Orphan Drugs

Growing Hope For Rare Disease Patients

Journalist | Jimin Seo | jmdemi@hanmail.net Designer | Seungwoo Lee | seungwu210@yonsei.ac.kr

Orphan drugs are, per definition, pharmaceutical agents that are developed for the prevention, diagnosis and treatment of specific rare medical conditions. In the US, rare diseases qualify when they affect fewer than 200,000 people while in Europe the standard is fewer than 5 in 100,000 people. In South Korea, a rare disease is defined as a disease or condition that affects less than 200,000 people of its population with no available treatment. Currently in Korea, orphan drugs are supplied to patients via pharmaceutical companies or the Korea Orphan Drug Center.

No more than four decades ago, patients suffering from life-threatening, chronically debilitating conditions were presented with very few - if none - options. The nature of such ailments poses many challenges not just to the patients, but to their families, communities, healthcare systems, and healthcare professionals as well. Developing orphan drugs that uniquely target rare conditions can be seen as risky and complex for pharmaceutical companies since the pool of patients is small and widely dispersed. Additionally, there are relatively fewer clinical centers or expertise available, which leads to major regulatory and logistical issues. The prices o f drugs naturally skyrocket to reflect R&D investments, while the difficulty of carrying out randomized controlled trials provides limited clinical evidence compared to other drugs.

Prior to 1983, a mere number of 38 drugs were approved to treat rare diseases.

1983, the Turning Point

The United States was the first to take legislative action to address this niche problem. In 1979, the Food and Drug Administration (FDA) task force issued a report that called for action to tackle the “orphan drug problem”, labeling it a significant healthcare issue. This cause was supported by a group of lawmakers, celebrities like the Klugman brothers, along with the tireless efforts of parents and patients, and combined they finally managed to push the Orphan Drug Act (ODA) over the finish line. The bill was signed into law by President Reagan on January 4th, 1983.

Since then, the ODA has paved the way for innovation and change. It financially incentivized pharmaceutical companies to allocate more of their time and resources into research, development, and distribution of therapeutics for patients with rare diseases, who before had been ‘orphaned’ by the medical community. The benefits include tax credits for qualified clinical testing, a Waiver of the Prescription Drug User Fee (which is almost $3 million for a new drug), and potential 7 years of market exclusivity. The impact of this law was undeniable - since its passage, more than 7,000 rare diseases have been identified and over 1,100 orphan treatments have obtained approval from the FDA.

Similar bills and policies that encourage the development of orphan drugs have been issued in 1993 in Japan, 2000 in the EU, and 2015 in Korea. The market exclusivity in Korea is 4 years.

2023 marks the 40th anniversary of the ODA.

The Trend

Currently, orphan drugs are the fastest growing segment of the pharma market and dominate FDA approvals. The number of orphan drug designations being awarded has rapidly increased in the last 20 years, although this cannot be attributed singularly to the ODA. The acceleration in the development of orphan drugs can also be due to the growing understanding of the underlying disease pathophysiology which has greatly improved thanks to advances in genomic research, the identification of new disease subtypes and their molecular etiology, the development of personalized medicine, growing public awareness and patient advocacy, and the integration of technology and artificial intelligence (AI) tools in research.

According to the trajectory, the top ten biggest orphan drugs will be worth $64 billion globally by 2028, in which orphans will make up almost a fifth of all non-generic drug sales. Over a third of global drug sales at Johnson & Johnson and AstraZeneca in 2028 will come from orphans (mostly in oncology). The trend is familiar - orphan drugs have outgrown their non-orphan counterparts apart from Covid-19 boosted 2021 and 2022, and even a global pandemic wasn’t enough to fundamentally affect this trajectory. Consensus predicts that orphan drugs will grow two-thirds faster than non-orphan drugs, and by 2028, they will be worth a staggering $300 billion.

The statistics speak for themselves - there is no doubt that orphan drugs will be a major focus in the pharmaceutical industry this year and upcoming years.

Notable Breakthroughs

Complicated by financial incentives, the ethical concerns of advertising strategies lead to the question: How can drugs be ethically marketed? In order to further reduce illegal rebates and rising prices, the implementation of DCTPA seems to be an effective solution, with some adjustments.

Product-specific ads should be prohibited and DCTPA should be focusing more on non-branded information such as common medical conditions and classes of prescription drugs. Quantitative Information should also be included, removing qualifying statements in order to display the realistic benefits and the risks. Through these crucial modifications, we move a step closer to achieving ethical marketing of pharmaceutical products. B

Despite the growing graphs and increasing pie of orphan drugs currently being developed, the scene is far from perfect when it comes to the drugs actually being administered to the patients that need them. Extended market exclusivity, while definitely a giant incentive for pharmaceutical companies, is often associated with high drug pricing and limited patient access. Apart from financial uncertainty, there are also inherent scientific risks since the small patient population makes designing clinical trials much more complicated. The lax standards for clinical evidence used to obtain regulatory approval - as well as the sustainability of drug prices - are still major concerns among stakeholders in the industry. Orphan drugs, when released, hit the market with high prices that sometimes do not reflect the clinical benefits. Also, the prices rarely go down even when additional indications are added. Some have even found a loophole in the ODA that allows them to maintain exclusivity for diseases that affect 200,000 or more patients by ‘piggybacking’ on older orphan drug designations. This problem is expected to be alleviated if the Fairness in Orphan Drug Exclusivity Act is passed by the senate, which will be able to close the loophole. As for the clinical trials and the quality of trial evidence presented by the companies, the FDA collects patient experience from patients, family members, caregivers, advocacy groups and foundations in the form of patient-focused drug development meetings. This is an attempt to help drug developers determine relevant endpoints for clinical trials.

The US Inflation Reduction Act (IRA) was also signed in 2022, and put the costliest Medicare drugs on course for price cuts. This includes 6 out of 2028 forecast’s top 10 orphan drugs. Meanwhile, as several blockbuster drugs will lose their exclusivity within this decade, the “big pharma” might do better to look towards drugs for big diseases to fill in the gaps left by Humira or Keytruda. For instance, Pfizer announced in January that it will cut in-house R&D in rare neurology and cardiology indications.

Now, there are ongoing court cases and petitions to amend the ODA. Lore Wilkinson, a 91-year-old patient diagnosed with Lambert-Eaton myasthenic syndrome (LEMS), is a patient advocate. She is now faced with having to pay $9,000 a month for her medication after Firdapse was granted orphan drug status from the FDA in 2018, making it impossible for her to be supplied with any alternative drugs. Similarly, there was a prior case concerning the exclusivity of Gralise, an orphan drug that treats nerve pain. Although Gralise was not deemed to be clinically superior to another drug already on the market, it was still granted exclusivity following the conditions laid out by the ODA.

“They have to change the law,” Wilkinson said. She claims that pharmaceutical companies should be designated orphan drug status and be granted exclusivity only when a “really new medication” is developed, not when they simply change one molecule.

“I’m an old lady, and I don’t know if it is going to get fixed.”