Rare Diseases and Clinical Trials: Discovering Suitable Drugs for Adults and Children

by Assunta Ginanneschi

Recently we received an official blog request about a very delicate theme: Better medicine for children. Dr. Rose came to us through the pediatric & rare disease congress that took place in Basel in February 2016.

My colleagues Rieka and Nicole attended on behalf of CheckOrphan. After the conference, the three of them  exchanged ideas and thoughts about rare diseases as well as the actual status for clinical trials with children. A couple of meetings later, we started  collaborating with him. We are really very glad to arise awareness about this topic, thank Dr. Rose for approaching us about it.

Current Situation

Many rare diseases begin in childhood. Pharmaceutical companies develop drugs to save or improve the life and/or life quality, but they also need a return on their investments, that’s the way it works. With few exceptions, pharmaceutical development has focused on the more common adult diseases.

Today, there is an increased focus on rare disease for several reasons: frequent diseases are more or less defeated, generics are sufficient for most patients, and no more money can be earned by developing yet another beta-blocker. The only area where pharmaceutical companies still can make money with new medicines is the realm of rare diseases. Another reason is incentives from the USA and the EU for rare diseases research and drug development. A third reason is that science and communication are progressing, and parents of children with rare diseases try to find cures for the disease their child has. In a few cases parents of children with rare diseases could pushed and supported drug development. This has for example happened recently for new treatment in cystic fibrosis.

Modern medication is also heading more and more towards personalized medicine. Personalized health care helps patients mitigate risks, prevent disease and to treat it with precision when it occurs.

Scientific progress also helps us detect new conditions. Examples are metabolic diseases where enzymes can be replaced, mothers who are ultra-fast metabolizers and thus must be cautious what medication they take while breastfeeding their baby, or enzymatic deficiencies (like favism) that don’t allow the use of certain drugs for specific classes of patients.

Two major catastrophes —  the case of sulfanilamide elixir in 1936 and the thalidomide in 1961 —  opened the path to modern drug regulation, where the safety and efficacy of any drug must be proven by clinical trials. This led to modern labels, i.e. the medicine has to have proven efficacy for a given condition, and off-label use, i.e. the use of the drug outside its approved purposes, i.e. for other diseases or age groups. Off-label treatments can be life-saving, so off-label use in not bad per se. It can be dangerous, however, if too little is known about the drug. Off-label use can be recommended in disease areas or populations where there is evidence it could be beneficial, or in a desperate, life-or-death situation.

There are several types of off-label use of drugs. One is when pharmaceutical companies get a license for a first indication but promote the use of the drug in other indications. That is forbidden. If the respective company wants to promote its drug in a second or further disease, they must run the appropriate clinical trials and get additional licenses.

With children, there is another challenge. Traditionally, drugs were often given a license for adults only. When modern drug labels were introduced in 1962, nobody thought of children. When a medical doctor prescribed an antibiotic to a child, this prescription was technically “off-label”.

It’s clear, drugs for children is a quite delicate and complex topic. When does it make sense to develop and test drugs for children?

If the drug is to be used also in paediatrics or during pregnancy, it has to be tested also for children. There are differences between how the child body and the adult body work (e.g. lack of lung surfactant in preterm newborns or lack of growth hormone in children). Children are not small adults, their bodies have their own ways of handling drugs. The medically correct expression for these processes is ADME: Absorption, Distribution, Metabolism, Excretion.

1 ADME-v4_EN

This because some organs, like the liver, immune system and kidneys are not mature yet and cannot work as in adults. In adolescents almost all organs are mature, brain and reproductive organs are still in development.  

For example, the dose cannot be always deduced just from the patient’s weight or body surface. The risk is no clinical effect or intoxication i.e. too small a dose to be effective, or a dose so large it causes harm.  

This is specifically true and important for neonates and babies. On the other hand, adolescents have already an almost adult body, and most of their organs and organ systems can be treated with the same doses as adults. Modeling and simulation can help to reduce the number of patients required per age group in a clinical trial. The specific pediatric guideline ICH E 11 of the International Conference on Harmonization (ICH) ich-logogives guidance about when extrapolation from adult data is acceptable and when proper clinical tests are required for children, but it’s not always possible to do that. The degree of extrapolation from adult to adolescents and from there to younger age groups depends of many dimensions, of which the metabolic pathway is one of the more important ones.

Clinical trials are a key instrument to compare therapies and what works, what doesn’t work and what works better. Without them it is not possible to distinguish between safe, efficacious drugs and quack medicine, there is  no doubt about that.

Clinical trials are also necessary in children – how else would we know that a new drug can also be used in children?

As this video explains, clinical trials mean running experiments on humans, be they adult or children. Clinical trials are divided into different stages, called phases.


Timeline showing the process of drug development through the various stages of clinical trials.


Phase 0 trials

Phase 0 studies usually only involve a small number of people and they have a very small dose of a drug. Because the dose of the drug used in phase 0 trials is so small you won’t benefit from the drug. But you are also less likely to have side effects.

The main aim of these studies is to speed up the development of promising new drugs. Testing them in very small doses in humans rather than in animals can be more reliable and means scientists get useful information more quickly.

Phase 1 trials

They are usually small trials, recruiting only a few patients. Phase 1 trials are done to find out: how much of the drug is safe to give; what the side effects are; how the body copes with the drug; if the treatment shrinks the disease.

Patients are recruited very slowly onto phase 1 trials. If all goes well, the next group  (or cohort) have a slightly higher dose. The dose is gradually increased with each group. The researchers monitor the effect of the drug until they find the best dose to give. This is called a dose escalation study. Phase 1 trials aim to look at dosages and side effects. This work has to be done first, before we can test the potential new treatment to see if it works.

Phase 2 trials

Not all treatments tested in a phase 1 trial make it to a phase 2 trial. These trials may be for people who all have the same type of disease or for people who have different types of disease.

Phase 2 trials are often larger than phase 1. There may be up to 100 people taking part. Sometimes in a phase 2 trial, a new treatment is compared with another treatment already in use, or with a dummy drug (placebo). If the results of phase 2 trials show that a new treatment may be as good as existing treatment, or better, it then moves into phase 3.

Some phase 2 trials are randomized. This means the researchers put the people taking part into treatment groups at random.

Phase 3 trials

These trials compare new treatments with the best currently available treatment (the standard treatment), or different doses or ways of giving a standard treatment.

Phase 3 trials usually involve many more patients than phase 1 or 2. This is because differences in success rates may be small. So, the trial needs many patients to be able to show the difference.

Sometimes phase 3 trials involve thousands of patients in many different hospitals and even different countries. Most phase 3 trials are randomized. These are the definitive, large randomized trials that are submitted to the authorities in order to obtain approval of a drug.

Phase 4 trials

Phase 4 trials are done after a drug has been shown to work and has been granted a license. The main reasons for running phase 4 trials are to find out more about the side effects and safety of the drug, what the long term risks and benefits are, how well the drug works when it’s used more widely.

Regarding clinical trials, especially on children, there are many regulatory, medical, and ethical aspects to be considered.

Please follow Dr. Rose’s upcoming posts on this blog. He will be a guest blogger over the next few months, presenting a series about how medicines for children, particularly those for treating rare diseases, can be developed safely.


2 thoughts on “Rare Diseases and Clinical Trials: Discovering Suitable Drugs for Adults and Children

  1. My son Sarthak has diagnose Niemman pick c2 last january 2015 at KEM hospital mumbai. Please any help for my son disease clinical trial or therapy.


  2. Pingback: Working with Huntington’s Patients, Seizing the Damocles Sword | CheckOrphan

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