The definition of rare disease is a condition or disease that affects less than 200,000 people in the US. In 1983, The Orphan Drug Act was introduced to provide financial incentives for research and commercialization of drugs for rare diseases. Prior to the Orphan Drug Act, only 38 orphan drugs had been developed. After 1983, over 220 orphan drugs were on the market in the US and more than 800 drugs in R&D.

However, despite this success Congress felt even more emphasis and funding should be allocated to rare diseases and in 2002, The Rare Disease Act was passed. This formed a network of regional centers of excellence for rare disease and increased funding for the diagnosis and treatment of rare disease through the Office of Rare Disease at the NIH

Indications for use in children apply to both the medical device and pharma/biotech industry.

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Rare Disease

When a drug is approved as an orphan drug, the financial reward is seven years of market exclusivity before another product can enter the market. The Orphan Drug Act also allows companies to receive a 50 percent tax credit on certain clinical trial expenses and waives FDA user fees.  In September 2010, the FDA announced that they were prepared to be flexible in the review of products for rare diseases. "The FDA has approved several products based on small clinical trials, with as few as 10 subjects, and often on one trial, Jesse Goodman, the FDA's deputy commissioner for Science and Public Health, told the Senate Health, Education, Labor and Pensions Committee during a hearing on developing therapies for rare pediatric diseases."

Can a company sustain a business focusing on just rare diseases? Most large companies have a diverse portfolio of products, while smaller companies take on a large risk with an orphan drug since most small companies only have one product. Very few companies pursued orphan disease therapeutics until Genzyme Therapeutics, a division of Genzyme Corporation, demonstrated success in this area. Genzyme Therapeutics not only focused on orphan diseases, but they also built a platform technology that specifically targeted lysosomal storage disorders.

Lysosomal storage disorders, such as Gauchers disease, Fabry Disease, and Huntington Disease, have 100% mortality and, and before Genzyme, had no treatments. Developing drugs to treat these diseases had a profound effect on the healthcare industry. CMS reimbursed drugs to treat lysosomal storage disorders even at a higher cost because the cost of therapy to reduce mortality and increase the quality of life for patient far out weighed the cost of caring for the patient until the end of life.

Since the success of Genzyme, a number of other companies have also targeted lysosomal storage disorders, including Shire with Replagal® (from TKT) for Fabry disease, Amicus Therapeutics developing a drug called Amigal to treat Fabry disease and Denmark's NeuroSearch developing Huntexil for Huntington's disease.

Due to the current economic environment and healthcare reform, a number of Big Pharma has formed rare disease business units such as Sanofi- Aventis who just acquired Genzyme for their rare disease business.

In the later part of 2010, GSK bought the worldwide rights to Amicus Therapeutics' Fabry disease drug Amigal (migalastat HCl). Marc Dunoyer, Global Head of GSK Rare Diseases commented, "Our focus now is to continue to advance Amigal for Fabry disease and it is our hope to deliver a first-in-class, oral medicine to the thousands of people worldwide living with this devastating rare disease."

Amgen is considering Actelion Ltd. to acquire their drugs for rare diseases. "Actelion, the world's biggest maker of pulmonary arterial hypertension drugs, may generate $2.1 billion by 2015 from Tracleer, (and)...from two experimental drugs in final-stage tests for the rare condition... said Olav Zilian, an analyst with Helvea AG."

In September 2010, Pfizer acquired FoldRx based in Cambridge, MA for its lead molecule to treat a neurodegenerative disorder called TTR amyloid polyneuropathy. This disorder only affects 8,000 patients worldwide.

In addition, Pfizer and Novartis have focused on expanding their cancer drugs Sutent and Afinitor respectively to treat a rare form of pancreatic tumor. " Both (drugs) used to treat kidney cancer, more than doubled the time that patients lived without their pancreatic neuroendocrine tumors spreading, according to company-funded research reported today (Feb. 9th, 2011) in the New England Journal of Medicine."

In the last four months 7 companies have obtained "orphan drug" designation for their drugs in development. To view the list of companies, click here.

Indication for Use in Children

In addition to the FDA's focus on rare disease, a group of bipartisan senators, Sherrod Brown (D-Ohio), Sam Brownback (R-Kan.) and Al Franken (D-Minn.) introduced to legislation the "Creating Hope Act" to encourage drug makers to have a primary focus on rare children's diseases. This Act would expedite the FDA approval process for pharmaceutical companies that develop drugs for the treatment of rare pediatric diseases. Congress is hoping that this financial incentive of early market approval would encourage companies to target the "lesser needed treatments."

Conducting clinical trials in children presents two challenges 1) higher standards for safety and efficacy in a child verses an adult and 2) recruitment.

1) Safety and efficacy in children vs. an adult - in any drug development, not only does one have to be concerned with safety and efficacy but more importantly the long- term affect of the drug on the future development of a child. This is the reason why drugs are contraindicated in pregnant women. A child is still developing their full immune system and other systems that make a child biologically different from an adult. For example, when a child greater than 6 months has a temperature of 101-104 degrees, the pediatrician will be concerned if it is accompanied by symptoms and/or the duration of the fever. For adults having a temperature of 103 degrees or higher is considered dangerous.

2) Recruitment- it is difficult to recruit children into trials particularly in rare disease because the disease may be difficult to diagnose by your average MD who has not seen a case before, and who then refers the child to a specialist. Depending on the disease, the severity of the disease and the mortality rate, by the time a child is identified to enroll into a trial, the child may be nearing his or her life expectancy. In some cases the parents may not want their child to be in the control arm knowing that there is a medication that might help their child.

Alexion Pharmaceuticals Inc. has taken on these challenges when they acquired patents and assets from Orphatec Pharmaceuticals GmbHm in Germany to treat a very rare genetic disorder. The disorder is molybdenum cofactor deficiency (MoCD) Type A, which results in severe brain damage and rapid death in newborns because of buildup of neurotoxic sulfite. The deal included Alexion entering "into a research collaboration with certain MoCD researchers from Orphatec to speed up development of the possible therapy."

In addition, vaccine makers, AstraZeneca and Novartis have recently received EU approval for a Nasal Flu Vaccine for Children and FDA approval for Meningitis Vaccine in Children respectively.

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An expedited approval process and financial incentives have encouraged a greater proportion of companies today to focus on this area than ever before.  These companies include not only established companies but also start-up companies spurring innovation. 

What is the reaction from industry leaders about targeting rare diseases? "For me, every sign here that more people are getting involved in rare diseases and gene therapy is a great thing," says Nick Leschly, president and CEO of Bluebird Bio, a biotech company developing gene therapies for rare diseases such as beta thalassemia and childhood cerebral andrenoleukodystrophy.

Sylvie Gregoire, president of Shire Human Genetic Therapies said "I think that the whole sector of rare diseases has gained more attention, not just from companies but from the FDA and the NIH.  In a way, that's good for the science in terms of investment."

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The indications for medical devices vary widely from diagnostic uses to treatment. Medical devices are usually employed to treat physical defects, whereas biological defects are usually treated with drugs as in the case with most rare diseases.

Is there enough indication for use in treating children? In April of 2010, the FDA proposed a new rule that required medical device manufacturers, who were applying for an HDE, PMA or a new "product development protocol for a device intended to treat adults, will have to provide information about possible pediatric populations.  This information, which CDRH says should be readily available, includes a description of any pediatric subpopulations that suffer from the disease or condition the device is intended to treat and the number of affected pediatric patients." The rule would take affect August 16, 2010.

However, the FDA withdrew its proposal after they received "significant adverse comment on what it intended as noncontroversial amendments to existing regulations, the FDA says."

Indications for use in treating children are an unmet need and like pharma and biotech, the device manufacturer face similar challenges with respect to the cost for R&D, clinical trials, and concerns with the development issues in children. Some devices can be tailored to children without extensive R&D and clinical trials and some manufacturers have tried to accommodate this demand. For example, SyberMed Enterprises LLC has launched two new versions of its intravenous-tube-securing device, with the new products aimed at children and infants this past January.

Compared with adults, children are more delicate and the space to maneuver in a child is much smaller thus pediatric surgical devices and instruments must not only be smaller, shorter, or thinner, but at the same time, for the surgeon, the instrument has to be comfortable, easy to use and precise.

In addition, the device companies and physicians are concerned about the future development of the child with any surgical treatment. For example, in my February newsletter under the "new technology" link, an Orthopedic surgeons at Emory Sports Medicine Center and colleagues at Emory Univ. have developed a 3-D MRI technology (device) that allows surgeons to pre-operatively plan ACL repair on children without harming their growth plate. In the case of implants, the concern is whether the device will be able to accommodate the child's growth to adulthood and the safety of the implant long term.

With minimally invasive surgery, such as a cardiac catheterization, developing devices is even more difficult technologically. When you develop a device such as a guidewire smaller in diameter or thinner, by the laws of physics and material properties, it will be less stiff and therefore harder to maneuver the guidewire making the procedure more difficult. There is always a trade off in developing devices specific for pediatrics. Clinical trials are usually required no matter which treatment method is chosen since studies have never been conducted on children before.

The FDA together with the Society for Cardiac Angiography and Interventions (SCAI) has formed a group called The Bioabsorabable Working group to address the needs of the pediatric population. According to Carol Devellian, Vice President of Research & Development at NMT Medical Inc. and part of the Bioabsorbables Working Group, "The Group is drafting guidelines on pre-clinical and clinical evaluation of bioabsorbable stents and cardiac occluders for pediatric indications which will hopefully help to facilitate more device approvals for specific pediatric indications. We are hoping that by leveraging some of the testing conducted for the adult indication, the burden to industry will be minimized, hopefully resulting in more development and approvals in this area."

To address the cost of development and clinical trials, Devellian commented that "the FDA is working to minimize the regulatory burden and NIH has grant funding available to assist manufacturers in this area. There are also non-profit medical device companies that are developing products for certain pediatric applications as well, so there is a movement attempting to promote increased development of medical devices to meet the needs of children."

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