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Challenges abound as researchers search for rare disease treatments

Doctors may go years without seeing a rare disease -- also known as an orphan disease -- but they affect 30 million Americans.

There are about 7,000 diverse diseases classified as rare in America alone, which according to the United States Government, means that less than 200,000 individuals have this particular disorder at one given time. On Feb. 28, advocates are putting the spotlight on rare diseases during Rare Disease Day and promoting the message of "Rare Disorders without Borders," to aid in the international effort to work together to battle these conditions.

The U.S. currently has more than 420 medications approved to treat various rare diseases. While legislation has provided incentives to encourage pharmaceutical companies and sponsors to research rare diseases, much stands in the way of finding cures for these illnesses.

Motivating research

Today, about 20 medications are approved to treat rare diseases annually, and about one-third of brand new drugs the agency approves are for these uncommon conditions, Anne Pariser, associate director for rare diseases at the Food and Drug Administration, told Last year, 13 brand new drugs were approved for 14 different indications and an additional 12 existing medications were approved to treat various rare diseases.

"There's an aggressive push over rare disease research, and researchers have much more tools in their toolbox," Michael Kelly, the chief scientific officer of Cure Duchenne, said to Kelly was a former pharmaceutical executive who served as president and U.S. site head for Renovis, Inc. and held senior positions at Amgen, Wyeth (Pfizer) and Wellcome (GlaxoSmithKline).

"We've also seen both large pharmaceuticals and small get interested. The pharmaceutical industry has changed in the last few years, and orphan diseases have become an important part of their portfolio," he added.

There's more at stake than saving these patients: Looking into these uncommon diseases has already been shown to create a pathway for treating and curing some of our most prevalent ailments.

For example, Nobel Prize-winning research about a rare, genetic condition has lead to groundbreaking information about how to fight high cholesterol. Michael Brown and Joseph Goldstein were researching familial hypercholesterolemia -- an inherited condition that causes high levels of low density lipoprotein (LDL) cholesterol from birth -- when they won the Nobel Prize in Physiology or Medicine in 1985. They discovered that 20 percent of all heart attack survivors had one of three single gene-determined types of inherited high cholesterol disease, and one heterozygous form of familial hypercholesterolemia (meaning only one of the inherited genes was mutated) was found in 1 out of every 25 heart attack victims.

Through their research, they were able to discover a pathway of how cholesterol is absorbed in the cells, providing invaluable information for anyone who is battling high cholesterol, Dr. William Gahl, clinical director of the National Human Genome Research Institute (NHGIRI) and director of the National Institutes of Health's Undiagnosed Disease Program, told

The U.S. recognized the potential rare disease research could have on other illnesses, and Congress approved the Orphan Drug Act in 1983. The legislation states that if an organization can prove through animal models and clinical data that a particular drug is promising for a specific rare disease, it can receive tax credits toward future clinical trials. This includes the ability to write-off some of the research and development (RND) costs. It also includes a waiver for fees associated with submitting a medication to the FDA for marketing approval, which can average $1.9 million per drug.

One of the most lucrative parts of the act for pharmaceutical companies is that if their medication is approved, they get seven years of market exclusivity. No other drug can go to market for that disease, unless it is proven that a newer, not similar, medication is better at treating the disease.

In the decade before the act, only 10 medications were approved to treat rare diseases. Today, the FDA currently receives about 300 requests a year for developmental medications to be designated for rare diseases, and about 70 percent receive that approval, the agency aid.

In addition, a number of patient advocacy groups for rare disorders petitioned Congress to fund the Rare Disease Clinical Research Network in 2003. Ten million dollars was given to the NIH Office of Rare Diseases Research to establish a network of scientists who were researching various illnesses.

Prior, there had always been a struggle to find enough rare disease patients in one area for a clinical trial because the incidence rate was so low. Now, companies could just tap into a database of hundreds of patients who have full histories and have been placed on the same protocols, ready to enter clinical trials.

"Drug companies have been historically less interested in investing money to develop drugs because of the expense of doing that and the return on patients," Dr. Mark Batshaw, the chief academic officer for Children's National Medical Center and the professor and chair of the department of pediatrics at The George Washington University School of Medicine and Health Services, which are both in Washington, told "With the Orphan Drug Act and the Rare Disease Clinical Research Network, drug companies are now looking at the global market rather than just the U.S. market."

Batshaw's group was among the first 10 research centers funded through the initiative. His research focuses on urea cycle disorders.

When people usually eat protein, it is broken down into amino acids, which help form hormones that maintain the body's well-being. Components that are not required, like nitrogen and ammonia, are metabolized with enzymes primarily in the liver and released through the urine. Someone who has a urea cycle disorder, however, has an enzyme defect that causes ammonia to accumulate in the body. It becomes very toxic to the brains of young children and can cause death.

Through the funding, Batshaw was able to pool together 15 sites that were studying urea cycle disorders, including 12 in the U.S., one in Canada and two in Europe. Before the consortium was formed, the largest study involved 23 patients. Now, they have over 600 patients representing 20 percent of all the people identified with urea cycle disorders.

"You can cut down the cost of getting a drug to market for a rare disorder if you have a consortium that includes many sites," Batshaw explained. "If you have a large enough number of individuals to perform the study and if all those individuals are following a single clinical guideline and followed longitudinally over a period of time, it cuts costs enormously."

The development process

Drug development can vary with disease, depending on many factors including how much is known about the medication previously and how big the population with the disease is.

The first step to get any drug approved involves basic research and discovering what new compounds can potentially do for certain patients, Pariser said. Animal testing may begin at this state.


It isn't until human trials are necessary that the FDA steps in. The medication, which is designated as an investigational new drug (IND), is then submitted for approval for "phase 0" testing. Phase 0 is a very small test that checks what the drug will do to the body and how the body affects the drugs. Next it moves into phase I (typically focuses on making sure that the medication will be safe for a general population); phase II (figuring out how effective and safe the drug is for patients); phase III (continued testing on a larger patient population) and phase IV (monitoring the drugs effectiveness outside a research setting). The entire process takes on average six years, according to Pariser.

However, for rare disease drugs, the population of affected patients may be much smaller and the need might be much greater, considering that many of the disorders are fatal and affect children. To address these problems, the FDA provides several expedited pathways that aid with the development and eventual marketing approval.

During the developmental phase, drugs can receive a "Fast Track" or "Breakthrough" designation. Fast Track opens up more interaction with the FDA so that it is easier to get meetings and companies can submit parts of their research instead of waiting for the study's completion. A Breakthrough designation, which was just initiated in 2012, is given when a drug shows through clinical data that it can provide an advantage over what's available. This pushes it further along "as quickly as feasible," Pariser said. So far, the small number of medications given a Breakthrough designation have been for rare diseases.

"The developmental phase can take years, and this is where we'd like to be more efficient," she explained.

In the marketing application phase, drugs can get a "Priority Review" designation -- cutting down the standard review time from 10 months to six months (usually given to cancer and HIV drugs) -- or an "Accelerated Approval." A drug can get approved before finishing all testing if the company can provide an endpoint that suggests the outcome of a study will be positive or present a midpoint outcome that shows this drug would be beneficial.

There is no requirement that drugs go through all the phases. Pariser explained that the FDA can approve a medication as soon as there is "substantial evidence of effectiveness and safety." About two-thirds of rare disease drugs are approved after one trial and supporting evidence, she said.

"This can vary widely because of what you're studying," she stated. "In rare disease situations, it is common for drugs to be approved after one adequate and well-controlled trial that is well enough to discern the effects of the drug in the population being treated."

Patient challenges

Because these diseases affect such a small group of people, it can be difficult to gather enough people for a clinical trial even with the Rare Disease Clinical Research Network is in place. Kelly explained that while heart disease studies may have tens of thousands of patients, the best a lot of rare disease researchers can recruit is about 100 patients.

Pariser added that doctors are often facing complex diseases that they are not used to. It's not uncommon for a patient to go three to five years without a proper diagnosis, and it can be even harder for researchers to identify a potential candidate. Batshaw pointed out that doctors seeing these patients may not know the best approach on how to treat them or who to refer them to.

"The scientific foundation -- we wish it was better for a lot of people," Pariser said. "It's difficult to design a clinical trial when you don't understand the disease."

Another problem is that there is often a discrepancy between what the FDA finds out about a medication and what advocates understand happened, Dr. Gayatri Rao, director for the office of orphan products development (OOPD) at FDA, told

"The patient community is active and very vocal, which is great, but often there is a knowledge gap between what they are looking for and what the agency is willing to do (approve)," Rao said. "The FDA is not in a position to share that information with the public, and it turns the notch up on a lot of issues."

Money problems

Despite all the strides made in rare disease research, money -- both for funding and to pay for the drugs once they hit the market -- remains the biggest hurdle.

It's especially problematic for researchers like Batshaw who are reliant on NIH funds. When Batshaw entered the field of research in 1975, about 30 percent of research grants were being funded. Now, the percentage might dwindle to as low as 6 percent.


"The NIH has been flat funded and is facing sequestration," Batshaw explained. "It's very important to get a next generation of scientists to enter the field of rare disease or even research in general, but if they are facing the possibility of only 6 percent of their grants being funded, it's making it very difficult."

Costs also mount during the animal testing phase, when drug toxicity is tested. While other parts of clinical trials may be able to get written off, animal toxicity studies are often not counted as part of the "research," Gahl said.

Then there's the actual cost of the drug once it reaches market. One drug that has been approved to treat urea cycle disorder called Ravicti costs $250,000 a year, which will be available soon. The patient will need to take the medication for their whole life.

While most insurance companies will pay for treatment for rare diseases, Batshaw said it boils down to what your policy actually says. In the best case scenario, some companies have people designated to help work with the pharmaceutical companies to get their patients a lower rate and others pitch in to help with the cost.

However, there's also some companies that might ask patients to try an older, cheaper drug. In the case of Ravicti, there is another medication called Buphenyl that appears to have more side effects -- but it only costs $40,000 to $60,000 a year. He's heard of many companies covering this drug. He fears that some companies might only consider covering Ravicti if they've tried Buphenyl, and it doesn't work for the patient.

In recent years, there has been a push by patients who are not covered by insurance, Medicare and even insurance companies themselves to lower the cost of medications, Kelly said. In small ways, they have made some headway.

"The question is if these children are kept healthy by these drugs and are not coming into the intensive care unit in comas, there are going to be cost savings in terms of health care costs (for the patient and insurance company)," Batshaw pointed out. "If you can prevent these children from sustaining brain damage, they can ultimately become taxpayers."

"It's not just the cost of the drugs," he added. "If the patients are not adequately treated, what's the cost to the insurance company and the cost to society?"

But, Kelly fears another problem. While some of these drugs might help against a disease, he believes their exorbitant price might not be worth the little help they provide.

"It's a problem that's going to come to a head in a year or two," Kelly said. "There are some oncology drugs cost hundreds of thousands of dollars a year, but the actual clinical benefit is marginal at best... Quite often it's not clear if the price is worth it."

The future

To combat a lot of these hurdles, Gahl believes the introduction of induced pluripotent stem cells (IPS cells) -- a type of stem cell that can be made express different kinds of genes -- might be able to help. While we do have some animal model systems right now in mice, zebrafish, worms and flies, they aren't as ideal as human trials. The IPS cells can be coded to mimic the disease, and can be used in lieu of finding actual people with the disease -- saving time, effort and money.

"If we had IPS cells that you could pull of the shelf for pancreas and bone marrow, that would be a real boon to researchers," Gahl said.

Rao also believes that the field of rare disease research is lacking when it comes to devices, which are often need by the pediatric community. Not enough easy-to-use devices or protocols to diagnose rare diseases exist, leading to longer detection time.

"The incentives that exist on the drug side don't exist on the device side," she stated.

Most importantly, Rao said if there is going to be progress in rare disease research, the global community has to work together, harkening back to this year's Rare Disease Day theme.

"There's a lot of countries that are focused on orphan issues," Rao said. "They have designations that are similar to ours and modeled to ours. We have to collectively deal with the issues that arise... If we're going to find solutions, it has to be international."

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