Abstract
Developing a new drug for a disease that affects relatively few people poses unique challenges that do not apply to medical products for more prevalent diseases. One relatively new strategy to help address the special needs of the orphan drug development process is through better understanding the natural progression of rare diseases. This information is then used to facilitate the product development and approval process. National Organization for Rare Disorders (NORD) is actively engaged with the National Institutes of Health and FDA in collaborating on programs to advance the development of increased and improved natural history data. One of the unique contributions that NORD is making is that it is bringing the patient voice to the process of data generation.
1. The importance of natural histories for rare diseases
Developing a new drug for a disease that affects relatively few people poses unique challenges that do not apply to medical products for more prevalent diseases. One relatively new way of addressing the special needs of the orphan drug development process is by better understanding the natural progression of rare diseases and using this information to facilitate the product development and approval process.
The National Organization for Rare Disorders (NORD) is playing a central role in advancing our understanding of disease progression through more and better natural history studies. This is an important priority for NORD because we believe that understanding natural histories will facilitate the development and approval of orphan drugs to treat rare diseases and its member organizations can directly benefit from our investment in such activities. In this effort, NORD is closely collaborating with the US FDA and the National Institutes of Health (NIH).
FDA requires that all drugs be shown to be safe and effective before approval, and even though FDA applies a degree of flexibility to its reviews of orphan drugs, the agency still requires that its standard of ‘substantial evidence of efficacy’ be met. For drugs intended to treat diseases that affect large numbers of patients, the pathway to meeting FDA’s requirements for approval is clear. Companies initially evaluate the toxicity and tolerability of a new drug in healthy volunteers in Phase I studies. Then, they test the new drug for safety and early evidence of effectiveness in a limited number of patients in Phase II. The next phase, Phase III, involves expanded testing in patients with the disease or condition for which the drug is intended. By the end of Phase III trials, there should be sufficient knowledge about the new drug for the FDA to decide whether the benefits outweigh the risks for a specific patient population. Usually there are two pivotal trials plus additional data that support the marketing application, and hundreds and sometimes thousands of patients have been exposed to the new drug.
While orphan drugs are developed in the same sequence, the number of patients available for clinical trials obviously is smaller. An orphan drug is defined under US law as a drug intended to treat a disease affecting 200,000 or fewer patients. (The definition in the EU is different; a disease is defined as rare in Europe when it affects less than 1 in 2000 patients, which may be as many as 245,000 patients) Citation[1].
A major challenge in developing new drugs for orphan or rare diseases is that there may not be enough patients to undertake the phased approach used for more prevalent diseases. There are some rare diseases that affect a few dozen or just a few hundred patients worldwide. It seldom is feasible for investigators to design and conduct the kinds of studies needed for new therapies for diseases that affect larger patient populations.
An offshoot of the challenge of having small patient populations for rare diseases is that trials inherently require careful statistical analysis, so that the drug’s effects can be measured and compared with the effects of either a placebo or treatment with the standard of care. The traditional basis for drug approvals is a statistical analysis that evaluates whether a drug’s effect is real or by chance. With small numbers of patients in a study, such an analysis cannot always be achieved. However, statistical significance can be achieved if a drug shows a high degree of effectiveness over the standard of care and for most rare diseases there are no proven therapies.
FDA has demonstrated flexibility in evaluating applications for orphan drugs. A study initially commissioned by NORD established that between 1983 and 2011, FDA consistently demonstrated flexibility in evaluating non-oncology orphan drugs Citation[2].
These challenges in the clinical development of orphan drugs have intensified the need to generate greater knowledge about these diseases per se, to aid in understanding the effects that new drugs have. The more we know about how a rare disease progresses, the easier it is to evaluate the effects of certain treatments in development and to measure whether a particular treatment changes the course of disease progression or affects the longevity or quality of life of the patients.
Much of the information needed to gain a better understanding of how a disease progresses can be derived from ‘natural history’ studies. In the past few years, under the leadership of Dr. Francis Collins at NIH and Dr. Margaret Hamburg at FDA, there has been a significant government focus in the United States on the need for the medical and scientific communities to gain a better understanding of the natural histories of rare diseases.
NORD has played a central role, working closely with NIH and FDA, in identifying the need for more natural history data and for creating programs to generate these data. NORD, established in 1983 when the US Congress passed the Orphan Drug Act, is the leading advocate in the US for patients with rare diseases (www.rarediseases.org). One of our basic missions is to support and encourage programs that advance and facilitate research into new therapies for rare diseases; in recent years, a third of the new drugs approved by FDA have been for rare diseases, but even so, only about 280 of the 7000 identified rare diseases have approved drugs. There is a long way to go, and developing more data about the natural progression of diseases in order to facilitate medical research obviously is one of our priorities.
On May 16 – 17, 2012, the FDA and NIH co-sponsored a ‘Workshop on Natural History Studies of Rare Diseases.’ It was subtitled ‘Meeting the Needs of Drug Development and Research.’
This workshop brought together the key thought leaders in the field. The summary of the workshop is available and includes specific examples, such as cystic fibrosis and urea cycle disorders, of how natural histories have played a key role in the development of a number of orphan drugs Citation[3].
At the meeting, Dr. Christopher Austin, head of the NIH’s National Center for Advancing Translational Sciences, said that “the top reason why rare disease development programs fail at FDA is the lack of natural history information.”
According to the summary of the meeting, Dr. Austin also said that “natural history studies can shed light on the full spectrum of genotypic and phenotypic features associated with a rare disease, how the disease develops over time, and potential biomarkers. These studies can also collect biospecimens. Another reason why rare disease therapeutic development efforts fail is that natural history studies that are designed to result in academic journal publications do not address the requirements for regulatory submissions”.
Dr. Anne Pariser, the then associate director for rare diseases within the Center for Drug Evaluation and Research at FDA and now the center’s associate director for knowledge management, said the following:
Natural history studies describe a disease in the absence of investigational agents.
Rational, scientifically based drug development requires an understanding of the disease, which natural history studies can provide.
Natural history studies are most informative when their data are available early in the drug development process, ideally before efficacy trials are designed.
Patients and caregivers must be involved in natural history studies, including in planning and overseeing studies.
Rare diseases are a highly diverse collection of disorders, requiring different types of clinical development programs based on an understanding of the intervention and its likely impact on the disease.
Drug development for rare diseases is a continuum in which data on natural history, pathophysiology, mechanisms of action, and intervention effects inform the design of efficacy, early-phase clinical, and IND-enabling studies as well as endpoint identification and development Citation[3].
Patients who have a rare disease, or whose family members do, have the most direct interest in generating data about the natural progression of the disease. Patients have played a direct role in the development of a number of drugs but what is lacking is a systematic and uniform approach to using patient experiences and knowledge in developing data about the natural history of diseases that patient organizations can afford to acquire and maintain over time.
Participating in natural history studies empowers patients and families not only through their contribution to research, drug development and future clinical trials but also by providing them with an opportunity to learn more about the disease, current treatments and ways to improve quality of life. Patients and families in the rare disease community are highly motivated to collaborate, share, and learn from one another.
To empower patient organizations, patients, and families, NORD is collaborating with NIH and FDA to advance the development of more and better natural history data. The cornerstone of this effort is a practical and affordable platform NORD developed for the design, launch, and maintenance of rare disease natural history studies. NORD’s online system provides for the collection and easy access of longitudinal research data and by doing so empowers patient organizations to direct, manage, and utilize disease data in order to increase knowledge and share research for rare diseases. The opportunity to expedite the identification of patients who may be eligible for a clinical trial is an additional benefit to patients, researchers, and drug developers.
The VHL Alliance was the first organization to launch its IRB-approved natural history study for von Hippel–Lindau syndrome on the NORD platform in March 2014. The study included over 1200 possible questions and within the first year had over 400 participants. The study has begun to attract researchers to the disease and has provided the patient community with preliminary data on oral health issues that they intend to pursue further.
The Foundation for Prader–Willi Research (FPWR) launched its Global Prader–Willi Syndrome Registry on the NORD platform and recently announced its largest philanthropic gift of $1 million in support of the organization’s research programs and clinical initiatives. The community’s global registry and natural history study will complement the external research FPWR funds.
NORD’s efforts to collaborate with the NIH and FDA ultimately will lead to more systematic and validated methods for collecting and collating information about rare diseases and their natural histories, in a way that will be valuable not only for individual patients but also to researchers and the regulatory community. The goal is to develop the kind of information that will make it easier for drug developers and researchers to assess the effects of drugs being developed sooner and with greater confidence than they now can, based on a clearer understanding of how a particular disease has been shown to progress over time.
The more knowledge we acquire about specific rare diseases and the development of drugs to treat them, the more we can contribute to our understanding of more common diseases and research into new products to treat them. Thus, the benefits of natural history studies go beyond just the rare disease community, and merit greater attention and support from everyone who supports medical progress.
Declaration of interest
P Gavin is employed by the National Organization for Rare Disorders, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Bibliography
- EURORDIS, Rare Diseases Europe website. Available from: http://www.eurordis.org/about-rare-diseases
- Sasinowski FJ. Quantum of Effectiveness Evidence in FDA’s Approval of Orphan Drugs. Chairman of the Board, NORD. Available from: http://nordphysicianguides.org/wp-content/uploads/2012/02/NORD-study-of-FDA-approval-of-orphan-drugs.pdf
- Workshop on Natural History Studies of Rare Diseases: Meeting the Needs of Drug Development and Research. Available from: https://events-support.com/Documents/Summary-NHS.pdf