News & Events
Investigational New Drugs
William Raub, Ph.D
Deputy Assistant Secretary for Science Policy
Department of Health and Human Services
the Subcommittee on National Security, Veterans Affairs, and International Relations
House Committee on Government Reform
November 9, 1999
Mr. Chairman and Members of the Committee, I am Dr. William Raub, Deputy Assistant Secretary for Science Policy at the Department of Health and Human Services (DHHS). I am pleased to be here today to discuss Federal policies governing the administration of investigational new drugs to U.S. military personnel, including the safeguards and protections recently announced in the Executive Order 13139 issued by the President and the interim rule on waiver of informed consent issued by the Food and Drug Administration (FDA or the Agency). The issuance of these documents represents a long, cooperative, interagency effort aimed at providing the best protection possible for military personnel needing investigational drugs during particular military operations.
DHHS was a party to this cooperative effort and believes that the resulting criteria take into account the protection of individual military personnel while accommodating the national security interests that arise during the conduct of military operations. Protection of individuals receiving health care services, including those receiving investigational new drugs, is an issue of paramount concern to DHHS. This stance is reflected in the positions taken by DHHS concerning the Patient Bill of Rights, medical data privacy, the allocation of human organs for transplantation and many other issues involving the provision of medical care to individuals. This is particularly appropriate in the use of investigational products. There may not be any FDA approved medical products to treat or prevent certain diseases or conditions. The lack of approved products becomes particularly critical in the context of military operations when investigational products may constitute the best treatment for a particular disease or exposure to a chemical or biological warfare agent. DHHS believes, however, that exceptions from informed consent should apply rarely and only when sufficient additional protections are provided to the military personnel affected. We believe that the new interim rule and the Executive Order provide those protections.
ESTABLISHMENT OF NEW STANDARDS AND CRITERIA UNDER THE 1999 INTERIM RULE
On October 5, 1999, FDA published in the Federal Register a new interim rule that contains new strengthened criteria and standards the President can use in making informed consent waiver determinations. Among other things, the interim rule requires that each member involved in the military operation be given, prior to the administration of the investigational new drug, a specific written information sheet providing full information on the product. It also requires the Department of Defense (DOD) to provide, consistent with classification requirements, public notice in the Federal Register describing the waiver of informed consent determination, a summary of the most updated scientific information on the products used, as well as other pertinent information. The interim rule also requires DOD to provide training to the appropriate medical personnel, and potential recipients, on the specific investigational new drug to be administered prior to its use.
The President may waive the prior consent requirement for the administration of an investigational new drug to a member of the armed forces in connection with the member's participation in a particular military operation if it is determined that obtaining consent is not feasible, is contrary to the best interests of the military member, or is not in the interests of national security. If a determination is based on the grounds that it is infeasible or contrary to the best interests of the military member, the President must apply the standards and criteria that are set forth in the relevant FDA regulations for a waiver of the prior informed consent requirements. Executive Order 13139 also specifies that the President will consider the standards and criteria even under grounds of national security. This new interim rule contains those standards and criteria.
The interim rule requires the Secretary of Defense to certify and document to the President that the standards and criteria in the interim rule have been met. Section 50.23(d)(1)(i) through (d)(1)(iv) contains the fundamental information necessary to make an informed assessment of risks and benefits within the context of the specific military situation. Under these paragraphs, the Secretary of Defense must certify and document that:
(1) the extent and strength of evidence of the safety and effectiveness of the investigational new drug in relation to the medical risk that could be encountered during the military operation supports the drug's administration under an investigational new drug application (IND);
(2) the military operation presents a substantial risk that military personnel may be subject to a chemical, biological, nuclear, or other exposure likely to produce death or serious or life-threatening injury or illness;
(3) there is no available satisfactory alternative therapeutic or preventive treatment in relation to the intended use of the investigational new drug; and
(4) conditioning use of the investigational new drug on the voluntary participation of each member could significantly risk the safety and health of any individual member who would decline its use, the safety of other military personnel, and threaten the accomplishment of the military mission.
In order to help ensure that the President is provided all relevant information related to the effects of the investigational drug, the rule requires the Secretary of Defense to certify and document in his or her request for a waiver determination that DOD has explained:
(1) the context in which the investigational drug will be administered;
(2) the nature of the disease or condition for which the preventive or therapeutic treatment is intended; and
(3) to the extent it is available, information on conditions that could alter the effects of the investigational drug (21 CFR 50.23(d)(1)(vi)).
In order to improve record-keeping over that which occurred during the Gulf War, the Secretary of Defense is required to document and certify that DOD's record-keeping system is capable of tracking, and will be used to track, the proposed treatment from the supplier to the individual recipient; and, that medical records of members involved in the military operation will accurately document the receipt by members of the notification required by Section 50.23(d)(1)(viii) as well as any investigational new drugs in accordance with FDA regulations (21 CFR 50.23(d)(1)(vii), (d)(1)(ix), and (d)(1)(x)).
As noted earlier, the rule requires the Secretary of Defense to document and certify that each member involved in the military operation will be given, prior to the administration of the investigational new drug, a written information sheet describing the investigational new drug, the risks and benefits of its use, potential side effects, and other pertinent information about the appropriate use of the product (21 CFR 50.23(d)(1)(viii)). In addition, the information sheet is required to contain the following: (1) Clear notice that the drug being administered is an investigational new drug or a drug unapproved for its applied use; (2) the reasons why the investigational new drug or drug unapproved for its applied use is being administered; (3) information regarding the possible side effects of the investigational new drug or drug unapproved for its applied use, and (4) such other information that, as a condition of authorizing the use of the investigational new drug or drug unapproved for its applied use, the Secretary of Health and Human Services may require to be disclosed. FDA intends to review the information sheet as part of its review of the use of the investigational product under an IND in order to determine its adequacy.
The Secretary of Defense must document and certify that DOD will provide training to the appropriate medical personnel and potential recipients on the specific investigational new drug to be administered prior to its use (21 CFR 50.23(d)(1)(xiv)). DOD must also document and certify that DOD will provide adequate follow-up to assess whether there are beneficial or adverse health consequences that result from the use of the investigational product (21 CFR 50.23(d)(1)(xi)).
The requirements for Institutional Review Board (IRB) review of protocols for military use of investigational drugs without informed consent have been strengthened and further specified beyond those required for conventional INDs. The provisions of the interim rule include the following:
* The duly constituted IRB is to be responsible for reviewing the study. It must review and approve the investigational new drug protocol and the administration of the investigational new drug without informed consent as a prerequisite for the study to proceed (21 CFR 50.23(d)(1)(v)).
* DOD's request for a waiver must include the documentation of minutes of IRB meetings at which the protocol was reviewed (21 CFR 56.115(a)(2)).
* The IRB must include at least three nonaffiliated members who are not employees or officers of the Federal Government (other than for purposes of membership on the IRB) Section 50.23(d)(2).
* The IRB must review and approve the contents of the required written information sheet on the investigational product; the adequacy of the plan to disseminate information; the adequacy of the information and the plans for its dissemination to health care providers; and an informed consent form in those circumstances in which DOD determines that informed consent may be obtained from some or all personnel involved (Section 50.23(d)(3)).
The rule provides for FDA to complete its review of the investigational new drug protocol and conclude that it may proceed subject to a decision by the President on the informed consent waiver request (Section 50.23(d)(1)(xiii)). FDA will provide a written notification to DOD after it has completed its review, either granting permission for the protocol to proceed subject to the President's decision on the informed consent waiver request or, if appropriate, placing the study on clinical hold.
The rule contains two provisions to help ensure that informed consent waiver determinations continue to meet the standards and criteria of this rule after an initial waiver has been granted by the President. Section 50.23(d)(1)(xv) requires the Secretary of Defense to certify and document that DOD has stated and justified the time period for which the waiver is needed, not to exceed one year. For a waiver to exceed one year, this paragraph requires such a waiver to be separately renewed under the standards and criteria contained in 21 CFR 50.23(d). Section 50.23(d)(1)(xvi) places a continuing obligation on DOD to report to FDA and to the President any changed circumstances relating to these standards and criteria or that otherwise might affect the determination to use an investigational new drug without informed consent.
To encourage public access to information about products for which an informed consent waiver is granted, Section 50.23(d)(1)(xvii) requires DOD to provide public notice as soon as practicable and consistent with classification requirements through notice in the Federal Register describing each waiver of informed consent determination, a summary of the most updated scientific information on the products used, and other pertinent information.
Finally, in order to help ensure that DOD adheres to applicable statutes and laws, Section 50.23(d)(1)(xviii) requires the Secretary of Defense to document and certify that the use of the investigational drug without informed consent otherwise conforms with applicable law. Section 50.23(d)(5) states that "[n]othing in these criteria or standards is intended to preempt or limit FDA's and DOD's authority or obligations under applicable statutes and regulations."
As noted above, DHHS believes that exceptions to the informed consent requirement should be made rarely and in narrow circumstances and that it is preferable to establish the safety and efficacy of products before their general use in large populations. The new rule, 21 CFR 50.23(d)(1)(xii), therefore requires the Secretary of Defense to certify and document that it is pursuing drug development and marketing approval for the investigational drug with due diligence.
ANTECEDENTS TO THE EXECUTIVE ORDER AND INTERIM RULE
As noted above, the interim rule was the result of much effort and took into account the interests of all affected parties. It is important to understand the background of the rule and the actions leading up to its promulgation.
The use of investigational drugs is regulated by provisions of the Food, Drug and Cosmetic (FD&C) Act. In order for clinical testing to proceed with unapproved products, an IND application must be filed with FDA. The IND must contain information sufficient to demonstrate that it is reasonable to study the drug in humans, including information on drug composition, manufacturing and control data, the results of animal studies and, if available, prior human testing, and the protocol for the planned study. More importantly, the investigator must agree to a number of commitments designed to protect the rights and safety of human research subjects, including obtaining written informed consent from subjects, obtaining approval of an IRB before proceeding, and reporting to the sponsor of the study adverse effects that occur in research subjects. An IRB is a board or committee that reviews, approves and provides continuing oversight of biomedical research involving human subjects to ensure the right and welfare of the human subjects. (21 CFR Part 56).
Under the FD&C Act, sponsors must require investigators to certify that they will inform subjects receiving drugs under an IND that the drugs are investigational and "obtain the consent of such human beings or their representatives, except where they deem it not feasible, or in their professional judgment, contrary to the best interests of such human beings" (21 USC (505). There have been few instances in which obtaining informed consent has not been considered feasible or contrary to patients' interests.
There are three limited exceptions to FDA's informed consent requirements. These exceptions are: 1) for a physician to preserve the life of an individual patient; 2) for the conduct of a narrow class of research in emergency settings; and 3) for use by DOD of specific investigational products in military operations. FDA regulations governing all three of these informed consent exceptions are primarily focused on protecting the rights and safety of patients. The third exception to our informed consent requirements, the use of an investigational drug or biologic in certain situations related to military exigencies is the focus of this hearing.
During the months preceding the Persian Gulf War, DOD had discussions with FDA regarding the potential use of specific investigational products in military personnel serving in the Gulf region. It was thought that the products discussed represented the best preventive or therapeutic treatment for diseases endemic to the area and in providing protection against the possible use of chemical or biological weapons.
Thus, in response to DOD's request, FDA published in the December 21, 1990, Federal Register (55 FR 52813) an interim regulation amending its informed consent regulations at 21 CFR 50.23(d). The interim regulation allowed Commissioner of Food and Drugs to determine, upon receipt of an appropriate request from DOD, that obtaining informed consent from military personnel for use of a specific investigational drug or biologic would not be feasible in certain circumstances, and to grant a waiver from the requirement for obtaining such consent.
On December 28, 1990, DOD submitted protocols under INDs and requests for waiver of informed consent for pyridostigmine bromide 30-milligram (mg) tablets and the botulinum toxoid vaccine. Pyridostigmine bromide was considered a potentially useful pretreatment against certain nerve gases; the botulinum toxoid vaccine is widely accepted as offering potential protection against toxins produced by Clostridium botulinum, the bacterium that causes botulism. The Commissioner approved DOD's waiver requests for pyridostigmine bromide 30-mg tablets and botulinum toxoid vaccine on December 31, 1990, and January 8, 1991, respectively. Both products were administered to portions of the military personnel who participated in Operation Desert Storm. Following the cessation of combat activities, the DOD notified the Commissioner in a letter dated March 15, 1991, that DOD considered the two waivers granted under the interim rule to be no longer in effect. DOD also informed the Commissioner that DOD had ultimately decided to administer the botulinum toxoid vaccine on a voluntary basis.
There has been extensive examination of the use of the 1990 interim rule during the Persian Gulf War. The Presidential Advisory Committee on Gulf War Veterans' Illnesses' final report reviewed these issues in detail. In its' interim report (February 1996), the committee described a number of shortcomings in DOD's use of investigational products during the Gulf War and recommended, among other things, that FDA should issue a Notice of Proposed Rulemaking to revisit the adequacy of disclosure to service personnel; adequacy of record-keeping; long term follow-up of individuals who receive investigational products; and additional procedures to enhance understanding, oversight, and accountability. The report further suggested that FDA should explore possible alternatives to the 1990 interim final rule, such as an approval standard that recognizes surrogate endpoints and other data indicative of efficacy for vaccines, drugs, devices, and antibiotics to protect against chemical and biological warfare agents.
DOD's experience during the Gulf War with pyridostigmine bromide and the botulinum toxoid vaccine was described in detail in the request for comments on the 1990 interim rule. Concurrent with the request for comments on the interim rule, FDA was also evaluating DOD's experience in implementing INDs, as well as waivers under the interim rule during the Gulf War, in order to obtain specific factual information and to assess DOD's compliance with FDA requirements. In the ongoing evaluation of the use of investigational products in the Persian Gulf, significant deviations were identified from Federal regulations. These deviations were set forth in July 22, 1997, and December 2, 1997, letters from FDA to DOD.
Experience with the use of the waiver provision of the 1990 interim rule suggests two conclusions: (1) To the extent possible, military personnel should receive treatments whose safety and effectiveness have been fully evaluated; (2) where it is necessary to utilize investigational agents and to waive informed consent, new standards and criteria for doing so should be developed that will better ensure protection of the troops receiving the investigational product.
In the July 31, 1997, Federal Register (62 FR 40996), FDA published a "Request for Comments" that discussed the use of investigational drugs and biologicals in military and other emergency settings to treat or prevent toxicity of chemical or biological substances. The public comments received on the 1990 interim rule pointed out significant areas that needed to be strengthened, including: provision of adequate information about an investigational product before its use; adequate follow-up to assess whether there are adverse health consequences that result from the use of the investigational product; adequate oversight, accountability, and record-keeping when investigational agents are used; and involvement of non-DOD personnel in decisions to use investigational products without informed consent. All of these areas have been addressed in the new interim rule that establishes the criteria and standards for the President to use in making an informed consent waiver determination.
The new interim rule also necessitates a change to the regulations for human drugs so that those regulations are consistent with this rule. In the interim rule, 21 CFR 312.42 is amended to explicitly state that an investigation may be placed on clinical hold pending a determination by the President to waive the prior consent requirement for the administration of an investigational new drug. If FDA invokes this reason for a clinical hold, it will mean that review of the protocol is completed and FDA has concluded that the study may proceed; however, subjects may not be enrolled in the study until a positive decision on the informed consent waiver request has been made by the President and FDA has provided written notification to DOD that the clinical hold has been removed.
Section 731 of the Defense Authorization Act
Public Law 105-261, the Strom Thurmond National Defense Authorization Act for Fiscal Year 1999 (Defense Authorization Act) answers the controversial question of whether waiver of informed consent in military operations is ever appropriate. In passing this legislation, Congress has concluded that the President may waive the informed consent requirement for military personnel engaged in a particular military operation in certain situations. The President is established as the sole authority for making such a waiver of informed consent determination. FDA will be involved in this process through its traditional role of reviewing specific protocols under its investigational new drug regulations. The Commissioner of Food and Drugs will also play a key role in reviewing the waiver of informed consent request to the President.
Section 731 of the Defense Authorization Act, amending 10 U.S.C. 1107(f), became effective on October 17, 1998. Under new 10 U.S.C. 1107(f), the Commissioner of Food and Drugs no longer has the authority to issue a waiver of informed consent with respect to military operations. Section 1107(f)(1) of Title 10 provides for the President to grant such a waiver in the case of the administration of an investigational new drug or drug unapproved for its applied use to a member of the armed forces in connection with the member's participation in a particular military operation.
Section 1107(f)(1) of Title 10 authorizes the President to waive informed consent if the President finds that obtaining informed consent is: (1) not feasible; (2) contrary to the best interests of the member; or (3) not in the interests of national security. The first two grounds (lack of feasibility or contrary to the best interests of recipients) are specified in Section 505(i) of the FD&C Act (21 U.S.C. 355(i)). Section 1107(f)(2) provides that, in making a determination to waive informed consent on the grounds that it is not feasible or contrary to the best interests of the armed services member, the President shall apply the standards and criteria that are set forth in the relevant FDA regulations for a waiver of the prior consent requirement on that ground. Because Section 1107(f)(1) of Title 10 refers to waiver of informed consent in connection with military operations, the relevant FDA regulations referenced in Section 1107(f)(2) of Title 10 would be any regulations dealing with waivers in this context.
Executive Order 13139
FDA's October 5, 1999, interim rulemaking coincided with the publication of Executive Order 13139, entitled "Improving Health Protection of Military Personnel Participating in Particular Military Operations" and implementing Section 1107 of Title 10.
The Executive Order explicitly states the expectation that the United States Government will administer products approved for their intended use by FDA. In the event that the Secretary of Defense considers an investigational product to represent the most appropriate countermeasure for diseases endemic to the area of operations or to protect against possible chemical, biological, or radiological weapons, the product may, under certain circumstances and strict controls, be administered to provide potential protection for the health and well-being of deployed military personnel in order to ensure the success of the military operation.
Under the Executive Order, the Secretary of Defense shall develop the waiver request in consultation with FDA. The Commissioner of FDA shall expeditiously review the waiver request and certify whether the standards and criteria of the relevant regulations have been adequately addressed and whether the investigational new drug protocol may proceed subject to a decision by the President on the informed consent waiver request. FDA shall base its decision on, and the certification shall include an analysis describing, the extent and strength of the evidence on the safety and effectiveness of the investigational new drug in relation to the medical risk that could be encountered during the military operation. Finally the Executive Order establishes FDA review of training and health risk communications plans.
FUTURE USE OF FDA-REGULATED PRODUCTS BY DOD
There are important ways that FDA can contribute to DOD's mandate to protect military personnel that are consistent with FDA's mission and regulations and also mesh with DHHS's initiatives on bioterrorism and commitment to human subject protection. FDA's existing mechanisms for providing access to investigational products under an IND will continue to be available to any entity that complies with the Agency's specified requirements. Both DOD and FDA recognize, however, that some of the IND requirements may not be feasible in certain military situations. Based on the lessons from use of investigational agents during the Gulf War, DHHS believes that DOD's needs can best be met through DOD's support of drug development efforts leading to approval of products found to be safe and effective. We share DOD's goal of getting the best products to military personnel. Thus, we are committed to working with DOD to resolve the safety and effectiveness questions that may allow FDA to approve the drug and biological products for use in military operations and during military exigencies.
In order to provide pharmaceutical agents that are safe and effective in protecting military personnel, FDA believes that DOD must focus its efforts on drug development. Under existing regulations FDA can expedite access to new drugs by accelerating approval (subpart H of 21 CFR part 314 and subpart E of 21 CFR part 601). In addition, consistent with the recent changes to the FD&C Act on fast track products made in the Food and Drug Administration Modernization Act of 1997 (FDAMA), FDA is committed to facilitating development and expediting the review of drugs for serious and life-threatening conditions that address unmet needs (( 506, FDAMA (21 U.S.C. 356)).
Moreover, FDA has proposed an additional mechanism for product approval that relates to the evidence needed to demonstrate safety and efficacy for drug and biological products for use against lethal or toxic substances when efficacy studies in humans cannot ethically be conducted. FDA is proposing to amend its new drug and biological product regulations to identify the information needed to provide substantial evidence of the efficacy of new drug and biological products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances. This proposal would apply when the traditional efficacy studies in humans are not feasible and cannot be ethically conducted under FDA's regulations for adequate and well-controlled studies in humans. We recognize the need for adequate medical responses to protect or treat individuals exposed to these lethal or permanently disabling toxic substances.
In these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions could be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans (21 CFR 314.126). Under the proposed rule, FDA could rely on the evidence from animal studies where:
(1) There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
(2) the effect is independently substantiated in multiple animal species, including species expected to react with a response predictive for 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; and;
(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, and it is therefore reasonable to expect the effect of the product in animals to be a reliable indicator of its efficacy in humans.
In order to minimize the need to use investigational products during military exigencies, FDA has been working with DOD in its drug development efforts related to these products. DOD has agreed to identify those products that may provide protection to military members, develop appropriate drug development plans for each product, and establish a timeframe for completion.
Mr. Chairman, we hope the information presented here is useful to the Committee in examining the difficult issues surrounding the use of investigational drug products by the armed forces. DHHS has learned an enormous amount through our experience with the waiver of informed consent during the Persian Gulf War, and we are putting those lessons to work as we prepare for future exigencies. Thank you.