The History of Clinical Research

History Clinical Trails Past Present Future
Neucruit

Neucruit

Author

605BC Book of Daniel

The very first recorded example of what could be described as a simple, experimental design was found in the book of Daniel, following Nebuchadnezzar (King of Babylon) in his attempts to keep his people healthy. Nebuchadnezzar went on a 10-day long vegetable-based diet, while the other ‘participants’ were enjoying meat and wine, on a quest to test the effects and benefits of a vegetarian diet. Although the design and assessment would receive quite a few criticisms nowadays, Nebuchadnezzar was found to be healthier than the other subjects, suggesting that a vegetarian diet is more beneficial than a meat- and wine-based diet. 

500BC The Hippocratic Oath 

Hippocrates, often referred to as ‘the father of Western Medicine’ created an oath all physicians and healthcare professionals need to swear to. By taking the oath, healthcare professionals agree to practice medicine in a just and ethical way. The same responsibility carries over to clinical research – not only is practicing medicine ethically, looking after participants’ protection and wellbeing in trials is vital.

History Clinical Trails Past Present Future

1537: Ambroise Pare and the Wound Oil 

Ambroise Pare was a surgeon and used to treat soldiers’ wounds with oil. However, when he ran out of oil he applied ‘egg yolks, oil of roses and turpentine’ on the wounds of some soldiers, and the next morning he realised that the wounds of the soldiers on the ‘experimental mixture’ were looking and feeling much better than those treated with oil. Although using experimental mixtures is prohibited nowadays, many of the discoveries (e.g. Penicillin) are owed to similar ‘accidents’. 

 

1747 James Lind: The Scurvy Experiment 

Vitamin deficiencies have been associated with many neurometabolic disorders, as well as neuropsychiatric symptoms. When sailors spent a long time on the boats, they would suffer from poor wound healing, skin changes, loosening of teeth, and eventually die. British Nave James Lind believed that citric acids could prevent and cure this condition known as scurvy. He thus decided to divide 12 sailors into six groups each of which were given a different supplement in addition to their regular diet. James Lind tested the effects of cider, sulfuric acid, vinegar, seawater, oranges, lemons, and a spicy paste with barley water. He observed that sailors receiving the citrus fruit immediately began recovering. This supports the suggestion that vitamin C, e.g. citrus fruit, is necessary for a healthy immune system.

1863: Placebo 

In 1863 scientists introduced the ‘placebo’ – a key feature in most clinical trials to this day. Researchers use inactive substances (e.g. starch or sugar) that look like the real drug used in the trial. Placebo pills allow researchers to understand the effects a new drug or treatment may have on a certain condition. 

1887 National Institute of Health (NIH)

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

History Clinical Trails Past Present Future

1887 National Institute of Health (NIH)

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

1906 FDA Pure Food and Drug Act 

Although drugs contribute to the management of symptoms and diseases, they may have unwanted side effects. In 1906 US President Theodore Roosevelt signed the FDA Pure Food and Drug Act law. The FDA law prohibited interstate transportation on unlawful food and drugs, and banned trade of products for indications outside the labeling. The FDA is now responsible for approving new drugs, but also removing them from the market if and when adverse effects are observed. Temafloxacin (Omniflox) is an example of a withdrawn antibiotic from the US market; initially approved for treatment of lower respiratory tract infections, genital, urinary and skin infections, it was associated with severe allergic reactions and hemolytic anemia in over 100 patients within 4 months of its use, and three patient deaths. 

1928: Sir Alexander Fleming Discovers Penicillin 

His cluttered and untidy lab led to the growth of mold on a stack of staphylococci cultures. This unintentional result led to the discovery of penicillin, which soon thereafter was globally recognised as an efficacious life-saving drug. Fleming’s discovery of the penicillin was a turning point in the treatment of bacterial infections. 

History Clinical Trails Past Present Future

1932-1972: The Tuskegee Syphilis Study 

The US Public Health Service recruited 600 participants to study the effects of syphilis. The sample included syphilis-positive African Americans and 201 health controls. The longitudinal study was unethical and would have not received approval today given the maltreatment of subjects, the lack of informed consent and ability to withdraw, as well as denied access to Penicillin – which is a treatment for syphilis. Participants not only died and infected others, but they congenitally passed it to their children. Not only is this study highlighting the need of looking after participants’ wellbeing and only designing ethical protocols, it also sheds light to the ingrained systemic racism in science and the need for a radical change. 

1937: Elixir Sulfanilamide Disaster 

S.E. Massengill Company was a pharmaceutical founded in the late 1890s. The company was responsible for the 1937 Elixir Sulfanilamide disaster, one of the deadliest mass poisonings of the 20th century. Elixir Sulfanilamide was liquified by dissolving it into diethylene glycol, a toxic compound, ignoring its dangerous properties. The drug was released without any safety testing and killed Americans across 15 different states. The Chief Chemist died while awaiting trial and the company was only charged a minimal fine for mislabelling the product – the only penalty they were subject to under the 1906 FDA Act. To prevent similar scandals, the 1938 Federal Food, Drug, and Cosmetics Act was created.

1938: Federal, Drug, and Cosmetic Act 

Failure to prove drug safety prior to its release led to one of the deadliest poisonings (Elixir Sulfanilamide) of the 20th century. With the 1938 law change, the FDA’s primary focus of seizing production and marketing of adulterated drugs was changed. The FDA became a regulatory agency involved with supervising the evaluation of all new drugs. The 1938 Act was extensively amended but remains the principal foundation of FDA regulatory authority to this day. All drugs need to have safety demonstrations prior to market approval, and must have clear labels with adequate directions for safe use. 

History Clinical Trails Past Present Future

1939-1945: World War II Experiments 

While people around the world were experiencing the social, economic, political consequences of global tension, the German Nazi Party was also conducting a series of monstrous experiments on its concentration camp prisoners. The experiments, which were part of the Holocaust, aimed to develop new weapons, treatments for the injured German soldiers, and to advance their eugenic racial ideologies. The prisoners often died, or suffered disfigurement, or permanent disability. Such experiments should not be conducted, and informed consent should be obtained prior to involvement in trials. Although scientists are not allowed to carry out grotesque medical experiments, they now need to ensure that their publications do not encourage racist assumptions – instead science should be used as a weapon to re-educate people and fight racial injustice. 

1943: Patulin and the first double-blind controlled trial 

The first double-blind controlled trial, i.e. a trial in which neither the researcher nor the participant know whether they are being administered a drug or a placebo, was recorded in 1943. The UK Medical Research Council (MRC) tested patulin for the treatment of the common cold, and while the procedure was carried out very carefully patulin treatment was deemed ineffective. Although the researchers did not obtain the results they had hoped, the patulin trial was a pivotal moment and paved the way for the first randomised control trial in 1946.

1944: Multicentre Studies 

Conducting studies with small sample sizes has several limitations, such as lack of generalisability, and inability to control for factors significantly affecting outcomes. By introducing multisite studies researchers were able to use the same protocol at different centres and assess all results together. This allowed researchers to not only recruit larger numbers of participants, but also to recruit a wider range of populations, strengthening the experimental designs and analyses. Most large trials are now being carried out at multiple clinical research centres. 

1944-1974: Human Radiation Experiments 

Over 4,000 secret studies were sponsored by the US government during the Cold War era and exposed thousands of naive US citizens to atomic radiation to study its effects on the human body. Thousands of victims, the majority of whom belonged to vulnerable groups (e.g. prisoners, pregnant women, patients, children), were exposed to harmful doses. What patients often thought was ‘just another injection’ was actually toxic radioactive material injections which led to the development of life-threatening conditions.

1946: The first randomised controlled trial 

In 1946 the UK MRC conducted the first randomised controlled trial (RCT), investigating the effects of streptomycin in pulmonary tuberculosis. RCTs allow reduction of biased sources when testing the effectiveness of new treatments as subjects are randomly allocated to 2 or more testing groups. Those involved in the trial carefully monitored and assessed participants throughout a 15-month period. The trial became a model of design and policy implementation. 

History Clinical Trails Past Present Future

1947: Nuremberg Code 

A pivotal moment in the history of protocol approval and informed consent for participation in experiments was the outcome from the Nuremberg Trials. German Nazi Party members were tried for their inhumane acts against the victims of their experiments, in particular on their unwilling prisoners of war. A set of 10 ethical principles for human experimentation was created and the Code demands that all experiments include participant informed consent, clear and appropriate designs, no coercion, and beneficence towards all participants. Nowadays, no researcher is allowed to carry out an experiment unless ethical approval has been granted and faces serious consequences if fails to do so.

1951: Henrietta Lacks 

Henrietta Lacks was receiving treatment for cervical cancer when George Otto Gey, a researcher, took cells from her tumour and realised that he could keep them alive in culture. Her cells are known as the HeLa immortal cell line and are used in biomedical research. Over 20 tons of cells have been grown from the HeLa line and researchers from all over the world are using them to develop and test new treatments. The HeLa cells were used to test for the first polio vaccine in the 1950s, and have been used for AIDS and cancer research, among many other experiments. Henrietta Lacks never found out about her impactful contribution to science – at the time permission to harvest cells was not required. After her death some family members expressed some concerns and studies resulting from the cells’ DNA sequence should acknowledge her contribution. Two family members were also given a place to the 6-member committee which regulates access to the sequence data.

1950s: The “Thalidomide case” and the importance of human clinical trials

Thalidomide was a drug released on the market in the 1950s, given to pregnant women to treat morning sickness. The drug was only tested in animal trials before it became available to the public. Unfortunately, it was soon observed that when given in the first trimester of pregnancy, it caused significant birth defects to infants from moderate malformation to life threatening conditions. The “Thalidomide case” changed the way treatments were approved by regulatory authorities. Following the scandal, it became mandatory that all human clinical trials received regulatory approval before starting to trial the protocol.

1960’s: Harvard Psilocybin Experiments 

Timothy Leary and Richard Alpert, two Harvard professors, gave psilocybin (a psychedelic drug) to students and prisoners to examine whether the then-lethal drug could lead to radical, and positive behaviour changes. The two professors’ research was heavily questioned as they were taking the drugs with the students during the experiments, and two students were admitted to a psychiatric hospital. The professors were invited into a meeting which turned into a trial against them, and a controversial article was later published in the Crimson in 1962. Although the state authorities decided to approve use of psilocybin in experiments under the conditions that a (sober) physician is always present during the study, Alpert refused. It is believed that Alpert and Leary were stocking up for another experiment, the Zihuatanejo Project. They were both dismissed by the university soon after that and their advocacy of psychedelic use made them significant figures in the nascent counterculture, an anti-establishment cultural phenomenon in the Western world between the mid-1060s and the mid-1970s.

History Clinical Trails Past Present Future

1960s: The Polio Vaccine

Polio is a disease caused by the poliovirus, a virus that can infect the nervous system and cause significant limb paralysis. The polio vaccine was tested in the largest human clinical trial in history with approximately 1.8 million children taking part. The large number of participants provided strong evidence that the vaccine was both safe and effective and was quickly approved and distributed to the wider population.

1962: Kefauver-Harris Drug Amendment

The Kefauver-Harris Drug Amendment ensured that drug manufacturers provided proof of effectiveness and information about all side effects to avoid marketing of cheap and dangerous drugs as expensive ‘breakthrough’ drugs. 

1964: Declaration of Helsinki 

The World Medical Association used the 10 principles from the Nuremberg Code to develop a detailed document on human research ethics. It has been revised six times from June 1964 until 2008 and focuses on respect for the subject, their right to self-determinate, and their right to make informed decisions regarding their participation in research. It highlights that human rights should not be compromised for science’s sake. 

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

1974: The National Research Act

After the appalling treatment of participants in the Tuskegee Syphilis Study, President Richard Nixon signed the National Research Act which demands all research using human participants to be reviewed by an Institutional Review Board. This was another step to protecting the rights of human participants. 

History Clinical Trails Past Present Future

1974: FDA Bureau of Medical Devices and Diagnostic Products & 1976: Medical Device Amendments 

To meet the needs of the rapidly-growing medical device field, the FDA created the Bureau of Medical Devices and Diagnostic Products, as they were not previously covered by the regulations from the 1938 Federal Food, Drug, and Cosmetic Act. President Gerald Ford then signed the Medical Device Amendment to increase the FDA’s power over the production of new devices. The new legislation introduced the concept of risk-based classifications for medical devices. All devices need to be proven safe and effective prior to entering the market. 

1979: The Belmont Report 

The Tuskegee Syphilis study also led to the development of the Belmont report, which brings attention to unethical research conducts and explains the three principles to guide human experiments: Respect for persons, Beneficence, and Justice. It is now used as a primary ethical framework for protection of US research participants. 

1981: FDA Regulations Title 21

Title 21 was created in addition to the Belmont Report (1979) and includes regulations for the Protection of Human Subjects (Part 50), Financial Disclosure (Part 54), IRBs (Part 56), Investigational New Drug Applications (Part 312), Investigational Device Exemptions (Part 812), and Electronic Records (Part 11).

1990: International Conference on Harmonisation Guidelines 

The ICH guidelines were created in April 1990 in response to the global harmonisation plans of many European countries, Japan, and the US. With several products being marketed globally, nations had to reduce redundant, and expensive procedures while ensuring safeguards on quality, safety, and efficacy – the three basic criteria for approval of new medical products. In 1996 the ICH released the Good Clinical Practice (GCP) Guidelines, one of the most significant documents in clinical research. 

1990: The Safe Medical Devices Act 

The Safe Medical Devices Act is an extension of the Medical Device Reporting Legislation, and highlights the importance of patient safety when using medical devices. The act requires hospitals and healthcare professionals to always report any serious injury or death incidents caused by the devices to the FDA and manufacturers. In turn, the FDA is allowed to order device product recalls and take action when a device may be defective and dangerous.

History Clinical Trails Past Present Future

1991: The Common Rule 

The Common Rule is a set of ethics rules for the protection of human participants in biomedical and behavioural experiments. Its main elements include: requirements for assuring compliance by research institutions, obtaining and documenting participant informed consent prior to participation, and requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping. It additionally protects vulnerable subjects, including pregnant women, prisoners, foetuses, and children.

1993: MedWatch 

The MedWatch was launched by the FDA – the MedWatch allowed collection of data regarding adverse events in healthcare settings. When an adverse event involving a medical product is reported, the FDA issues safety alerts or orders product recalls, and may also withdraw the product or make label changes to protect the general public health. From 1993 to 2011 40,000 hazards were detected. 

1996: Health Insurance Portability and Accountability Act 

In 1992 President Bill Clinton signed the Health Insurance Portability and Accountability Act but the final HIPAA rule only went into effect in 1996. The HIPAA ensures that all patients are informed of how their health data will be stored and kept confidential when participating in research trials.

History Clinical Trails Past Present Future

1996: National Bioethics Advisory Commission 

The National Bioethics Advisory Commission looks into any ethical issue which may arise in science and medicine, and in turn advises the President on bioethical issues. The Commission created by President Bill Clinton examines topics such as cloning, human stem cell research,  and research with human participants.

1996: The World Health Organisation Guidelines for Good Clinical Practice 

The GCP Guidelines are one of the most significant documents in clinical research, addressing justifications for a trial and protocol, protection of participants, all investigators’, sponsors’ and monitors’ responsibilities, assurance of data integrity and product accountability, and the roles of regulatory authorities. One way the guidelines facilitate understanding and implementation of GCP is by explaining in detail how each GCP Principle is routinely applied and implemented. 

1996: Hoiyan (Nicole) Wan 

In 1996 a 19-year-old girl, Hoiyan (Nicole) Wan took part in a minimal-risk study on smoking and air pollution. The girl underwent bronchoscopy to obtain brush biopsies from lung tissue. The girl died two days after the procedure from complications. It was later revealed that she was administered four times the maximum tolerated dose of lidocaine, a topical anaesthetic. The physician involved was found guilty as the protocol failed to clearly state the maximum dosages, the stated guidelines were violated, and the girl’s condition post-bronchoscopy was not carefully and properly monitored. 

1999: IMARC Research, Inc. 

In 1999 Sandra Maddock founded IMARC Research, Inc. IMARC started as a monitoring company and is now a leading full service medical CRO (Contract Research Organisation), delivering high-quality clinical research monitoring, auditing and training, as well as development and consulting to any companies looking to correctly follow legal and ethical guidelines for research trials.

1999: Jesse Gelsinger 

Researchers’ and investigators’ failure to strictly adhere to protocols may lead to serious adverse consequences. In 1999, Jesse Gelsinger, a sufferer of a rare x-linked genetic disease of the liver was enrolled in a university-based gene therapy. At the time of recruitment Jesse did not suffer any effects, however the 18-year-old boy died four days after partaking in the procedure. The University of Pennsylvania had a financial interest in the trial and did not report serious side effects experienced by other patients, and the informed consent Jesse received prior to participation did not disclose known deaths during animal trials. Jesse had high ammonia levels as his body was unable to metabolise it. Although his ammonia levels should have been an exclusion criterion, the investigators enrolled him in the trial, leading to multiple organ failure and brain death.

History Clinical Trails Past Present Future

2004-2007: Ketek

Ketek was an antibiotic used to treat a type of pneumonia caused by bacteria. Although the drug received FDA approval in 2004, it was linked to numerous severe liver injury cases and four patient deaths. The drug received a series of urgent safety warnings and the Congress investigated the FDA’s acceptance of fraudulent safety data despite being reviewed three times. The FDA was accused of using inappropriate safety review methods, and failure to present any issues of data integrity. 

Recent Years

Technological advancements increased scientific knowledge, greater funding and improved equipment are few of the factors that have significantly contributed to the improvement of current clinical trials – from study conception to execution. Although the clinical research community has been affected by delays in protocol design, recruitment of eligible participants, coordination of administrative work, amongst other challenges, COVID-19 has expedited collaborative and innovative trials, and promising changes in clinical research practices. Specifically, COVID-19 has propelled the clinical research industry toward a need for streamlined and expedited drug development. The discovery of a vaccine against COVID-19 proved that accelerated trial approval, in conjunction with timely participant recruitment, funding and training of trial managers and staff would lead to significant improvements in the timeline of drug development. Recent, global collaborations have underlined the importance of transparency in clinical trials, sample diversity for generalisable results, raising awareness and educating the public – this would increase the likelihood of engagement and participation – and finally, adopting decentralised practices. 

Conclusion 

To conclude, the history of clinical trials – from the very first recorded example of a trial to today’s practices – has evolved dramatically. Ethical and safe practices, together with improved transparency and digitalised, decentralised designs could positively shape the future of clinical trials, improving drug development, and ultimately refining patient experience, prognosis and quality of life.  

References

Bhatt, A.

(2010). Evolution of clinical research: a history before and beyond James Lind. Perspectives in clinical research1(1), 6.

FindMeCure.

 2018. The History of Clinical Trials. [online] Available at: <https://www.findmecure.com/blog/the-history-of-clinical-trials/> [Accessed 3 February 2022].

Junod, S. W.

(2008). FDA and clinical drug trials: a short history. A quick guide to clinical trials, 25-55.

Khera, A.

2021). Clinical research in 2021: A new era of collaboration and innovation –. Pharmaphorum.com. Retrieved 3 February 2022, from https://pharmaphorum.com/r-d/views-analysis-r-d/clinical-research-in-2021-a-new-era-of-collaboration-and-innovation/

Maddock, S.

The History of Clinical Research. Retrieved 3 February 2022, from https://cdn2.hubspot.net/hub/149400/file-410979295-pdf/docs/CRT_Timeline_download.pdf

Direct to Patient Clinical Trials

Neucruit

Neucruit

Author

Direct to patient clinical trials are a decentralised clinical trial model where aspects of the trial occur outside the main trial site.

In traditional clinical trials, patients travel to the investigator site and commit to this for the entirety of the study, which can present a significant burden for patients depending on their disease profile or even location. As approximately 70% of US potential participants live more than two hours away from a study centre, many may be reluctant to contribute to clinical trials (1).

D2P Direct Patient Trails Virtual

In decentralised clinical trial models, the phases of traditional trials are monitored with the same blinded protocols but often are conducted at the patient’s home, workplace or pharmacy instead of a study centre, significantly increasing the likelihood of participation and improving patient experiences. There is also an increasing integration with digital technology such as wearable sensors and telemedicine to allow for remote and direct patient monitoring.

A recent study comparing clinical trial designs found that the decentralised arm with virtual telemedicine visits had an 89% patient completion rate, compared to the 60% completion rate in the conventional on-site study arm, in addition to the expedited recruitment observed in the decentralised arm. This decreased attrition rate is promising and highlights that adapting trials  to patient lifestyles and schedules would reduce delays in the clinical trial timeline, and benefit those involved, including the clinical trial administrators, pharmaceutical companies and other sponsors and other parties involved (2). 

“Demand for DTP has dramatically increased since 2014. In fact, it more than doubled between 2015 and 2016 alone.”

Michael Sweeney of World Courier Group

 

The COVID-19 pandemic increased the demand and use of technology for healthcare visits, e.g., via telemedicine. Similar needs and trends were also seen in the clinical trial. Digital consent forms and remote monitoring have been used in some trials to continue testing in a safe yet controlled setting. Those who partake in remote or direct to patient studies feel more secure, directly influencing retention rates and patient satisfaction. Another advantage of these new digitalised and direct to patient settings is the ability to constantly collect real-time, continuous data and in turn improving the quality of the research outcomes.

Without the hostility of some clinical settings, direct to patient settings facilitate the communication of insights and patient-centred endpoints. This almost “collaborative” nature of direct to patient trials provides valuable patient feedback that can shape treatment or product experiences (1).

Taking advantage of this changing trend in decentralised clinical trials, Neucruit has recruited individuals with high self-reported levels of worry to take part in the ‘Worry Reduction Training’ Study conducted by a clinical and academic team at King’s College London. Eligible users were recruited in October and November 2020, and completed assessments after receiving a virtual training on coping mechanisms for worrying, all from the comfort of their home. 

Allowing Neucruit-users to choose the studies they would like to participate in we hope to contribute to the improvement of clinical research practices and outcomes. 

References

Anderson DF, Jonathan, Elsner N.

Digital R&D: Transforming the future of clinical development. Deloitte; 2018.

Sommer C, Zuccolin D, Arnera V, Schmitz N, Adolfsson P, Colombo N, et al.

Building clinical trials around patients: Evaluation and comparison of decentralized and conventional site models in patients with low back pain. Contemporary Clinical Trials Communications. 2018;11:120-6.

Open to Better: Site Nurses on New Technology

Neucruit

Neucruit

Author

Clinical research nurses (CRNs) play a vital role in clinical trials, such as caring for trial patients, preparing trial protocols and other documentation, dealing with data collection, and improving patient recruitment and retention. Due to the broad nature of the role, there are significant improvements to be made in several aspects of the clinical trial process, to reduce the heavy burden on nurses.

While CRNs are vital in running clinical trials successfully, equipping them with tools to increase the efficiency and reduce their workload has been less than successful, partly due to the lack of tool availability and hesitancy in using new technology (1). At Neucruit we aim to challenge and change this hesitancy.

 

Following Neucruit’s interview with Kelly, a CRN working for Imperial College London and Cancer Research UK, some surprising pain-points and promising technological advancements were discussed.

 

Firstly, nurses often have highly emotional conversations discussing clinical trial eligibility with patients diagnosed with difficult-to-treat cancers, which leads to patient excitement at the prospect of novel drug trial, only to be told by nurses that they are no longer eligible for a study for reasons beyond anyone’s control (e.g., tumour growth).

Explaining this further, Kelly noted that there is a “small window of opportunity” when patients are at a certain stage of their disease. For instance, patients with metastatic cancer may become eligible for different lines of treatment depending on the location(s) and rate of the metastasis. However, Kelly noted that clinical trial treatment options are not being offered fast enough to patients – in her opinion this is largely due to clerical delays. Hence, patients become ineligible for a specific trial treatment, resulting in these emotionally-heavy and difficult conversations with CRNs. 

Nurses Technology Clinical Trails

Kelly suggested that the aforementioned issues could be largely avoided through advances in technology and automating data input for nurses. When using Neucruit, these patients could be flagged much earlier based on their pre-screening information, matched to eligible trials for treatments which could improve individual outcome and also contribute to research breakthroughs (2). Kelly was very open to the suggestion of using automated services to  stratify patients more efficiently. 

Another pain point for CRN nurses that Neucruit aims to solve, is the recruitment of patients. For some studies there are very few eligible patients, making recruitment even more strenuous and challenging – an issue nurses are aware of from the beginning of the trial design. Often, recruitment relies on collaborations ‘with hospitals or shared multidisciplinary teams in order to suggest eligible patients”, but sometimes there is “competition” for patients between hospitals which also hinders the pace at which eligible patients can be screened and onboarded on the trial. This not only adds to the limitations of biased and non-diverse sampling, but recruitment also becomes dependent on maintaining connections with hospitals and unspoken agreements between trial sites and hospitals or other patient-centred services. 

The backlog of patients and the overwhelmed healthcare system does not always give the opportunity to clinicians to get involved with trials, and they might forget to refer eligible participants to clinical trials. According to Kelly, when they do so, they might refer certain demographics only, adding onto the issues of small and non-diverse clinical trial samples (3).

Nurses Technology Clinical Trails

Kelly was extremely eager and open to the idea of using Neucruit’s API after we explained how our tool would work behind the scenes, and how it could benefit nurses and clinicians working with clinical trial teams. Specifically, we suggested that by automating some of the recruitment steps such as matching large patient databases to researchers and pre-screening large volumes of patients much faster and more efficiently, there would be more time for nurses to focus on patient care and on the research itself. This could provide a more positive outcome for nurses and patients in trials too.

Using Neucruit’s natural language processing (NLP) tools too (a tool we are currently in the process of incorporating), patients would be able to see terms they understand when using search engines to look for trial-relevant information, increasing their likelihood to get involved and stay engaged in a clinical trial. 

Neucruit aims to introduce this tool to CRNs to improve recruitment and patient outcomes, and to allow CRNs to focus on other aspects of clinical trials too.

References

Kelly Imperial College London and Cancer Research UK.

A Clinical Research Nurses’ Perspective on Recruitment Issues. 2021.

Sethi N.

ALS Patient Advocate interview. In: Neucruit, editor. 2021.

About Neucruit

A female-led team transforming clinical trial efficiency, transparency and diversity by improving accessibility to all patient communities. Neucruit is an intelligent software for clinical trial recruitment that redefines patient recruitment. Our technology aggregates real-time data from the over 25 million health-related conversations initiated online everyday to facilitate planning and recruitment in clinical trials. We support biopharmaceutical companies, site teams and investigators enhance site selection, optimise recruitment materials and reach groups that cannot be easily accessed through traditional methods.

Insights from Clinical Trial Participants

Neucruit

Neucruit

Author

Countless lives have been saved by clinical trial breakthroughs. With clinical trials we have been able to discover and test the effectiveness and safety of drugs that have resulted in direct improvement of patient care and illness prognosis. 

One remarkable example of trials saving lives is the story of cancer survivor Laurie Adami.

Clinical Trails Cancer Treatment Research

Diagnosed with stage IV non-Hodgkin lymphoma in 2006, Laurie’s prognosis was bleak, and her experience with several different chemotherapies even worse. After 12 years of unsuccessful treatments, Laurie was enrolled into a novel CAR-T immunotherapy trial. In CAR-T immunotherapy white blood (T) cells are taken out of the patient’s body and engineered to recognise antigens on the cancer and infused back into the patient’s bloodstream a few weeks later, targeting the cancer cells – an example of personalised medicine. 

In Laurie’s case, this clinical trial for innovative CAR-T therapy was successful, eliminating all 3kg of cancerous lymphoma from her body, and saving her life.
Due to the positive experience Laurie had, she has since devoted much of her life to raising awareness for lymphomas and for similar trial therapies which could prove lifesaving for other patients too.

CAR-T immunotherapy has since saved thousands of lives, both during the clinical trial period, and after receiving FDA approval.

While Laurie’s story is of hope, not all who are interested in finding a treatment manage to participate in clinical trials. Neucruit recently interviewed Nadia Sethi, an Amyotrophic Lateral Sclerosis (ALS) patient advocate regarding her own views on clinical trials. Over the last two years, Nadia has passionately advocated to bring more patients to trials for ALS, after losing her husband to ALS. Nadia shared her frustrations, but also her hopes for the future of clinical trials.

Initially, Nadia found no-responses and dead-ends from neurologists when seeking ALS treatments. She then turned to the US-focussed website to look for relevant trial information, and attempted to get in touch with clinicians, researchers, coordinators in order to get some advice or referrals.

The opportunities and engagement were poor so she eventually, sought hospital research team staff and contacted them too, to increase the likelihood of finding a clinical trial for ALS patients. Despite calling study centres and contacting them through their websites, few responded, and the very restrictive inclusion criteria made the recruitment and screening process “to “move surprisingly slowly.” Most alarmingly, in her research she found that only one or two ALS patients are successful recruits per site each month.

This harrowing statistics highlights the need to facilitate and streamline the administrative and managerial work clinical trials require as currently only a very small percentage of the population can access clinical trials. This poor and slow recruitment has devastating effects on the outcomes, limiting the speed at which novel therapies can be trialled, delaying life-saving treatment opportunities for those in need, and increasing the burden on patients, carers, and the healthcare system.

Nadia’s interview is a reminder of the need to advocate for clinical trials, to increase awareness and to encourage participation. 

Recruitment in the Time of COVID-19

Neucruit

Neucruit

Author

Never before have clinical trials been so heavily popularised and never before have people been so educated on clinical research – this has been reflected in recruitment timelines and this creates a model for how patient recruitment should move forward, to include more in-depth conversations with patients.

 

The COVID-19 pandemic has given rise to a set of new challenges for the recruitment of patients for clinical trials but has also been a welcome catalyst for change.
Through the international response and collaboration to try and slow the pandemic, this novel virus has led to greater global awareness of the role and importance of clinical trials in research and healthcare. 

The rise of telemedicine

For clinical trial managers, several adaptations and novel solutions have been implemented in order to resume currently paused trials and launch new trials.  Solutions include respective governments responses in fast-tracking any clinical trials directly linked to the COVID-19 virus itself, due to the virus being a global threat and a public health issue; approximately 35% of the studies that were approved between February and September 2020 concerned COVID-19 related trials (1). 

Despite the initial drop in recruitment due to restrictions and worldwide fear, the world has quickly adapted and technology has been used as tool to decentralise parts of the clinical trial recruitment process, such as to undertake the consent process remotely (1). While giving consent digitally is still an uncommon practice, digitalised methods have been used instead.  Studies using both online and printed consent forms saw an increase in patient recruitment, since the consent process was sped up and in-person visits were prioritised.

While many of us enjoy things being ordered in a certain way these behaviours are ordinary until they start interfering with and affecting one’s quality of life, functioning, and relationships. The debilitating symptoms of the disorder make it a disabling condition, especially now, during the pandemic, that behaviours and actions OCD sufferers are encouraged to control and minimise are behaviours and actions preventing the spread of a virus and contributing to personal and societal protection.

“Doctors and research nurses are spending way too long recruiting patients to research studies… Patients are not getting the experience they deserve, and these effects snowball into delays in scientific advancements… and into people getting lifesaving treatments.” – Livia Ng, CEO Neucruit

Livia Ng / CEO Neucruit

Patient centricity and AI to gauge patient attitudes

Trends in patient centricity have been a recent hot topic. Through the design of more patient-centric trials, conversations with patients now have a much larger part to play in clinical trials than before, and these more detailed conversations with patients will likely contribute to lower attrition rates (2).


Techniques that emerged during the course of the pandemic in order to improve these patient-researcher conversations included consulting patient advocacy groups when designing trials, personalising pre-screening questions to gain trust, and to acknowledge that one’s views of clinical trials may change over time (3).

Clinical Trails Pandemic

Through this exploration of patient views towards clinical trials, Neucruit aims to improve the recruitment process.  So far, Neucruit successfully optimised the pre-screening and recruitment for three clinical and academic studies in 2020:

– Repeated Assessment of Mental health in Pandemics (RAMP) study (King’s College London): pre-screened 101 participants for a study examining the impact of the pandemic on mental health. (Target sample size requested by the research team was met).

– Impact of Covid-19 on Mood and Alcohol Study (The University of Liverpool): pre-screened a total of 96 participants to investigate the impact of COVID-19 on their alcohol consumption levels (Target sample size requested by the research team was met).

-The Long Tail Study (University College London): pre-screened 65 participants, to identifying eligible individuals for a study exploring the long-term effects of COVID-19. (Target sample size requested by the research team was met).

Following this, Neucruit received the Innovate UK COVID-19 Government Grant, with an aim to optimise patient recruitment three additional COVID-19 trials. With this funding, Neucruit also aims to better target patients using natural language processing (NLP) and artificial intelligence (AI) to modify outreach messages, for faster recruitment, and from more diverse patient samples at a much lower cost than traditional recruitment methods.

Using the tools provided by Neucruit we can improve recruitment practices and clinical trial outcomes for patient groups, clinicians, nurses and researchers. 

References

Mitchell EJ, Ahmed K, Breeman S, Cotton S, Constable L, Ferry G, et al.

It is unprecedented: trial management during the COVID-19 pandemic and beyond. Trials. 2020;21(1):784.

Baker W.

CLINICAL TRIAL OPTIMIZATION. Applied Clinical Trials. 2020;29(3):9.

About Neucruit

A female-led team transforming clinical trial efficiency, transparency and diversity by improving accessibility to all patient communities. Neucruit is an intelligent software for clinical trial recruitment that redefines patient recruitment. Our technology aggregates real-time data from the over 25 million health-related conversations initiated online everyday to facilitate planning and recruitment in clinical trials. We support biopharmaceutical companies, site teams and investigators enhance site selection, optimise recruitment materials and reach groups that cannot be easily accessed through traditional methods.

AI in Patient Recruitment 2021

Alkistis Saramandi

Alkistis Saramandi

Author

85% of clinical trials fail to retain enough patients, and approximately 86% of all trials are delayed by over 6 months, in part due to recruitment issues, indicating a significant and urgent need for improvement (1, 2).

The manual recruitment and processing of patients is one of the major obstacles to running financially and clinically viable trials, and currently, traditional methods rely on doctors to recruit patients, or via word of mouth which directly contributes to clinician and clinician bias. These biases affect representation of certain races, ages and genders – there is an over-representation of individuals from Western, Educated, Industrialised, Rich and Democratic societies, and an under-representation of individuals from societies that do not fall within this categorisation (3).

This recruitment method is time-consuming and error-prone – little awareness of what a clinical trial is, what the benefits and adverse effects is linked to a reduce interest in participating. On the other hand  up to 80% of individuals with a certain condition may not be aware that they are eligible and suitable for impactful trials, highlighting the need to expedite and streamline participant recruitment and concomitantly increase diversity and inclusion to tackle misrepresentation in research practice. 

 

A modern solution to the issues of (1) recruitment and (2) representation could be found in the recent technological developments of cognitive technologies that include artificial intelligence (AI; the mimicking of human cognition in data analysis, and dissemination) and natural language processing (NLP; a subfield of linguistics, computer science and AI used to process and analyse communication data).

AI relies on machines and computers to carry out tasks that were once deemed only feasible for humans.  It enables the gathering and processing of large amounts of data from very disparate sources with extreme accuracy and organisation, eliminating the effects of cognitive and emotional bias that occurs when humans undertake a task. The field of AI has several subfields, including machine learning. With machine learning. The machine or computer is programmed to continuously learn and adapt through experience, constantly improving the algorithms of interest. 

Clinical Trails AI Recruitment

These cognitive technologies are becoming increasingly popular not only in healthcare, but also in recruitment for clinical trials.

Prevention and the development of treatment techniques and improved patient outcomes are at the heart of the AI health-related aims. A crucial application of AI would be in analysing the diagnostic pathways, and practices such as treatment protocol development, drug development, and other patient-centred goals such as monitoring and care. Next, AI and its subfields could also be used to scan patient forums, public search results and websites to provide a rapid search of potential patients, and use the data to signpost interested and eligible participants to relevant trials.

Another possibility would be to filter data based on specific geographical locations, for site-specific recruitment. Taken together, these applications would have some key implications: improved patient satisfaction, reduced backlog in the healthcare and associated research fields, increased cost saving, and accurate and expedited research recruitment and trial phase completion.

There are already some preliminary findings suggesting that patient centric recruitment via web-based tools such as patient communities better engages patients, in comparison to traditional recruitment methods.  Novel and targeted AI strategies focussing on participant outreach have directly contributed to higher engagement in younger age groups, highlighting the benefits of using AI for patient recruitment (4). 

Next, NLP could be used to gather insights on (1) patient needs related to clinical trials (e.g., information about safety, role as a participant, implications), (2) specific wording used in search engines. NLP data could then we used for targeted messages to individuals in order to increase the likelihood of engagement and participation in trials of interest. At the same time, machine learning applications would be able to adapt to the individual’s engagement levels, and tailor the timing they would see relevant campaigns to ensure maximum engagement, and improve retention rates. Ultimately this would lead to improved clinical trial outcomes, conferring benefits to the patients, clinical research organisations, and the pharmaceutical companies that sponsor the trials (5).  

Clinical Trails Recruitment AI

Neucruit’s application programming interface (API) identifies all channels related to the inclusion criteria of trials, identifies eligible patients and launches targeted campaigns for specific demographics. Then, Neucruit will pre-screen interested participants and exclude those who do not meet the clinical trial’s inclusion criteria. 

Additionally, Neucruit’s NLP will alter phrasing and clinical language for each user to provide personalised engagement throughout the recruitment process, which will allow us to immediately identify and address any concerns in order to maintain user engagement and retention.

Our aim at Neucruit is to guide future clinical trial recruitment using cognitive technologies and improve the design of clinical trial for the targeted demographics. Our goal is to make recruitment and participation accessible to all in order to expedite research with broad and poignant implications. 

References

Gul RB, Ali PA.

Clinical trials: the challenge of recruitment and retention of participants. 2010;19(1‐2):227-33.

Ghosh I.

How Artificial Intelligence is Transforming Clinical Trial Recruitment2018. Available from: https://www.visualcapitalist.com/artificial-intelligence-transforming-clinical-trial-recruitment/.

About Neucruit

A female-led team transforming clinical trial efficiency, transparency and diversity by improving accessibility to all patient communities. Neucruit is an intelligent software for clinical trial recruitment that redefines patient recruitment. Our technology aggregates real-time data from the over 25 million health-related conversations initiated online everyday to facilitate planning and recruitment in clinical trials. We support biopharmaceutical companies, site teams and investigators enhance site selection, optimise recruitment materials and reach groups that cannot be easily accessed through traditional methods.

Investigators Perspective on Patient Recruitment

Alkistis Saramandi

Alkistis Saramandi

Author

We had the pleasure of interviewing a research fellow from the Anna Freud Centre (AFC), Dr Saul Hillman, who used Neucruit (formerly known as CT-X) for participant recruitment. Dr Hillman is an honorary lecturer at UCL and a clinical tutor in the MSc in Psychoanalytic Developmental Psychology. He also works as a researcher within the Child Attachment and Psychological Therapies (ChAPTRe)  unit – a unit that bridges UCL and the AFC. He has carried out extensive research on adoption and foster care, attachment in early childhood and adolescence, bereavement, and trauma and through his involvement with UCL and the AFC for over 20 years he has taught and supervised numerous students in the program. Dr Hillman has also been involved in several research projects, including a longitudinal Attachment and Adoption research project in collaboration with the Anna Freud National Centre for Children and Families, Coram Family, and the Institute of Child Health and is actively engaged in the development of research tools. We recently helped Dr Hillman find some adult volunteers for a study exploring linguistic markers in social media and how they relate to mood. 

 

Here, we interviewed him to find out more about his experiences with participant recruitment during his career, his opinions on streamlining scientific recruitment, and conclude with some insight into his most impactful work, and hopes for the future.

Dr Hillman reflecting on his recruitment experiences

I do not have huge amounts of experience trying to collect clinical data and doing NHS ethics applications; it has not been an area I have had to be involved with, but I know that it is  becoming more and more challenging and time-consuming. So, we tend to stay away from those applications.’ In fact, this is a frustration shared by many researchers, and clinicians, who are wishing to take on meaningful projects with clinical populations, or to trial new treatment options, but the bureaucracy and difficulty in receiving approval often hinders opportunities.

Instead, Dr Hillman and his group have looked into the benefits of different study designs and sampling opportunities (e.g., collecting community data from adolescents or children). For other studies, such as the one promoted via Neucruit, he has had to resort to online recruitment platforms and hope sample size targets are met on time.


However, recruitment has not always been easy and successful – instead, recruitment is usually delayed, sample size targets might not be met on time, in turn hugely affecting research outcomes and implications. ‘At the AFC, through UCL, we have always had some sort of links; for example, if you are trying to recruit through schools or other organisations. But I think it is becoming more and more problematic to recruit; I think schools in particular are getting saturated with requests from people like me.

’ With an increased need to conduct impactful research unless efficient recruitment methods are put in place, researchers are unable to meet their targets and they often need to bend or change their study’s aims. ‘I have been told [that when trying to approach people] that my research is interesting, but they are already involved in a couple of studies and just cannot take any more on. And so much research benefits from collecting data from a big population of children and adolescents, and there is no better way in doing that than trying linking with the schools. I think it has become harder – there are more challenges to find the right person, more bureaucracy in schools,

They way forward for efficient recruitment and impactful research 

 

Imagine getting a study approved at the end of January, and needing data by May – ‘that sounds like a good amount of time, but it really is not, especially when there is a pandemic. So, I guess it is something a lot of supervisors I know have staved away from – they have ensured that their students either have data to analyse, or they have avoided going down those routes where the student needs to collect data. So it does feel like we need a quicker, more accessible way of getting data – representative data, big numbers if we want to do something meaningful.

 

’With research practices having changed significantly over the past few months, many researchers have had to put a halt to their research, or as Dr Hillman mentioned, drastically change their expectations. Such recruitment drawbacks and changes in research practices will be influencing the quality and quantity of robust and novel outcomes we will be seeing in the following years. Dr Hillman highlighted the need to create a large pool of participants so studies with niche criteria can successfully have direct and vigorous contributions with implications for the academic-research communities, but also for the general public.

Anna Freud Centre Children Families Recruitment

Dr Hillman’s most impactful work

Having extensive experience in the clinical and research worlds, Dr Hillman has successfully managed to design and conduct research that has allowed us to better understand the mechanisms of attachment. As a researcher he has been involved in numerous projects, with diverse outcomes, but we decided to focus on his singularly most influential project.

 

Dr Hillman has designed and currently coordinates a tool called Story Stem – ‘Story Stem is an attachment, narrative tool used to access a child’s internal world. We used it with maltreated late-placed adopted children, when they were placed and one and two years later to see what happened in their internal world. This was the selling point of the tool, in which I train people in, but also very informative as it allows us to explore what happens if a child has had a bad start in life. It is quite realistic – it does not always get rose-y and perfect the next year. The positive themes often go up, some of the negative things go down, the child is less avoidant but they’re less incoherent and negative. And of course,

 

two years later they have improved, but it is still organised in an incoherent internal world. If we are talking about a 6-year-old child who has had years of adversity, of course even if placed in the most stable, loving new home, we could not possibly expect all the issues from the past to be eradicated.’ This area of research is paramount – understanding how early experiences shape us, and how adversity impacts our development and personality will enable us to better support those in need. 

Future outlook

Even though I am in the world of academia, have a PhD, write papers, analyse data, I struggle a lot with how we disseminate. We disseminate things in ways which of course are written in very academically, articulate ways but they are not accessible. We have a responsibility in academia to make sure that we open people up to all those things, in all areas. I think possibly, up until now it has just not been made relevant and digestible enough. And I know if it is an area outside my field, and I do try to engage, I quite often find it is not presented in a way that is clear.’

 

Although science needs people’s support more than ever, people are unaware of research opportunities, they drop out of trials, or participate in a short online survey and then completely disengage. Among the factors influencing this, is the huge gap between the general population and the science world. Researchers like Dr Hillman are seeking support, but unless science is made accessible to all, and communicated in interactive and educational ways, interest is lost. At Neucruit, our mission is to bridge this gap between people and science, ultimately contributing to our understanding of human behaviour, interaction and pathology, while helping researchers practice the science they love. 

 

We thank Dr Hillman for his time and insights. 

 

Disclaimer: All posts and information shared here are Neucruit members’ opinions and there is no intention to harm or mislead any individual. Where needed appropriate credit or source of information is provided. Finally, none of the material (e.g., blogposts, studies) is intended to substitute for professional advice, diagnosis, pharmacological or psychological treatment. Please seek the advice of a healthcare professional should you have any questions regarding any mental and/or physical symptom. Do not use Neucruit material to disregard any professional psychological or medical advice you have received, and do not delay in seeking professional advice and help if you need to. 

 

Dr Hillman’s most impactful work

Having extensive experience in the clinical and research worlds, Dr Hillman has successfully managed to design and conduct research that has allowed us to better understand the mechanisms of attachment. As a researcher he has been involved in numerous projects, with diverse outcomes, but we decided to focus on his singularly most influential project.

Dr Hillman has designed and currently coordinates a tool called Story Stem – ‘Story Stem is an attachment, narrative tool used to access a child’s internal world. We used it with maltreated late-placed adopted children, when they were placed and one and two years later to see what happened in their internal world. This was the selling point of the tool, in which I train people in, but also very informative as it allows us to explore what happens if a child has had a bad start in life. It is quite realistic – it does not always get rose-y and perfect the next year.

The positive themes often go up, some of the negative things go down, the child is less avoidant but they’re less incoherent and negative. And of course, two years later they have improved, but it is still organised in an incoherent internal world. If we are talking about a 6-year-old child who has had years of adversity, of course even if placed in the most stable, loving new home, we could not possibly expect all the issues from the past to be eradicated.’ This area of research is paramount – understanding how early experiences shape us, and how adversity impacts our development and personality will enable us to better support those in need.