The development of any drug is a very complicated process … for RARE diseases the task is especially difficult due to the limited patient populations. Typically the disease is less well understood and there are fewer patients to access for testing to prove the drug works.

We’re hoping this simplified overview of the process will help you better understand the complexity.  Subsequent posts will review the legislative process and introduce several bills we are supporting to to make the process more efficient.

1.  Compound Discovery

This is the process by which scientists work to discover at the molecular level a compound  to affect diseased cells with a certain type of “drug”. Based on the biochemistry of the disease, the scientists can either rescreen/repurpose existing drugs or they can develop an entirely new compound. See Bio’s detailed description of the process here.

2.  Pre-clinical Research

The proposed compound  is refined in the laboratory, usually using cell cultures of some sort. The compound is optimized for safety and efficacy and then further tested, often with animals, to determine whether or not the “drug” is safe enough and has enough promise of efficacy to test on humans.

3.  IRB and FDA Approval for Studies in Humans

The researcher packages up all of their lab and animal study data, along with a proposed clinical trial design and applies to both their local IRB (Institutional Review Board) and the FDA for approval for a Clinical Trial. The FDA application is often in the form of a IND (Investigational New Drug) application. Either the IRB and/or the FDA may ask the researcher to provide more data and/or to make changes in the design of the clinical trial.  The clinical trial design includes specific criteria for who can participate in the trial, what is being tests, how it is being tested, and very specific “endpoints” that will be monitored determine whether the drug worked or not.

The guidelines for clinical trial design and review are established by Congress and enforced by the FDA. Rare diseases place a special burden on the trial designer and regulators due to often somewhat limited knowledge about the natural course of the disease, its biochemistry, the very limited patient populations, and the fact that many of these disease are very aggressive and affect children. The FDA often struggles applying regulations designed for chronic diseases to the quite different rare disease environment.

4.  Phase I, II, and III Clinical Trials

Clinical Trials are performed on humans, usually those affected by a particular disease. The purpose of a clinical trial is to prove or disprove a hypothesis. Active Clinical Trials are listed at ClinicalTrials.govand can be filtered by disease and study type.

These trials are very structured with specific inclusion and exclusion criteria as well as very specific endpoints and outcome tests that determine if the hypothesis is correct or not. This criterion is set in advance and is normally not able to be changed during the trial. The Principal Investigator (PI) is in charge of the trial. The PI often wants very close control of the trial, perhaps even by limiting the number of sites to reduce variability and to maintain close tabs on all adverse events, all of which, no matter how small, must be reported to the FDA for review.

Phase I is a safety study- usually performed on a small group of patients.

Phase II is a dosing study- to determine the dosing for the larger efficacy trials.  With rare diseases, Phase I & II are often combined into a Phase I/II Study.

Phase III tests efficacy – the FDA wants efficacy studied on a large population, but in rare diseases this many only be one or two dozen individuals. With rare diseases, Phases II & III are sometimes combined into a Phase II/III Study.

5.  NDA (New Drug Approval) Application

With rare diseases, the NDA Applicationusually comes after Phase III (with chronic condition research it’s after Phase IV).  The NDA is a very lengthy document covering all aspects of the basic research and clinical trials, including all adverse events.  The FDA has a specified period of time to review NDA’s and to respond to the application. The guidelines for NDA review and Final Approval  are established by Congress.

6.  Post-Approval Studies & Final Approval

Phase IV study for rare diseases often comes after market release to continue to study the drug across a broader population while still gathering review data in a structured fashion. Phase IV studies for rare disease may involve the entire eligible patient community making Final Approval somewhat moot as all patients are already receiving treatment.

Many of you may have heard of the Orphan Drug Act of 1983.  It gives industry some market protection and potentially some financial incentives to develop drugs for rare diseases.  It should be pointed out that the Orphan Drug Act does not change the FDA’s Clinical Trial Requirements or their Final Approval and Review criteria – today, all drugs, chronic & rare, must meet the same criteria.  And while some flexibility is taken based on very small rare disease patient populations – there is no relaxation of the any scientific aspects of the criteria simply because the diseases are rare.

And finally, while it seems like a straightforward process when we lay it out on paper, the reality is that drug development takes a long time, is full of laboratory and trial iterations, success, & failures, and usually takes many years to complete.  Preclinical discovery and lab work can take years, if not decades. Each phase of a Clinical Trial can take 2+ years start to finish by the time you add in IRB & FDA approval, recruiting, and data analysis.  The development, trial, and approval costs today are estimated in the many 10’s of millions, if not low hundred’s of million of dollars for a typical drug development program from start to market when you include the many failures and project cancellations along the way to one successful market launch.

Be sure to look for related posts in this series on the legislative/regulator process that guide the FDA and some current legislation in congress that will expedite and optimize the RARE disease drug development process.

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