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Orphan Drug Act turns 30
September 2013
by Lori Lesko  |  Email the author


CHAPEL HILL, N.C.—Voted into law in 1983 to encourage pharmaceutical and biotechnology to develop therapies to treat rare diseases, the Orphan Drug Act turns 30 this year—and looks as robust as ever.
The orphan drug market's increased popularity has proven to be a windfall for contract research organizations (CRO) like North Carolina-based Rho. But the orphan disease field is filled with pitfalls. With this in mind, David Shoemaker, senior vice president of research and development at Rho, shares five tips for selecting the right development partner to accelerate approval for orphan drug products and get much-needed medicines into the hands of patients quickly and efficiently.  
DDNEWS: What are some examples of life-threatening conditions that many orphan diseases represent?
Shoemaker: Many of the smaller oncology populations (ovarian, head and neck cancer, soft tissue sarcomas, malignant melanoma, cutaneous T-cell lymphoma) qualify as orphans and many of the metabolic gene mutations such as amyotrophic lateral sclerosis and glycogen storage diseases such as Pompe disease.
DDNEWS: What is the biggest reason why some orphan drugs do not get approved? 
Shoemaker: The same reason any product is not approved: The product is not safe and effective.  
DDNEWS: In your first tip, "Work with CROs that have strong scientific, regulatory and statistical expertise," how does one find a CRO with the necessary strengths and ability to conduct clinical trials, knowledge of the regulatory process and the statistical and marketing expertise to reach a quick approval?
Shoemaker: Unfortunately, all of this information comes by reputation and word of mouth. Most CROs are focused on conducting Phase III clinical studies and only provide lip service to marketing applications inasmuch as they don't have the scientific, regulatory or statistical horsepower to guide a product through the approval process.  There is no publication that lists the best CROs for orphan product development, so the best question to ask is, "how many orphan products has the CRO obtained marketing approval for in their recent history?"  
DDNEWS: What is the most important factor for guaranteeing success in working with a CRO? 
Shoemaker: Upfront and thoughtful strategic planning. The sponsor company must plan for success from the earliest stages of development and not conduct studies haphazardly based on inexperienced advice from employees or CROs that have not succeeded in getting a product approved for the marketplace. Each clinical study should be a means to an end, or the company is wasting time and money. I would estimate that at least 75 percent of all clinical studies are doomed prior to being initiated due to faulty design from a scientific or regulatory perspective.  
DDNEWS: We especially like your second tip: "Know the ins and outs of the FDA approval process to help speed orphan drug approval." It's hard to believe that drug companies would go into the CRO/orphan drug business without knowledge of the approval process. Because by the time a company gets to the FDA approval, months or possibly years may have been spent getting the orphan ready for approval, correct?
Shoemaker: Correct.  
DDNEWS: In your third tip, "Apply for U.S. and European Orphan Drug Designation simultaneously," couldn't this be seen as a drug company marketing an orphan drug for profit, rather than filling an unmet medical need?
Shoemaker: The incentives for orphan products were provided by the regulators to get companies to develop products that otherwise would never be developed, so they do not take issue with a company for developing them in both regions simultaneously. In many cases, these patients would be left with no therapeutic alternative otherwise.  
DDNEWS: Is the European drug approval process faster than the U.S. Food and Drug Administration? How do they differ in their approval processes?
Shoemaker: Unfortunately, this is a topic that would require a research effort far beyond the scope of this article. Both regions have claimed to have faster approval processes at various times in the last 20 years. It really comes down to a case-by-case basis of the benefit/risk profile for a given product and the knowledge of the regulatory strategists and their ability to work with the respective regional regulators that will determine the time to approval in either region.  
DDNEWS: In your fourth tip, "Look for a CRO partner with experience working in small patient populations," you state: "Working with small patient populations requires building communities and developing close connections with research foundations, advocacy groups, patients and healthcare providers for a purpose-driven approach to product development. It will also be important to gain buy-in from key opinion leaders." What do you mean by small patient populations?
Shoemaker: Orphan designation is conferred on products used to treat diseased populations of less than 200,000 in the United States and 5 in 10,000 patients in the EU.  However, orphan diseases can sometimes be much smaller, requiring a company to open sites all over the world in order to get a sufficient number of subjects to evaluate the efficacy and safety of their orphan product. This requires tremendous coordination and distribution of the clinical study information.  
DDNEWS: And who are key opinion leaders?
Shoemaker: Key opinion leaders are experienced and knowledgeable physicians at academic centers who treat specific diseases, publish peer-reviewed journal articles on standard of care for the disease and speak at international conferences.  
DDNEWS: In your fifth and final tip, "Validate your population," you advise, "before investing time and energy in an orphan drug application, make sure you are eligible. Regulators are on the lookout for developers who try to 'slice the salami,' meaning that your orphan population is really just a subset of a larger population from which there is no substantive difference." What do you mean by "slice the salami"?
Shoemaker: Some companies attempt to obtain orphan product designations for populations that are really a subset of a larger population. If you have a product that effectively treats ovarian cancer, breast cancer and vaginal cancer, you have a population that is greater than 200,000 in the United States and 5 in 10,000 patients in the EU.  Consequently, you cannot submit an orphan product designation application for ovarian cancer, even though that meets the requirement of 200,000 in the United States and 5 in 10,000 in the EU.  

The promise and pitfalls of the orphan disease market  
The National Organization for Rare Disorders (NORD) reports nearly 7,000 orphan diseases affect nearly 30 million Americans. As more drug companies search for new approaches after mass-market drug revenues are lost to generic competition, orphan drug development is gaining momentum.  
Orphan drugs have grown at a significant compound annual growth rate (CAGR) of 13.1 percent, or $2.3 billion, in 2010, to a projected $6 billion in 2018 in the United States and the top five countries of Europe and Japan, according to Medical Marketing & Media (MM&M).  
Increasing awareness of the disease and drugs among patients and physicians, patent protection and the anticipated launch of new molecules such as ACR-16, AMR-101 and HD-02 for the treatment of HD and the approval of Avastin for the treatment of advanced ovarian cancer in Europe will drive the global orphan disease therapeutics market in the forecast period, according to MM&M.
"Companies are looking carefully at the rare disease area now, especially given last year's robust wave of approvals," says Noah Pines of MM&M. "But there's a steep curve. Beyond small patient populations, firms in this burgeoning space face a host of unique challenges."  
As the ODA turns 30 this year, "those who had a hand in facilitating its passage would be taking heart now that innovative medicines for rare diseases are roaring into the spotlight," Pines says. "Of the 39 products that the FDA approved in 2012, about a third carried orphan status. That includes NMEs as well as existing, re-tasked products."  
"The market is hot—it is a space companies are looking at very carefully right now," says Peter Saltonstall, who heads NORD.  
Pines counters that few of these will achieve the commercial stardom of Alexion's hematology drug Soliris or Novartis' cancer med Gleevec. Among the first orphan blockbusters, these drugs showed that premium pricing and the ability to push into multiple indications could offset the typically small patient population (per the ODA, less than 200,000 in the United States).  
With the exception of a few big drugmakers like Sanofi, those active in the space tend to be small- to-medium size biotechs, says Saltonstall.
"We're not likely to see more big pharmas look to orphan drugs as an antidote to the patent cliff," according to Bernstein Research analyst Dr. Tim Anderson. The rare disease model is one "that they [Big Pharma] don't have long experience with. "It is about hands-on, long-term, deep approaches. It is not like pharma can just pick it up. It is out of their wheelhouse," he adds.
Mike Scott, executive vice president at Independence HealthCom Strategies Group and the current chairman of NORD, stated in MM&M's report, "It is not a matter of mass marketing; it is a highly targeted form of communication, in terms of identifying patients and the doctors who treat them, and working very closely with the rare disease advocacy organizations, who know this, to be able to get the right information to the right people.
For instance, Kalydeco (ivacaftor, or VX-770) won FDA approval last year, Scott says. Years prior to launching the cystic fibrosis drug, Vertex Pharmaceuticals nurtured a close partnership with the Cystic Fibrosis Foundation. Besides helping Vertex identify patients for trials, the foundation assisted with an extensive campaign to educate the community about the need for genotype testing, which determines their eligibility for the product.  
Today, education about diagnosis is more important than product promotion. That's because patients with rare diseases are often hard to diagnose, and once diagnosed, they tend to take an approved drug, according to healthcare specialist. Companies have also discovered that many patients of rare diseases go years before they are even diagnosed.  
Given that 80 percent of rare diseases affect children, the emphasis for orphan drugs shifts from an all-knowing family physician to the healthcare expert of the house: Mom or Dad, according to Peter Nalen, president and CEO of Compass Healthcare Marketers.
Drug companies seeking to market orphan drugs must also demonstrate how use of the product is somehow more cost effective than no treatment or other modalities, and may fall outside traditional healthcare outcome measurements, he says. For this reason, other factors come into play such as societal benefit, seriousness of the condition and the small populations for statistical studies.  
Aside from the commercial implications of pharma's interest in small disease populations, the trend has multiple effects on development. For instance, orphan drugs provide nice tax benefits for manufacturers.
"Fifty percent of R&D efforts come back as tax credits," says Dr. Chris Tobias, chief medical officer at Dudnyk. "You have seven years of exclusivity, and the FDA waives the fees for the drug approval application. Orphan drugs also can get approved in a shorter time frame."  
On the other hand, manufacturers face a host of technical challenges in rare diseases, says Shire Human Genetic Therapies President Sylvie Grégorie. With many rare diseases, the company seeking to develop orphan drugs has to do its own original research, which is costly and time-consuming. Then there is also the challenge of finding patients who are at the same point in their illness, questions of how long it will take before demonstrating a benefit and/or whether the parents give consent.  
With such small numbers, it is difficult to find a robust patient base, get them enrolled in a clinical study and demonstrate a statistically meaningful effect, according to healthcare specialists. One example is mantle cell lymphoma (which constitutes 5 percent of all non-Hodgkin's lymphoma). There are numerous options for initial therapy and at relapse, so comparison studies are difficult given the different possible "control" group options, says Dr. John Leonard, who heads the new clinical trials office at Weill Cornell Medical College and specializes in clinical trials in oncology.
Frank Sasinowski, a lawyer who helped draft the 1983 ODA, stated in the MM&M report, "What you're seeing is a window on the future of drug development—people who know a disease, who are committed to it, who get the funds and who organize the trials themselves."
Unfortunately, the reality is that all too few companies are willing to invest in low volume, low-return research programs. Thus the needs of the few are lost to corporate profit/loss statement, says Rare Disease Therapeutics Inc. on its website.  
However, Rho is on record, stating it shares a passion for discovering new treatments and has experience successfully helping companies navigate the FDA's orphan product approval processes.
"But just like anything that sounds too good to be true, sound product development program decisions should stem from a keen understanding of the requirements and potential benefits of each approach," says David Shoemaker, Rho senior vice president of research and development. "Selecting the right product development services partner can help deliver new treatments to improve and save lives as quickly as possible."
Code: E091308



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