FDA Releases Primer on Rare Disease Drug Development, Discusses Utility of Natural History Studies

August 26, 2015

By Alexander J. Varond & James E. Valentine* –

FDA recently released a draft guidance, titled “Rare Diseases: Common Issues in Drug Development.”  The fourteen-page document amounts to more of a primer than a focused discussion of technical issues.  It serves as a useful reminder of the broader themes that confront orphan drug sponsors, and it is particularly helpful for those that are new to the rare disease space.  In a number of ways, the Draft Guidance is similar to another draft guidance published in May 2015, entitled “Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators,” which, as the title suggests, provides a high-level overview on how to prepare and submit an IND.

By publishing the Draft Guidance, FDA may be seeking to increase the consistency and flexibility exercised in the review of orphan drugs in CBER and CDER as well as across the Centers’ various review divisions.  To be certain, the Draft Guidance highlights a number of ways FDA can exercise flexibility in its review of orphan drugs.  For example, the Draft Guidance discusses FDA’s views on the acceptance of historical controls, and reliance on a single trial with confirmatory evidence.  FDA also notes that “[t]here is no specific minimum number of patients that should be studied to establish effectiveness and safety of a treatment for any rare disease.”


The Draft Guidance addresses the following aspects of developing a drug for a rare disease:

  • Adequate description and understanding of the disease’s natural history;
  • Adequate understanding of the pathophysiology of the disease and the drug’s proposed mechanism of action;
  • Nonclinical pharmacotoxicology considerations to support the proposed clinical investigation or investigations;
  • Reliable endpoints and outcome assessment;
  • Standard of evidence to establish safety and effectiveness; and
  • Drug manufacturing considerations during drug development.

Natural History Studies

Perhaps the most interesting aspect of the Draft Guidance document comes in its discussion of natural history studies.  FDA’s Draft Guidance urges sponsors of drugs for rare diseases to develop an understanding of the natural history of the disease early in the development program so as to better inform the design and analysis of clinical trials. 

Natural history has been defined as “the natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without external intervention.” Stephen C. Groft and Manuel Posada de la Paz, “Rare diseases-avoiding misperceptions and establishing realities: the need for reliable epidemiological data,” Rare Diseases Epidemiology (2010).  In May 2012, FDA hosted a helpful workshop on natural history entitled, “Workshop on Natural History Studies of Rare Diseases:  Meeting the Needs of Drug Development and Research.”

The Draft Guidance accepts that the natural history of rare diseases is often poorly understood.  Although natural history studies are not required, FDA counsels that, for an orphan drug, “a well-designed natural history study may help in designing an efficient drug development program.”  Such studies, FDA notes, can help by:

  • Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes;
  • Understanding and implementing critical elements in clinical study design, such as study duration and choice of subpopulations;
  • Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures; and
  • Developing new or optimized biomarkers that may provide proof-of-concept information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy.

The Draft Guidance also notes that, because rare diseases are “highly diverse . . . with wide variations in the rates and patterns of manifestations and progression,” natural history studies should be broad and based on features of the disease, including those morbidities most important to patients.  The Draft Guidance then sets forth a number of helpful considerations in developing a natural history study, including:

  • Selecting data elements that are broad and based on features of the disease, including morbidities that are most important to patients, among others.
  • Because of the substantial phenotypic variability in many rare disorders, natural history studies should include patients across as wide a spectrum of disease severity and phenotypes as possible, rather than focusing too early on a particular subset;
  • Natural history data should be collected for a sufficient duration to capture clinically meaningful outcomes and determine variability in the course of the disease; and
  • The data for natural history studies can be collected prospectively or retrospectively, but prospective longitudinal natural history studies are likely to generate the most useful information about a disease.

It is important to note, however, that prospective longitudinal natural history studies can span years and even decades and waiting for the results of a such trials, prior to designing pivotal studies, may substantially delay drug development programs.  As such, patients with serious and life-threatening conditions may be denied access to promising therapies.  In addition, companies may find that conducting such prospective longitudinal natural history studies is not commercially viable.  This is particularly true for small companies, which make up a large percentage of the orphan drug space.

While the Draft Guidance emphasizes the utility of natural history studies as “critical background information” to inform sponsors’ decision-making regarding clinical trial design and provides guidance on developing natural history registries to support that activity, when it comes to the use of natural history data as a historical comparator, the Draft Guidance minimizes the credibility of using historical controls.  While the challenges associated with the use of historical controls are well recognized, FDA fails to recognize that natural history studies have been used in this way to support important approvals in the rare disease space; for example:

  • Myozyme (alglucosidase alfa), the first treatment for patients with Pompe disease, was approved on the basis of two studies with historical controls where a natural history database was used to create a subgroup-matched historical control based on certain prognostic factors;
  • Cresemba (isavuconazonium sulfate) was approved in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis, rare but serious infections, with one of the two studies’ effectiveness comparisons using a combination of both matched and unmatched historical controls; and,
  • Cholbam (cholic acid) was approved in 2015 for both bile acid synthesis disorders due to single enzyme defects and as an adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders, which in the absence of sufficient natural history information was based largely on uncontrolled studies.

The use of natural history data as a historical control remains an area where a greater understanding of FDA’s flexibility in previous approval decisions would benefit the rare disease community.

Comments on the Draft Guidance are due by October 16, 2015 here.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.