Posted 07 August 2014 | By Alexander Gaffney, RAC,

Unless you've been living under a rock this month, you've undoubtedly heard about a massive outbreak of the Ebola virus in western Africa. The virus is poorly understood, exceedingly rare and, most importantly, incredibly deadly.

But what you probably haven't heard about is how treatments for Ebola are regulated—an oversight we at Focus are keen to correct.

In this Regulatory Explainer, we're taking a look at the regulations that surround the development of a potential treatment or cure for Ebola, and why creating one is so conceptually difficult.

Let's Start at the Beginning—What Does the Drug Development Process for a Drug Usually Look Like?

A shortened version of the regulatory process followed by companies goes something like this:

Company discovers (or purchases) an investigational compound

Company does research to determine if the product is likely to have an effect on the target (i.e. disease or condition)

Company moves the compound into pre-clinical testing phases, which is meant to develop data about the drug's toxicological profile, which should provide early indications if the drug is safe for use in humans and/or results in birth defects.

testing phases, which is meant to develop data about the drug's toxicological profile, which should provide early indications if the drug is safe for use in humans and/or results in birth defects. If a drug is safe, a company can then move a drug to Phase I testing, which is typically conducted on between 20 and 80 healthy volunteers. In some instances, such as when a drug is intended to treat a serious disease, volunteers may include patients affected by the disease the drug is intended to treat. This stage of research is intended to show that a drug is safe for use in humans.

testing, which is typically conducted on between 20 and 80 healthy volunteers. In some instances, such as when a drug is intended to treat a serious disease, volunteers may include patients affected by the disease the drug is intended to treat. This stage of research is intended to show that a drug is safe for use in humans. If a drug is found to be safe in the Phase I trial, the drug will then move into Phase II testing, which is intended to provide additional information about the safety of the drug, as well as evidence about its efficacy in humans. These trials typically enroll between several dozen and several hundred patients. The effectiveness of a drug is generally either compared with a placebo (sugar pill) or an active comparator, such as an already-approved drug or drugs.

testing, which is intended to provide additional information about the safety of the drug, as well as evidence about its efficacy in humans. These trials typically enroll between several dozen and several hundred patients. The effectiveness of a drug is generally either compared with a placebo (sugar pill) or an active comparator, such as an already-approved drug or drugs. If the drug is found to be safe and effective in Phase II testing, it then proceeds into Phase III testing, which involves hundreds, thousands or even tens of thousands of patients, depending on the demands of the trial. Phase III testing is intended to provide strong evidence of a drug's safety and effectiveness that can be used to support its approval. FDA most often requires evidence from two Phase III studies to obtain approval.

For more information on this process, please see the US Food and Drug Administration's (FDA) website for more information.

That Sounds Straightforward. Does That Process Work for Drugs Intended to Treat Ebola?

No, it does not. To understand why requires an understanding of FDA's Animal Efficacy Rule, sometimes referred to as just the "Animal Rule."

The Animal Rule, a 2002 rule passed in the wake of a series of anthrax attacks in the US, is a process which permits the approval of some products based on safety testing in humans and efficacy testing in animals.

The rule, located at 21 CFR 314.600-650 (drugs) and 601.90 (biologics), is meant to allow FDA to approve products for "serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances."

In plain terms, the rule is meant to allow companies and the government to develop countermeasures to medical problems before they exist, since the normal drug development process takes years, if not decades.

Why is the Animal Rule Necessary?

Testing drugs on humans has always been tricky, but most drugs being developed can count on one thing: an available population of patients. For example, if a company is developing a diabetes drug, it can find diabetics willing to enroll in a clinical trial. Even for rare diseases, where the entire patient population may be just 100 patients, companies can usually count on finding those patients and convincing a few to enroll.

But what happens when there are literally zero patients?

Such is usually the case with Ebola and other dangerous pathogens that are either man-made or naturally exist in animals. With no patients to test a drug on, drug development can't continue along traditional development routes.

But that's only half the problem. Hypothetically, if a disease didn't exist in the human population, you could potentially induce the disease in a test subject to see if your treatment would cure the individual. But that's a non-starter with most dangerous diseases—and especially Ebola—given the high probability that test subjects would die. FDA will generally place what is known as a "clinical hold" on any trial where the risks to patients potentially outweigh the benefits, and the agency would likely never approve a trial where those risks are known to exist in advance.

That's where the Animal Rule comes into play.

The rule allows FDA to approve drugs based on efficacy testing in animals, and only safety testing in healthy humans (i.e. disease-negative patients are given the drug to make sure they aren't harmed).

While the Animal Rule has been in effect since 2002, FDA has approved just a small handful of products based on the rule, and most of them only within the last few years. For example, FDA approved the first product under the Animal Rule, J&J's Levaquin (levofloxacin, plague), in April 2012. Later that year, in December, FDA approved the first biologic product under the rule, GSK's raxibacumab (inhalation anthrax). A botulism antitoxin manufactured by Cangene was approved in March 2013.

In all cases, approval was based on FDA's findings that a product was safe for use in healthy humans, indicating that the drug was unlikely to cause harm to sick patients, and data indicating that the drug was effective in animals known to have similar disease pathways as humans. For example, raxibacumab was tested in one trial of monkeys and three trials involving rabbits.

While animal studies aren't a perfect substitute for studies involving humans—the government has no way to tell if a drug actually works before it's needed—regulators have said the rule represents the best chance they have to develop medical countermeasures before they're needed.

The rule gets even more complicated when it's applied to children, by the way.

For more on the Animal Rule, please read FDA's May 2014 guidance document, Product Development Under the Animal Rule.

What Happens if an Ebola Drug is Being Tested, but Has Not Yet Obtained FDA Approval? Can it Still be Used?

Yes, it can be used under FDA's Expanded Access ("Compassionate Use") program. The program—extensively explained in our Regulatory Explainer on the Expanded Access Program—is meant to allow companies to test their products on a consenting adult outside a traditional clinical trial.

Expanded access works, in general, in one of two ways: Either a company with an experimental product creates a new clinical trial for a patient through the use of an investigational new drug (IND) application, or it amends an existing clinical trial to add new types of participants through the use of a "protocol amendment."

Once a company determines which approach it wants to take, it then needs to decide on how many patients it is willing to accommodate. There are four general types of expanded access INDs and protocols:

Single Patient (Emergency Access): Used to grant access to a single patient who does not have time to obtain written permission from FDA

Single Patient (Regular Access): Used to allow a single patient access to a trial

Intermediate Size: Used for intermediate-sized patient populations

Treatment: Used for large patient populations (i.e. widespread use).

A company—not FDA—has the final say on whether a person or group can have access to an experimental treatment, though FDA can always veto its use. Based on data provided by the agency, it almost never exercises this veto option.

Can FDA Grant Emergency Approvals to Ebola Drugs?

Yes, though technically the process "authorizes" the use of an ebola drug, and doesn't "approve" it.

First, some background information to help you explain what that means in practical terms. In March 2013, FDA was given a host of new authorities and responsibilities under the Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA), a piece of legislation meant to bolster the government's ability to respond to health crises, and especially those of a biological nature.

Among the law's many provisions is one that allows FDA to temporarily authorize a medical product ("Emergency Use Authorization") if it determines that an emergency is likely to occur—a "threat justifying emergency authorized use," to quote the legislation. That is a big change from prior legislation, which required a finding that such an emergency already existed in the US, and left little time for proactive efforts.

The law also allows FDA to authorize those products without first ensuring that they meet current good manufacturing practice (CGMP) regulations, which makes it easier to bring products to market without the usual regulatory burdens.

Since the law's March 2013 passage, FDA has approved a small handful of medical products—all diagnostic tests intended to allow health officials to diagnose emerging diseases like the H7N9 influenza virus and the Middle East Coronavirus (MERS CoV).

On 5 August 2014 HHS announced that it had determined that "the Ebola virus presents a material threat against the US population sufficient to affect national security," allowing FDA to authorize the use of a diagnostic device for Ebola Zaire, the Department of Defense's EZ1 Real-Time RT-PCR Assay.

I Heard of Some Ebola Patients Being Given an Experimental Product Which Hadn't Obtained FDA Approval—Did They Obtain Approval Through the Expanded Access Process?

The best answer Focus has been able to get so far is "maybe."

Due to commercial confidentiality laws, FDA isn't allowed to confirm if a company has or has not filed an investigational new drug (IND) application, which is used to start a clinical trial. As such, the agency wouldn't confirm to Focus if any experimental treatments (like Mapp Biopharmaceutical's ZMapp) have been cleared through FDA's Expanded Access program. The company's CEO, Larry Zeitlin, told The Washington Post that the company is "discussing with the FDA the right path to make the drug available to people as quickly and safely as possible."

However, it largely confirmed that if any drug was being used experimentally, it would need to go through FDA.

Here's FDA's statement on the matter: "Currently there are only experimental treatments for Ebola virus infection in the earliest stages of development. When a drug is not approved, the FDA can authorize access to potentially promising products through other mechanisms, such as through an emergency Investigational New Drug (IND) application. In order for an experimental treatment to be administered in the U.S., such a request must be submitted to and authorized by the FDA. The FDA cannot comment on the specifics of ongoing drug development programs and cannot reveal information that is not otherwise public concerning submissions covering such programs such as IND applications submissions. The FDA stands ready to work with companies and investigators treating these patients."

FDA confirmed to Focus that an emergency IND request can be authorized by the agency "within a very short period of time, depending on the urgency of the situation and the nature of the available information." There are currently no FDA-approved treatments for Ebola, FDA confirmed.

What's This I Hear About a "Top Secret" Drug to Treat Ebola?

There's no such thing as a "Top Secret" drug. That's a designation given by the government to government documents, not to drugs.

What CNN and other outlets touting the "secret serum" line are probably implying is that the drug was not previously well known outside scientific and regulatory circles.

FDA Sometimes Uses ‘Enforcement Discretion’ in Emergency Situations. Is it using that with Ebola?

It's not yet clear. FDA's use of enforcement discretion is essentially an acknowledgement by the agency that while it has the authority to regulate a product, it will choose not to regulate that product in a particular circumstance. It has been used in recent years to permit the import of death penalty drugs into the US, for example.

However, in a statement to Focus, FDA would not confirm if it was using its enforcement discretion to allow the import or export of Ebola treatments, saying only that it "generally does not discuss its exercise of enforcement discretion, except in particular circumstances in which a public statement about that exercise is considered appropriate."

In other words, maybe it has, and maybe it hasn't.

I've Heard Quite a Bit About an Ebola Treatment Called ZMapp. Are There Any Other Experimental Drugs in Development?

Yes, though at least one has run into trouble.

In July 2013—before the Ebola outbreak emerged—Tekmira Pharmaceuticals issued a statement indicating that its experimental RNA interference (RNAi) Ebola treatment, TKM-Ebola, had been put on clinical hold by FDA.

Under 21 CFR 312.42, clinical holds—orders to stop a clinical trial—are ordered by FDA when a clinical investigation reveals information that indicates an "unreasonable and significant risk of illness or injury."

The company said one of its healthy volunteers had experienced a cytokine release when given an elevated dose of the drug—a condition which can be life-threatening and potentially fatal. FDA reportedly asked the company for more information about the drug, and the company expects the drug's development to resume in Q4 2014.

Under federal regulations (21 CFR 312.42(e)), FDA might also lift the hold on the clinical trial if the agency is satisfied that the investigation can proceed. It remains to be seen if an elevated clinical need would be sufficient to lift a clinical hold.

In a statement to Focus, FDA stated that it would consider lifting a clinical hold based on the "context for use for the product and the patient population being studies."

"A clinical hold is based on the risk-benefit assessment for a proposed study," FDA continued. "A future proposal for a study or emergency use in a different population, for example in patients with disease, might have an acceptable risk-benefit balance. If there is a reasonable prospect that the benefits of investigational use may outweigh the risks for a specific population, we may consider permitting that study to proceed."

In other words, Tekmira's product could be made available to patients in the absence of other suitable treatments, but likely only for patients with Ebola.

Some Americans Have Reportedly Obtained Access to Experimental Therapies. Why Aren't More People Receiving the Drug?

The reason is very likely related to production issues.

"Production-stage facilities to make these drugs usually aren't online until the time of approval," explained Scott Gottlieb, an AEI scholar and a former associate commissioner at FDA, in a recent news segment. "They only have a limited supply of drug."

During the clinical or pre-clinical testing process, most companies—and especially smaller ones—utilize small-scale methods of production. The simple fact is that if a clinical trial only needs to treat 20 people, a company probably won't invest in the equipment to produce enough to treat 5,000 patients. In the majority of cases, that's a smart decision since most drug products fail during clinical testing and are never approved for use. And in the case of biological drugs, such as monoclonal antibodies, the cost to produce the drugs can be steep, further necessitating a "lean" manufacturing process that produces only as much as is needed.

Production shortfalls are particularly pronounced if a company is developing a drug for a disease that usually doesn't exist and doesn't have a ready market. In those cases, a company typically won't scale up production unless it receives a government contract for a supply of the drug.

News reports have indicated that for the most highly touted Ebola serum, manufactured by Mapp Pharmaceutical, "There are only a handful of doses available." The company is reportedly working on ways to increase production of its product with the help of a bioprocessing facility, and has said it did not anticipate using the drug in humans for at least another year prior to the Ebola outbreak.

FDA Regulates Drugs in the US—How did Treatments Get Approved to be Sent to Africa?

The details are as of yet unclear, but Mapp Pharmaceutical could have obtained approval to export the drug under 312.110(b)(4), which allows a drug to be exported for investigational use. However, FDA confirmed to Focus that the agency was "not involved in the shipment of [the] experimental treatment to West Africa or the administration of the experimental treatment there."

That raises the prospect of another agency—perhaps the National Institutes of Health (NIH) or the CDC—exporting the drug.

FDA would theoretically have to grant a new exemption for the drug if it were to be used on the same persons once they were brought back to the US (or exercise its enforcement discretion), however.

If There's no Ready Market for These Drugs, Why Would Any Company Make Them?

The US government actually maintains several programs for developing and purchasing drugs it doesn't currently need, but anticipates potentially needing during a future emergency.

One of these best examples of this is the Strategic National Stockpile (SNS), a collection of products purchased by the government and kept around the country in secret locations in a ready-to-ship condition that allows their rapid deployment. The FDA, Centers for Disease Control and Prevention (CDC) and other government agencies are responsible for maintaining this stockpile.

Some of those drugs are also developed with the help of the Biomedical Advanced Research and Development Authority (BARDA), which gives grants to companies to develop products under Project Bioshield, a 2004 law which seeks to proactively defend the US against potential bioterror threats.

BARDA's development grants ensure that even if a product doesn't have a market, incentives will still exist for a company to recoup its development costs.

Are There Other Incentives to Develop Treatments for Ebola?

Yes. One notable one is known as a Neglected Tropical Disease Priority Review Voucher.

So-called "tropical diseases" are defined by statute as infectious diseases which do not affect developed nations and disproportionately affect poor and marginalized nations. Such diseases are typically not subject to the same levels of investment and research as are other diseases, in part because the markets for those products are generally less affluent, leaving companies less able to obtain a positive return on their investment (particularly if research and development was conducted in regions with higher costs).

Accordingly, tropical diseases can often be left "orphaned" by drug development—that is, left without an adequate supply of treatments or cures.

To help alleviate this dearth of treatments, in 2007 US legislators passed the Food and Drug Administration Amendments Act (FDAAA), Section 1102 of which established a new and powerful incentive to help spur tropical drug development: Tropical Disease Priority Review Vouchers.

Under the new incentives, companies that receive approval for a tropical disease treatment are eligible to receive a transferable voucher that allows the bearer to receive six-month priority review status for any future product. Products undergoing priority review are generally given an approval decision—positive or negative—within six months after the applicant's filing date instead of the usual 10.

Those vouchers can fetch huge sums. The first-ever sale of a voucher in July 2014 was for $67.5 million —a hefty prize for any company which can get an Ebola treatment approved by FDA.

Are There Other Ways of Getting new Ebola Treatments to Patients More Quickly?

Yes. In the US, FDA maintains several "expedited" pathways meant to accelerate the approval of new drug and device products.

On the drug side, FDA has four expedited approval processes worth knowing:

Fast track designation - A designation given to a drug application for which there is evidence that it has the potential to address an unmet medical need or one that has been designated as a qualified infectious disease product. Allows for a rolling review of an application by FDA and the ability to expedite certain aspects of development and review.

Priority review designation - A designation given to applications (either new or supplemental applications) for which there is evidence that a treatment would provide a significant improvement in the standard of care for a patient. The designation shortens FDA's timeline for reviewing the application from 10 months to six.

Accelerated approval - An approval pathway through which a drug that provides a "meaningful advantage over available therapies" can obtain approval based on data in support of a surrogate endpoint. No change in the review timeline.

Breakthrough product designation – An approval pathway first introduced into law under the 2012 FDA Safety and Innovation Act (FDASIA), breakthrough product designation is intended for first-in-class products that treat a serious condition based on preliminary clinical evidence that indicates the drug may demonstrate substantial improvement on clinically significant endpoints over available therapies.

FDA can grant a new drug one, or even several, of these designations, which can greatly accelerate the speed with which a product is able to come to market. For more, please see FDA's May 2014 guidance, Expedited Programs for Serious Conditions—Drugs and Biologics.

On the device side, FDA has only recently unveiled its new Expedited Access Premarket Approval (EAP) program, which is meant to offer faster approvals to device products intended to treat life-threatening or "irreversibly debilitating" diseases or conditions. To date, it has not been used by any product, however. For more information, see FDA's April 2014 guidance, Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions.

However, even with the speed these expedited approval programs offer, it remains unlikely that a company would attempt to seek full approval for a product during an Ebola outbreak since it can allow patients to access therapies more quickly using expanded access programs.

It's also worth noting that President Barack Obama has weighed in on "fast tracking" approval of Ebola drugs, saying that he thinks it would be "premature" to do so right now.

What Other Testing Hurdles Exist?

Because of the virulence and dangers of Ebola, it is treated as a Biosafety Level 4 pathogen by the Centers for Disease Control and Prevention (CDC), meaning that any laboratory that handles the virus needs to be extremely thorough in its safety practices.

As the CDC explains in this biosafety guide, BSL4 facilities must meet an extraordinarily long set of restrictions which cover everything from the design and layout of the facility to the equipment needed to contain any pathogens and keep employees safe.

These restrictions, though necessary, increase the cost of drug development and make it difficult to conduct research.

You Mentioned the Animal Rule Earlier—What Happens if a Drug Undergoing Testing is Used in Humans with Ebola? Will FDA Look at its Use for the Purposes of Approval?

FDA confirmed to Regulatory Focus that yes—it will accept data on an experimental drug used in (Ebola) patients, even if the drug was going through the Animal Rule pathway.

"FDA encourages development of protocols that could generate interpretable data when circumstances arise in which it is feasible and ethical to study an investigational product," FDA told Focus. "FDA would review the totality of the data from non-clinical studies, human safety trials, clinical trials and any anecdotal data to discuss whether sufficient data exist to support the safety and efficacy of a product."

The key phrase there: "Anecdotal data." Since most patients being treated in Africa (and maybe even the US) probably would not be treated as part of an approved trial, most of the data generated during treatment would be imperfect at best and perhaps anecdotal at worst. That FDA is willing to consider this data speaks volumes to the seriousness of the disease.