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FREQUENTLY ASKED QUESTIONS THE FIRST PUBLISHED CLINICAL TRIAL WORD SEARCH WHAT IS CLINICAL RESEARCH?
Surveys show only modest interest in clinical trials among the general public (31-50%)
In contrast, patients with previous clinical trial experience strongly embrace another opportunity
Over 97% of experienced research patients would participate in another trial.
WHAT IS CLINICAL RESEARCH?
Clinical research aims to answer specific questions related to human health, such as the effectiveness of a new treatment, the causes of diseases, or the impact of lifestyle factors on health outcomes.
A randomized clinical trial is considered the gold standard for evaluating treatments or interventions
Clinical trials are divided into different stages called phases The earlier phase trials look at drug safety and potential side effects Later phase trials aim to test whether the new treatment is better than existing treatments.
PHASES OF CLINICAL TRIALS
Phase 1
Evaluate safety
Determine safe dosage
Identify side effects
Phase 3
Confirm effectiveness
Monitor side effects
Compare to other treatments
Collect information
Phase 2
Test effectiveness Further evaluate safety
Phase 4
Provide additional information after approval including cardiovascular outcomes
WHY TAKE PART IN CLINICAL RESEARCH?
By taking part in clinical research, you contribute to the advancement of medicine and improve healthcare for future generations. Every FDA-approved treatment owes its success to volunteers like you, who helped test its safety and effectiveness. By volunteering, you become a vital part of shaping the future of healthcare
advance science, and push medicine forward
Receive extra attention from doctors and medical professionals who are invested in your safety
Receive additional monitoring to ensure your safety, including blood draws and imaging
Undergo treatment overseen by impartial Investigational Review Boards and the FDA
Investigational products and treatments can give hope after standard treatments have failed
I ENJOY BEING A PART OF THE FUTURE OF MEDICINE. I THINK IT TAKES A LOT OF PEOPLE TO MAKE A DIFFERENCE AND I’D LIKE TO HELP IN ANY WAY THAT I CAN.
- JOHN, RESEARCH PATIENT
EXPECTING SIDE
EFFECTS WITH NOCEBO
Sticks and stones may break my bones, but words can never hurt me. But what if words could hurt you? Meet the nocebo effect, the evil twin of placebo. The nocebo effect is an increase in negative symptoms in response to patient expectations This occurs in both clinical trials and normal clinical care. In clinical trials, this frequently presents as adverse events occurring during a placebo administration (such as a sugar pill instead of a blood pressure med), but it’s important to note that nothing needs to be administered for an increase in symptoms Nocebo effects may sound like no big deal, but symptoms can be significant. In clinical trials, 4-26% of patients who discontinue medication do so because of nocebo reactions.
Unfortunately, this burden isn’t evenly spread. Women experience an outsized effect, as do those suffering from certain psychiatric illnesses, such as anxiety and depression Furthermore, both pessimistic and type A individuals experience higher rates of nocebo effect.
So how does it work, and are the effects real? Nocebo effects are due to our own expectations. When a doctor, nurse, or researcher states the potential side effects of a medication or procedure, patients are more likely to experience those effects This has been shown in several anecdotal settings, but also in multiple research studies. During the COVID clinical trials, patients were reporting serious side effects that tracked popular media
descriptions - even when they were given saline instead of the real vaccine!
These effects show the power of negative expectations, one of the three psychological mechanisms underpinning the nocebo effect
Negative results are a direct result of expectations. Researchers in one study tested the effect of word phrasing on pain outcomes. When pregnant women were preparing to get an anesthesia injection the researchers talked them through what might happen Half the patients were given the standard spiel, “You are going to feel a big sting and burn in your back now”. The other half were given the same information in much more neutral language: “We are going to inject the local anesthetic that
Placebo nocebo
will numb the area ” The neutral language group experienced significantly less pain during the injectionjust from phrasing! Scientists think the negative expectations might increase focus on symptoms. The expectations don’t have to come just from doctors or nurses, however. Seeing someone else suffer a side effect or hearing stories can produce the same effect!
Two other psychological underpinnings for the nocebo effect are less direct.
Misattribution is the blaming of normal aches and pains to a new medicine. Progressive disease effects can also be misattributed to placebo medication Finally, conditioning has a large effect Conditioning is the long-term association
we make between seemingly related things. Some patients feel nauseous at the smell of a hospital, for instance. This can also be very specific; the color of a pill can induce distinct side effects Patients taking blue sugar pills are more likely to experience and report drowsiness than those taking pink sugar pills.
Psychology shows us the framework for understanding what’s happening, but what’s going on under the hoodie?
Our brains experience changes at suggestions
Scientists think these changes may be due in large part to anticipatory anxiety
Anticipatory anxiety activates at least two pathways in the brain: pain and stress. Part of the pain pathway is called the CCKergic pronociceptive [prono-si-cep-tive] system. It is activated by a peptide called cholecystokinin [kow·luh·si·stuh·kai·n uhn] (CCK), and increases our perception of pain at the spinal level This undermines
anesthesia and increases our feelings of pain. The stress pathway moves through a few brain regions along the hypothalamus–pituitary–adrenal (HPA) axis and produces cortisol
Cortisol is a hormone that causes all of the classic signs of stress - increased heart rate and blood pressure, sweating, and breathing, among others. The activation of these two major pathways primes our brain and bodies to experience worse symptomsespecially those we are expecting. So what can be done? Well, reading this article is a great start! Around 75% of patients haven’t heard of or don’t believe in the nocebo effect, even though they experience it.
Thinking about risks in terms of percentages instead of raw numbers can help. Four in a thousand may increase anxiety by more than 0.4%. Other methods may be in the hands of medical professionals
Positive framing, such as with the injection
example above, can make a lot of difference. In addition, identifying risky patients may help with how information is presented. Fortunately, understanding the mechanistic nature behind the nocebo effect can help lessen your anxiety - and symptoms!
PHENOMENONS
Placebo Effect
Did you know that your mind can play a significant role in healing? The placebo effect occurs when a treatment with no active ingredients produces real, positive results simply because you believe it will work. This powerful phenomenon highlights the connection between mind and body, demonstrating that optimism, trust, and expectations can stimulate genuine physical improvements.
Nocebo Effect
The changes to the body that come from our expectations don’t stop at healing. With the nocebo effect, negative expectations influence our body's response and can cause real harm. This emphasizes the power of mindset in shaping treatment outcomes.
Hawthorne Effect
In the 1920s, Western Electric's Hawthorne Plant study showed that when people know they are being watched, productivity increases. This revealed that employee motivation is influenced by psychological factors, as well as physical ones
FREQUENTLY ASKED QUESTIONS
How much do they charge?
Sponsors such as pharmaceutical companies, governments, and foundations fund medical research through study grants. These grants provide the funding to conduct studies at local research sites, so it is usually no cost to you.
How long do the programs last?
Depending on the type of research, studies can last from a few weeks to several years Each program is designed to collect specific data. Volunteers will know how long the study is expected to last and how many visits to the research site will be required before enrollment
How do I know if I am qualified?
Each research program is unique and has specific enrollment criteria, so the best way to determine if you qualify for a clinical research study is to call your local research office to learn more. Whether you have a medical issue and want to explore research solutions or are a healthy volunteer, visit a research location and learn more. Participation is strictly voluntary and research experts are happy to serve you.
Will I experience major side effects?
There is always a risk of side effects when taking any medication or participating in clinical trials. However, investigational drug safety must be supported by research and testing, verified by an independent review board, and must inform all patients of potential side effects
What's the benefit to me?
There are numerous benefits! Volunteers appreciate access to cutting-edge treatments, potentially expensive study medications and treatments at no cost, and compensation for their time and travel Clinical research patients also love the sense of community and civic service they feel, knowing that their participation contributed to the advancement of medicine
Yes, you are always able to withdraw from a clinical trial. Always be open and honest with your clinical team about leaving a trial. Can I withdraw from a trial?
Can I be in more than one study at a time?
No, each clinical trial studies the effects of a single medication. Enrolling in multiple trials would skew any data from the trials. And drug interaction could be unsafe!
“PEOPLE OF COLOR CAN FEEL SKEPTICAL TO PARTICIPATE, BUT I THINK IT’S NECESSARY.”
ANGELINA, RESEARCH PATIENT
EXPERIENCE THE HAWTHORNE EFFECT
The Hawthorne Effect is a term used to describe a very beneficial effect seen in clinical trials. It occurs when participants change their behavior because they know they are being studied or observed in a clinical study. The origins come from a productivity study in Hawthorne Works, a Western Electric factory in the 1920s and 30s. The study attempted to discover a link between the amount of light and workers' productivity. When increasing the amount of light, productivity increased Strangely, when lowering the amount of light, productivity also increased! Researchers attributed the increase in productivity simply to the workers being
observed. In research, we tend to see increased participant engagement in their health simply because they are being observed in a study
Let’s analyze a 2014 sleep study. Researchers measured 195 patients’ amount and quality of sleep at night. Eighty-one days later, before any medical intervention, researchers measured the patients again They found that patients slept an average of 30 minutes longer per night and had an increased sleep quality This was before any medication or intervention! The change was attributed to the Hawthorne Effect
patients comment on the excellent quality of care they receive during clinical trials Instead of seeing a doctor for a few minutes once a year, patients see doctors and medical staff for much longer and are encouraged or required to call and report changes in health. Quality of care is increased and makes for a pleasant and healthful patient experience. Patients in clinical trials may also experience more observation time from medical professionals due to the attention to detail that clinical trials require for data integrity in studies.
better patient outcomes, even when they are part of a placebo or standardof-care group
Clinical research
Finally, patients are found to adhere better to medication requirements while undergoing clinical trials The increased emphasis on accuracy and adherence results in
In clinical trials, we see these benefits and must account for them Randomization of patients helps spread the effect. Everyone sees increased baseline results on average; we are interested in determining if those receiving investigational treatment do even better. Join a clinical trial today and experience the Hawthorne Effect for yourself.
Today’s clinical trials are precise, controlled, and highly regulated. Government and sponsor oversight ensure patient safety After the studies are completed, the results are published 2500 years ago, the process was not well established, but at least one trial still made it to publication. In Daniel 1:5-16, the Ketuvim and Old Testament describe Daniel performing the earliest clinical trial
Inclusion criteria dictated that the children had “no blemish” and that they had an aptitude for “all wisdom, cunning in knowledge, and understanding science ” Children also had to be able to stand and learn the language. All children were part of a vulnerable population - captives. These days research involving vulnerable populations is wellregulated and must be justified to a high
era. Babylonian rules were decidedly more lax.
The trial had a simple setup with two groups It was a dietbased trial The “control” group consisted of an unknown number of children who ate meat and wine. The “experimental” group contained only four children who did not want to desecrate their bodies with the meat and wine of the King. They ate pulses (beans) and water instead. The protocol specified that the trial should occur for ten days At the end of the experimental period, the experimental group was “fatter in flesh” and “ten times better than all the magicians and astrologers that were in all [Nebuchadnezzar’s] realm.” It is unclear what data points
were used to determine this, but the results were hard to argue with.
Daniel’s clinical trial had some serious pitfalls The sample size was very low Patients and investigators were unblinded - aware of what trial group they were in. No literature review was performed, and no hypothesis was stated. Additionally, though the results were published, they lack a methods section or other information to allow for replication of the study We should acknowledge the trailblazing effort of this trial We should also appreciate the gains in oversight, accountability, documentation, and safety that have taken place in the millennia since.
History that Changed Clinical Trials
GOOD BAD
UGLY
Clinical Trial in the Bible
Daniel conducted one of the earliest recorded clinical trials In a 10-day comparison study, he pitted his vegetarian diet against the rich royal food and wine. The results: those on the vegetarian diet appeared healthier and stronger. This ancient experiment demonstrates fundamental principles of clinical trials, highlighting the connection between diet and well-being.
The Bad
Thalidomide Babies
The 1960s Thalidomide tragedy highlighted the need for rigorous clinical trials and informed consent Thousands of babies were born with deformities after mothers took the drug The disaster led to:
Mandatory disclosure of experimental status
Informed consent
Enhanced safety monitoring
These reforms prioritize patient protection and safeguard human subjects.
The Good The
1946 Nuremberg Trials
Nazi physicians' brutal experiments on prisoners of war led to the Nuremberg Trials and the establishment of the Nuremberg Code of Ethics This landmark document protects human subjects with principles including:
Voluntary informed consent
Animal studies before human trials
Right to withdraw
Minimization of harm
The Nuremberg Code remains a cornerstone of medical ethics, safeguarding human dignity.
BE YE WONDERING ABOUT HOW CLINICAL TRIALS FIRST HIT THE SALTY SEA?
Ahoy ye mateys! Have you ever wondered which enemy was the most dangerous to sailors during the 1700’s? James Lind, a Royal Navy surgeon, described a foe which “proved a more destructive enemy, and cut off more valuable lives, than the united efforts of the French and Spanish arms.” In order to conquer this threat, Lind employed a brand new weapon. This weapon was previously unknown to science, and has now been used to defeat countless foes. The enemy was scurvy, and the weapon was a clinical trial.
May 20th marks the anniversary of that first well-documented clinical trial. Scurvy could lead to muscle pain, gum disease, fatigue, jaundice, and death. Remedies at the time varied widely and only anecdotal, word-ofmouth evidence for them was available Every sailor who was afflicted with scurvy sought a cure, but the overall disease was caught in the doldrums without a solution for 150 years Lind had bigger ambitions His big insight wasn’t trying to treat just a few individuals for scurvy, but instead trying to solve the problem of scurvy on the scale of public health. Though he only had 12 participants in that first trial, how Lind compared different remedies showed his big-picture thinking. He sought not to give relief
to just those 12 patients, but to quantify and share his results to cure the whole of the Royal Navy
In this effort, Lind laid the groundwork of the modern clinical research study He started with a set of 12 patients with conditions “as similar as I could have them.” He controlled extraneous variables, giving all patients the same diet during the study and keeping them on the same boat.
He split them into 6 random groups:
A quart of cider per day
Elixir vitriol (sulfuric acid and alcohol), 3x daily
2 spoonfuls of vinegar, 3x daily
½ pint of seawater per day
2 oranges and 1 lemon per day
Bigness of nutmeg (a medicinal paste made of herbs and spices)
The results were clear; citrus gave quick and significant relief Importantly, Lind didn’t leave his findings high and dry He recorded and reported what what he saw Probably the most important aspect of Linds clinical trial was that he looked at the results in an unbiased way. He
wrote extensively on the need to remove personal and societal bias: “it is no easy matter to root out old prejudices, or to overturn opinions which have acquired an establishment of time, custom, and great authorities; it became therefore requisite for this purpose, to exhibit a full and impartial view of what has hitherto been published on scurvy.”
Today the same core ideas guide clinical trials, but there are many more safeguards for participants A good clinical trial today is grounded in science, provides benefits to patients that should outweigh any risks, and treats patients with respect. Critically, clinical trials have informed consent; all participants join voluntarily and must have full knowledge of any risks before signing up. Trials also have oversight from Institutional Review Boards and have medical staff on-site to help with any adverse reactions. Following Lind’s example, clinical trials also target specific conditions, have randomized patients, control conditions (as much as possible), and dutifully record and report their findings.
James
Lind, Royal Navy Surgeon
Though he aimed to blow scurvy out of the water, Lind ended up making waves in how scientists solve medical problems in general. His quantitative, balanced approach gave the world a system to tackle medical problems. You can help keep up the bounty of Lind’s legacy by volunteering as a clinical research trial participant and sending some diseases to Davy Jones’ Locker!
WHY ARE YOU INTERESTED IN CLINICAL RESEARCH?
“ I WAS ACCIDENTALLY DIAGNOSED WITH CELIAC DISEASE I HAD A RANDOM GI BLEED, AND THEY DID THE TEST, AND THAT'S HOW THEY FOUND IT YOU CAN’T REALLY GO OUT TO EAT, IT'S HARD TO DRINK OUT, IT'S HARD TO GROCERY SHOP I WAS INTERESTED IN ANY HELP OR RESEARCH ON THIS DISEASE BECAUSE I HAVE REALLY BAD REACTIONS TO GLUTEN ANY MEDICATION THAT COULD POSSIBLY ELIMINATE THAT WAS VERY IMPORTANT TO ME ”
- MAKAYLA, RESEARCH PATIENT
SOURCES
Why take part in clinical research?
Friedman, A , Robbins, E , & Wendler, D (2012) Which benefits of research participation count as ‘direct’?. Bioethics, 26(2), 60-67. https://doi.org/10.1111%2Fj.1467-8519.2010.01825.x Lantos, J D (1999) The “inclusion benefit” in clinical trials The Journal of pediatrics, 134(2), 130-131. https://doi.org/10.1016/S0022-3476(99)70400-2
Expecting Side Effects with Nocebo
Kong, J , Gollub, R L , Polich, G , Kirsch, I , LaViolette, P , Vangel, M , & Kaptchuk, T J (2008) A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. Journal of Neuroscience, 28(49), 13354-13362. https://www ncbi nlm nih gov/pmc/articles/PMC2649754/ Planès, S., Villier, C., & Mallaret, M. (2016). The nocebo effect of drugs. Pharmacology research & perspectives, 4(2), e00208. https://www ncbi nlm nih gov/pmc/articles/PMC4804316/ Varelmann, D , Pancaro, C , Cappiello, E C , & Camann, W R (2010) Noceboinduced hyperalgesia during local anesthetic injection. Anesthesia & Analgesia, 110(3), 868-870 https://doi org/10 1213/ANE 0b013e3181cc5727
Hawthorne Effect
Benedetti, F., Carlino, E., & Piedimonte, A. (2016). Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects
Lancet Neurol, 15, 736-47 http://dx doi org/10 1016/S1474-4422(16)00066-1
Cizza, G., Piaggi, P., Rother, K. I., Csako, G., & Sleep Extension Study Group. (2014) Hawthorne effect with transient behavioral and biochemical changes in a randomized controlled sleep extension trial of chronically short-sleeping obese adults: implications for the design and interpretation of clinical studies. PLoS One, 9(8), e104176. https://doi org/10 1371/journal pone 0104176
ENCORE Research Group. (2020, October 14). Hawthorne effect.[Video]. Youtube. https://www.youtube.com/watch?v=1DH7jwqFlyw Mayo, E (1993) The human problems of an industrial civilization The Macmillan Company.
McCarney, R., Warner, J., Iliffe, S., Van Haselen, R., Griffin, M., & Fisher, P. (2007) The Hawthorne Effect: a randomised, controlled trial BMC medical research methodology, 7(1), 1-8 https://doi org/10 1186/1471-2288-7-30
The First Published Clinical Trial
King James Bible. (1979). Holman Bible Publishers. (Original work published 1611)
Neuhauser, D , & Diaz, M (2004) Daniel: using the Bible to teach quality improvement methods Quality & safety in health care, 13(2), 153 https://doi.org/10.1136/qshc.2003.009480
Be ye wondering about how clinical trials first hit the salty sea?
Lind, J. (1753). A treatise of the scurvy: in three parts, containing an inquiry into the nature, causes, and cure, of that disease, together with a critical and chronological view of what has been published on the subject Bulletin of the World Health Organization: the International Journal of Public Health 2004; 82 (10): 793-796.From https://www.jameslindlibrary.org/lind-j-1753/
