Photo ID 9988195 © Serialcoder Dreamstime.com Introduction Orphan drugs are therapeutics that treat rare diseases, defined as affecting 200,000 or fewer people in the United States, that normally would not receive investment given the small patient population. Passed in 1983, the Orphan Drug Act (ODA) promoted orphan drug development through incentives, including seven years of exclusivity.[1] However, a 2021 court decision undermined the original spirit of the ODA, resulting in fewer incentives for researching and developing critical therapeutics necessary for treating patients suffering from rare diseases, particularly children. The Retaining Access and Restoring Exclusivity Act (RARE Act),[2] would rectify the impacts of this decision and restore the ODA to its original intent. This would also fulfill the state’s obligations to justice under the application of the difference principle to drug development priority-setting. Background Under the ODA, drug companies obtain an orphan designation prior to clinical trials.[3] If the drug is proven to be safe and effective, then the FDA approves the drug for a specific use or indication. For example, the FDA could approve a cystic fibrosis drug for adults with a given genetic mutation. The exclusivity would then apply only to the use of the drug in that population.[4] The orphan drug designation gives the pharmaceutical company seven years of market exclusivity. Catalyst v. Becerra In 2009, Catalyst received an orphan drug designation for its drug Firdapse (amifampridine) for the treatment of Lambert-Eaton Myasthenic Syndrome (LEMS), an autoimmune disease that affects less than 0.001 percent of the population. The FDA approved Firdapse for adults with LEMS in 2018 and granted Catalyst exclusivity through 2025. Jacobus had developed Ruzurgi (amifampridine, the same drug) to treat LEMS and received an orphan drug designation in 1990. In 2019, the FDA approved Ruzurgi for patients less than 17 years old.[5] Catalyst sued the FDA, challenging the FDA’s long-standing interpretation of market exclusivity. The case, Catalyst Pharmaceuticals v. Becerra, centered on how broad exclusivity is and sought to answer the question of whether or not the statutory phrase “same disease or condition” contained in the ODA was ambiguous.[6] The 11th Circuit determined that the phrase was not ambiguous, broadening the traditional FDA interpretation of “same disease or condition.” The court found that FDA approval of Ruzurgi for pediatric patients violated Catalyst’s exclusivity. The court held that Congress would have included specific language for “use or indication” if it had intended the statutory phrase to be interpreted to limit exclusivity to the specific use and indication and to allow other brands to market to subgroups after demonstrating safety and efficacy in those groups.[7] Prior to Catalyst, the FDA interpreted the ODA to limit exclusivity to particular uses and indications. The FDA encouraged other companies to engage in clinical trials to serve subpopulations and approve existing drugs for additional subgroups within a disease. That way, FDA approval of a drug for adults would not discourage others from researching the same drug for pediatrics.[8] The RARE Act would clarify and codify the FDA’s long-standing interpretation of the ODA limiting exclusivity to use or indication. The Ramifications of Catalyst The court’s interpretation of orphan drug development has created a policy landscape that deters orphan drug research, straying from the ODA’s intent. For example, a company that studies an existing drug with an orphan designation but for a different population subgroup, such as children, and demonstrates its safety and effectiveness, would be unable to receive a period of exclusivity.[9] Without that key incentive, many companies would likely focus on other areas of research. Exclusivity is meant to promote rare disease research and eventually lead to new treatments for patients, not constrain them. The court’s ruling has jeopardized the underlying purpose of the ODA in serving the needs of rare disease communities. The downstream effects of Catalyst on drug development are already being observed in FDA approval rates for new drugs. In the 16 months preceding the Catalyst decision, the FDA approved 217 orphan drugs.[10] After Catalyst, that dropped to only 95 drugs being approved.[11] The interpretation proposed by Catalyst and held by the 11th Circuit also ignores important scientific truths recognized by both medical experts and Congress. Children are not simply “small adults.”[12] Children can have different manifestations of the same diseases as adults, as well as respond differently to treatment.[13] In the context of rare diseases, advancing drug treatments is especially important for pediatric populations, as many rare diseases develop during childhood.[14] Congress has sought to address the need to promote drug treatment research in children by passing both the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.[15] The interpretation in Catalyst ignores this fact and errs in ignoring the critical need to distinguish indications for granting exclusivity. Without clarification of the RARE Act, drug companies might also be deterred from future orphan drug development, given the existing confusion on the approval process and ambiguity in regulatory guidance. In Catalyst, the court ordered the FDA to set aside the drug in question. While the FDA complied with the court, it also posted a notification in the Federal Register in 2023 regarding its continued intent to grant approvals beyond the scope of Catalyst, using the standard of use or indication.[16] The FDA justified this decision by saying continued adherence to the ambiguous language of the statute would “best serve the public health by facilitating patient access to orphan drugs, especially for difficult-to-study patients such as young children.” The RARE Act would remove any confusion in the approval process by granting the FDA the explicit statutory authority to approve the same drug from different manufacturers if they are able to treat different patient populations. It would also remove the possibility of future drug sponsors challenging competing orphan drug approvals on the basis of the reasoning in Catalyst. The Difference Principle in Context Only about 5 percent of rare diseases have an FDA-approved therapy, and this is after four decades of targeted research and development incentives through the ODA.[17] Subgroups like pediatric populations fail to attract investment and research attention from industry because barriers like confusion over exclusivity exist. Some might argue that incentivizing research into subgroups for rare diseases is a misguided approach, as it encourages investment into drugs which would benefit only a very small population. Why should we promote the use of significant resources for these small populations when those resources could go to drug research that could benefit more people? The difference principle, as proposed by John Rawls, enriches and supports our understanding of the state’s obligations in the context of drug development and priority-setting in research incentives. The principle holds that social and economic inequalities are justified only if they benefit the least advantaged members of society.[18] Applied here, it supports prioritizing research for pediatric rare diseases—even if only a small group benefits—because doing so helps those who are most disadvantaged in the healthcare system, providing them with opportunities to live a good life, as they conceive it, that they would not otherwise have. Congresswoman Doris Matsui (CA-07), co-chair of the Rare Disease Congressional Caucus, answered the question more concisely by stating that “access to medicine shouldn’t be sacrificed for drug companies’ bottom line.”[19] If you believe that children with rare diseases deserve a fighting chance and should not be neglected for the sake of profit, the RARE Act is a necessary and urgent step to fulfilling that moral commitment. Some argue that without broad exclusivity for an entire disease, companies might not invest in orphan drug development at all. But this concern is overstated. The FDA’s earlier approach still gave companies meaningful protection for specific indications, like adults, while allowing others to step in and develop treatments for different groups, such as children. Broad exclusivity shuts that down, blocking follow-on research that could reach patients with no other options. The RARE Act would fix this by restoring a more practical balance between rewarding innovation and expanding access. Conclusion The House passed the RARE Act in September 2024, although it fell short of being signed into law. Although there has been consistently strong bipartisan support for the legislation, confounding political tensions concerning government inefficiency have caused these provisions to be left in a state of legislative suspension. The language of the RARE Act has been introduced once again as a part of the Give Kids a Chance Act and introduced to the House by Representative Michael McCaul (R-TX) this March. Catalyst has jeopardized the original spirit of the ODA as a means of helping those who need it most. Congress must pass the RARE Act to realign the function of the ODA with its intended purpose and fulfill the state’s obligations under an ethical framework that is committed to prioritizing the most vulnerable and worst-off. - [1] Katie Cohen, “A Catalyst For Reform: Charting A Future For Orphan Drug Exclusivity,” University of Pennsylvania Law Review vol. 173, iss. 3 (2025): 909. https://scholarship.law.upenn.edu/cgi/viewcontent.cgi?article=9883&context=penn_law_review [2] Now included as Section 6 of the Give Kids a Chance Act (H.R. 1262), [3] Karin Hoelzer, “Congress should protect the intent of the Orphan Drug Act and pass the RARE Act,” NORD, https://rarediseases.org/pass-the-rare-act/ [4] Ibid. [5] Catalyst Pharmaceuticals, Inc. v. Becerra, No. 20-13922 (11th Cir. 2021), 7-9. [6] Catalyst Pharmaceuticals, Inc. v. Becerra, No. 20-13922 (11th Cir. 2021), 2. [7] Catalyst Pharmaceuticals, Inc. v. Becerra, No. 20-13922 (11th Cir. 2021), 13. [8] “FDA’s Overview of Catalyst Pharms., Inc. v. Becerra,” https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/fdas-overview-catalyst-pharms-inc-v-becerra [9] Ibid. [10] Katie Cohen, “A Catalyst For Reform: Charting A Future For Orphan Drug Exclusivity,” University of Pennsylvania Law Review vol. 173, iss. 3 (2025): 920. https://scholarship.law.upenn.edu/cgi/viewcontent.cgi?article=9883&context=penn_law_review [11] Ibid. [12] Thomas R. Welch, “Children are not Small Adults,” Journal of Pediatrics vol. 271(2024). [13] Ibid. [14]Apoorva Kakkilaya, Mahnum Shahzad, and Florence T. Bourgeois, “FDA Approval of Orphan Drug Indications for Pediatric Patients, 2011-2023,” JAMA Pediatr. 179, 2 (2025): 203-205. https://doi.org/10.1001/jamapediatrics.2024.5280 [15] Michael Christensen, “Best Pharmaceuticals for Children Act and Pediatric Research Equity Act: Time for Permanent Status,” J Pediatr Pharmacol Ther. 17 (2) (2012):140. [16] “Clarification of Orphan-Drug Exclusivity Following Catalyst Pharms., Inc. v. Becerra; Notification,” Federal Register, https://www.federalregister.gov/documents/2023/01/24/2023-01179/clarification-of-orphan-drug-exclusivity-following-catalyst-pharms-inc-v-becerra-notification [17] Hannah-Alise Rogers, “The Orphan Drug Act and Catalyst Pharmaceuticals, Inc., v. Becerra,” Congressional Research Service (2023). https://sgp.fas.org/crs/misc/R47653.pdf [18] John Rawls, “A Theory of Justice,” Harvard University Press (1971): 65. [19] “Legislation Included as Part of Rare Disease Package,” https://matsui.house.gov/media/press-releases/house-passes-matsuis-rare-act

Photo ID 93567823 © Nataliia Mysik Dreamstime.com Introduction Many parents diagnosed with debilitating anxiety disorders fear their children will suffer from the same psychiatric illness that has plagued their entire lives. While Preimplantation Genetic Diagnosis has long allowed parents to screen out embryos with a predisposition to certain disorders, the practice collides with many religious or personal beliefs. With the advancement of genetic-engineering technologies, such as CRISPR-Cas9, scientists have speculated about using such techniques to alter genetic material to reduce the risk of acquiring – or passing along – complex psychiatric disorders. Although somatic cell engineering could theoretically correct genetic variants associated with anxiety in any one individual, the prospect of editing the germline to permanently induce genetic changes for multiple generations proves enticing. However, the unforeseen consequences of applying germline engineering for complex anxiety disorders raise important moral considerations. The unpredictable health risks to future generations incurred by germline genetic engineering for anxiety disorders outweigh the potential probabilistic benefits through a consequentialist lens. Health and Genetic Risks of Germline Editing Editing the human germline to prevent psychiatric disorders poses serious health risks to individuals. Currently, scientists warn that genetically altering the human genome can result in off-target mutations that increase the risk of disease. For instance, gene-editing technologies like CRISPR-Cas9 can make unintended cuts in the genome, possibly preventing important genes from functioning properly. Additionally, cells may divide before gene-editing has completed, or the editing technology may inadvertently modify only one copy of the target alleles. Such mistakes produce a mixture of distinct genotypes within a single individual—a phenomenon known as genetic mosaicism.[1] However, even assuming germline editing has advanced enough for these off-target effects to prove negligible, serious consequences still may arise from the intended genetic alterations due to pleiotropy. Many individual genes impact various aspects of physiology or behavior. For example, the CCR5 gene encodes a macrophage receptor targeted by certain HIV strains. Interestingly, a naturally-occurring 32 base-pair deletion within the CCR5 gene confers greater resistance to these strains of HIV.[2] While inducing this deletion in the germline via genetic editing would seemingly reduce HIV transmission – a clear benefit to humanity – such a mutation may increase a person’s susceptibility to infection due to CCR5’s role in staging an immune response.[3] These pleiotropic effects extend to psychiatric disorders influenced by multiple genes, in which alleles associated with OCD risk, for example, positively contribute to educational attainment and performance.[4] Therefore, even if off-target effects are mitigated, editing anxiety risk genes can lead to unforeseen consequences due to their non-specific nature. There is a risk that genetic germline engineering would affect all of society due to its generational implications. While somatic engineering ensures any effects are contained to a single individual, altering the genetic material of germline cells may create pleiotropic consequences or genetic mosaicism that will persist for generations. Importantly, without sufficient quality control measures, researchers cannot know the precise effects of germline editing until after birth—and some problems may only emerge years later.[5] As a result, large portions of society may endure the unintended ramifications or elevated risks of editing anxiety-related genes for generations. In contrast, the British bioethicist John Harris equates the potential harms inflicted by germline editing as no more risky than natural sex: “Human reproduction involves genes being recklessly combined in the dark, with unforeseeable consequences for the resulting children, parents, and the generations to come.”[6] However, the risks associated with conception through “natural sex” do not justify conducting an expensive procedure with unknown effects given the mere probabilistic nature of anxiety-related genes. Proposing such a comparison assumes a cavalier attitude towards the real risk of pleiotropic effects and increasing the prevalence of ill-suited alleles. In essence, if germline editing is no different from conventional reproduction, why bother using the technique at all for anxiety disorders? At least with natural reproduction, parents avoid unnecessary costs and the potential guilt of unintentionally harming their child’s cognitive development or increasing their risk for other disorders. The Complex Heritability of Anxiety Disorders Because genetic germline engineering does not guarantee desired outcomes for anxiety-related disorders, its potential harms outweigh the anticipated benefits. The germline is not a sacrosanct entity considering its fluidity in everyday life: the genetic material of sperm modulates with age while sexual selection determines the combination of genes for potential offspring.[7] Researchers and clinicians should approach germline editing like any other medical procedure, weighing the benefits against potential harms. Of course, anxiety-related disorders lead to serious manifestations in patients, often requiring decades of psychopharmacology and psychotherapy.[8] However, genetic germline engineering does not provide a definitive and permanent solution to the underlying causes given the very nature of anxiety-related disorders. While anxiety disorders exhibit a heritability of 30-60 percent depending on the specific disorder, genes associated with such disorders behave probabilistically – not deterministically.[9] Whether a person develops a disorder and the severity of a disorder depend significantly on environmental factors.[10] As such, the variants associated with anxiety do not invariably lead to disorders. As a result, parents may be opting in to preemptively treat a disorder their child may not develop in the first place. Despite this, even if their offspring do develop an anxiety disorder, the magnitude of the condition may not warrant a treatment as drastic as germline engineering—one that risks unforeseen pleiotropic effects that last generations. Even if genes for anxiety could be edited with great predictive success, the line separating non-genetic anxiety from pathological versions is unclear. Emotions like fear and anxiety have evolved as important survival mechanisms for dangerous situations.[11] Gene editing could inadvertently weaken their protective functions. Safer and Less Intrusive Alternatives Genetic germline engineering offers a drastic option for individuals concerned about their high genetic risk for anxiety disorders, especially when safer and less extreme alternatives are available. Currently, multiple treatment options exist to improve the quality of life of patients living with mild anxiety disorders. For instance, medication and cognitive-behavioral therapy commonly manage many disorders, such as mild to moderate forms of social anxiety disorder (SAD) and obsessive-compulsive disorder (OCD).[12] Unfortunately, many individuals living with severe anxiety disorders do not respond to mainstream interventions. In these patients, overwhelming thoughts and compulsive tendencies that prevent basic facets of daily life may warrant treatments more aggressive than standard medication or therapy. Nonetheless, these patients could still explore the possibilities of genetic engineering technology without altering their germline and potentially endangering future generations. Somatic cell engineering more closely resembles standard medical treatments in that an individual weighs the benefits and harms to his or her own person. In the case of somatic cell editing, any unforeseen complications will die with the patient, preventing multiple generations from inheriting elevated health risks. Therefore, editing somatic cells to alter anxiety-correlated genes can yield similar results as genetic germline engineering without the added unknown ramifications. Although germline engineering may appear more cost-effective due to its long-lasting, multi-generational impact, the potential savings do not justify the risks of a therapy that could have severe consequences for many individuals. In addition, while the current costs of somatic engineering could be prohibitive, ongoing innovation may reduce its price over time. Considering individuals can benefit from less severe treatment plans if and only if they develop an anxiety disorder in the first place, germline engineering should not be offered for anxiety-correlated genes. Autonomy Concerns Genetic germline engineering violates the autonomy of potential offspring by imposing a procedure without their informed consent. Medical professionals and researchers must disclose enough information for individuals to weigh the benefits and risks of participation, enabling fully informed consent. However, germline editing causes repercussions that extend many generations into the future. It is clearly impossible to obtain consent of future individuals.[13] Proponents of genetic germline engineering refute this, citing the immense influence society generally allows parents to hold over their children’s education, medical issues, and more.[14] Although true, this argument assumes an absolute totalitarian view of parenthood in which parents never discuss medical risks with their child before making a final decision. Moreover, there is a huge ethical difference between genetically correcting a fatal disease caused by a single gene and altering anxiety-related genes in terms of autonomy. For instance, suppose a couple decides to genetically correct the gene that causes cystic fibrosis in their germline, obviously without clear consent from their potential offspring. This decision arguably promotes the overall autonomy of their children by removing the physical limitations imposed by the disease, thus outweighing any previous infringements on autonomy. In contrast, variants influencing anxiety-related disorders are not as concrete, given their complex genetic nature and susceptibility to environmental factors. Therefore, children would be subject to the risks and unknowns of germline editing all to preemptively treat a disorder they may or may not have developed. Rather, parents should allow future generations to dictate their own treatment – if any treatment is indicated at all – whether that entails medication, therapy, or (one day) somatic cell engineering. Conclusion While genetically engineering the germline to permanently reduce transmission of anxiety-related genes may seem like an ideal solution to prevent anxiety disorders, the practice presents substantial risks and unclear benefits. There is a risk of pleiotropic effects that could trigger health problems as serious or more severe than the targeted anxiety disorder itself. The potential complications not only endanger the recipient but jeopardize the health of future generations by altering the germline. These ramifications trump the prospective benefits of germline engineering for anxiety disorders considering anxiety-correlated genes act probabilistically – not deterministically — and are subject to a host of environmental influences. Based on a typical risk-benefit analysis, genetic germline engineering of anxiety-related genes crumbles in comparison to therapy, medication, and somatic cell engineering – all safer treatments that can be applied after birth, if necessary. - [1] Edward Lanphier and Fyodor Urnov, “Don’t Edit the Human Germ Line,” Nature; London 519, no. 7544 (March 26, 2015): 410–11, http://dx.doi.org.ezp-prod1.hul.harvard.edu/10.1038/519410a. [2] Alison P. Galvani and John Novembre, “The Evolutionary History of the CCR5-Δ32 HIV-Resistance Mutation,” Microbes and Infection 7, no. 2 (February 1, 2005): 302–9, https://doi.org/10.1016/j.micinf.2004.12.006. [3] Jean K. Lim et al., “Genetic Deficiency of Chemokine Receptor CCR5 Is a Strong Risk Factor for Symptomatic West Nile Virus Infection: A Meta-Analysis of 4 Cohorts in the US Epidemic,” The Journal of Infectious Diseases 197, no. 2 (January 15, 2008): 262–65, https://doi.org/10.1086/524691; Maximiliano Ruben Ferrero, Luciana Pádua Tavares, and Cristiana Couto Garcia, “The Dual Role of CCR5 in the Course of Influenza Infection: Exploring Treatment Opportunities,” Frontiers in Immunology 12 (January 20, 2022), https://doi.org/10.3389/fimmu.2021.826621. [4] The Brainstorm Consortium et al., “Analysis of Shared Heritability in Common Disorders of the Brain,” Science 360, no. 6395 (June 22, 2018): eaap8757, https://doi.org/10.1126/science.aap8757. [5] Lanphier and Urnov, “Don’t Edit the Human Germ Line.” [6] John Harris, “Germline Modification and the Burden of Human Existence” 25, no. 1 (2016): 6–18, https://doi.org/10.1017/S0963180115000237. [7] Harris. [8] Borwin Bandelow, Sophie Michaelis, and Dirk Wedekind, “Treatment of Anxiety Disorders,” Dialogues in Clinical Neuroscience 19, no. 2 (June 2017): 93–107. [9] In addition, many DNA variants linked to anxiety disorders are not exclusive to a single syndrome, further complicating the ability to predict risk scores for polygenic anxiety conditions. [10] The Brainstorm Consortium et al., “Analysis of Shared Heritability in Common Disorders of the Brain.” [11] Joseph E. LeDoux, “Chapter 21 - Evolution of Human Emotion: A View through Fear,” in Progress in Brain Research, ed. Michel A. Hofman and Dean Falk, vol. 195, Evolution of the Primate Brain (Elsevier, 2012), 431–42, https://doi.org/10.1016/B978-0-444-53860-4.00021-0. [12] Bandelow, Michaelis, and Wedekind, “Treatment of Anxiety Disorders.” [13] Lanphier and Urnov, “Don’t Edit the Human Germ Line.” [14] Harris, “Germline Modification and the Burden of Human Existence.”