The history of clinical research has evolved over centuries, between continents, and among disciplines into the modern era of clinical trials. The first recorded trial can be found in biblical writings between 605 and 562 BC. Records document an official order by King Nebuchadnezzar, a military leader in Babylon, that instructs people to eat a diet of meat and wine only, which he believed would keep them physically fit and healthy (Collier, 2009).
However, a group of young men rebelled against the order and the king allowed them to consume vegetables and water instead. After 10 days, those with the vegetarian diet appeared better nourished than those who consumed the meat and wine diet (Collier, 2009). Despite its simplicity, this record of the first trial shows how experimentation has guided decisions, which in turn has had a broader impact on the overall public health (Bhatt, 2010; Collier, 2009). Dr. James Lind is often credited with conducting the first clinical trial in modern times (Bhatt, 2010; Collier, 2009).
Although the study was not perfect, he implemented the first control group within his study and found that adding citrus fruit to the diets of sailors could prevent scurvy (Bartholomew, 2002). By 1863, another element of modern clinical trial protocols, the placebo, was added to research studies (de Craen et al., 1999). In the1900s, more advanced concepts such as randomization and treatment blinding were introduced and utilized in research studies (Bhatt, 2010).
As the nature of clinical trials evolved, the protection of human study subjects also increased. Before the 20th century, ethical principles for the care of patients were rooted in the ancient Hippocratic Oath but not strictly adhered to and efforts to protect human subjects from harm or mistreatment were often reactionary rather than anticipatory. This issue was addressed with the creation of the Nuremberg Code and The Declaration of Helsinki, which outlined global rules of conduct for human experimentation.
The United States also implemented its own laws and regulatory organizations to govern clinical trial research; however, many years, legislative acts, and unfortunate deaths passed before the U.S. Food and Drug Administration (FDA) in its current form was established to strictly regulate all stages of drug development, manufacturing, and marketing (Borchers et al., 2007). Today, clinical trials are the backbone of contemporary medicine. Randomized, double-blinded, placebo-controlled clinical studies are critical for the advancement of medicine and the field of dermatology.
Overview of clinical trials
Between 2005 and 2012, the FDA approved 188 new therapies for 206 indications on the basis of the results from 448 trials (Downing et al., 2014). Clinical research has led to the development of effective and life-changing treatment for cardiovascular and autoimmune diseases, skin conditions, diabetes, cancer, and an array of diseases that affect patients worldwide. Results from clinical trials have significantly improved the outcomes and quality of life of patients with dermatologic conditionsSince 2011, eight new therapies have been approved by the FDA for the treatment of patients with metastatic melanoma, including four immunotherapy agents and four targeted therapies.
Since the early 2000s, targeted immunotherapy for patients with psoriasis has become a strong focus in clinical research and resulted in the development of new therapeutics on a yearly basis and half a dozen agents that are currently under development. Skin conditions are among the most common health problems in the United States and one in three people are affected at any given time, which is more common than obesity, cancer, and hypertension (Bickers et al., 2006). Dermatologic diseases increase both direct and indirect medical costs and present a challenge to the quality of life of affected patients.
In addition to the clinical presentation, skin conditions can also manifest as severe pruritus and cause impaired movement and debilitating emotional effects (Bickers et al., 2006). Psoriasis, for example, is an autoimmune skin disorder that severely impacts health-related quality of life (Rapp et al., 1999) and patients report reduced physical and mental functioning that is comparable with that of patients with cancer, arthritis, hypertension, heart disease, diabetes, and depression. Measures of treatment efficacy within clinical trials should not only focus on clinical improvement but also incorporate patients’ perceptions of quality of life improvement to more holistically treat the psychosocial aspects of dermatological diseases (Charman et al., 2003).
The clinical trials unit
To maximize safety and efficacy, clinical trials are conducted in four separate phases. Phase I trials are initial tests on a small group of human subjects to determine treatment safety, dose range, and potential side effects (Collier, 2009). Phase II trials are conducted on a larger group of people to determine treatment efficacy (Sedgwick, 2014).
Phase III trials involve the randomized and controlled multicenter study of even larger populations to determine and confirm the effectiveness of the treatment or drug in question (Sedgwick, 2014). Lastly, Phase IV studies typically occur after marketing of the product and assess the long-term adverse events and effects in varying populations (Collier, 2009). Clinical trials can be conducted at academic medical centers and in private practice settings. Typically, the study sponsor is a pharmaceutical company that studies a drug, treatment, or device with the goal of marketing the product to the public.
The pharmaceutical industry has financially sponsored and supported approximately twothird of all clinical trials in the United States between 2008 and 2013. This estimate is even higher for studies that were conducted in the field of dermatology (Campa et al., 2016). Every study team includes a clinician who serves as the principal investigator (PI) who is responsible for the study conduct and oversight of the research activities. First, the PI is approached by a pharmaceutical company to determine the PI’s interest in conducting the research and generate an initial contract.
Next, the PI signs a confidentiality agreement to assure nondisclosure of any proprietary information that is related to the research. The sponsor of the study will then assess, through a questionnaire and communication with the PI, whether the trial can be conducted at the PI’s site. The questionnaire surveys the investigator’s experience, information on the site and patient population, and provides the PI with the full study protocol to determine whether the physician can feasibly conduct the study with use of the facility, available resources, and support staff.
Challenges of the clinical trials design
Randomized, controlled clinical trials are the optimal method to establish the efficacy of a drug compared with a placebo or another drug (Pincus et al., 2015). However, because of their design, these trials inherently carry some limitations. One important limitation is related to the relatively short time frame, which can limit the ability to address research questions related to the long-term efficacy, safety, and tolerability of a drug (Pincus et al., 2015). Another limitation is the potential distortion of the placebo effect.
There is a potential to exaggerate or attenuate the placebo effect when a patient is told that they are receiving treatment in a scientific experiment versus the best therapy from his or her doctor (Pincus et al., 2015). Additionally, study enrollment criteria typically exclude patients with certain chronic conditions that are common among the target population for the drug under investigation. Therefore, study results may not be representative of all potential patients who will eventually be administered the drug (Fahey, 1998; Pincus et al., 2015).
Recently, there have been efforts to increase the globalization of randomized clinical trials at multicenter sites. This too can present challenges for the validity of results if different regions have varying recruitment and regulatory procedures (Pocock and Gersh, 2014). As previously discussed, patient recruitment plays a vital role in a clinical trial; however, this process does not come without challenges.
Barriers that are associated with patient recruitment and enrollment include demands of the trial (i.e., time, blood draws, echocardiograms, etc.), uncertainty about the treatment and possible side effects, and concerns about information in the consent paperwork (Ross et al., 1999). Experienced study personnel can help address the concerns of patients who are interested in enrolling in a trial to allow patients to make an informed decision on the basis of correct information.
Author: K. Torre, M. Shahriari