Hippocrates, the 1980s and clinical trial technologies

The 1980s doesn’t seem that long ago, but maybe it’s just that time has passed quickly.??Once famous pop stars are now relegated to support acts, one hour photo processing shops are no longer even a memory (did we really do that?) and the expectation is no longer that we would get news updates once a day in print and once or twice a day on television news.??

At that time, the world of medicine and medical research had its own curiosities.??Medical records were 100% paper based, and while some aspects of clinical practice were based on rigorous published data that continues to this day (multidrug therapy for tuberculosis for example), others were based on empirical data, observational data or simply the preference of the practitioner.??As a fresh houseman in 1989 with the words of Hippocrates ringing in my ears (“Cure sometimes, treat often, comfort always”), I followed the directive of senior clinicians to prescribe what now seems quite prehistoric.??Rotating tourniquets in heart failure were standard of care (probably harmful, see Figure 1), and the use of magnets in hospital to accelerate the healing of large fractures was not uncommon (might work, although no evidence to suggest that I could find). Even then, some “nearable” diagnostic techniques like ballistocardiography (see Figure 2) were going out of fashion, supplanted by the more quantitative era of invasive cardiovascular assessment.

At that time patients were admitted to hospital for weeks for investigation and treatment.??Most of my fellow newly qualified junior doctors in the UK were on a “1 in 2” or “1 in 3” on-call Rota.?????That meant being on site and on the floor every day, but also every other or every third night.??Continuous contact with the patients who had themselves been admitted for long periods allowed the practitioner real time assessment of the progress of symptoms, and the resolution of physical signs, at the level of the individual patient.??By apprenticeship you were exposed to the art of taking a history and performing a detailed physical examination, and then recording what you detected in the medical record. Sometimes that was very important.??It is difficult to know how much painkiller to prescribe, or even which painkiller to prescribe unless you can directly observe the patient and take a history.??As an example, changes in mental state in recovery from severe infection can be subtle and only apparent from frequent interaction.??It can be quite challenging to understand whether the trend in improved strength following a stroke is real or not, unless it is the same person examining the patient every day.

The modern era has lost some of that.??Lengthy hospital visits and face to face clinic appointments have been replaced by the telehealth visit (now bookable via amazon in some cases), and wearables are commonly used for exercise performance, behavior monitoring, glucose monitoring and many others.??The Covid pandemic has made all of us experts in at home diagnostic testing.??I can’t say whether the commoditization of medicine is a good thing or a bad thing for our society.??The introduction of artificial intelligence could well enable a computer to make a more accurate diagnosis and prevent overprescribing of some tests than a human doctor.??Perhaps treatment algorithms and flows of patients through the medical system will change in ways we can only speculate now.

The world of clinical research is currently caught between the 2 extremes of former and emerging clinical practice in the real world.??Access to patients for clinical trials is already evolving from the hospital or doctor’s office to the patient’s home or place of work. Younger and more elderly patients in many countries are becoming increasingly sophisticated with their ability to interact with a device, receive information and directly input data.??Probably COVID accelerated that trend, but it is there.??Clinical technology has already entered the patient’s home.??Whether entered by the site or the patient, real time direct data entry, or capture, has got some other benefits that can be considered.??Operational data in a clinical trial is captured in clinical trial management systems (CTMS).??Unlike the dreaded excel spreadsheet approach of the past, it is now possible to use CTMS to track progress of a site in its journey to become activated, and to track rates of screening, of enrolment and of visits.

Traditionally (with notable exceptions) we have waited until the end of a trial to perform detailed assessment of clinical data, but real time continuous visualization of objectively captured symptoms (electronic outcome assessments) and quantitation of physical signs (by use of digital biomarkers) does have meaningful advantages to the success of a clinical trial.??Yes it is important to select the right kinds of outcome assessments for capture, so that the effect of the drug, if present can be detected in the individual patient as well as the population. Yes the digital biomarker has to have clinical relevance. But as I think about these measures, probably of equal importance are the ability to verify the correct patients are in the trial, real time identification of treatment responders (the patients who must stay on treatment for the trial to succeed), and early detection of patients who are deteriorating.??The latter may need urgent medical intervention or require a dose adjustment.??Continuous detection of safety trends is going to become a standard technique using this kind of a dashboard approach.??This is already seen in some hospital systems where the electronic health record has programmatic functions to alert the physician for out-of-range blood tests or reminders to order tests or even refer for surgery.??Certainly, in the clinical trial setting, direct contact with the patient is as important as the patient having direct contact with their physician at such a time, which is a necessary feature of these kinds of enabling technologies.

As the research and clinical environments start to merge in the real and virtual world, clinical trial sponsors, investigators, sites vendors and patients will interact with enabling technologies in novel ways that will make today’s standards as distant a memory as the 1980s seem today.???

Figure 1 Rotating Tourniquet in heart failure

Figure 2: Ballistocardiography to measure cardiac function.