Clinical Trials in a Petri Dish Closer to reality

Clinical trials are pilot studies conducted on human volunteers and patients in a phased manner to evaluate the investigational new drugs developed before introducing into the market. Innumerable registered and well planned clinical trials fail every year regardless of promising animal and preclinical modelling. By the power of the grey star, human sourced stem cells, organoids modelling in the in vitro conditions simulating human systems has the potential to revolutionise the way clinical trials and the phases could be directed in future.

Clinical trials include experiments and the related observations done in clinical settings as part of prospective biomedical research studies on human participants. The studies on human participants are usually designed and performed to answer specific questions about biomedical or behavioural interventions, new treatments, and known interventions/medicines. These studies generate data on safety and efficacy surrounding the medical intervention. The concept of clinical

trials has undergone several mutations while modern trials design and principles have precipitated on the importance of randomisation, replication, and factorial experiments.

Clinical trials are conducted on humans while designed to specifically address set questions and broadly to improve health, quality of life. Experiments and evaluations have been part and parcel of medical field, without which there would be no evidence to know the safety and effectiveness of any treatment given to the real patients. In other words, without clinical trials phased and designed as being practised, there is a big risk that patients are given treatments which may not work or which may be harming instead of serving the purpose of treatment.

There are 4 known phases of clinical trials being practised for ages:

Phase 0 is conducted on a small sample size using a small dose of medication under investigation to make sure that it is not harmful to human healthy volunteers before testing higher doses. In this phase, if the test medications effect is different than expected, the study is bound to go back to preclinical research to revisit the functions, re-evaluations. Phase 1 is conducted on a slightly bigger sample size but again on healthy individuals with key objectives like establishing the highest dose of the medicine tolerated with no serious side effects. Additionally, the best route of administration visa vis the efficacy as well becomes secondary objective of the trial in Phase 1.

Phase 2 is known to involve the patients as subjects but with inclusion and exclusion criteria met as per the design of the trial. Phase 2 is known to involve bigger sample size than Phase 1 while the data collected during this phase supports the strategy and design for Phase 3.

With all the ethical issues surrounding Phase 1 clinical trials where the inves-tigational new drug candidates would be clinically applied for the first time with no data available from clinics, into healthy volunteers, alternative strategies like clinical trial in a petri dish utilising healthy donors-sourced stem cells prepared as platforms for in vitro read outs that can match the clinical settings.

Phase 3 requires patients’ participation in larger cohorts while the purpose of conducting is to evaluate the new medication’s efficacy in comparison to the one already being practised for the same condition. Phase 3 is traditionally double blinded and built on a process called randomisation to help eliminate any bias interpreting results.

Phase 4 is undertaken after the regulatory approval on the use of medication is obtained involving thousands of participants. Phase 4 delivers the new medication’s long term safety and efficacy with study duration lasting for several years.

Phase 1 – the most controversial clinical trial stage For long and forever, Phase I studies have been debated and the debate dates back to the history of human experimentation to discover medicines. In Phase 1, the drug is being tested in humans for the first time with no data available on the species and no benefit to the participant. Participants are asked to be willing volunteers to subject themselves as guinea pigs in research, which is questioned and argued by bioethicists on ethical principles as therapeutic misconception. For a healthy volunteer enrolling in a toxicity trial, there is only risk but no medical benefit. Correspondingly, Bioavailability and Bioequivalence (BA/BE) studies are conducted to establish the generic drug’s equivalence to the new drugs and are usually carried out in healthy human volunteers. They are non-therapeutic in nature without any direct benefit to the participants.

“Bioethics and the principles include that we ought not to deceive others, we ought not to harm others or allow harm to come to others, and we ought not to use others as means to an end.” By Christopher K. Daugherty, M.D., of the University of Chicago

Monetary reparation and the supplications to altruism for the benefit of humankind involved as part of the informed consents obtained by the

volunteers who are participants are only opportunities for ethical misapplication. Phase 1 first-in-human studies in Oncology differ from other Phase 1 studies in that they are conducted on cancer patients rather than healthy volunteers. Here, objectives as well alter from the definition of a maximum tolerated dose to the estimation of a recommended Phase 2 dose. Other challenges related to the efficacy and safety profile of novel targeted anti-cancer drugs are conspicuous in Phase 1 for anti-cancer new drugs trial. Likewise, Phase 1 first-in-human studies for progressive Neurodegenerative diseases conducted on human volunteers do not yield data that can justify the design, dose and method of treatment.

Drug repurposing in clinics – A totally new wine in an old bottle Drug repurposing (repositioning or re-profiling or re-tasking) is a new approach for identifying new uses for approved or investigational drug candidates that are outside the scope of the original function attributed.

Preclinical trials dictating clinical trials To determine whether a drug is ready for clinical trials, it involves wide-ranging preclinical studies that produce data

PHARMA FOCUS ASIA ISSUE 38 - 2020 on efficacy, toxicity, pharmacokinetics and safety of application. After pre-drug discovery research establishing either target or function discovered, wide doses of the drug candidate are tested using in vitro and in vivo (animal) experiments while insilicoprofiling of the drug–target interactions is an integral tool in the framework. Much like clinical trials, there are certain types of preclinical trials such as exploratory toxicology leading to regulatory studies, and other trials that are specific to the particular question. The only goal of preclinical trials is to move into the clinical stage while the preclinical exploratory and regulatory studies are designed around this goal.

Preclinical model systems There are broadly five different preclinical model systems in use: insilico, in vitro, ex vivo, in vivo and xenografts based. In all the systems, there are fundamental cell based platforms that have found their spot re-creating the tissue or organ of importance to the extent of humanising animal models. When it comes to cell based platforms, primary cells and transformed cell lines are the only variations put in use. The sources of these cells have been broadly human or animal tissues relevant till date in drug discovery pitch. There are stem cells giving rise to

tissue specific cells and tissue derived terminally differentiated cell types known to the researchers. Stem cells – Classification Stem cells are unspecialised cells of the human body that have the capacity to become any cell of the body with an ability to self-renew. Stem cells are present both in embryos and adult tissues/organs. Totipotent stem cells divide and differentiate into cells of the whole organism. Totipotency is the power to form both embryo and extra-embryonic structures. Zygote is a totipotent cell. Pluripotent stem cells form cells of all germ layers but not extra-embryonic structures, such as the placenta. Embryonic stem cells, Induced pluripotent stem cells are pluripotent cell type examples. Multipotent stem cells can specialise into discrete lineage specific cell types. Haematopoietic and Mesenchymal stem cells are classical examples of this stem cell type. Oligopotent & Unipotent are the types with narrower differentiation capabilities.

The role of stem cells in preclinical modelling – the role less spoken in comparison to clinical applications Owing to their unmatched properties, stem cells have been found to be acting like base platforms available for multiple genetic diseases, including neurological disorders like Parkinson’s, blood diseases, cardiac syndromes, diabetes and hepatic disorders. The tissue models created can be scaled up to systems that mimic entire organs. Stem cells can be harvested from either patient’s body or healthy donor while transcriptomics and proteomics of the stem cells vary between patient and healthy donor.

Patient sourced stem cells are usually utilised in re-creating disease microenvironment in the petri dish while preclinical stage in vitro assays specific to the disease of interest are performed. Healthy donor harvested stem cells have been trialed and in vitro systems developed are best suited in high throughput screening of chemical libraries, toolbox, exploratory toxicity related testing proto

cols, drug repurposing. These in vitro model systems used in toxicity testing are known to have diverse advantages on top of human relevance together with the decrease in the number of animals used for experimenting, the reduced price of maintenance, shortening of the time needed, and increase in throughput for evaluating larger number and their metabolism related data points.

If healthy donor is the source chosen, biopsy as the starting material to harvest stem cells cannot be the ethically accepted mode especially when the preclinical research involves volumes and reproducibility. The only option left to the serious researcher or the industry is to consider human biological discards that have proven credibility as ethically immuned, available in large quantity to access sterile, residing stem cells that are shown to be multi-pluripotent in nature, as the raw material. Human umbilical cord blood, cord tissue, deciduous teeth and adipose tissue are the most popular biological discards qualifying as raw materials to produce stem cell based platforms in petri dish mimicking human physiology. The only way to source this raw material is from the biobanks cryopreserving biosamples as there is no second chance that human life gives to collect these biosamples other than the destined event. Some of the well accepted in vitro cell based assays in preclinical research that include regulatory need are: Cell viability, Apoptosis, Necrosis, Membrane integrity, Mitochondrial toxicity, DNA damage, Cytokine signatures, Toxicity pathways, Toxicogenomics, Proteomics, Embryotoxicity, Tumorogenicity, Lethal dose, Neurotoxicity, Hepatotoxicity, Cardiotoxicity.

Advantages and features of stem cell-based platforms for preclinical trials The alternatives to stem cell-based platforms in preclinical research stage that have been (low hanging), tried and tested

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but not with any specific advantages are: cell lines and animals

Human sourced stem cell based platforms have distinct advantages owing to their origin that is closer to clinical reality, their ability to proliferate in culture conditions simulated in petri dishes, their ability to self-renew to result in volumes that can be managed while retaining Stemness, their ability to differentiate under controlled conditions to other lineage specific cell types like: neurons, adipocytes, osteocytes, chondrocytes, heart cells, liver cells, their ability to humanise 3D models.

Clinical trials in a Petri dish Clinical trials in a petri dish or in vitro clinical trials use specimens collected from humans to test how a particular disease will react to a specific therapy or combination of therapies. This strategy can be also used for the development of drugs for specific populations, for precision medicine purposes to predict

responses in individual patients or for establishing safety of investigational drug candidates. US FDA has the history of engaging and participating in a publicprivate partnership involving the Health and Environmental Sciences Institute, the Safety Pharmacology Society, and the Cardiac Safety Research Consortium, multiple global regulators, pharmaceutical companies, and academic laboratories, to develop a comprehensive in vitro proarrhythmia assay with a goal to use a combined in vitro and insilico (computational) testing strategy to predict the risk of drug-induced arrhythmias. This was planned to be part of regulatory clinical trial performed for all new drugs in place of a current clinical trial in drug development - An example for clinical trials in a dish in real time.

Phase 1 of Clinical trials – A compelling case for surrogation in Petri dish With all the ethical issues surrounding Phase 1 clinical trials where the investigational new drug candidates would be clinically applied for the first time with no data available from clinics, into healthy volunteers, alternative strategies like clinical trial in a petri dish utilising healthy donors-sourced stem cells prepared as platforms for in vitro read outs that can match the clinical settings. The success of the strategy in real time application purely depends on the standardised assays with integrated tools measuring end points evaluating safety related clinical end points.

CaseStudy Transtoxbio A unique portfolio that can be integrated into preclinical and clinical trials For pluripotent imagination of user’s mind

Transtoxbio has all primary, stem cell-based in vitro real time platforms that can predict: biocompatibility, target, functional efficacy, and safety profiles of simple to complex molecules that are being investigated or developed as drug candidates. This real-time platform technology has the potential to

support next-generation phenotype based drug discovery (PDD), which is believed to be forward pharmacology. The portfolio’s bandwidth and power to read high throughput screens, phenotype, genotype, proteomics that play crucial role in target identification, pathways recommends integration in preclinical exploratory drug discovery and trials in the labs. Also, some of the platforms of the portfolio can humanise animals in developing human disease models to test the investigational new drug candidates’ efficacy; listing the platform’s wherewithal to participate in preclinical in vivo trials.

Owing to it’s human sourced stem cell compositions, primary with

proliferating capacities (to passage and mimic prolonged drug candidate’s exposure time), the platform has the power to read human safety related toxicology specific, measurable endpoints when exposed to lead compounds.

It is the predictive property that answers critical concerns like Embryotoxicity, Genotoxicity, Metabolomics, Transcriptomics, Toxicity related predictive markers (Toxicogenomics), Stem cell cytotoxicity (IC50 on human primary stem cells), Stem cell permeability, Cell distribution of druggable candidates to the extent of mimicking regulatory studies compelling the platform’s adoption in not just preclinics but also in early stages of futuristic clinical trial modalities like that of Phase 1.

The portfolio’s eligibility as surrogate podium to be considered for Phase 1 clinical trial emerges from the following features surrounding

the suitability: Source, Abundance of source, Availability and access of the sources chosen, Established protocols in harvesting primary, progenitor cell types either from healthy donor or patient, Producing phenotypically responsive large scale cell based platforms as products that have the power to predict and read the assay end points simultaneously in real time, Bandwidth to access large sample size, Relevance to human species, Not genetically manipulated

Any cell-based platform is of great use for a researcher, user to reproduce the results and obtain meaningful, consistent, statistically significant data output, if it is available in large, batch wise required quantities, which is possible only if the source is available in abundance. Transtoxbio portfolio falls under the category where the source is not donors’ biopsies that has limitations with harvest, yield, and reproducibility; has all new league of human biological discards sourced (ethically immuned) primary progenitor cell-based platforms for speciality next generation invitro to in vivo applications in pre and clinical research.

AUTHOR BIO

S Dravida is the Founder CEO of Transcell Biologics, Hyderabad, India. She is a technocrat with track record of commercialising research driven findings to business opportunities through Transcell.

PATIENT ENROLMENT Doing it the phygital way

Patients form the centerpieces in determining the validity, efficacy and success of clinical trials. With identification, screening and enrolment of the patients tricky enough, the retention of enrolled patients proves to be an insurmountable hurdle as trends state that nearly 85 per cent of the clinical trials are unable to retain patients till the end of the trial. Various techniques have been discussed and employed for attaining a healthier statistic including incorporation of patient inputs in designing the trial. Innovation today has helped boost this further in the forms of utilisation of technology in effective patient engagement.

R B Smarta, Chairman & MD, Interlink Marketing Consultancy Pvt. Ltd.

Introducing a new drug or treatment regimen is a laborious task which is filtered at various levels before it reaches the general populace. One of the final filters is Clinical trials which establishes the efficacy and safety of the regimen; improves patient outcomes and maximises the success of the new entity in the later stages. Although testing of a regimen prior to the efficacy and safety establishment poses a risk to the participants voluntarily enrolled in the trial, the clinical trials today are under strict regulations and take sufficient meas

ures to minimise the risk. Additionally, the patients enrolled are benefitted by being administered a treatment not only before it is publicly available but also with personalised attention, care and frequent monitoring.

Despite the numerous benefits, enrolment of patients in clinical trials often proves a bottleneck for the researchers. Enrolment of patients for the process of clinical trials is a long and multistep screening process critical for achieving the objectives for a clinical trial. The first hurdle is identifying the right patients that fit your requirements. Once identified, the patients are screened for suitability, educated and informed about the trial and finally randomised. At each step of the process, the pipeline of the patients leaks and tapers to give a final randomised patient list which are enrolled. Figure 1 Enrolling patients successfully is only half the battle won. Since participation in a trial is a voluntary activity, it becomes strenuous to ensure the retention of participants till the complete schedule of the generally lengthy clinical trials. As research shows, only 7 per cent participants of the initially identified participants successfully complete the trial. The validity of these trials depends largely on the discipline of the patients enrolled and their adherence for the regimen.

Improving patient enrolment and retention The foremost requirement for improving patient enrolment and retention is to understand the roadblocks and hurdles in the process. Considering patients an integral part of the process, it is important to understand the concerns and expectations of the patients with respect to all the stakeholders while designing a clinical trial. Figure 2 maps the clinical trial process and the problem areas encountered in each phase which generally leads to low enrolment and poor retention. Figure 2 Once the barriers are identified and understood, the improvement strategy in each stage can be chalked out and implemented. To maximise the retention of participants through the length of the trial, the regimen must ensure transparency covering the length of the trial and beyond.

Various studies have been carried out to determine these factors and optimise the trials. Despite the palliative steps undertaken to reduce the ‘leakage’ of the participants through the trial, it remains an uphill task. With the advent of technology which is so closely associated and accessible to the participants, an enormous potential emerges for their effective engagement. It is important to tap this potential for not only improving the enrolment and retention but also enhancing patient outcomes.

Identified Screened Consented Randomised

Phygital transformation of Clinical trials As the industry is getting disrupted by introduction of digitisation and artificial intelligence at every step of the drug development process, clinical trials have not been untouched. Digitisation has wriggled its way to the minutia of the process and opened an entirely new horizon of possibilities. Coupled with the current physical ways of handling the task, it paves way for a novel ‘Phygital’ strategy which provides end-to-end interventions and decongests the common bottlenecks encountered. Fig. 3

Let us have a look at the common bottlenecks encountered during clinical trials and how Phygital transformation helps them.

i. Creating awareness: The skepticism of patients to enroll in a clinical trial stems from the lack of trust on the reliability of the trial. It is significantly improved with the presence of an expert whom they perceive to be dependable such as a

Creating awareness

doctor or other healthcare professionals. Engaging influential figures for creating awareness about clinical trials can help to motivate the patients. Influencers from the digital sphere are increasingly getting engaged with clinical trials and promote such trials to rope in participants.

ii. Identification of patients in qualitative and quantitative spectrum: A clinical trial is designed to achieve a set of objectives which can be attained through data obtained from a specific group of individuals. The parameters for screening these individuals often involve a complex web of requirements including but not limited to disease conditions, ethnicity, genetic profile, gender and age to develop a robust trial. Traditionally, each prospective participant was identified and screened to determine their suitability. With digitisation and AI, apps have been developed that take the profiles of the participants through a network of algorithms and find the right match suitable for you! Not just qualitatively, the intervention greatly reduces the time frame required thus increasing the number of patients identified in the given time period.

iii. Ensuring transparency of the trial: Misunderstood expectations and incomplete understanding of the particulars of the trial prove to be a hindrance in the smooth running of a trial. Recent technological advancements allow creation of interactive web experiences that provide a walk-through of the process and empower the participants. Such a platform is helpful not just at the beginning of the trial but also assists, guides and counsels them at every step. iv. Communication: Through the course of the trial, patients often find themselves demotivated due to lack of any significant improvement in their condition or even the lack of appreciation for their effort. Creating milestones and providing a regular feedback recognising and applauding their effort can go a long way in motivating the patient.

Ensuring transparency and consent Side effects

Identification of patients

ENROLMENT PROCESS RETENTION

Lack of motivation

Number of patients Effective and continuous communication

Non-compliance

PHYSICAL

Presence of influencers creates awareness, ensures trust and builds motivation

Figure 3 Phygital transformation of clinical trials

Automation of a personalised feedback mechanism presents an opportunity for regular positive communication highlighting the significance of the contribution the participant is making towards better healthcare.

v. Minimising risk of side effects: The biggest hitch in patients enrolling for clinical trials is the possibility of encountering side effects. Often, identification and reporting of side effects are delayed. These can be curbed by continuous monitoring which is at our disposal by the benefit of the internet and interactive ‘chat-bots’. This additional dimension makes the process of trials conducive for the patients since assistance is just a click away.

vi. Maintaining compliance: A major reason that proves a hurdle for successful data collection is that compliance for the regimen is not maintained at the patients’ end due to various reasons such as incomplete knowledge or simply forgetting the schedule for visits and dosage. An easily accessible digital planner and reminder which provides consistent updates of the schedule can markedly improve the compliance and thus the validity of the trial. It ensures the collection of right information from the right patient at the right time!

Phygital

Digital interventions promote ease of access, personalised care and efficient operations

DIGITAL

Way towards qualitative and costeffective clinical trials Nearly 85 per cent of the clinical trials are unable to retain the enrolled patients till the entire cycle of clinical trial. They lose about 15-40 per cent of the participants on an average due to various reasons. This leads to discrepancies in the data and sometimes even an inconclusive trial result. The reasons for drop-outs are varied and are generally difficult to control through a broad scale of measures. Retention calls for a more personalised care and constant mentorship for each participant. Having a personal mentor which patients can perceive to be dependable, capable and trustworthy greatly motivates them to adhere to the requirements. Such personalisation for a large population becomes manageable through digital platforms and AI along with the physical presence of a trustworthy influencer such as a doctor.

On the whole, incorporation of Neuro-linguistic programming and machine learning can provide a holistic solution wherein the key lies in execution and flexibility of the platform.

Optimised clinical trials can prove highly cost-effective in the areas of recruitment and retention of the patients as demonstrated by a pioneering app in this field — a 92 per cent reduction in resource requirement for conducting the study. With higher enrolment, clinical trials would lead to introduction of better and advanced care for the world and help us combat diseases better in a reduced time frame.

AUTHOR BIO

R B Smarta is the Chairman and Managing Director of Interlink Marketing Consultancy Pvt Ltd. Through Interlink he has added value to corporate brands, therapeutic brands, fast moving healthcare brands, in-organic and organic growth of corporates and sales & marketing ROI of corporates. He is also a member of CII Drugs and Pharma National Committee for the Year 2007-08. He is currently working on Business Models, Business Strategy, Emerging Markets and Global Business Opportunities for Pharma, Healthcare Industries.

SPRAY DRYING ISOLATOR FPS solutions for Pharmaceutical and Fine Chemical industries

Frederic Le Pape, General Manager, FPS

FPS is an Italian company specialised in the production of containment systems and micronisation equipment for Pharmaceutical, Biotech and Fine Chemical companies.

In the past 18 years FPS has grown to become the world leader for High Containment Isolators for fine powders with over 1,200 systems installed. FPS has a global technical team that supports these systems in the 40 countries where they are installed.

One of the reasons for this success is the high level of expertise of our staff. This expertise has been gained over 18 years of innovating in our field. The entire design and production process of the systems takes place in our state-of-the-art plant of Fiorenzuola d'Arda in Italy. This allows for optimum knowledge sharing & team work. As a result, each team player becomes an expert in his/her field and it really shows in the level of innovation and quality delivered.

Another reason for FPS success is our ability to listen to the specific needs of the customer, to focus on its process and to design a custom solution to address all those needs. It has been one of the strengths of FPS over the years.

Once the needs are well understood, the next step is to conduct the initial study of the project: a specialised team proposes a solution and works closely with the customer to ensure compliance with the technical specifications required.

As far as containment systems are concerned, spray-drying is a commonly adopted technology in pharmaceutical to obtain a powder from a liquid solution. Given that pharmaceutical companies are handling High Potent API more than ever before, high containment solutions are necessary to safely operate the equipment.

In the past year, some of the isolators that FPS has designed and manufactured have been specifically to contain spray drying equipment. By using an isolator, pharmaceutical manufacturers want to ensure full operator protection without the need for bulky

Personal Protection Equipment full-suits that can be cumbersome, costly and may provoke falls.

One of the key requirements that pharmaceutical companies have for isolator manufacturers is not to alter the current process. The goal is to avoid lengthy and costly process re-validation. Another requirement is to ensure excellent ergonomics to avoid operating errors, product loss and work injuries. The FPS design team is very familiar with those aspects and can also accommodate others. For example, one of FPS customers flagged that their multi-cultural team had a very wide variation in height. Their workers were very concerned that the isolator would be too low or too high for their own height and they worried about potential long-term health issues. Another customer had to fit the isolator into a very tight space and the equipment had to be brought in the installation room through narrow doors.

To address those issues FPS engineers worked in close collaboration with the end-user technical, safety and process engineering departments to design the isolator. Mock-up of those systems were built to simulate the activities and validate the technical solutions. Operators were also part of the process.

In the end these isolators had the following features:

- adjustable height for isolator optimum access to the processing equipment, with

- proper rating to work in hazardous conditions (according to the area classification)

- cooling of working chamber to keep the temperature constant (to counter heat created by the spray dryer)

- isolator creatively designed and delivered in small sections to pass narrow doors and assembled on site as one unit

"The users were very excited to do away with the cumbersome personal protective equipment. The ergonomics are much improved to perform the process and they like the flexibility of going in and out of the lab without gowning and disgowning" says Frederic Le Pape, the FPS America General Manager.

One customer uses a micronisation step in a separate chamber of the spray drying isolator and sees many benefits. For example, there is no need to use a split butterfly valve for product collection which are costly and time consuming to assemble, disassemble and clean.

Finally, the isolator protects the product from moisture during feeding and collecting phases for the spray dryer (and for the jet mill when used after the spray drying).

As always, the objective of FPS is to be of service to the Pharmaceutical and Fine Chemical industries. The mock-up is one of the tools that help us fulfill 100 per cent of the needs of our customers.

Frederic Le Pape has 20 years of technical sales experience in the Pharmaceutical industry in North America. He was first involved with solid dosage applications before joining FPS and focusing on containment of potent powders and sterile liquids. The containment can be provided by custom rigid-wall isolators but also by RABS (Restricted Access Barrier Systems), Downflow booths and LAFs. He is also well versed in powder micronisation from R&D, to pilot, to commercial applications.