Posted 22 September 2014
By Alexander Gaffney, RAC
Canadian biopharmaceutical company Tekmira has announced that the US Food and Drug Administration (FDA) will allow its investigational Ebola drug, TKM-Ebola, to be used by patients under an emergency expanded access program—a stark reversal for the product, which two months ago was subject to a complete clinical hold.
As Regulatory Focus extensively explained in August, developing new treatments for Ebola is a long and arduous process. Because Ebola, a hemorrhagic fever, is very rare and extremely deadly, companies must utilize FDA's Animal Efficacy Rule ("Animal Rule") in order to bring a drug to market.
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."
At its most basic, the rule allows FDA to approve products based on safety and efficacy testing in animals infected with the Ebola virus, and safety testing (but not efficacy testing) conducted in humans.
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.
Clinical Setbacks Yield to Progress
As of July 2014, Tekmira's RNA interference drug TKM-Ebola was seeking approval in the US under FDA's Animal Rule pathway. However, FDA issued what is known as a clinical hold on the drug after some patients in Tekmira's human safety study experienced "cytokine release" at higher doses, indicating that the product could cause the body's immune system to overreact and cause harm to patients.
At the time, the hold was seen as essentially ending the company's development of the drug.
But as an Ebola outbreak in western Africa began to grow rapidly, FDA revisited its hold on TKM-Ebola, and granted the company a partial reprieve.
Under FDA's clinical trial regulations (21 CFR 312.42(e)), FDA can lift—either completely or partially—the clinical hold if the agency is satisfied that the investigation can proceed. "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," FDA explained to Focus in a statement. "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."
And based on the emerging Ebola epidemic, FDA apparently reconsidered its evaluation of TKM-Ebola's risks, and partially lifted its clinical hold on the drug on 8 August 2014. While the original hold on healthy patients remains in effect, FDA permitted Tekmira to test the safety of its drug in patients with Ebola.
Ebola Drug and Compassionate Use
Now Tekmira has announced FDA is going one step further. In a statement on 22 September 2014, Tekmira announced FDA has granted its request to provide TKM-Ebola to "emergency use" patients under an expanded access program—something we predicted would happen in August 2014.
Under an expanded access (sometimes called "compassionate use") program, FDA allows a company to provide its products to a limited segment of patients in dire need of access.
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).
Tekmira said FDA has approved the use of a protocol amendment to its existing trial which will allow access to "multiple patients" outside its already-approved clinical trial. Health Canada has "established a similar framework," the company said.
Tekmira, while seeming generally upbeat in its press statement, also expressed caution. "It must be kept in mind that any uses of the product under expanded access, does not constitute controlled clinical trials. These patients may be infected with a strain of Ebola virus which has emerged subsequent to the strain that our product is directed against, and physicians treating these patients may use more than one therapeutic intervention in an effort to achieve the best outcome," said Mark Murray, CEO of Tekmira, in a statement. And even if the drug is successful in treating patients, supplies of the company's drugs "are limited," Murray added.
Other companies, including Mapp Biopharmaceutical, whose product Zmapp has been used to treat several Americans infected with the disease, have also experienced chronic shortages of their investigational Ebola treatment drugs. Most of those drugs were still in the early stages of development, and as such companies had not yet scaled up their production or distribution processes.
Regulatory Explainer: EbolaRegulatory Explainer: Expanded Access