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White House Sets Rules for Use of Investigational Drugs

By Douglas J. Gillert
American Forces Press Service

WASHINGTON, Nov. 29, 1999 – DoD gave pyridostigmine bromide tablets to troops during Desert Storm to protect them during suspected chemical attacks.

The Food and Drug Administration has approved and licensed "PB" for treating the muscular disease myasthenia gravis, but not for countering chemical warfare agents. Instead, the FDA authorized DoD to use PB as an "investigational new drug" to protect troops against certain nerve agents thought to be in the Iraqi arsenal.

Although a new literature review has indicated that PB should not be ruled out as a possible cause of Gulf War illnesses, defense leaders stand by their predecessors' decision to issue the medication. They say they'd do the same if the threat is imminent and PB is the best protection available to U.S. service members.

The White House, DoD and the FDA concur that investigational new drugs can and should continue to be viable options for force protection. President Clinton made it official Sept. 30 by issuing Executive Order 13139, which spells out ground rules for giving such drugs to service members -- with or without their consent.

"Military personnel deployed in particular military operations could potentially be exposed to a range of chemical, biological and radiological weapons as well as diseases endemic to an area of operations," the Clinton directive reads. "It is the policy of the United States government to provide our military personnel with safe and effective vaccines, antidotes and treatments that will negate or minimize the effects of these health threats."

The directive lays down stern guidelines for the use of unlicensed drugs. In most cases, such use would be voluntary and administered only after a service member understands how the drug works and possible side effects, then signs a letter of consent. However, the president can waive the consent rule if a theater or area commander can show why delay would harm the force and hinder operations.

Dr. Sue Bailey, assistant secretary of defense for health affairs, explained to Congress Nov. 9 how DoD will apply the executive order. In prepared testimony for the National Security, Veterans Affairs and International Relations subcommittee of the House Government Reform Committee, she said a DoD directive to be published next year will regulate the use of investigational new drugs and reinforce DoD's role in developing new drugs to meet future threats.

"DoD will make every effort to utilize products approved by the FDA, when available, to provide the needed medical countermeasure," Bailey said. "When no FDA-approved product is available to meet a foreseeable threat, DoD will carry out appropriate research and development program activities directed toward obtaining ... approval by the FDA of safe and effective medical countermeasures."

In limited circumstances, when no FDA-approved drug is available to meet the current threat, DoD components may ask the defense secretary to approve use of an investigational new drug, Bailey said. Such requests, she said, would rigidly follow a chain of command from the combat commander through the chairman of the Joint Chiefs of Staff to the secretary. The request must document a confirmed high threat and consider the drug's risks and benefits. DoD then must develop a treatment protocol for FDA review.

Bailey said investigational new drugs would be administered on a voluntary basis in most cases.

"If we're giving you a force health protection medication not yet approved by the FDA and under an IND, the FDA requires you give your informed consent first," said Army Dr. (Maj. Gen.) Robert Claypool, deputy assistant secretary of defense for health operations policy. "For instance, if we were offering you a drug for a certain condition, I would tell you the risks and benefits of taking it, the risks and effects of not taking it, and the alternatives we could do to help protect you. You would have to give your written consent that you've been informed and agree to take the medication."

Such consent was sought in Bosnia to protect troops from tick borne encephalitis. The vaccine that exists is manufactured in Europe and is not approved by the FDA. Its use for US troops was as an investigational new drug, Claypool said. The use of informed consent was acceptable to commanders because effective insect repellents and mosquito netting were available and the threat wasn't thought high enough to warrant requiring the vaccine.

In Desert Storm, however, the potential threat posed by soman was considered high enough to waive troops' informed consent for taking PB, Claypool said. Lack of records from back then, however, hinders investigations now into how, when and to whom the drug was administered. Records also don't show whether service members were advised of the risks and side effects involved, he said.

"Our record keeping wasn't what it should have been or what we will do in the future," Claypool said.

He said the defense secretary can approve use of an investigational new drug with informed consent. Approval is only bumped up to the president when a waiver of consent is sought. Ideally, however, DoD would prefer to use FDA-licensed drugs as much as possible, he said.

"Our first preferred method is to use drugs and vaccines that are approved by the FDA for their intended use," he said. "If we are going to resort to using an investigational new drug, we would prefer to use it with informed consent."

Claypool said DoD won't use any drug that hasn't reached a certain level of developmental maturity.

"The counteragents we would use against chem-bioterrorism under an investigational new drug protocol would be the more mature ones, the ones for which we have a great deal of information," he said. "It is with those agents that we might request a waiver of informed consent. We would never do that on the early side of a new drug."

Claypool also dispelled concerns DoD might hide behind the waiver authority instead of rigorously pursuing the development and licensure of a new drug.

"We do not intend to do that," he said. "We will do all we can to progress toward licensing."

The Joint Vaccine Acquisition Program at Fort Detrick, Md., funds commercial research and development of new force health protection drugs, and much of the initial research is carried out in laboratories at the Army Medical Research Institute for Infectious Diseases at Detrick. Once a candidate vaccine reaches a development level where it's ready for testing on humans, the acquisition program hands it off to one of the funded contractors.

It takes about 10 years for a new drug to pass research tests, receive FDA licensing and be stockpiled in sufficient quantities to protect troops. So, Claypool said, DoD must try to assess what threats lie ahead. Besides anthrax, other bioweapon threats of concern include Q fever, smallpox, tularemia, encephalitis, botulism, plague and hemorrhagic fevers.

In the meantime, Executive Order 13139's guidance on the use of investigational new drugs greatly enhances DoD force health protection effort, Claypool said.

"It think it's a boon, because it will enable us to do the right thing," he said. "It will provide the infrastructure for us to execute an investigational new drug protocol and do it right from the standpoint of protecting the interests of our service members, protecting our national security interests, obtaining the kind of information we need and obtaining the force health protection we must have."

The text of Executive Order 13139 is available on the White House Web site at http://www.pub.whitehouse.gov/uri- res/I2R?urn:pdi://oma.eop.gov.us/1999/10/1/8.text.2.

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