Editor's Note: The issue of compassionate use of unapproved therapies has been brought to the attention of all healthcare providers recently after the decision to treat 2 Americans infected with the Ebola virus with an experimental serum never before used in humans. With the Ebola epidemic deemed to be out of control by the World Health Organization (WHO), the need for effective treatments has researchers and regulators scrambling to find, test, and potentially approve previously untested therapies.
In a press release in August, WHO discussed the ethics of using Ebola drugs that have never been cleared for human use, wary of a long history of medicines being tested on people who were never properly informed of the risks. In the countries hardest hit by Ebola, suspicion of foreign medical workers is already widespread.
Medscape spoke with Luciana Borio, MD, at the US Food and Drug Administration (FDA) about the issue of compassionate use and their efforts to respond to this crisis. Dr. Borio serves as the Acting Deputy Chief Scientist and Assistant Commissioner for Counterterrorism Policy in the Office of Counterterrorism and Emerging Threats at the FDA. In this capacity, Dr. Borio is responsible for providing leadership, coordination, and oversight for FDA's national and global health security, counterterrorism, and emerging threat portfolios. She serves as FDA's point of entry on policy and planning matters concerning counterterrorism and emerging threats, and collaborates across the US government and internationally on actions to advance global health security and US national security.
Medscape: Can you define "compassionate use" as a regulatory and legal concept?
Luciana Borio, MD: I'd like to begin by taking a step back. Ultimately, the goal for the FDA is to have products that are approved, licensed, or cleared to prevent or treat diseases. However, during a public health emergency, such as the one we are currently facing with Ebola, we don't always have these approved products available, and the best way for us to meet patients' needs might be the use of an unapproved product.
FDA has mechanisms that we can use to facilitate patient access to investigational products; one of these is the Emergency Investigational New Drug (IND) application, often referred to as "compassionate use." It is one of a number of mechanisms under our expanded access program.
Through this emergency IND mechanism, we can allow the use of an investigational product outside of a clinical trial being conducted to develop the product toward approval, in order to treat a patient with a serious or immediately life-threatening disease when the patient has no comparable or satisfactory alternative treatment option.
To evaluate a request for an emergency IND, we have to assess whether the benefits outweigh the risks on the basis of the best available scientific evidence that we have because, clearly, the data package at this point is often quite incomplete. The product may be effective or may not, and we also may see sometimes unexpected serious side effects. Sometimes we don't know exactly what is the most appropriate dose, for example, to give to a sick patient. We have only incomplete information about the use of these products, but we do the best we can to conduct a proper benefit/risk assessment with the available scientific data.
Under this mechanism, it is usually the patient's clinician who contacts the FDA requesting the emergency IND or compassionate use exemption. If, after an evaluation of the application, FDA believes the use is appropriate, the doctor will then make arrangements directly with the product developer to obtain the product. The manufacturer may or may not be willing to make the product available outside of the clinical trial, and FDA cannot compel the company to do so. So when the company provides expanded access to its product, it is doing so voluntarily.
Medscape: In an emailed statement issued in early August, the FDA said it "stands ready" to work with companies and investigators working with patients "in dire need of treatment." Can you describe FDA's efforts to date?
Dr. Borio: First and foremost, our goal is to facilitate access to any available medical products that we believe may help mitigate disease in patients.
Clearly, this is a very serious situation, and the supply of available therapies is quite limited. The pipeline is in very early development. But even in those circumstances, we do work hard to see what we can do to facilitate product access if we believe the benefits outweigh the risks for the individual patient.
For example, we have utilized the emergency IND mechanism to facilitate providing patients being treated at Emory University Hospital in Atlanta with an investigational drug candidate. In addition, we have used another regulatory mechanism, the emergency use authorization (EUA), to enable access to yet another unapproved product. Under the EUA authority, we authorized the use of an Ebola diagnostic test that was under development by the Department of Defense (DOD), and those tests are now being deployed to the Laboratory Response Network of the Centers for Disease Control and Prevention (CDC) to improve the nation's capability to diagnose or rule out Ebola in patients who may present with symptoms in conjunction with epidemiologic risk factors consistent with Ebola at our clinics.
We also reach out to developers of products that are still in the very early phase of development. In some cases, the manufacturer has not even contacted the FDA to discuss an IND. But if we are aware of a potential therapeutic candidate, we will contact the company to get more information and make sure they understand how we would work together to facilitate development of their candidate.
We also work with our US government partners. In addition to the CDC and DOD, we are collaborating with the National Institutes of Health and the Biomedical Advanced Research and Development Authority in the Department of Health and Human Services (HHS). We will be working in tandem with them to support development and eventual deployment of medical products.
For example, we provide technical assistance, clarify regulatory pathways, and look for ways to speed up clinical trials. The whole idea here is to increase the likelihood of success and accelerate the timelines for product availability.
We support international response efforts by providing technical assistance on requests by the WHO. We also answer questions from our international regulatory counterparts. For example, we have recently interacted with Japan, Canada, Germany, and Spain on requests for information, and we do so under established confidentiality agreements.
Finally, but very important, we protect consumers by monitoring fraudulent products and false product claims related to the Ebola virus and implementing enforcement actions as warranted to protect the public health.
Medscape: Clearly, treatment for patients dying of hemorrhagic fever falls into the category of serious or life-threatening conditions that warrant an exemption. But what about prevention of this serious illness? Do efforts at developing an effective vaccine warrant a compassionate use exemption that might speed testing and use of a vaccine?
Dr. Borio: Emergency INDs or compassionate use exemptions may also apply to vaccines. There are significant efforts to facilitate the availability of investigational vaccines and obtain much-needed data about them.
Remember, again, that all of these products in the pipeline are in very early stages of development. Right now, all federal agencies are looking for ways to accelerate and compress the development timelines and to resource these programs to a higher degree than they have been resourced previously. Vaccines are definitely one of the cornerstone components of the pipeline. A lot of people don't realize that FDA has one of the most flexible regulatory frameworks in the world, so we have several mechanisms, and we use them to facilitate access and accelerate product development on the basis of scientific information and the best interest of public health.
Medscape: WHO recently convened a panelist of medical ethicists to address concerns about use of untested therapies in patients infected with Ebola virus. Their panel concluded that the use of unregistered interventions for prevention and treatment was ethical given the special circumstances of the current outbreak. The panel emphasized the moral obligation to share data from use of these agents in order to better understand safety and efficacy. What safeguards are in place to attempt to preserve safety with compassionate use exemptions?
Dr. Borio: It is very difficult to ensure safety because there are so many unknowns. We have to make assessments on the basis of the totality of the scientific evidence. If we are dealing with, for example, a new candidate in a broader class of drugs, we will look at our safety experience with that entire class of drugs. Of course, the safety profile can be different from product to product, but looking more broadly may sometimes give us an idea about what to expect. Again, we don't have the full picture for that specific product, so we look broadly at all the science we have.
Clearly, the goal is to develop products for approval. And the best way to do that is through properly structured clinical trials. However, even outside of a clinical trial, collecting information about the use of the product under expanded access is still critical. It is particularly important when we are talking about Ebola countermeasures, because all of these products were contemplated to be developed under the FDA's animal efficacy rule, which is used when it would not be ethical or feasible to conduct clinical trials for efficacy in humans. The nature of this disease, including the fact that outbreaks are sporadic and unpredictable and the disease does not occur naturally in the United States, all combine to make it not feasible to conduct standard clinical trials in the United States. Developers then must rely on animal models to show a product's efficacy. When we use a product like that in a human, we believe it is a real imperative to collect data about the product's use in humans.
Medscape: Assuming that a therapy is approved to use under a compassionate use exemption, another hurdle that must be overcome is the need to ramp up manufacturing and distribution. Can you speak to the FDA's role in ensuring safety, yet not inhibiting this production surge?
Dr. Borio: Ensuring product quality and integrity is an important component of our regulatory oversight. We do inspect manufacturing facilities and provide oversight if they have to scale up or transfer to a different facility. In a situation such as this, we also accelerate site visits.
We provide support and technical assistance, as needed, to our government partners who are actually responsible for working with the private sector to expand manufacturing capacity for these product candidates. These partners include DOD, and the Biomedical Advanced Research and Development Authority at HHS. They will be the ones executing contracts to increase manufacturing capacity, and again, we will be right there with them as they work to augment manufacturing capacity.
Medscape: We have been speaking so far about legitimate therapies -- but unfortunately, there are also illegitimate products being promulgated directly to the worried public. Can you discuss how the FDA protects consumers against fraudulent products that claim to prevent, treat, or cure Ebola?
Dr. Borio: We continue to provide the marketplace surveillance necessary to protect consumers from fraudulent products and false product claims. When we identify such products or claims, we implement any and all enforcement actions at our disposal as warranted to protect the public health. But there are many unscrupulous entities that will take advantage of a tragic situation such as this and play on the fear of consumers to try to sell products that have no basis for their claims.
We also do what we can to educate and inform consumers about these types of fraudulent activities.
We are still in the process of doing some of our research in this area, and not just here in the United States. These products are frequently found online. We work with other countries to ferret out some of these fraudulent products that proliferate not only here, but internationally as well. We are looking pretty holistically at this issue and bringing it to the public's attention.
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Cite this: Responding to Ebola: The View From the FDA - Medscape - Aug 20, 2014.
