Patient Registries F

NORD-FDA Natural History Study Frequently Asked Questions

What is the NORD Registry Program?
The NORD Registry Program is a compilation of services that assist member organizations through all the steps of developing, launching and running a Registry.
What is the NORD Natural History Study Database Project?
The NORD Natural History Study Database Project is one component of the greater NORD Registry Project. The natural history study database project seeks to enable the collection of disease-specific natural history information for rare diseases. A natural history study is a systematic collection and analysis of comprehensive information from people with a disease intended to advance the understanding of the disease and how it is expressed over time. NORD has developed a platform for designing, deploying, and maintaining natural history studies that is designed to provide a cost-effective and efficient way to conduct disease-specific longitudinal natural history studies. Through a cooperative agreement with the FDA, NORD will be expanding its natural history study database in 2015-2016 to develop and launch 20 new natural history studies on the NORD platform.
What is a Registry?
A Registry is an organized online program for collection, storage, retrieval, and dissemination of a clearly defined set of data collected on identifiable individuals for a specific and specified purpose.
What types of data can be collected in a Registry?
All types of data can be collected, including data related to the following:

  • Natural history data that captures longitudinal information about the disease
  • Diagnosis and treatment
  • Management of care
  • Quality of life
  • Clinical testing samples
  • Clinician reporting
  • Healthcare providers
What are the uses of having a Registry?
Data from a patient registry can help to:

  • Unite the patient and research community,
  • Learn about a disease/condition,
  • Improve quality of care,
  • Develop treatments,
  • Develop research hypotheses, and
  • Improve the management of healthcare.
How are the data collected?
The data are collected online by users that register and grant consent to enter their own personal data or the data on behalf another participant if he or she is legally authorized to do so.
Can data be collected worldwide?
Yes, a registry can be accessed from anywhere in the world, and international participation by the patient community and research collaborations are supported.
Where are the data stored?
The data are stored on NORD’s secure Registry Platform that is hosted on an IIS server in concert with a Microsoft SQL Server database.
Are the data safe?
Yes, the registry follows strict government guidelines to assure patient information is protected. The Platform is also served over HTTPS, providing encryption of traffic to prevent eavesdropping and prevent man-in-the-middle attacks. Communication between the registry platform application server and the database are also encrypted.
Who owns the data?
The identifiable and de-identifiable data are owned by the specific patient organizations. Each organization decides how and with whom to share the data. A subset of the de-identified data collected from registry participants across the Platform is shared with NORD to support research on all rare diseases, including studies comparing diseases.
How is the Registry maintained?
Member organizations provide the day-to-day management of their registry, and NORD provides technical support and ongoing periodic releases of new features.
What do you need to run a Registry?
  • The desire to have a registry
  • Patient engagement
  • Disease expertise to support the registry
  • Resources to fund and manage the Registry

Patient Registries E

Jan. 15, 2015

TOPIC: Research

Registries for Rare Diseases: Involve the Patient 

Posted by Jennifer Huron

In a new interview with Medscape, Marshall L. Summar, chief of genetics and metabolism at Children’s National Medical Center in Washington, D.C. and NORD marshallboard member, talks about the importance of patient registries for rare diseases, and the role that NORD’s patient registry program has in helping patients and educating doctors.

According to Dr. Summar, registries can accelerate the process of treatment and help physicians address the big knowledge gap about what happens in the day-to-day lives of patients.  By better understanding what is happening with rare disease patients, “we can develop better therapies by understanding the comorbid conditions and the long-term consequences of rare disease…  Try to get your patients with rare diseases enrolled in registries. You will learn more. Your patients will learn more, and it will actually be easier to take care of them. You will have access to information that you might not otherwise have.”

To learn more about or sign up for NORD’s patient registry program, read the FDA blog post written by  Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, or visit the NORD Registry Platform information page.

Patient Registry D

Natural Histories Patient Registry

To address the special needs of those developing treatments for rare diseases, NORD has created a Natural Histories Patient Registry Platform, with extensive input from FDA and NIH. The first disease-specific registry was launched in the summer of 2014 with the VHL Alliance.

In 2015, NORD was awarded with a $250,000 grant to develop more registries to support better understanding of rare diseases and the research and drug development processes. Twenty rare disease patient groups were chosen in 2016 to work with NORD on the development of registries for their patient communities.


20 Rare Disease Patient Groups Selected for Natural History Studies Project

Twenty rare disease patient groups have been chosen to develop natural history studies with the assistance of the National Organization for Rare Disorders (NORD) supported in part by a cooperative agreement with the U.S. Food and Drug Administration (FDA). Read the full announcement here.

Hereditary Neuropathy Foundation

Organic Acidemia Association

XLH Network, Inc.

CCHS Family Network

Pitt Hopkins Research Foundation

The OMSLife Foundation

Platelet Disorder Support Association

Global Foundation for Peroxisomal Disorders

APS Type 1 Foundation

Scleroderma Research Foundation

Galactosemia Foundation

Desmoid Tumor Research Foundation

International Pemphigus & Pemphigoid

The Morgan Leary Vaughan Fund

Adult Polyglucosan Body Disease (APBD) Research

Bridge the Gap-SYNGAP Education and Research Foundation

United Leukodystrophy Foundation

Lipoprotein(a) Foundation

Worldwide Syringomyelia & Chiari Task Force.

Patient Registries C



A databank constructed by the National Organization for Rare Disorders and the VHL Alliance could serve as a model for how patient organizations can generate natural history data to help speed development and FDA review of new treatments.

The Cancer in Our Genes International Patient (CGIP) Databank was formally unveiled in May and discussed at NORD’s Rare Diseases and Orphan Products Breakthrough Summit held Oct. 21-22. CGIP is the first public launch from a NORD platform designed to help patient organizations manage their own registries as a vehicle for natural history studies and other research.

NORD developed the platform because it saw a need for patient registries that are extensive and sophisticated enough for longitudinal studies of diseases that are not well understood, but also inexpensive and user-friendly so small patient communities can use them.

VHLA’s goals for the registry are twofold: helping patients share data and connect with researchers, and helping patients and researchers better understand the disease’s natural history and variables involved in disease progression.

Pamela Gavin, COO at NORD, said the platform’s focus on natural history helps patient organizations increase their role in researching and developing treatments.

“From a functional perspective, it takes a simple contact registry and gives it more dimensions. It enables patients and patient organizations to contribute and participate in the drug approval process,” she said.

At the summit, both FDA Commissioner Margaret Hamburg and Director of the Center for Drug Evaluation and Research Janet Woodcock hailed the CGIP Databank as a tool that can improve the agency’s ability to review treatments for rare diseases.

“Having such a resource can yield vital information about biomarkers, demographic, genetic and environmental factors that correlate with thedisease,aswellashelpingtoidentifypatientsubpopulationswith di erent characteristics and e ects,” Hamburg said at the meeting.

In an Oct. 23 post on the FDAVoice blog, Woodcock wrote, “Knowledge of natural history is essential for developing more e cient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute towards greater predictability of clinical development programs.”

Anne Pariser, a medical o cer in FDA’s O ce of New Drugs at CDER, told BioCentury that FDA hopes other groups will explore similar methods of studying natural history.

“NORD’s natural history study platform is flexible and can accommodate many rare disease natural history studies, and can be customized for di erent rare diseases,” she said.



“Given the many unmet medical needs for rare diseases and the value that natural history studies can provide for furthering research, patient care and drug development, we encourage rare disease groups to explore initiating and conducting natural history studies through NORD or other available venues,” she added.


von Hippel-Lindau disease is a textbook example of a rare disease where lack of understanding presents challenges in both treating the condition and developing new treatments.

VHL is an autosomal dominant disorder caused by inactivating mutations of the vHL protein. It occurs in roughly one in 35,000 people worldwide.

The protein is a tumor suppressor responsible for targeting hypoxia- inducible factor 1 alpha (HIF1A; HIF1-alpha) and endothelial PAS domain protein 1 (HIF2A; EPAS1) to the proteasome for degradation. Elevated HIF levels lead to an angiogenic response that predisposes patients to developing benign or malignant tumors at multiple sites, such as the eyes, cerebellum, brainstem, spine, pancreas, adrenal glands and kidneys.


Eric Jonasch, associate professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center, said a lack of knowledge about VHL’s natural history a ects all stages of drug development, from the ability to write research grants to supporting regulatory approval.

He said understanding the disease is challenging because despite the common genetic defect, it’s not known how specific mutations in the vHL protein correlate with phenotypes, or the roles that other proteins play.

Jonasch, who is also head of the Clinical Advisory Council and Research Council at VHLA, said the condition is managed by surgical removal of malignant lesions or nonmalignant lesions that are troublesome, such as those that occur in the eyes or CNS.

No treatments are approved for VHL, and Jonasch wasn’t aware of any companies developing them. He said most trials are investigator-initiated studies of products developed for kidney cancer.

Jonasch said renal cell carcinoma (RCC) often is driven by mutations in the vHL protein, and that kidney cancers are similar whether arising from sporadic or hereditary conditions.

He said while endpoints like lesion regression are appropriate to measure in clinical trials, lack of knowledge about when and how lesions develop hinders interpretation of study results, as well as physicians’ ability to recommend treatments.

“I treat patients, and if they have stability, I don’t know if that stability is because of me or despite me,” he said.





CGIP was designed to collect data from as many patients as possible and track enough variables to spur researcher interest and reveal correlations that are entirely unknown or only suspected from anecdotal data.

Thedatabankwillincludeinformationondemographics,medicalhistory, genetics, nutrition and exercise, and physical and emotional health.

CGIP includes patients diagnosed with conditions related to VHL, such as Birt-Hogg-Dube syndrome, succinate dehydrogenase complex subunit B (SDHB) genetic cancer syndromes, and hereditary leiomyomatosis and renal cell cancer (HLRCC; also known as Reed’s syndrome), an autosomal dominant disorder that predisposes development of tumors of the skin, uterus and kidney.

Vincent Tsugranes, director of information technology at NORD, said 361 people are providing data to the registry so far. Patients are the primary data source and provide input by completing interactive online questionnaires and uploading medical information.

Gavin said the databank includes over 1,200 questions. However, each patient is unlikely to have to answer that many, as tumors can manifest in di erent ways and many questions may not apply.

“The broad-based questionnaire allows us to capture things we don’t know we should be asking, which allows us to gain more insight into the overall e ect that this disease has on people,” Jonasch said.

Gavin said the project has already yielded at least one unexpected finding: VHL patients have a 40% increased risk of oral health problems.

Jonasch hopes CGIP will eventually yield insights into disease biology that could suggest targets for treatments.

“As we start layering more information in there, it may allow us to move forward into elucidating the mechanisms,” he said.

VHLA Executive Director Ilene Sussman said only anonymous patient data from CGIP are shared outside of the VHLA, and that researchers interested in using CGIP can submit study proposals for review and approval by a VHLA committee.


In addition to working directly with patients, VHLA and NORD courted feedback from stakeholders at NIH and FDA to ensure the tool is broadly applicable.

VHLA is responsible for the questionnaire content, data curation, analysis and patient management. Sussman said FDA provided feedback on the VHLA’s database design and the content of the questionnaires.

NORD is responsible for software development and data storage. Gavin said NORD’s platform was developed to let groups collect large amounts of data longitudinally, and FDA requested that the platform be constructed to facilitate natural history studies, which could help mitigate some of the risks of trying to get rare disease products approved.

Gavin added that the platform incorporated elements developed by NIH’s O ce of Rare Diseases Research to help standardize data collection across diseases.

Tsugranes said both FDA and NIH gave advice on research protocols to be used with CGIP, and that NORD will continue to partner with them and with patient organizations to validate research performed on its platform.

Tsugranes said the platform contains some tools tailored toward the needs of smaller patient organizations, like ease of administration and automated tools for patient follow-up.

Gavin said NORD is working with several other organizations on registries that can support natural disease studies.

She said NORD hopes to eventually incorporate electronic health records in the platform, but will first need to resolve challenges related to lack of standardization and getting patient consent.


National Institutes of Health (NIH), Bethesda, Md.
National Organization for Rare Disorders (NORD), Danbury, Conn. University of Texas MD Anderson Cancer Center, Houston, Texas U.S. Food and Drug Administration (FDA), Silver Spring, Md.
VHL Alliance (VHLA), Boston, Mass.


Woodcock, J. “The more we know about rare diseases, the more likely we are to find safe and e ective treatments.” FDAVoice (Oct. 23, 2014)


Patient Registry B

The more we know about rare diseases, the more likely we are to find safe and effective treatments

By: Janet Woodcock, M.D.

Janet WoodcockYou may be inclined to think that rare diseases affect only a tiny fraction of the more than 320 million people in our country. That’s true about a single rare disease. But there are about 7,000 rare diseases. If you add them all together, there are about 30 million – or almost one in ten — people in the U.S. with some form of rare disease. Sadly, although great progress has been made in some areas, many of these people have no FDA approved drug to cure their condition, help them feel better, or even slow the disease’s progress.

That’s why I am pleased about FDA’s support for an exciting new tool researchers are using to study rare diseases. It’s a new database with information about the diseases’ “natural history.”

“Natural history” is the scientific term to describe how a disease would progress with no treatment. Since a disease can affect different people differently, scientists must study many cases of a disease to acquire a thorough understanding of its natural history. Well-conducted studies of natural history can yield vital information about:

  • Biomarkers, demographic, genetic, and environmental variables that correlate with the course and stages of the disease;
  • Identification of patient subpopulations with different characteristics and effects of the disease;
  • Patient perspectives on what aspects of disease are most important to treat; and,
  • How to quantify those aspects so that they can serve as useful outcome measures for clinical trials.

But when it comes to rare diseases, their natural histories frequently are not fully understood because there are simply not enough cases that have been observed and studied. This lack of knowledge limits researchers’ ability to study rare diseases and develop new treatments. Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.

Recently The National Organization for Rare Diseases (NORD), has teamed up with the patient advocacy group that represents people with the rare disease known as Von Hippel Lindau disease. This is a condition with many debilitating symptoms that also predisposes individuals to benign and malignant tumors. The Von Hippel Lindau Alliance and NORD have created an online tool that enables people with this rare disease to enter information about their experiences with the disease, such as the progression of symptoms, and to add to this information at intervals throughout their lives.

This tool is now helping researchers compile valuable data about the natural history of Von Hippel Lindau disease. The even better news is that this tool is universal.  If it can be used effectively to help researchers better understand Von Hippel Lindau disease, it can do the same for other rare diseases as well!

Importantly, this online tool was developed with direct input from patients, as well as patient organizations, researchers, FDA, and other international drug regulatory agencies.

The natural history tool has important features such as these:

  • It protects  the security and privacy of personal information, while making valuable information available to a researcher or drug developer interested in creating a new therapy for a rare disease;
  • It can be used by patients or health care professionals;
  • It helps make sure that text and online tools data are accurate.

FDA is committed to working with patient advocates and other organizations to support natural history studies for rare diseases.  We encourage the use of natural history data collection tools to describe natural history for many rare diseases. It is our deeply felt hope and wish that we can then take steps toward developing and approving new therapies for persons with rare diseases.

Janet Woodcock, M.D., is the Director of FDA’s Center for Drug Evaluation and Research

Patient Registry A

NORD-FDA Natural History Study Project Page

NORD is partnering with disease specific advocacy organizations to launch patient-centered registries to gain a better understanding of rare diseases. The registries will allow patients around the world to share relevant data, connect with researchers, and support research on how variables such as diet, exercise, environmental factors and other variables may affect disease progression.




The goal of the registries is to document natural history data to help medical researchers better understand how diseases develop and progress over time. The databanks utilize best practices from NIH, expertise from medical professionals in the specific disease state and insight from the FDA on questionnaire design to help future development of promising therapies.

Praise for NORD’s Patient Registries

FDA Senior Official says NORD’s platform is “an exciting new tool researchers are using to study rare diseases.” Read the blog here >

BioCentury writes article Charting Rare Stars: How NORD is putting patients in control of rare disease natural history studies. Read the article here >

Signs & Symptoms of PRP

From the Editor…

How does pityriasis rubra pilaris present? What are the “signs and symptoms” available to a dermatologist that signal the possibility of a pityriasis rubra pilaris diagnosis. What are the clues dermatologists seek?

Here is what a search of the internet will find. #1
Pink, red, or orange-red scaly patches on your skin. The patches are usually itchy. You may have the scaly patches only on some parts of your body. They most often occur on the elbows, knees, hands, feet, and ankles. (Revised 9, 2016 #2
PRP causes pink, red, or orange-red scaly patches on your skin. The patches are usually itchy. You may have the scaly patches only on some parts of your body. They most often occur on the elbows, knees, hands, feet, and ankles. The skin on the palms of your hands and the soles of your feet may also become red and thickened. The scaly patches may eventually spread over the entire body.

National Organization for Rare Disorders
Pityriasis rubra pilaris is initially characterized by skin lesions described as, sharply pointed, horn-like, brownish-red to rosy yellow- colored papules. These papules usually occur on the back of the wrists, the outside of the forearms, underarm folds, elbows, knees, backs of the hands, and fingers. When the papules grow and connect together they produce dry, scaly, rough, red plaques over large areas of the skin. Gray, brittle nails and excessive oiliness of the glands on the scalp (seborrhea) and face may also occur. Often the edges of the eyelids are turned outward (ectropion).

DermNet New Zealand #1
Classical adult-onset PRP most often starts on the head, neck and upper trunk as a red scaly rash. Often there is a solitary lesion but within a few weeks multiple patches appear and they join together to form groups of reddish-orange lesions. Over a few weeks these spread downwards and may cover most of the body (erythroderma).

Rough, dry plugs can be felt within the patches and are due to plugged hair follicles, often most obvious on the backs of the fingers. Patients may also complain of itching in the early stages of the disease.
The palms and soles become thickened and yellow coloured in PRP. Cracks may develop which can be painful and make walking and using the hands difficult. The nails may become thickened and discoloured at the free nail edge and may show linear black streaks (splinter haemorrhages). The hair may thin considerably.

DermNet New Zealand #2
PRP in childhood can be classical (generalised) or circumscribed (limited in extent). The appearance is similar to in adults, with prominent thickening of the skin of the palms and soles. Other affected areas can be orange-red in colour with follicular prominence.

Genetic and Rare Diseases Information Center
Features of this condition vary greatly between affected individuals. The onset is gradual in the familial type and can be more rapid in the acquired type. Redness and scaling of the face and scalp are often seen first, followed by redness and thickening of the palms and soles. Overall, the elbows, knees, backs of the hands and feet, and ankles are most commonly affected.[5] A more widespread eruption consisting of scaling orange-red plaques can be observed on the trunk and extremities. The lesions may expand and coalesce and eventually cover the entire body. When the disease becomes widespread, the nails, mucous membranes and eyes may be affected. The familial type often persists throughout life, but the acquired form may have periods of remission (periods of time where symptoms improve or completely resolve).

British Association of Dermatologists
The rash can be itchy in its early stages. Thick skin on the palms and soles can split and become painful. Walking may be sore. Shivering, heat and fluid loss may occur if the rash covers large areas of skin.

Orange-red scaly patches and thick skin develop on the hands and feet.
The scaly areas cover much of the body. Small islands of normal skin (islands of sparing) are seen within the areas of the scaly skin. The scaly areas may be itchy. There may be changes in the nails.

For PRP patients:
What signs and symptoms did your dermatologist see?
What clues did you provide?

Signs & Symptoms of PRP

Testing Your Liver — Food for Thought

Editor’s Note: For many PRP patients and caregivers, the importance of “Liver Numbers” cannot be overstated. The following information was harvested from three credible websites. Please feel free to add your experiences and insights on this topic. Use “Leave a Reply” at the end of this webpage.


AST (SGOT) and ALT (SGPT) are reasonably sensitive indicators of liver damage or injury from different types of diseases or conditions, and collectively they are termed liver tests or liver blood tests. However, it must be emphasized that higher-than-normal levels of these liver enzymes should not be automatically equated with liver disease. They may mean liver problems or they may not. For example, elevations of these enzymes can occur with muscle damage. The interpretation of elevated AST and ALT results depends upon the entire clinical evaluation of an individual, and so it is best done by physicians experienced in evaluating liver disease and muscle disease.

Do AST and ALT test results indicate liver function?

It is important to clarify that ALT and AST levels do not reflect the function of the liver, even though in the medical community and in medical publications they commonly, and incorrectly, are referred to as liver function tests. Even in conditions when AST and ALT are very elevated, the liver still may function properly. Consequently, if you have “…elevated liver enzymes” or a high or abnormal liver test, you need to ask your physician exactly what all of the tests indicate

See Source:


Normal Levels of AST and ALT

Normal levels of AST and ALT may slightly vary depending on the individual laboratory’s reference values. Typically the range for normal AST is reported between 10 to 40 units per liter and ALT between 7 to 56 units per liter.

Mild elevations are generally considered to be 2-3 times higher than the normal range. In some conditions, these enzymes can be severely elevated, in the 1000s range.

Elevated Levels of AST and ALT

Elevated levels of liver enzymes in general signify some form of liver (or hepatic) damage or injury. These levels may be elevated acutely (short term) indicating sudden injury to the liver, or they may be elevated chronically (long term) suggesting ongoing liver injury.

In addition to the duration, the level of abnormal elevation of the aminotransferases is also significant. In some conditions the elevation could be mild, consistent with a mild injury or inflammation of the liver. They can also be severely elevated, possibly up to 10 to 20 times the normal values, suggesting more significant damage to the liver.


From the Mayo Clinic

Many diseases and conditions can contribute to elevated liver enzymes. Your doctor determines the specific cause of your elevated liver enzymes by reviewing your medications, your signs and symptoms and, in some cases, other tests and procedures.

More common causes of elevated liver enzymes include:

✽ Certain prescription medications, including statin drugs used to control cholesterol

✽ Drinking alcohol

✽ Over-the-counter pain medications, particularly acetaminophen (Tylenol, others)


Testing Your Liver — Food for Thought