Orphan Drug Act turns 30

CHAPEL HILL, N.C.—Voted into law in 1983 to encouragepharmaceutical 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 tobe a windfall for contract research organizations (CRO) like North Carolina-basedRho. 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 accelerateapproval for orphan drug products and get much-needed medicines into the handsof patients quickly and efficiently.

DDNEWS:What are some examples of life-threatening conditions that many orphan diseasesrepresent?

Shoemaker: Many ofthe smaller oncology populations (ovarian, head and neck cancer, soft tissuesarcomas, malignant melanoma, cutaneous T-cell lymphoma) qualify as orphans andmany of the metabolic gene mutations such as amyotrophic lateral sclerosis andglycogen storage diseases such as Pompe disease.

DDNEWS:What is the biggest reason why some orphan drugs do not get approved?

Shoemaker: The samereason any product is not approved: The product is not safe and effective.

DDNEWS: Inyour first tip, "Work with CROs that have strong scientific, regulatory andstatistical expertise," how does one find a CRO with the necessary strengthsand ability to conduct clinical trials, knowledge of the regulatory process andthe 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 providelip service to marketing applications inasmuch as they don't have thescientific, regulatory or statistical horsepower to guide a product through theapproval process. There is nopublication that lists the best CROs for orphan product development, so thebest question to ask is, "how many orphan products has the CRO obtained marketingapproval for in their recent history?"

DDNEWS: What is the most important factor forguaranteeing success in working with a CRO?

Shoemaker: Upfrontand thoughtful strategic planning. The sponsor company must plan for successfrom the earliest stages of development and not conduct studies haphazardlybased on inexperienced advice from employees or CROs that have not succeeded ingetting a product approved for the marketplace. Each clinical study should be ameans to an end, or the company is wasting time and money. I would estimatethat at least 75 percent of all clinical studies are doomed prior to beinginitiated due to faulty design from a scientific or regulatory perspective.

DDNEWS: We especially like your second tip: "Know the insand outs of the FDA approval process to help speed orphan drug approval." It'shard to believe that drug companies would go into the CRO/orphan drug businesswithout knowledge of the approval process. Because by the time a company getsto the FDA approval, months or possibly years may have been spent getting theorphan ready for approval, correct?

Shoemaker: Correct.

DDNEWS: Inyour third tip, "Apply for U.S. and European Orphan Drug Designationsimultaneously," couldn't this be seen as a drug company marketing an orphandrug for profit, rather than filling an unmet medical need?

Shoemaker: Theincentives for orphan products were provided by the regulators to get companiesto develop products that otherwise would never be developed, so they do nottake issue with a company for developing them in both regions simultaneously.In many cases, these patients would be left with no therapeutic alternativeotherwise.

DDNEWS: Isthe European drug approval process faster than the U.S. Food and DrugAdministration? How do they differ in their approval processes?

Shoemaker: Unfortunately,this is a topic that would require a research effort far beyond the scope ofthis article. Both regions have claimed to have faster approval processes atvarious times in the last 20 years. It really comes down to a case-by-casebasis of the benefit/risk profile for a given product and the knowledge of theregulatory strategists and their ability to work with the respective regionalregulators that will determine the time to approval in either region.

DDNEWS: Inyour fourth tip, "Look for a CRO partner with experience working in smallpatient populations," you state: "Working with small patient populationsrequires building communities and developing close connections with researchfoundations, advocacy groups, patients and healthcare providers for apurpose-driven approach to product development. It will also be important togain buy-in from key opinion leaders." What do you mean by small patientpopulations?

Shoemaker: Orphandesignation is conferred on products used to treat diseased populations of lessthan 200,000 in the United States and 5 in 10,000 patients in the EU. However, orphan diseases can sometimesbe much smaller, requiring a company to open sites all over the world in orderto get a sufficient number of subjects to evaluate the efficacy and safety oftheir orphan product. This requires tremendous coordination and distribution ofthe clinical study information.

DDNEWS: Andwho are key opinion leaders?

Shoemaker: Keyopinion leaders are experienced and knowledgeable physicians at academiccenters who treat specific diseases, publish peer-reviewed journal articles onstandard of care for the disease and speak at international conferences.

DDNEWS: Inyour fifth and final tip, "Validate your population," you advise, "beforeinvesting time and energy in an orphan drug application, make sure you areeligible. Regulators are on the lookout for developers who try to 'slice thesalami,' meaning that your orphan population is really just a subset of alarger population from which there is no substantive difference." What do youmean by "slice the salami"?

Shoemaker: Somecompanies attempt to obtain orphan product designations for populations thatare really a subset of a larger population. If you have a product thateffectively treats ovarian cancer, breast cancer and vaginal cancer, you have apopulation that is greater than 200,000 in the United States and 5 in 10,000patients 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 in10,000 in the EU.

The promise and pitfalls of the orphan disease market

The National Organization for Rare Disorders (NORD) reportsnearly 7,000 orphan diseases affect nearly 30 million Americans. As more drugcompanies search for new approaches after mass-market drug revenues are lost togeneric competition, orphan drug development is gaining momentum.

Orphan drugs have grown at a significant compound annualgrowth rate (CAGR) of 13.1 percent, or $2.3 billion, in 2010, to a projected $6billion in 2018 in the United States and the top five countries of Europe andJapan, according to Medical Marketing & Media (MM&M).

Increasing awareness of the disease and drugs among patientsand physicians, patent protection and the anticipated launch of new moleculessuch as ACR-16, AMR-101 and HD-02 for the treatment of HD and the approval ofAvastin for the treatment of advanced ovarian cancer in Europe will drive theglobal orphan disease therapeutics market in the forecast period, according toMM&M.

"Companies are looking carefully at the rare disease areanow, especially given last year's robust wave of approvals," says Noah Pines ofMM&M. "But there's a steep curve. Beyond small patient populations, firmsin this burgeoning space face a host of unique challenges."

As the ODA turns 30 this year, "those who had a hand infacilitating its passage would be taking heart now that innovative medicinesfor rare diseases are roaring into the spotlight," Pines says. "Of the 39products 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 atvery carefully right now," says Peter Saltonstall, who heads NORD.

Pines counters that few of these will achieve the commercialstardom of Alexion's hematology drug Soliris or Novartis' cancer med Gleevec.Among the first orphan blockbusters, these drugs showed that premium pricingand the ability to push into multiple indications could offset the typicallysmall 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, saysSaltonstall.

"We're not likely to see more big pharmas look to orphandrugs as an antidote to the patent cliff," according to Bernstein Researchanalyst 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, deepapproaches. It is not like pharma can just pick it up. It is out of theirwheelhouse," he adds.

Mike Scott, executive vice president at IndependenceHealthCom Strategies Group and the current chairman of NORD, stated inMM&M's report, "It is not a matter of mass marketing; it is a highlytargeted form of communication, in terms of identifying patients and thedoctors who treat them, and working very closely with the rare disease advocacyorganizations, who know this, to be able to get the right information to theright people.

For instance, Kalydeco (ivacaftor, or VX-770) won FDAapproval last year, Scott says. Years prior to launching the cystic fibrosisdrug, Vertex Pharmaceuticals nurtured a close partnership with the CysticFibrosis Foundation. Besides helping Vertex identify patients for trials, thefoundation assisted with an extensive campaign to educate the community aboutthe need for genotype testing, which determines their eligibility for theproduct.

Today, education about diagnosis is more important thanproduct promotion. That's because patients with rare diseases are often hard todiagnose, and once diagnosed, they tend to take an approved drug, according tohealthcare specialist. Companies have also discovered that many patients ofrare diseases go years before they are even diagnosed.

Given that 80 percent of rare diseases affect children, theemphasis for orphan drugs shifts from an all-knowing family physician to thehealthcare expert of the house: Mom or Dad, according to Peter Nalen, presidentand CEO of Compass Healthcare Marketers.Drug companies seeking to market orphan drugs must alsodemonstrate how use of the product is somehow more cost effective than notreatment or other modalities, and may fall outside traditional healthcareoutcome measurements, he says. For this reason, other factors come into playsuch as societal benefit, seriousness of the condition and the smallpopulations for statistical studies.

Aside from the commercial implications of pharma's interestin 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 yearsof 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 technicalchallenges in rare diseases, says Shire Human Genetic Therapies PresidentSylvie Grégorie. With many rare diseases, the company seeking to develop orphandrugs 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 pointin their illness, questions of how long it will take before demonstrating abenefit and/or whether the parents give consent.

With such small numbers, it is difficult to find a robustpatient base, get them enrolled in a clinical study and demonstrate astatistically meaningful effect, according to healthcare specialists. Oneexample is mantle cell lymphoma (which constitutes 5 percent of all non-Hodgkin'slymphoma). There are numerous options for initial therapy and at relapse, socomparison studies are difficult given the different possible "control" groupoptions, says Dr. John Leonard, who heads the new clinical trials office atWeill 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 ofdrug development—people who know a disease, who are committed to it, who getthe funds and who organize the trials themselves."

Unfortunately, the reality is that all too few companies arewilling to invest in low volume, low-return research programs. Thus the needsof the few are lost to corporate profit/loss statement, says Rare DiseaseTherapeutics Inc. on its website.

However, Rho is on record, stating it shares a passion fordiscovering new treatments and has experience successfully helping companiesnavigate 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 keenunderstanding 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 newtreatments to improve and save lives as quickly as possible."