the body. On occasion, it may also be necessary to collect genotype samples to help assess whether the metabolizer status impacts on drug absorption.

How are samples processed in the clinic?

Samples are collected on the ward and transferred to our sample processing laboratories to be processed. We have a barcode tracking system in place to track the samples through the collection/processing pathways, which typically include centrifugation followed by plasma/serum isolation.

Our in-house laboratories have the capability to perform PD sample processing, including the collection and processing of peripheral blood mononuclear cell (PBMC) samples for isolation. There are several processing techniques available that may be utilized during sample processing, with Quotient Sciences typically using the Cell Preparation Tube (CPT) or LeucoSep methods. PBMC collection and processing require specific blood collection tubes, reagents, and equipment to be available and for each step in the method to be followed accurately to ensure isolation of the cells can occur.

Samples are processed in accordance with the Lab Manual for appropriate storage until they are shipped to the nominated bioanalytical laboratory for analysis. Once analyzed, the data is returned to the data sciences PK function for PK analysis to be performed.

How does Quotient Sciences ensure the safety of study volunteers?

All studies conducted at Quotient Sciences are risk-assessed to ensure we can determine the appropriate levels of oversight and monitoring needed to safely conduct the study. We meet regulatory GCP requirements by having best practice procedures that encompass the highest standards for protecting trial volunteers.

Our clinical teams are made up of experienced physicians, nurses, and clinical technicians. Clinical staff are trained in Basic and Immediate Life Support, with all of our physicians trained in Advanced Life Support. Our clinical units have all the necessary emergency equipment and medicines available to handle any medical emergency.

How do you ensure that Quotient Sciences volunteers have a positive experience while they take part in clinical studies?

Our volunteer-centric approach takes into account the key touchpoints at each stage of our volunteer’s journey and includes feedback questionnaires. 

Our Volunteer Centricity group is specifically focused on ensuring feedback is acted upon and priorities around volunteer wellbeing are considered. The group engages with a Volunteer Advocacy panel, made up of some of our long-standing volunteers, to ensure that feedback is sought on topics such as the wording of patient information summaries, admission times, transportation to the site, and study design.

Additionally. our clinical units have recreational and dining spaces for our volunteers to relax and unwind, and our Volunteer Liaison Officers are responsible for arranging activities and providing a comfortable environment for them. 

I am proud of our highly skilled teams and the steps that they take to ensure volunteers feel safe, valued, and looked after while participating in a trial with us.

Mental illnesses, such as depression and post-traumatic stress disorder (PTSD), are a leading cause of disability worldwide. Conventional anti-depressants have a high rate of partial or no response, often fail to improve symptoms, and can cause unpleasant side effects, thus identifying a great need to expand the range of available treatments. Could psychedelics provide a solution?

In the 1950s and 1960s, psychedelics were intensively studied and seen as a breakthrough in psychiatry, but their ban in 1970 under the United States’ Controlled Substances Act put a stop to most research. Over the past few decades, there has been a gradual change in perspective, owing to a lack of innovation in conventional psychiatric medications and expanding knowledge of how psychedelics work.       

In the last 10 years, there has been a surge of interest in psychedelics within the pharmaceutical industry, and there is growing evidence from scientific studies that psychedelics could be effective treatments for a variety of mental illnesses. Examples of psychedelic drugs that have been studied include: psilocybin, N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and 3,4-methylenedioxy​methamphetamine (MDMA).

At Quotient Sciences, our scientists are experienced at handling controlled substances and actively working on drug development projects with psychedelic compounds in both the laboratory and the clinic, including psilocybin, psilocin, DMT, and analogues. 

In this article, we explore what psychedelics are, how they are thought to work, and what scientific research is currently being done on them. We also discuss the challenges of conducting clinical research on psychedelics and handling them in the laboratory and in the clinic, and what the future holds for this somewhat controversial research area.

What are psychedelics?

Psychedelics are a class of psychoactive substances that produce changes in perception, mood, and cognitive processes. They have been known to cause different types of both visual and auditory hallucinations, including seeing or hearing things that do not exist or that are distorted. Psychedelics also have a high potential for misuse as recreational drugs and are classed as controlled substances, making them illegal to possess, produce, and supply without a license in most parts of the world.

How are psychedelics thought to work?

There is a belief that psychedelics could help to treat depression, possibly more effectively than the current marketed treatments, because they may target different areas of the brain that current methods do not access.

Currently, the most common category of anti-depressants is selective serotonin reuptake inhibitors (SSRIs). Serotonin is a neurotransmitter that is thought to help regulate your mood, and SSRIs work by increasing the amount of serotonin available to bind to serotonin receptors in the brain. SSRIs are typically taken as tablets 1–3 times a day. It can take up to 6 weeks to tell if an SSRI is working, and if it does not work, the patient must taper off the drug and try a different treatment.

In contrast, it is thought that psychedelics may be able to impart neuroplasticity, which is the ability to reorganize connections in the brain’s synapses. This may provide longer-lasting effects than conventional treatments and require less frequent doses, but more research and data is needed to obtain a deeper understanding of how psychedelics work.

LSD and MDMA are synthetic psychedelics, whereas psilocybin and DMT are naturally occurring psychedelics. DMT is one of the key active ingredients in the hallucinogenic drink ayahuasca. Psilocybin is the active ingredient in “magic mushrooms”, and it is a prodrug that is converted by the body to psilocin. Psilocin, DMT, and LSD have similar chemical structures to serotonin, so they are able to cross the blood-brain barrier and activate serotonin 2A receptors. This is thought to be what produces the psychedelic effects. MDMA has a different type of chemical structure, and it is thought to act by increasing the reuptake and release of serotonin, dopamine, and norepinephrine.

What scientific research is currently being done on psychedelics?

The US Food and Drug Administration (FDA) has designated psilocybin and MDMA as “breakthrough therapies”, which is a priority status given to promising drugs targeting an unmet need. This means that companies receive ongoing support from the FDA throughout the clinical trial process and priority review when data is available. There are currently hundreds of clinical trials registered on clinicaltrials.gov to test the effects of psychedelics on a variety of mental illnesses.

While some pharmaceutical companies are focusing on first-generation psychedelic compounds, others are tweaking the chemical structures to see if they can improve safety and effectiveness. Some companies are even hoping to create new chemical entities (NCEs) that remove all hallucinogenic effects while retaining the features responsible for therapeutic benefits. However, it is not yet known whether this is possible, and many scientists argue that the psychedelic “trip” brings about a change in perspective that is critical for treating mental illnesses. There is also the potential to look at fundamentally different molecules that can act on the same targets as psychedelics.

Recent notable breakthroughs in this field include the 2019 FDA approval of Spravato, developed by Janssen Pharmaceuticals, for treatment-resistant depression [1]. Spravato is a nasal spray with the S enantiomer of ketamine. While ketamine is not technically a psychedelic compound, this approval lent credibility to the idea of using a controlled substance to treat mental illness. In May 2021, the Multidisciplinary Association for Psychedelic Studies (MAPS) published results of a Phase 3 clinical trial on PTSD, where MDMA combined with psychotherapy showed sustained improvement in symptoms 2 months after treatment compared to placebo [2]. In November 2022, Compass Pathways published encouraging results from the Phase 2b clinical trial of Comp360, a patented polymorph of psilocybin, for treatment-resistant depression, which is the largest trial of psilocybin reported to date [3].

What are the challenges with conducting clinical research on psychedelics?

Conducting clinical research on psychedelics presents many challenges. In clinical trials, a synthetic form of the drug is tested on healthy volunteers or patients with specific mental illnesses under strict medical conditions, and expert psychological support must be provided before, during, and after the drug is taken.

It is difficult to conduct a truly double-blind trial with a psychedelic drug, as it is likely that participants will know whether they have received the active drug or a placebo. This raises the question of whether people are truly seeing therapeutic benefits, or if they just think they are because they know they received the active drug.

Currently, clinical trials of psychedelics typically exclude vulnerable populations, such as people with bipolar disorder, who might be vulnerable to psychotic episodes when taking psychedelics. However, these people would be exposed to the drug when it reaches the market, so it is important to include vulnerable populations in clinical trials to assess safety.

In addition, depression and anxiety can sometimes last for many months and can also recur in susceptible individuals. For this reason, long-term studies in different patient populations will ultimately be required to assess if the potential benefits in early trials can be sustained over time. 

Quotient Sciences has recently started performing clinical trials with psychedelic investigational medicinal products (IMPs) on healthy volunteers for customers. As a precaution, a trained psychologist is present during the clinical trial to manage any adverse events and to help the volunteer manage the experience in a calm and relaxed environment.

How do you legally and safely handle psychedelics in the laboratory?

There are stringent regulations in place for handling controlled substances like psychedelics, which presents many challenges for drug developers. Pharmaceutical companies need to be licensed to handle controlled substances, and strict security is required for production and storage. Safety is a critical consideration in order to protect employees and the facility from cross-contamination. While acute toxicity is typically low with psychedelics, they can exhibit observable effects at very low doses. The main risks are altered perception, poor decision-making, and subsequent accident or injury in the laboratory. Therefore, ensuring containment and minimizing exposure of staff is important. Capabilities and facilities for handling controlled substances can be prohibitively expensive for small pharmaceutical companies, so this creates opportunities for contract development and manufacturing organizations (CDMOs) that are licensed to handle controlled substances.

Quotient Sciences is licensed by the UK Home Office to possess, produce, and supply Schedule 1–4 controlled substances under the Misuse of Drugs Regulations 2001. Psilocybin, DMT, LSD, and MDMA are all classed as Schedule 1 drugs, which means they have no currently accepted medical use and a high potential for abuse. To ensure security, controlled substances are stored in a defined locked cabinet, and key access is restricted. All usage and production are recorded on controlled substance usage forms, and all activities are signed and witnessed. To ensure safety, a specific risk assessment is conducted for all laboratory activities involving psychedelics. All dispensing, packaging, and weighing of materials is done in a Class 3 isolator, and personnel must wear appropriate personal protective equipment (PPE). To avoid cross-contamination, there is a dedicated project-specific high-performance liquid chromatography (HPLC) and rotary evaporator for each psychedelic project, and use of the house vacuum is forbidden. Additionally, the transfer of material between laboratories requires double containment in high-density polyethylene (HDPE).

What does the future hold for psychedelics?

Psychedelics are a rich and fertile research area. While results from scientific studies appear promising, most research is still in the early stages, and there are many challenges to overcome before medications can become widely available.

Even if pharmaceutical companies can succeed in formulating psychedelics into effective drugs, commercial success will heavily depend on overcoming pre-conceived opinions of regulatory authorities, doctors, and patients on the use of recreational drugs as safe and effective medications.

There is also the question of how scalable psychedelics could be to meet the high occurrence of mental illnesses. How do you make treatment convenient, controllable, accessible, and affordable? With the current generation of potential medicines necessitating close medical supervision, it would only be possible to administer psychedelics at a doctor’s office. Treatments would be time-consuming, taking patients away from work and other responsibilities. Access to treatments may also be difficult for patients living in rural locations. While the potentially long-lasting effects of psychedelics might make them more cost-effective than conventional treatments in the long term, there could be large, up-front costs, which insurance companies may be reluctant to cover.

As an organization with a culture focused on science and innovation, the team at Quotient Sciences is excited to see how developments will progress in this space.

References

1. https://www.spravato.com

2. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine 2021;27:1025–1033.

3. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med 2022;387:1637–1648.

Find out more about Quotient Sciences’ drug substance and clinical pharmacology services.

With a draft FDA guidance on Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies currently under review, there is considerable interest in the design and conduct of human absorption, distribution, metabolism, and excretion (ADME) studies. At the International Society for the Study of Xenobiotics (ISSX) conference in September 2022, Quotient Sciences presented a poster reviewing the approximately 200 radiolabeled studies the organization has performed over the past decade.

The poster included examples where study designs have been adapted to address specific challenges presented by new drug candidates such as:

• Molecules with a long half-life: When the half-life of a drug would make a main residency period too long to be practical, a main residency period of 14–21 days and then several 24-hour return visits can be scheduled to enable the collection of excreta samples for total radioactivity analysis. The recovery curve can then be extrapolated to demonstrate what the likely outcome would have been if a full residency period had been feasible.
   
• Integrated intravenous microtracer (IVMT)/ADME studies: Integrating an IVMT with a conventional human ADME study is a highly efficient method to assess absolute bioavailability, mass balance, routes and rates of excretion, and metabolite characterization. Extending the overall sample analysis to assess intravenous (IV) mass balance can enable an understanding of key parameters impacting bioavailability, such as fraction absorbed (f_a), fraction surviving gut metabolism (f_g), and fraction surviving hepatic elimination (f_h).
   
• Potent drugs: Given the challenges of completing the synthesis of the radiolabeled drug at the required specific activity and/or the limitation on the sensitivity of methods and instrumentation for sample analysis, potent drugs often require a hybrid approach to sample analysis, involving both conventional methods and accelerator mass spectrometry (AMS)-enabled methods.
   
• ADME at steady state: ADME can be investigated at a steady state by administering a single radiolabeled dose after establishing a steady state by multiple dosing of the non-radiolabeled drug. This approach only evaluates the clearance pathway of the radiolabeled drug after a single administration, but it is a practical compromise. An alternative approach is to divide the radiolabeled dose across the multiple doses required to achieve a steady state, but this can result in more challenging analysis requirements.
   
• Particular study populations: While most human ADME studies can be conducted in healthy male volunteers, occasionally different subject populations may be required (e.g. female subjects, target patient populations, or healthy volunteers with a specific genotype status). Having to identify and recruit patients or provide additional characterization of healthy subjects before they can be recruited adds complexity to the subject recruitment process for the study.

Human ADME study designs should be adapted to address the particular challenges of each molecule under investigation. The approaches described to obtain human ADME data demonstrate the advances in technology available to investigate and understand the disposition of drugs in development. 

Access poster

At the International Society for the Study of Xenobiotics (ISSX) conference in September 2022, Quotient Sciences [1], AB Science [2], the Netherlands Organisation for Applied Scientific Research (TNO) [3], and Pharmaron-UK [4] presented a poster investigating the absorption, metabolism, and excretion of masitinib, an oral tyrosine-kinase inhibitor that targets mast cells and macrophages and is currently in development as a potential treatment for neurology, inflammatory diseases, oncology, and viral diseases.

The key objectives of the open-label, single-period, radiolabeled study were to assess mass balance recovery, determine routes and rates of elimination, and enable metabolite profiling and identification for masitinib.

Six healthy male volunteers received a single oral dose of ¹⁴C-masitinib in the fasted state. Blood, plasma, urine, and faeces samples were collected until 168 hours post-dose and analyzed for total radioactivity (TRA) by accelerator mass spectrometry (AMS). Samples collected during the study were pooled across time points and subjects, and metabolite profiling and identification were performed using an ultra-performance liquid chromatography (UPLC) system coupled to a high-resolution accurate mass spectrometer (HRMS).

On average, 69% of the radioactive dose was recovered by the end of the sampling period, with the majority recovered in faeces. The main metabolites were identified, and the study results led to a hypothesis that there may be covalent binding of some masitinib metabolites to plasma proteins.

Overall, this study provided valuable insights on the absorption, metabolism, and excretion of masitinib, which informed the drug development program and regulatory filings.

Access the poster

Poster authors

1. Quotient Sciences: I Shaw, S Mair

2. AB Science: F Pitré, F Bellamy

3. TNO: W Vaes, R de Ligt

4. Pharmaron-UK: R Cooke