RARE Toolkits

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Drug development is a complicated process. The science behind new medical treatments is necessarily full of trial and error, as researchers must explore many possibilities to identify the most promising, safe and effective treatments. The process can be lengthy, requires significant funding and is strictly governed by regulatory agencies to ensure that new drugs will be safe and effective and have the utmost benefit for patients.

What is the Basic Process?

The drug development process begins with drug discovery—scientists explore many chemical and biological compounds to identify those with the potential to treat a particular disease or impact a particular biological function. Scientists then go on to study the compound as a potential treatment in the lab and in animals. If these studies show the drug may be effective and safe, an application is filed with the regulatory agency for approval to begin clinical trials. In the U.S., this application is an Investigational New Drug (IND) application. The drug is next studied in people who volunteer for clinical trials. Clinical trials are done in three phases, or steps, each of which answers a specific research question. Once all three clinical trial stages have been completed successfully, meeting strict standards for safety and effectiveness, a potential new treatment can be submitted to the regulatory agency for approval. In the U.S., this is done through a New Drug Application (NDA). Approval of an NDA means that doctors can now provide the new treatment to patients. After approval, the FDA continues to monitor new drugs to make sure there are no side effects or issues that were not found during clinical trials. In the U.S., the FDA may require that post-marketing surveillance studies, also known as Phase 4 studies, be done after a drug is approved for marketing to get additional information on the drug’s risks and benefits or best use.




Small Rare Disease Trials

While drug development can be a lengthy endeavor for any disease and requires participation in each phase of clinical trials, for rare diseases, the number of participants in those trials in some circumstances can look very different from a trial for a common condition such as diabetes or heart disease.

It is essential to demonstrate safety and effectiveness throughout the clinical trial process. With rare diseases it can be possible to demonstrate safety and effectiveness using small enrollment clinical trials that has been accepted by FDA and has led to approvals. However, the need to work with regulators to accept smaller clinical trial enrollment for rare disease treatments continues to be an important issue for the rare community. Following are some examples of relatively small clinical trials for orphan therapies.

Human Fibrinogen Concentrate (HFC) treats congenital fibrinogen deficiency, was approved in 2009 for this rare disease, which had no treatment. The prevalence of the disease is around 300 people in the U.S. The approval of HFC was a result of a pivotal study of 15, a retrospective clinical study of 100, and two additional studies of 12 and 6 patients.

Elosulfase is an enzyme replacement therapy, which treats MPS IVA, a rare lysosomal storage disorder with a prevalence of 500 – 800 patients in the U.S. The therapy was approved with one pivotal trial of 176 patients followed by open-label extension where all patients received elosulfase. The entire program comprised six clinical trials which also included a Phase 1/2 with 20 participants and two ancillary Phase 2 trials with 35 participants.

Sources: Human Fibrinogen Concentrate Briefing Document (BLA 1253 i 7/0), 2009; Rare Disease Clinical Trials, Anne Pariser, MD, Office of Translational Science, CDER, FDA, November 4, 2014.


In drug discovery, scientists are looking for chemical or biological compounds that may have an impact on a particular disease or mechanism. For example, if a disease is known to cause certain proteins to be over-produced, scientists may try to discover a new compound that prevents that from happening. Drug discovery happens in academic research labs and within biotechnology and pharmaceutical companies.


Once a promising new compound is found, preclinical testing can begin. At this stage, many laboratory and animal tests are completed to see whether the compound is safe enough to be used in people. Before testing any possible new drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity.

Usually, preclinical studies are not very large. However, these studies must provide detailed information on dosing and toxicity levels. After preclinical testing, researchers review their findings and decide whether the drug should be tested in people.

If researchers want to take the next step and begin testing in people, they must submit an Investigational New Drug Application (IND) to the FDA. The FDA reviews the IND to make sure that the people who volunteer for the clinical trials will not face unreasonable risks. The IND includes detailed information on the safety of the new drug, the plan for clinical trials in people, and details on how the drug will be manufactured.

After the IND is approved, the drug can be studied in people in Clinical Trials.

Patients can help move drug discovery and pre-clinical development for rare diseases forward by taking part in patient registries, donating tissue to biobanks and sharing genetic data. Global Genes Toolkits are available on many of these topics.


Clinical Trials or Studies are usually run in three phases before marketing approval. Sometimes a fourth phase is required by regulatory agencies to monitor a new drug once it has been approved.  Trials require collaboration and coordination of many different teams including clinical investigators, the patients who volunteer to participate, and the statisticians, coordinators and managers who make sure that the trial is conducted according to regulations during the length of the study. The four phases of clinical trials are described briefly below. More detailed information is available in the From Molecules to Medicine: Clinical Research toolkit.

Phase I Trials 

Researchers test an experimental drug or treatment in a small group of people for the first time. The researchers evaluate the treatment’s safety, determine a safe dosage range, and identify side effects. Phase 1 trials determine the highest dosage of the drug that can be administered without causing serious harmful effects. Healthy volunteers (people who do not have the disease that the drug will treat) usually participate in phase 1 studies. However, for certain diseases, volunteers who have the disease may be recruited instead.

Phase 2 Trials

The experimental drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. Phase 2 studies determine if the drug will help patients who have the disease. If the drug is found to be effective in this small number of patients, then much larger phase 3 studies may begin. Phase 2 trials are often “placebo-controlled, randomized and double-blinded”.

Phase 2 Trials-Definitions

• Placebo-controlled– Some patients in the trial receive the drug; others receive a lookalike product that has no effect, called a placebo.

• Randomized– Patients are picked at random to get one of the study treatments.

• Double-blinded– Neither the patients nor researchers know who has received which treatment–drug or placebo,– until the study is over.

Phase 3 Trials

The experimental study drug or treatment is given to large groups of people. Researchers confirm its effectiveness, monitor side effects, compare it to commonly used treatments if they exist, and collect information that will allow the experimental drug or treatment to be used safely. Phase 3 studies usually take place at many study sites or clinics, take place over several years, and are usually randomized, double-blinded studies.

Patients can help move clinical trials for rare diseases forward by asking their doctors to help them find trials, sharing trial information with their communities and volunteering to take part. A Global Genes Toolkit is available on Clinical Research.

Phase 4 Trials

Post-marketing studies, which are conducted after a treatment is approved for use by the FDA, provide additional information including the treatment or drug’s risks, benefits, and best use.


After completion of the first 3 phases of a clinical trial, the drug company analyzes the data. If the data show that the drug is effective and safe, the company submits a New Drug Application, or NDA, to the FDA. An NDA may be more than 100,000 pages long and contains data gathered from all of the preclinical and phase 1-3 studies, plus analyses of that data. An NDA will include pharmacokinetics or what the body does to a drug—the movement of drug into, through, and out of the body, as well as information on how the drug is manufactured.

Review of an NDA by the FDA may take 10 to 12 months. During that time, scientists at the FDA go through all of the information in the application to see if there is solid evidence that the drug is safe and effective. The FDA compares the benefits of the drug to the risk for patients taking it. The FDA also decides what information should be included in the package insert to instruct doctors about how to use the drug and for which patients. Finally, the FDA ensures that the drug is being manufactured to a high quality. If the drug is approved, then manufacturing on a large scale begins and companies can market the drug to doctors and patients.

Phase 4: After Approval–Monitoring Safety 

After approval of a drug, its long-term safety may be studied in a phase 4 post-marketing study. Phase 4 monitoring of a new drug allows the reporting of any new, potentially harmful effects not seen during the other phases of clinical studies. This includes information about effects of the drug that are rare or unexpected, that last a long time, or that arise after the drug is taken for a long time. Any harmful effects found after a drug has been approved can be reported by patients and doctors through the FDA’s MedWatch voluntary system. When important new risks are found, the public is informed through letters and public health advisories. Usually the risks are added to the drug’s package insert.

Patients can help the FDA determine the benefit/risk of a potential new drug by taking part in meetings with the FDA to share how the condition affects their lives and what is most important to them about the care and treatments they seek.