From The Editor | December 6, 2018

How Can Government Promote Orphan Disease Research?

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader

orphan rare disease

Mallory Factor has spent the last 30 years of his career launching, developing, and investing in early-stage pharma and med device companies. But, he has always had an interest in helping patients with orphan diseases. Factor is now the chairman of IntraBio, a company focusing on the development and commercialization of drugs that treat common and rare neurodegenerative diseases.

Factor is passionate about orphan diseases. He believes the current process to bring therapies to patients with orphan diseases is flawed. In October 2018, when he had the opportunity to appear before the Senate Subcommittee on Children and Families (a subcommittee of the U.S. Senate Committee on Health Education Labor and Pensions) regarding the regulation of drug development for rare diseases, he jumped at the opportunity.

Factor has worked with regulatory agencies in both the U.S. and Europe on matters relating to clinical development programs. In doing so he had the opportunity to observe the obstacles that serve to delay and even restrict novel orphan therapies from getting to patients. He also believes that orphan drug developers and the FDA could collaborate more closely to bring more treatments to approval.

The Challenges In Orphan Diseases

The FDA defines an orphan drug as a “drug intended to treat a condition affecting fewer than 200,000 persons in the United States, or which will not be profitable within 7 years following approval by the FDA.” There are estimated to be over 7,000 rare (or orphan) diseases, many of which are debilitating or life-threatening. The number of patients afflicted with these diseases can often be in the hundreds. Still, in total, about 30 million Americans are affected by an orphan disease. A large majority of these rare diseases have no FDA-approved therapy.

“I believe a possible explanation for why a majority of orphan diseases do not have approved treatments is that the process for developing and getting marketing approval for orphan drugs is almost the same as for drugs with common, non-serious disorders,” says Factor. “In this pathway, there are several requirements for assessing the safety and effectiveness of a new drug. These are concerned with the need to: Establish the compound’s safety and tolerability profile; design feasible trials with clinically relevant outcome measurements that assess the clinical efficacy of a treatment; select the correct sample size and eligible patients; recruit trial subjects according to established ethical principles; and secure adequate resources and funds to execute the study and address the regulatory requirements.”

With some non-rare diseases, this may not be a monumental challenge. In the rare disease space, where there are ultra-small patient populations, diseases that progress quite rapidly, and a large clinical variability between patients, the challenges can seem insurmountable. 

According to Factor, orphan drug developers cannot feasibly conduct development programs without consent from expert clinicians and the patient community regarding the scientific and ethical rational of development programs. There must also be consent from regulatory agencies regarding the appropriateness of the development programs for regulatory approval.

“For orphan drugs, the traditional regulatory pathways for non-clinical and clinical development are less likely to be compatible with the scientific and ethical rational deemed appropriate by clinicians and the patient community,” says Factor. “The process of getting all three bodies of experts—regulatory agencies, clinicians, and patient communities—to agree is often time-consuming, expensive, and uniquely challenging for orphan drug developers.”

Challenges Are Greater For Small Pharma

The orphan drug development challenge is even greater for small pharma companies. Large pharmaceutical companies generally have the resources to navigate the complex and costly orphan development process. However, these companies have traditionally had little involvement in the orphan drug space due to the small market size and corresponding small return on investment. As a result, most orphan drug development falls to startups or small companies with significantly less resources and funding. Developing treatments for many rare diseases is simply not economically feasible.

In his subcommittee presentation, Factor cited GM1 Gangliosidosis as an example. GM1 Gangliosidosis is a rare, genetic lysosomal storage disorder that predominately affects infants and early juveniles. It is extremely debilitating, rapidly progressive, and has less than 200 known cases. Because the non-clinical and clinical requirements for novel GM1 therapies are almost the same as for drugs for common, non-serious indications, these long timelines and high costs cannot be justified due to the limited potential return.

“The costs and difficulty of conducting trials for GM1 are even greater than for other conditions because it is a challenge to develop a clinical trial program that accommodates the ultra-orphan patient population and rapidly progressive conditions, while also meeting the regulatory gold standard of a large, randomized, controlled trial,” says Factor. “Sadly, the unique challenges and costs mean that too many promising treatments are abandoned even before they are trialed with patients.”

Help Pharma Help Patients

Orphan drug developers are commercial ventures, but their work will ultimately benefit patients. Therefore, anything Congress can do to facilitate and encourage more efficient orphan drug development for these underserved patient populations would benefit those affected. Factor stated in his testimony that a lot more must be done.

To facilitate the development of orphan drugs, Factor proposes a new regulatory pathway which differs from the traditional development program. He believes this new pathway should be designed so that there are earlier and more frequent interactions between the FDA and drug developers. The goal is to foster greater collaboration and assist in the design of non-clinical and clinical programs that take into consideration the scientific and ethical considerations of clinicians and the patient community. Those considerations should include the small number of patients, the rapidly progressive and debilitating nature of many rare diseases, the clinical variability between patients, and fact that there are generally no approved treatments for patients.

Factor also notes that another way that the federal government can encourage investment in rare diseases is to allow conditional approval for drugs with an established safety profile. If a medication has a very favorable safety profile and has shown efficacy, he believes it should be conditionally approved for treating rare, fatal, rapidly progressing conditions with post-approval rolling monitoring of safety and efficacy in patient populations. This would allow promising drugs to reach patients sooner while still providing extensive safety monitoring.

“If these measures were implemented, I believe orphan drug development would become more efficient, as development programs would be conducted that are appropriate for the patients being treated and considerate of the product-specific risk/benefit profile,” he says. “As such, the much-needed orphan drugs would reach patients with rare, fatal, genetic diseases faster while maintaining the high standards for safety.”

Orphan Drug Act And Breakthrough Designation Not Enough

The industry currently has the Orphan Drug Act and Breakthrough Therapy Designation to assist companies focused on rare disease. But Factor states these efforts are insufficient. The Orphan Drug Act legislation was put in place in 1983 to encourage the development of drugs for rare diseases. It was pioneering legislation that resulted in the number of approved orphan drugs increasing from 38 before the legislation to 373 drugs by 2014. 

Still, this has not eliminated the problem, as the number of orphan drugs approved today is disproportionately smaller than the number of non-orphan drugs. Factor notes a plausible explanation for this difference is that most of the benefits of the Orphan Drug Act are not triggered until after clinical trials have already been conducted and NDA is sought.

Similarly, he states designations like the Breakthrough Therapy Designation are granted too late in the development process—only after IND applications for clinical trials are filed. In both cases, the interaction between orphan drug developers and the FDA is significantly limited when designing clinical trials and throughout the early research stage.

“Since orphan drug development still predominantly relies on the province of startups and small companies that have significantly less resources and funding than big pharma, these provisions do not actually help orphan drug developers bring new treatments through the trial approval process,” he says. “In the absence of early and frequent contact and collaboration between orphan drug developers and the FDA, novel therapies often fail. Orphan drug developers face too much uncertainty in designing non-clinical and clinical programs that satisfy patients, clinicians, as well as regulatory requirements. For that reason, many valuable treatments never become available to patients.”

If there were earlier interactions between orphan drug developers and the FDA, the regulators could make use of the flexibility it has to decide on the approvability of a new treatment, as well as the appropriateness of the “gold-standard” randomized controlled trial. These interactions could also provide regulators with a more complete scientific and ethical background of the risk-benefit of a proposed treatment. Given this “whole picture” view, regulators could exercise flexibility regarding both non-clinical and clinical programs based on what is already known about the pharmacological properties of the orphan drug and the patient population it intends to treat.

“Regulators would be able to identify what data is relevant and must be generated before trials can be approved, while setting aside other requests for additional data that would be nice to have but is not necessarily critical to the overall benefit-risk assessment,” says Factor. “Early and frequent interactions could also reduce the guesswork about what is acceptable in terms of trial designs and assessment endpoints. Early and frequent interactions would also help ensure that cost-effective nonclinical development programs, ethical trial design, and appropriate clinical outcomes for patients are being used. All of this would make orphan drug development a more expedited and streamlined process so that new treatments would reach and benefit patients sooner.”