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Compliance In Focus
Posted by Michael Marotta on Mon, Aug 25, 2014

Compassionate Use and the Animal Rule

In March of 2014, we wrote about Compassionate use in Unapproved Medical Devices. To briefly summarize, compassionate use refers to the use of an unapproved device or drug in a single Compassionate Use and the Animal Rulepatient or small group where the condition of the patient/group is serious and there is no alternative treatment. The FDA can use regulatory discretion to determine if an investigational drug/device can be used and FDA approval is required prior to use.  This clause has come under the spotlight recently with the treatment of two American health care workers and a Spanish priest with an experimental drug, ZMapp, developed by the pharmaceutical company MAPP Pharmaceuticals. ZMapp is a serum-based drug that previously had not been clinically tested in humans.  It represents a number of drugs and vaccines that are currently being developed  to combat Ebola, a single-stranded RNA virus that is highly pathogenic with a fatality rate of up to 90%. According to the World Health Organization, as of 16 August 2014 there have been 2240 reported cases and 1229 deaths from this disease spanning four countries in West Africa (Guinea, Liberia, Sierra Leone, and Nigeria).

In an 11 August 2014 interview with David Greene of NPR, Alta Charo, a University of Wisconsin bioethicist and former advisor to the Food and Drug Administration, broke down the ethical dilemma related to offering an experimental medication initially only to the two Americans when she said:

“No one can say that the optics here are not troubling. That is you have a very small amount of a drug that might work and the only people who get it are the Americans. But you need to also remember that if we had given it to non-Americans first there would be equally bad optics of testing drugs on people from developing countries before we’re willing to test it on ourselves."

On the same day, The World Health Organization (WHO) convened to discuss the ethical implications for the potential use of “unregistered interventions.”  As a result of this meeting, it was determined that “it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment or prevention.” To guide the delivery of these interventions, the panel listed a series of ethical criteria that included:

  • Transparency about all aspects of care
  • Informed Consent
  • Freedom of choice
  • Confidentiality
  • Respect for the Person
  • Preservation of Dignity
  • Involvement of the community

In addition, the panel stated that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’.”  This statement is important when dealing with rare and fatal diseases with no proven treatments, because often there is not a safe, effective, and ethical way to conduct a clinical trial to evaluate potential treatments.  In areas where human efficacy studies are not ethical or feasible, the FDA has issued an “Animal Rule”. Originally issued in 2002 and recently updated in May 2014, the “Animal Rule” was intended to expedite the development of new drugs and biologic products as medical countermeasures to chemical, biological, radiological, and nuclear threats.  The scope of the Animal Rule has also been extended beyond medical countermeasures to include other toxic chemical, biological, radiological, or nuclear substances (this is where Ebola treatment falls under the Animal Rule).  To be eligible for the Animal Rule, four criteria must be met:

  1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product.
  2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans.
  3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity.
  4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.

In addition to meeting these four criteria, subsequent approval of a drug or biological product under the Animal Rule requires three additional requirements:

  1. Postmarking studies (e.g., field studies) to provide evaluation of safety and clinical benefit if circumstances arise in which a study would be feasible and ethical (i.e., in the event an emergency arises and the drug is used). A plan or approach to conducting such a study must be included with the new drug application (NDA) or biologics license application (BLA).
  2. Restrictions to ensure safe use, if needed (e.g., restricting distribution to facilities or health care practitioners with special training, requiring specified types of follow up, or imposing record keeping requirements).
  3. Information to be provided in the labeling to patient recipients that explains that for ethical or feasibility reasons, the drug’s approval was based on efficacy studies conducted in animals alone. This drug labeling should also include all the other relevant information required by FDA at the time of approval (e.g., directions for use, contraindications, a description of any reasonably foreseeable risks, adverse reactions, anticipated benefits, and drug interactions). This information must be provided before administration or dispensing, if possible.

As the Ebola outbreak moves into its sixth month, it will be very interesting to see how the consensus of the WHO panel effects future treatment of the disease.  Just in the last few weeks, the FDA has modified a hold on a potential Ebola treatment produced by Tekmira Pharmaceuticals from “full clinical hold” to “partial clinical hold” clearing a hurdle for potential use in individuals infected with Ebola. And in respect to ZMapp, MAPP Pharmaceuticals issued a statement on 12 August 2014 that the available supply has been exhausted. 

Do you think that the WHO consensus will make more experimental treatments available to those suffering from the disease?  Do you think this decision aligns with FDA’s previous Compassionate Use requirements for Investigational Drug/Device Exemptions? 

 Photo Credit: NIAID

 FDA Regs vs ISO Whitepaper

Topics: World Health Organization, Compassionate Use, Animal Rule, Ebola Virus, FDA

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