The spread of Ebola virus is unsettling to many living in the United States, yet to date the U.S. FDA and the EMA (the FDA’s European counterpart) have not approved any medicines or vaccines that could treat a potential global outbreak. In October, both agencies released guidelines for companies that hope to get accelerated approval for potential Ebola treatments and if warranted, mechanisms for patients and clinicians to access unapproved treatments. Such emergency responses are unprecedented in recent regulatory history. Read more to understand why the FDA and EMA made these rules in the case of Ebola and how they change the course of drug approval.
The spread of Ebola virus represents one of the most severe public health crises in the 21st century and has dominated the headlines since the outbreak began. As of December 17, there have been 18,603 reported Ebola cases in eight countries, with 6,915 reported deaths . Although a handful of groundbreaking studies on Ebola have recently been published in high-profile journals like Science, they constantly remind us of the unrelenting toll exacted on not only patients but also researchers and health workers. For example, five out of 50 co-authors on the definitive genomic study on the origin of the outbreak contracted the virus and died .
To many living in the U.S., it is worrisome that, to date, no drugs or vaccines have been approved for the treatment or prevention of Ebola in case of a potential global pandemic. Yet, few of us can fathom the myriad of regulatory difficulties confronting drug manufacturers and government agencies before any treatment reaches the clinic. Recent actions taken by the US Food and Drug Administration (FDA) and its European counterpart, the European Medicines Agency (EMA) highlight the regulatory challenges in this process. In the face of the epidemic, these agencies seek to simplify the approval process and offer additional incentives for drug development.
Standard Drug Approval Processes in the US and Europe
In the U.S., the traditional drug approval process is excruciatingly long and expensive (Figure 1). Pharmaceutical and biotech companies, large and small, are required to submit an investigational new drug application (IND) for review by the FDA and a local institutional review board (IRB), before they can start testing new drugs in humans. Companies submit clinical trial protocols to the IRB, detailing criteria for enrolling patients in the trial, potential risks and benefits for enrollees, procedures for maintaining confidentiality of data, etc. The IRB chooses to approve or deny protocols based on if the trial is appropriately designed to protect the safety and well being of human subjects. Only after IND approval can companies conduct a multi-phase clinical trial establishing safety (Phase 1), efficacy (Phase 2) and later comparing the new treatment with the current standard of care in a larger population (Phase 3). With trial data at hand, companies then submit a new drug application (NDA) in order to seek FDA approval for marketing. Occasionally the FDA requests additional data about the product’s safety, efficacy and optimal dosage after the drug reaches the market through a process called postmarket requirement and commitment studies .
Conceptually, drug approval follows a similar procedure in Europe, in that separate applications are required for clinical trial protocol and marketing – the former at the level of individual member states, and the latter at both member state and the European Union (EU; centralized) levels. Companies may opt to pursue different regulatory strategies (i.e. following centralized, mutual recognition, or decentralized procedure), depending on if they intend to obtain authorization in multiple EU member states simultaneously .
Challenges of the Standard Drug Approval Process in the Case of Ebola
The traditional approval model clearly falls short in cases of exigency. It takes way too long to send a potential Ebola treatment through the pipeline during an imminent public health crisis. Even if the treatment successfully passes through the trials, regulatory agencies are likely to deal with limited data. Ebola is fast-progressing with a patient size too small for population-based trials. Moreover, due to dire prognosis, it is unethical to withhold patient access to any promising treatment, a scenario that precludes incorporation of a placebo control arm in trial design. Another challenge is the lack of incentive for companies to pour millions of dollars into development and clinical trials. Facing a small market, companies have to beat the grim odds for getting reasonable returns for their investment.
Addressing these Challenges
A good approval model for Ebola treatments has to address all three aforementioned challenges: time pressure, trial design, and incentive (Figure 2). To circumvent the first two challenges, the FDA has an expanded access program in place to enable clinicians to a) access investigational products outside of clinical trials under Emergency Use Authorization (EUA), and b) request the use of an unapproved or experimental medical product under an Emergency Investigational New drug Application (EIND) .
The third challenge, incentive, is not new. In 2007, the Food and Drug Administration Amendments Act (FDAAA) was passed in part to incentivize companies to invest in diseases that lack a lucrative market. In particular, the Tropical Disease Priority Review Voucher (PRV), if awarded, shortens the standard 10-month FDA review to six months . This may not seem like much, but if companies can get four extra months when they are the only ones making a certain drug, this monopoly could translate into millions of dollars in revenue. A PRV may be transferred from one company to another only once. A PRV transfer may be desired if a company a) wants to buy some time when its products are farther away from reaching the market than those of its competitors, or b) wishes to prevent its competitors from getting ahead by securing a shorter time window for review.
Unfortunately, until very recently, Ebola was not listed as one of the 16 tropical diseases eligible for the voucher system. To address this difficulty, the Adding Ebola to the FDA Priority Review Voucher Program Act was concurrently introduced in the Senate and the House in mid-November . The legislation sought to add a new category of Filovirus (which encompasses the Ebola virus) to the list, and cut the time that companies have to wait before redeeming the voucher by three-fourths from 365 days to 90 days. In addition, companies would be able to sell the voucher for an unlimited number of times, as opposed to just one sale. Under the old rule, companies might hold back from purchasing a voucher, because they were not allowed to transfer it later to a third party and would then have to use it. The bill was signed into law by President Obama on December 16, 2014 .
While the U.S. FDA and the bicameral legislature are trying to address the regulatory challenges for Ebola treatments, on October 20, the European Medicines Agency (EMA) announced that the agency encourages companies with potential Ebola treatments to apply for orphan designation to the EMA and the FDA at the same time . Orphan drugs get ten years of market exclusivity, a period in which similar medicines with the same indication cannot enter the market. In essence, the orphan drug designation grants a state of approved monopoly that allows the company to make exclusive profit from the consumer base and incentivizes investment and development of drugs with a small market. The EMA guarantees a fast-tracked evaluation and provides free scientific advice to companies designing studies for orphan drugs. The EMA also established a “rolling review” program to allow continuous assessment of study data as they become available, a policy that was considered as a special emergency measure. The program was once applied during the evaluation of vaccines of pandemic influenza in 2009 and resulted in several approvals . For most drugs, the EMA will not start review study data until all data are in finalized form in the submitted application. Currently, the EMA is advising a leading pharmaceutical company, GlaxoSmithKline (GSK), on a development plan for an Ebola vaccine .
Cartoon by Anna Maurer
In the face of global pandemics, it is worth noting that that the FDA and the EMA strive to work together to approve orphan drugs. The two agencies collaborate with each other to ensure prompt processing of applications and share information throughout the review process . Such collaboration is likely to expedite the review process and quickly get the drugs to a global patient population. On November 6, the European Innovative Medicines Initiative (IMI) launched another collaboration called Ebola+, a 280 million-Euro campaign calling for proposals for collaborative projects that tap on expertise in basic sciences, vaccine development, and regulation . As the Ebola outbreak remains a threat to global health, it is imperative to form and strengthen a global alliance between regulatory agencies and pharmaceutical industry.
Li Zha is a third-year graduate student in the Department of Chemistry and Chemical Biology at Harvard University.
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