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664715_11160870-pillRare diseases, including several autoimmune disorders, are getting more attention from drug-makers, according to a new report by the Pharmaceutical Research and Manufacturers of America (PhRMA), a consortium of 36 US-based pharmaceutical and biotechnology companies. In 2012 alone, 13 drugs for orphan diseases (“orphan drugs”) were approved by the Food and Drug Administration (FDA). Approximately 452 medicines and vaccines are in development for the nearly 7,000 orphan diseases worldwide.

orphan diseases are defined as diseases with fewer than 200,000 patients. In total, however, across the nearly 7,000 orphan diseases, 30 million people in the US, or about 10% of the population, are affected by an orphan disease. The pemphigus and pemphigoid (P/P) diseases are considered “ultra-orphan” diseases because they are extremely rare. It is estimated there are only about 50,000 new P/P cases each year worldwide, with only a few thousand of those being in the US.

Rare diseases tend to be more complex than common diseases, meaning that there are a number of factors that combine to cause disease. In the case of P/P, while there seem to be genetic risk factors, how these contribute, singularly or in combination, and to what extent the environment (like diet and other conditions that are present) also contributes is not well understood.

Somewhat fortuitously, complex diseases represent the next great frontier for drug developers. Having tapped into the ‘simpler’ diseases, making great strides in treatment of conditions like high cholesterol, these ‘low-hanging fruit’, as drug-makers like to call them, have been consumed. It is truly a time of paradigm-shifting mentality among drug makers.

That said, the costs of developing new medicines is extremely high, so companies must make their choices wisely. If we were to calculate the amount that pharmaceutical and biotechnology companies spend on research and development yearly and compare that to the number of drugs that are approved for clinical use by the FDA each year, the cost per successful drug is a staggering $1.2 billion. It’s not difficult to imagine, then, why companies aimed at developing new drugs are most interested in those that can recoup these huge costs — for instance, by developing drugs for very common conditions and risk factors such as diabetes and high cholesterol. As well, given the complex nature of rare diseases, they are not necessarily among the ‘low-hanging fruit’ that some diseases represent.

To incentivize companies to prioritize new drugs for rare conditions, they may apply for orphan drug status through the FDA, a result of passage of the Orphan Drug Act (ODA) of 1983. With this status, a drug receives seven years of market exclusivity. Market exclusivity is particularly appealing to companies developing drugs because the seven-year exclusivity period differs from laws applicable to other drugs in that it does not begin until the drug is approved by the FDA approval.

The ODA is considered a resounding success. Since its inception, there have been more than 400 medicines approved for a total of 447 orphan diseases. As well, there are hundreds of new medicines in development, including an impressive list available in the PhRMA 2013 report (phrma.org/sites/default/files/pdf/Rare_Diseases_2013.pdf).

While not all of the 452 orphan drugs in development will be approved for patient use, this is certainly a lot of activity. A search of the list included within the PhRMA report, as well as a search of clinicaltrials.gov (that lists all clinical trials in progress), shows a handful of drugs in testing for conditions related to or directed at P/P.

There are 18 new orphan drugs in phase I-III trials (there are three phases of clinical trials and drugs must pass all of them, indicating reasonable levels of safety and meaningful efficacy-effectiveness in treating the condition) that are indicated for autoimmune disorders.

New drugs are not the only source of treatment for disease. Another source is to use an existing drug, developed for another condition, for a different indication. Such is the case with Rituxan® (rituximab), which was originally developed for Non-Hodgkin’s lymphoma. In that disease, B cells of the immune system bearing a marker called CD20 (thus the name CD20+ B cells) have gone awry.

Since P/P shares this hallmark, Rituxan® has been successfully used ‘off-label’ for P/P. It is an antibody-based drug, which requires it to be injected into the patient. In general, any drug that acts as a suppressor of the immune system (immunosuppressant) is a potential candidate for treating a range of auto-immune conditions, including P/P. CellCept® (mycophenolate mofetil), another immune system suppressor that was developed for transplant patients to help prevent the body’s rejection of the ‘foreign’ organ, has recently been approved for use in P/P.

Besides the high cost of developing new drugs, companies that seek treatments for orphan diseases face difficulty in finding enough patients to participate. Indeed, patients tend to be dispersed geographically and may include small children. Physicians and patients who are interested in participating in trials or gaining more information should visit clinicaltrials.org.

Within the P/P community, the IPPF is also a great resource for learning about clinical trials. Members of our medical advisory board serve as investigators on trials and being in our patient database could lead to a company reaching out to you about participating in a trial.

For instance, among the new drugs aimed at treating P/P, drug-maker Novartis is studying VAY736, an antibody-based drug aimed at another B cell marker called BAFF-R. The study is in a very early stage and should be recruiting patients soon.

The time is ripe for development of new drugs for complex orphan diseases. The surge in new medicines in the first 30 years since the ODA should accelerate as less ‘low-hanging fruit’ exist for companies developing new drugs.

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A few weeks ago, I had the opportunity to interview Dr. Anne Pariser (US FDA Office of New Drugs, Rare Disease Program) and Dr. Gayatri Rao (US FDA Office of Orphan Products Development). We talked about the role of their departments, orphan drug development, repurposing drugs, and what the IPPF and our members can do to help.

BADRI RENGARAJAN: You work in the FDA’s Office of Orphan Products Development. What is the Office’s mandate, and what is its relationship with the rest of the FDA?

FDA: The Office was created over 30 years ago. At that time, there was very little focus on developing products for rare diseases. The primary mission of the Office is to promote the development of products for rare diseases. Prior to the passage of the Orphan Drug Act, companies did not have enough incentives to develop products for the rare disease space. The Orphan Drug Act was created to provide those incentives, including a designation and grants program. Our office administers these programs. We are not in the review divisions of the FDA that review marketing applications [i.e., applications that seek approval to market a drug], however, we work closely with them.
FDA: We deal with companies early on. We review products for purposes of orphan designation. There is a corollary designation program for devices. We also have two grants programs to stimulate research for rare diseases and pediatrics – the Orphan Products Grants Program and the Pediatric Devices Consortia Grants Program. Rare diseases have become a focus internally and externally, so, in addition to administering the designations and grants programs, we also serve as a cross-cutting function among all different parts of Agency. We encourage collaboration.

FDA: In addition, we are often the first stop for patients with rare diseases.

BR: It seems to be common wisdom that pharmaceutical companies do not develop drugs for orphan or rare diseases because the revenue opportunity is not attractive (due to small market)? Is the common wisdom correct? Why or why not?
FDA: This wisdom has evolved over time. When the Orphan Drug Act was initially passed, this was the case. Even after the Act was initially passed, we did not see a whole lot of designations come through. But this has changed over time.

Trial costs are rising, and exclusivity has been a good incentive. These days companies will generally see a return on their investment. The rare disease area is becoming a more attractive space – not just for small biotechnology companies but also for large pharmaceutical companies.
BR: How has the FDA made it easier or more attractive for drug companies to develop products in orphan/rare diseases?

FDA: With orphan designation, a company gets tax credits for clinical trial costs (up to 50%). If your product is the first to be approved for a particular rare disease indication [i.e., authorized use], you get 7 years of marketing exclusivity.

rphan designation also gets you a waiver of the FDA’s user fee ($1.9M), which is a fee companies who submit a marketing application to FDA must typically pay.

BR: How are the approval requirements for orphan drugs different?
FDA: To be approved in the U.S., all drugs must demonstrate substantial evidence of efficacy and safety, which is usually done through the conduct of at least one adequate and well-controlled clinical trial. There is no requirement that all drugs go through Phase 1, Phase 2, and two Phase 3 trials. This is often the case for common diseases, but each development program is different, and there has been considerable flexibility shown for rare disease development programs. The FDA can exercise flexibility and scientific judgment. It is important to work closely with FDA to discuss the design of clinical development programs for rare diseases that are able to demonstrate substantial evidence of efficacy and safety.

FDA: Most (about two-thirds) orphan drugs are approved based on one adequate and well-controlled clinical trial and supportive information. What constitutes substantial evidence of effectiveness and safety will depend on what is known about the disease and population studied, the drug, and several other factors.
BR: Are there even less strict requirements for drugs aimed at ultra-orphan diseases?

FDA: There is no official term of “ultra-orphan” diseases. All are rare (also known as orphan) diseases. In the U.S., an orphan disease is defined by law as one that has a prevalence of less than 200,000 in the U.S. Most rare diseases are low prevalence (10,000-20,000 patients or fewer). Most approved products are for low prevalence diseases.

BR: Are requirements for orphan/rare drugs the same in other countries? (for instance, Europe and Japan) If not, what are the key differences?
FDA: This is outside of our authority. The regulatory requirements are not completely harmonized. Most of the time, FDA and other International Conference on Harmonisation (ICH) regulatory agencies, such as the European Medicines Agency (EMA), agree on approval decisions for orphan drug applications, and orphan designations. Many programs are multinational and we do collaborate quite a bit with authorities in other countries.

BR: From a regulatory perspective, are all orphan/rare diseases the same? If not, what are the different categories?

FDA: There are 7,000 rare diseases. They affect different age groups, have widely varying symptoms, exhibit different disease severities, etc. We talk about rare diseases like they are monolithic, but they are highly diverse. When thinking about orphan designation, understanding the disease is very important (e.g., is it one single disease or two diseases?) We even give orphan designation for subsets of common diseases.
FDA: With rare diseases, there is limited opportunity for study so you have to understand what is feasible, but other factors about the disease, the drug, and the expected effects of intervention are very important. The general principles of clinical research still apply.
FDA: Product candidates that come to the FDA for review are routed by disease or therapeutic area to the review divisions. For instance, a drug for skin diseases would generally be reviewed by the Division of Dermatology and Dental Products (DDDP).

BR: Are pemphigus and pemphigoid different from other orphan diseases from a regulatory perspective?
FDA: We searched our orphan designation database. We haven’t seen a lot of orphan designations for pemphigus. Ultimately, the same fundamental regulatory, scientific and clinical research principles would apply to drug development for pemphigus as for other diseases; however, the specific considerations for clinical development of a drug for pemphigus should be discussed with the review division.
BR: For ultra-orphan diseases like pemphigus and pemphigoid, what happens if there just are not enough patients to enroll in a trial? For instance, people may be too frail to participate in the trial, or they may not live close enough to a clinical trial site such as an academic medical center.

FDA: Most of these diseases are low prevalence. Most rare diseases are serious disorders, and many have patients who are very ill and medically vulnerable. This is where the concept of flexibility comes in. There is considerable diversity in approaches to developing drugs for rare diseases. For instance, in two-thirds of situations, only one adequate and well-controlled (A & WC) trial or another non-traditional study design is done. In contrast, for most common diseases, two A&WC trials are usually done. In unusual cases for some diseases, a case series is submitted. There is an example of a drug development program in which a clinical study of 8 people supported the approval of a drug. The important thing is to collaborate and talk to the FDA early and to arrive at a good trial design. Through this, we can often be quite successful.

BR: The FDA approves drugs for particular uses or “indications.” However, physicians can prescribe drugs for non-approved uses. For instance, Rituximab is approved for several uses (e.g., rheumatoid arthritis, certain types of lymphoma) but not for pemphigus, yet some doctors use it to treat pemphigus. How is this possible?

FDA: Drugs are prescribed by practitioners off label all the time. Medication choice is governed by the practice of medicine. The FDA does not regulate clinical practice. Based on what a physician knows about a patient, he or she does what is in the best interests of that patient.

FDA: Whether a drug is on-label or off-label does have implications for reimbursement.

BR: If Rituximab™ were studied in a pemphigus trial, would it have a faster path for being approved for use in pemphigus?

FDA: It’s a complicated question. You are re-purposing the drug. If you have a new drug with no prior use in humans, you have a long path with toxicology and other preclinical work that needs to be done. With a repurposed drug, you may already have that early work completed. You may then be able to jump in right at phase 2 and phase 3, but it depends on the circumstance. One should contact the relevant FDA review division to discuss trial design. If Rituximab were studied in pemphigus or pemphigoid, it may be eligible for orphan drug designation and all the incentives, including exclusivity.

BR: Given off-label usage is possible, what would be the utility of conducting a trial of an already approved drug in a new disease indication like pemphigus?
FDA: If you are deliberately measuring outcomes in a group of people (versus simply prescribing the drug to single patients), it becomes more of a research situation and you need to consider conducting this under an investigational new drug application, which is a type of authorization for doing investigational work.
BR: What can patient organizations do to support and accelerate the development of drugs?
FDA: You can do a lot. For rare diseases, one of the biggest problems is that patients are sparsely dispersed. It can be difficult to enroll trials. Describing natural history is very important, and patient organizations can help here. Also, many physicians may not be trained to treat patients with this disease. Patient groups can start registries (with type of disease, geographic location, etc.). Some organizations have initiated treatment centers – so if a treatment becomes available, they would have expertise and best practices located at one site.

 

BR: Is there a particular stage of the drug development and regulatory process where patient organizations can be most impactful?

FDA: All phases. Early on, trying to establish research registries, centers of excellence, and clinical endpoints is helpful. With slow trial enrollment, patient organizations can turn around the situation. Patient groups can help all the way through.
BR: Is there anything a patient advocacy group can do to assist the FDA’s review and approval process?
FDA: The FDA has a patient representative program. Through this program, patients can provide perspective at FDA advisory meetings. It is also important to partner with sponsors [e.g., drug manufacturers]. Sponsors may be willing to share information from trials, whereas the FDA cannot provide such data.

BR: Are there particular orphan drug policy efforts at play in Washington, DC that we should be aware of?
FDA: It is hard for us to comment on legislative activities.

BR: Are there particular orphan/rare disease organizations or groups we should collaborate with?

FDA: More experienced and larger groups are always willing to mentor smaller groups (e.g., cystic fibrosis group will talk to you and give you advice). NORD and the Genetic Alliance also do a lot of mentoring. The Genetic Alliance has boot camps. Get in touch with the Office of Rare Diseases Research at NIH. They can be very helpful. Rare Disease Day seminars, web casts, and events can also be helpful.