Are clinical trials a last resort? Challenges in clinical trials for rare or terminal diseases

People believe that clinical trials are only for critical patients with serious health conditions, and while this is one of the most common misconceptions surrounding the world of research, many people suffering from a rare or terminal disease do have to resort to clinical trials as a last effort.

Rare disease research

Rare diseases are those that have a low prevalence, and therefore affect a small number of people. For a disease to be considered rare, it must affect less than 1 in every 1.000 to 200.000 people, but the exact cut off varies from one country to the next. Although they are not very prevalent, it is estimated that there are at least 7000 different rare diseases that affect around 300 million people worldwide.

Rare diseases are usually chronic and degenerative, this means that they get worse over time, and 65% of them are serious and disabling, affecting the quality of life of the patients and their families. Because they are uncommon, not that much is known about them, if they are ever diagnosed, it is usually only after consulting several specialists, and once other more common conditions have been ruled out.


Most rare diseases have a genetic origin, but they can also be caused by certain infections, immune disorders, degenerative, or proliferative disorders. Despite knowing how some of these diseases are caused, only 400 or so have an existing treatment. Due to the limited treatment options available for these rare diseases, participating in a clinical trial can often be the best option for many patients.

Taking all these factors into account, it is easy to see why it is so important to invest in research and help develop life-altering treatments for those suffering from these diseases. A great initiative is the Rare Disease Clinical Research Network (RDCRN), designed by the National Institute of Health (NIH) and established in 2002 in the US to advance medical research on rare diseases by promoting research in this area, facilitating the enrollment or participants in clinical trials, collaboration between research teams, and the sharing of data. This program currently provides support to research teams involved in the study of almost 200 rare diseases.

Rare disease clinical trials challenges:

So why isn’t more research being done to find a treatment or cure for these diseases? Developing any kind of new drug is complicated, very expensive, takes a lot of time and effort, and success is never guaranteed. Unfortunately, because of this, developing a drug that will only benefit a small group of people is not always economically viable.


This is where the concept of orphan drugs comes in. They are defined by the European Medicines Agency (EMA) as a medicine for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition that is rare, or where it is unlikely to generate sufficient profit to justify research and development costs.


Many entities provide incentives to promote research and development of orphan drugs, but even then, there are other factors that make carrying out clinical trials in rare diseases challenging for both the researchers and the participants. Here are some aspects that should be considered when designing this kind of clinical trial:

  •  Inclusion and exclusion criteria: Choosing what kind of patient is to be included in a clinical trial can be a double-edged sword. On the one hand, to be able to run a trial and prove that the results are not due to luck or chance, a minimum number of participants are needed. On the other hand, to make sure that the results are truly caused by the drug being tested, it is important to limit the number of factors that could interfere with the outcome. The latter can be done by creating very restrictive inclusion and exclusion criteria. However, the stricter the criteria, the harder it will be to find participants that meet the requirements, and in case of rare disease, where the number of possible patients is already low, this makes it even harder to find enough people to be able to carry out the trial.
  • Geographical problems: Because rare diseases are uncommon, it is possible that the few patients who suffer from it are scattered around the world. If this is the case, recruiting patients to a trial that is happening in a single clinic or hospital might not be the best option, and researchers would need to consider including other clinics or hospitals in the study in other parts of the world. Doing this would mean significantly complicating the logistics and organization of the study, as well as added cost.
  • Additional costs: Due to the previously mentioned geographical problem, it is common for patients to have to travel long distances to the clinical trial clinic or hospital for the study visits. This additional cost of travel and accommodation can be expensive. The design of the clinical trial is crucial to minimize travel and make participation as comfortable as possible for the patients.

Clinical trials for cancer: challenges and opportunities

Cancer is a disease that affects one in three people in the United States and is the leading cause of death worldwide. It can develop in any part of the body and is characterized by the uncontrolled growth of abnormal cells. These cancerous cells can form masses called malignant tumors, that can invade surrounding tissues and organs, and spread to other parts of the body.

Different stages of cancer are used to describe the extent and severity of the disease, and staging system varies depending on the type of cancer. The staging of a cancer is essential to determine the most appropriate treatment and to predict a patient’s prognosis or outcome.

There are many types of cancer treatments, and which one is used will depend on the type of cancer a person has, and how advanced it is. In some cases, only a single treatment will be available, and in other cases, there will be many options and combinations to choose from. The most well-known treatments are surgery, chemotherapy, and radiation therapy, but there are many more. However, the treatments that exist are not always effective, and some cancer patients might look for new or experimental options available only through clinical trials.

Considerations in drug development for cancer

Because of the multitude of types and subtypes of cancer, research and drug development for a specific cancer often faces similar difficulties as rare diseases. There are also other ethical, scientific, and practical aspects to be considered when conducting a study to develop a treatment for this type of disease.


For instance, in Phase 1 clinical trials, the main objective is to evaluate the safety and tolerability of a new experimental drug or therapy in humans, and they are normally carried out in healthy participants, but that is not always the case when developing cancer treatments.


Most of these treatments aim to attack the abnormal cancerous cells, but it is not always easy to target only these cells, meaning that many healthy cells might be damaged in the process. Therefore, Phase 1 cancer trials cannot be carried out in healthy participants, as being exposed to the treatment would endanger their health. In these cases, the participants of the Phase 1 trial would have to be cancer patients, for whom the potential benefits (effective treatment) outweigh the risk. It also means that these patients can receive potentially life-saving treatment earlier on. This is crucial for patients who have no effective therapeutic alternatives available. Another added benefit to carrying out these trials in cancer patients is that we can also see if the treatment affects the cancer, which may allow researchers to move quickly to later phases if promising results are observed.

Research to improve current cancer treatments

Clinical trials on cancer are not always focused on a last resort treatment for terminal patients. Research studies on cancer are also essential to improve current treatments and identify those that work best. For example, in some cases of pancreatic cancer, open surgery to remove part of the pancreas is an accepted and frequently used treatment option, but it has its downside. A clinical trial in 2021 showed that the same procedure done by minimally invasive surgery (laparoscopy) not only reduced the risk of blood loss, and resulted in shorter hospital stays and a faster recovery, it even had better oncological outcomes than open surgery, including overall survival and disease-free survival in early-stage pancreatic cancer.

Volunteer Clinical Trials

Clinical trials for degenerative diseases

Degenerative diseases are medical conditions that cause progressive deterioration of the body’s health and function and can eventually lead to death. These diseases often involve structural or functional changes in the body’s organs or tissues and usually worsen over time. Research in this type of disease is becoming more and more popular, which is allowing the scientific and medical community to learn more about how they work. However, drug discovery and development are a slow, challenging and expensive process that usually requires the investigating thousands of drug molecules before finding a few potential drugs that can be tested and used for clinical trials. Even after reaching the clinical trial phases, it is not guaranteed that these drugs will work or be approved by health authorities.

Alzheimer’s research

Alzheimer’s disease (AD) is a neurodegenerative disease that affects the brain and causes a progressive loss of memory and cognitive abilities. It affects over 6 million people in the United States and is the most common cause of dementia in older adults.


It is characterized by the presence of certain protein deposits in the brain that appear a decade or more before the onset of symptoms, which include personality and behavioral changes, language and reasoning difficulties, and even hallucinations, delusions and paranoia.


There is no cure for Alzheimer’s disease, and current treatment options focus on alleviating symptoms and improving the patient’s quality of life. Some medications and therapies can help slow the progression of the disease and manage its effects, but with what is available now, progression of the disease and the disability associated with it is inevitable, making clinical trials a last resort for patients.


The speed at which AD will progress is variable among patients, and it is very difficult to predict. Recently, a study was published in JAMA Neurology where measuring levels of a biomarker called P-tau217 in blood showed to be useful in identifying people with early stages of the disease, who do not yet show symptoms, but are at risk of developing cognitive impairment.


Although the interest in this disease has increased in the last years, further research needs to be done to identify possible therapeutic targets, and to develop effective treatments or preventative medications.

Parkinson’s research

Parkinson’s disease is a chronic neurological disorder that affects over 8.5 million people, and its prevalence has doubled over the last 25 years. This disease is characterized by the progressive degeneration of nerve cells of the central nervous system, affecting the coordination of movement and muscle control.


The main symptoms of Parkinson include tremors, muscle rigidity, slowness of movement and difficulty in maintaining balance. As the disease progresses, patients may also experience other symptoms such as speech problems, sleep disorders, depression, and cognitive difficulties.


Parkinson is a chronic and progressive disease, which means that symptoms worsen over time. Although there is no cure, treatments and medications can help reduce symptoms. It is important to note that Parkinson’s affects each person differently, so the treatment and approach is usually personalized to fit each patient’s specific needs.

Weighing the risks and benefits of clinical trials

When we look at rare diseases, degenerative diseases, and cancer, there is one thing in common: for many cases, there is no effective treatment available. Clinical trials can lead to potential breakthroughs and innovative treatments that can transform the perspective of those in urgent need. Without treatment these patients will have to suffer the disability, consequences caused by their condition, making participating in a clinical trial their last resource. This can be life-changing for some people and shows the importance of progress in medical science. Scientific research continues in search of more effective treatments and a deeper understanding of these devastating diseases, and clinical trials play a key role in this