Regulatory References

Section 610:  Expanded Access

    (a) PATIENT ACCESS TO INVESTIGATIONAL DRUGS
  1. PUBLIC MEETING–
    1. IN GENERAL.–   The Secretary of Health and Human Services (referred to in this section as “The Secretary”), acting through the Commissioner of Food and Drugs, in coordination with the Director of the National Institutes of Health, and in consultation with patients, health care providers, drug sponsors, bioethicists, and other stakeholders, shall, not later than 270 days after the date of enactment of this Act, convene a public meeting to discuss clinical trial inclusion and exclusion criteria to inform the guidance under paragraph (3).  The Secretary shall inform the Comptroller General of the United Stats of the date when the public meeting will take place.
    2. TOPIC.S—The Secretary shall make available on the internet website of the Food and Drug Administration a report on the topics discussed at the meeting described in subparagraph (A) within 90 days of such a meeting.  Such topics shall include discussion of—
      1. the rationale for, and potential barriers for patients created by, research clinical trial inclusion and exclusion criteria;
      2. how appropriate patient populations can benefit from the results of trials that employ alternative designs;
      3. barriers to participation in clinical trials, including –
        1. information regarding any potential risks and benefits of participation;
        2. regulatory, geographical, and socio-economic barriers; and
        3. the impact of exclusion criteria on the enrollment in clinical trials of particular populations, including infants and children, pregnant and lactating women, seniors, individuals with advanced disease, and individuals with co-morbid conditions;
      4. clinical trial designs and methods, including expanded access trials, that increase enrollment of more diverse patient populations, when appropriate, while facilitating the collection of data to establish safe use and support substantial evidence of effectiveness, including data obtained from expanded access trials; and
      5. how changes to clinical trial inclusion and exclusion criteria may impact the complexity and length of clinical trials, the data necessary to demonstrate safety and effectiveness, and potential approaches to mitigating those impacts.
  2. REPORT.—Not later than 1 year after the Secretary issues the report under paragraph (1)(B), the Comptroller General of the United States shall report to the Committee on Health, Education, Labor, and Pensions of the Senate and the Committee on Energy and Commerce of the House of Representatives on individual access to investigational drugs through the expanded access program under section 561(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb(b)).  The report shall include—
    1. A description of actions taken by manufacturers and distributors under section 561A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb—0);
    2. consideration of whether  Form FDA 3926 and the guidance documents titled “Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers” and “Individual Patient Expanded Access Applications:  Form 3926”, issued by the Food and Drug Administration in June 2016, have reduced application burden with respect to individual and physicians seeking access to investigational new drugs pursuant to section 561(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) and improved clarity for patients, physicians, and drug manufacturers about such process;
    3. consideration of whether the guidance or regulations issued to implement section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) have improved access for individual patients to investigational drugs who do not qualify for clinical trials of such investigational drugs, and what barriers to such access remain;
    4. an assessment of methods patients and health care providers use to engage with the Food and Drug Administration or drug sponsors on expanded access; and
    5. an analysis of the Secretary’s report under paragraph (1)(B).

    3. GUIDANCE.—
    1. IN GENERAL.— Not later than 1 year after the publication of the report under paragraph (1)(B), the Secretary, acting through the Commissioner of Food and Drugs, shall issue one or more draft guidance’s regarding eligibility criteria for clinical trials.  Not later than 1 year after the public comment period on each such draft guidance ends, the Secretary shall issue a revised draft guidance or final guidance.
    2. CONTENTS.—The guidance documents described in subparagraph (A) shall address methodological approaches that a manufacturer or sponsor of an investigation of a new drug may take to—
      1. broaden eligibility criteria for clinical trials and expanded access trials, especially with respect to drugs for the treatment of serious and life-threatening conditions or diseases for which there is an unmet medical need;
      2. develop eligibility criteria for, and increase trial recruitment to, clinical trials so that enrollment in such trials more accurately reflects the patients most likely to receive the drug, as applicable and as appropriate, while establishing safe use and supporting findings of substantial evidence of effectiveness; and
      3. use the criteria described in clauses (i) and (ii) in a manner that is appropriate for drugs intended for the treatment of rare diseases or conditions.
    (b) IMPROVING INSTITUTIONAL REVIEW BOARD REVIEW OF SINGLE PATIENTS EXPANDED ACCESS PROTOCOL.—Not later than 1 year after the date of enactment of this Act, the Secretary, acting through the Commissioner of Food and Drugs, shall issue guidance or regulations, or revise existing guidance or regulations, to streamline the institutional review board review of individual patient expanded access protocols submitted under 561(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb(b)).  To facilitate the use of expanded access protocols, any guidance or regulations so issued or revised may include a description of the process for any person acting through a physician licensed in accordance with the State law to request that an institutional review board chair (or designated member of the institutional review board) review a single patient expanded access protocol submitted under section 561(b) for a drug.  The Secretary shall update any relevant forms associated with individual patient expanded access requests under such section 561(b) as necessary.
    (c) EXPANDED ACCESS POLICY TRANSPARENCY.—Section 561(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb-0(f) is amended—
  1. In the matter preceding paragraph (1), by striking “later” and inserting “earlier”;
  2. by striking paragraph (1);
  3. by redesignating paragraph (2) as paragraph (1);
  4. in paragraph (1) as so redesignated, by striking the period at the end and inserting “; or”; and
  5. by adding at the end the following:
    “(2) as applicable, 15 days after the drug receives a designation as breakthrough therapy, fast track product, or regenerative advanced therapy under subsection (a), (b), or (g), respectively, of section 506.”.

(a) Scope. This subpart contains the requirements for the use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. The aim of this subpart is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or condition.

(b) Definitions. The following definitions of terms apply to this subpart:

Immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

Serious disease or condition means a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

The criteria, submission requirements, safeguards, and beginning treatment information set out in this section apply to all expanded access uses described in this subpart. Additional criteria, submission requirements, and safeguards that apply to specific types of expanded access are described in 312.310 through 312.320.

(a) Criteria. FDA must determine that:

(1) The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;

(2) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and

(3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

(b) Submission. (1) An expanded access submission is required for each type of expanded access described in this subpart. The submission may be a new IND or a protocol amendment to an existing IND. Information required for a submission may be supplied by referring to pertinent information contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND.

(2) The expanded access submission must include:

(i) A cover sheet (Form FDA 1571) meeting the requirements of 312.23(a);

(ii) The rationale for the intended use of the drug, including a list of available therapeutic options that would ordinarily be tried before resorting to the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available therapeutic options;

(iii) The criteria for patient selection or, for an individual patient, a description of the patient’s disease or condition, including recent medical history and previous treatments of the disease or condition;

(iv) The method of administration of the drug, dose, and duration of therapy;

(v) A description of the facility where the drug will be manufactured;

(vi) Chemistry, manufacturing, and controls information adequate to ensure the proper identification, quality, purity, and strength of the investigational drug;

(vii) Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at the dose and duration proposed for expanded access use (ordinarily, information that would be adequate to permit clinical testing of the drug in a population of the size expected to be treated); and

(viii) A description of clinical procedures, laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize its risks.

(3) The expanded access submission and its mailing cover must be plainly marked “EXPANDED ACCESS SUBMISSION.” If the expanded access submission is for a treatment IND or treatment protocol, the applicable box on Form FDA 1571 must be checked.

(c) Safeguards. The responsibilities of sponsors and investigators set forth in subpart D of this part are applicable to expanded access use under this subpart as described in this paragraph.

(1) A licensed physician under whose immediate direction an investigational drug is administered or dispensed for an expanded access use under this subpart is considered an investigator , for purposes of this part, and must comply with the responsibilities for investigators set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(2) An individual or entity that submits an expanded access IND or protocol under this subpart is considered a sponsor , for purposes of this part, and must comply with the responsibilities for sponsors set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(3) A licensed physician under whose immediate direction an investigational drug is administered or dispensed, and who submits an IND for expanded access use under this subpart is considered a sponsor-investigator , for purposes of this part, and must comply with the responsibilities for sponsors and investigators set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(4) Investigators. In all cases of expanded access, investigators are responsible for reporting adverse drug events to the sponsor, ensuring that the informed consent requirements of part 50 of this chapter are met, ensuring that IRB review of the expanded access use is obtained in a manner consistent with the requirements of part 56 of this chapter, and maintaining accurate case histories and drug disposition records and retaining records in a manner consistent with the requirements of 312.62. Depending on the type of expanded access, other investigator responsibilities under subpart D may also apply.

(5) Sponsors. In all cases of expanded access, sponsors are responsible for submitting IND safety reports and annual reports (when the IND or protocol continues for 1 year or longer) to FDA as required by 312.32 and 312.33, ensuring that licensed physicians are qualified to administer the investigational drug for the expanded access use, providing licensed physicians with the information needed to minimize the risk and maximize the potential benefits of the investigational drug (the investigator’s brochure must be provided if one exists for the drug), maintaining an effective IND for the expanded access use, and maintaining adequate drug disposition records and retaining records in a manner consistent with the requirements of 312.57. Depending on the type of expanded access, other sponsor responsibilities under subpart D may also apply.

(d) Beginning treatment –(1) INDs. An expanded access IND goes into effect 30 days after FDA receives the IND or on earlier notification by FDA that the expanded access use may begin.

(2) Protocols. With the following exceptions, expanded access use under a protocol submitted under an existing IND may begin as described in 312.30(a).

(i) Expanded access use under the emergency procedures described in 312.310(d) may begin when the use is authorized by the FDA reviewing official.

(ii) Expanded access use under 312.320 may begin 30 days after FDA receives the protocol or upon earlier notification by FDA that use may begin.

(3) Clinical holds. FDA may place any expanded access IND or protocol on clinical hold as described in 312.42.

Under this section, FDA may permit an investigational drug to be used for the treatment of an individual patient by a licensed physician.

(a) Criteria. The criteria in 312.305(a) must be met; and the following determinations must be made:

(1) The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and

(2) FDA must determine that the patient cannot obtain the drug under another IND or protocol.

(b) Submission. The expanded access submission must include information adequate to demonstrate that the criteria in 312.305(a) and paragraph (a) of this section have been met. The expanded access submission must meet the requirements of 312.305(b).

(1) If the drug is the subject of an existing IND, the expanded access submission may be made by the sponsor or by a licensed physician.

(2) A sponsor may satisfy the submission requirements by amending its existing IND to include a protocol for individual patient expanded access.

(3) A licensed physician may satisfy the submission requirements by obtaining from the sponsor permission for FDA to refer to any information in the IND that would be needed to support the expanded access request (right of reference) and by providing any other required information not contained in the IND (usually only the information specific to the individual patient).

(c) Safeguards. (1) Treatment is generally limited to a single course of therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.

(2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written summary of the results of the expanded access use, including adverse effects.

(3) FDA may require sponsors to monitor an individual patient expanded access use if the use is for an extended duration.

(4) When a significant number of similar individual patient expanded access requests have been submitted, FDA may ask the sponsor to submit an IND or protocol for the use under 312.315 or 312.320.

(d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written submission can be made, FDA may authorize the expanded access use to begin without a written submission. The FDA reviewing official may authorize the emergency use by telephone.

(1) Emergency expanded access use may be requested by telephone, facsimile, or other means of electronic communications. For investigational biological drug products regulated by the Center for Biologics Evaluation and Research, the request should be directed to the Office of Communication, Outreach and Development, Center for Biologics Evaluation and Research, 240-402-8010 or 1-800-835-4709, e-mail: ocod@fda.hhs.gov. For all other investigational drugs, the request for authorization should be directed to the Division of Drug Information, Center for Drug Evaluation and Research, 301-796-3400, e-mail: druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), the request should be directed to the FDA Emergency Call Center, 866-300-4374, e-mail: emergency.operations@fda.hhs.gov.

(2) The licensed physician or sponsor must explain how the expanded access use will meet the requirements of 312.305 and 312.310 and must agree to submit an expanded access submission within 15 working days of FDA’s authorization of the use.

[74 FR 40942, Aug. 13, 2009, as amended at 75 FR 32659, June 9, 2010; 80 FR 18091, Apr. 3, 2015]

Under this section, FDA may permit an investigational drug to be used for the treatment of a patient population smaller than that typical of a treatment IND or treatment protocol. FDA may ask a sponsor to consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use.

(a) Need for expanded access. Expanded access under this section may be needed in the following situations:

(1) Drug not being developed. The drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial.

(2) Drug being developed. The drug is being studied in a clinical trial, but patients requesting the drug for expanded access use are unable to participate in the trial. For example, patients may not be able to participate in the trial because they have a different disease or stage of disease than the one being studied or otherwise do not meet the enrollment criteria, because enrollment in the trial is closed, or because the trial site is not geographically accessible.

(3) Approved or related drug. (i) The drug is an approved drug product that is no longer marketed for safety reasons or is unavailable through marketing due to failure to meet the conditions of the approved application, or

(ii) The drug contains the same active moiety as an approved drug product that is unavailable through marketing due to failure to meet the conditions of the approved application or a drug shortage.

(b) Criteria. The criteria in 312.305(a) must be met; and FDA must determine that:

(1) There is enough evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and

(2) There is at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population.

(c) Submission. The expanded access submission must include information adequate to satisfy FDA that the criteria in 312.305(a) and paragraph (b) of this section have been met. The expanded access submission must meet the requirements of 312.305(b). In addition:

(1) The expanded access submission must state whether the drug is being developed or is not being developed and describe the patient population to be treated.

(2) If the drug is not being actively developed, the sponsor must explain why the drug cannot currently be developed for the expanded access use and under what circumstances the drug could be developed.

(3) If the drug is being studied in a clinical trial, the sponsor must explain why the patients to be treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would conduct a clinical trial in these patients.

(d) Safeguards. (1) Upon review of the IND annual report, FDA will determine whether it is appropriate for the expanded access to continue under this section.

(i) If the drug is not being actively developed or if the expanded access use is not being developed (but another use is being developed), FDA will consider whether it is possible to conduct a clinical study of the expanded access use.

(ii) If the drug is being actively developed, FDA will consider whether providing the investigational drug for expanded access use is interfering with the clinical development of the drug.

(iii) As the number of patients enrolled increases, FDA may ask the sponsor to submit an IND or protocol for the use under 312.320.

(2) The sponsor is responsible for monitoring the expanded access protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.

Under this section, FDA may permit an investigational drug to be used for widespread treatment use.

(a) Criteria. The criteria in 312.305(a) must be met, and FDA must determine that:

(1) Trial status. (i) The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use, or

(ii) All clinical trials of the drug have been completed; and

(2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and

(3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence would ordinarily consist of data from phase 3 trials, but could consist of compelling data from completed phase 2 trials; or

(ii) When the expanded access use is for an immediately life-threatening disease or condition, the available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug may be effective for the expanded access use and would not expose patients to an unreasonable and significant risk of illness or injury. This evidence would ordinarily consist of clinical data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evidence.

(b) Submission. The expanded access submission must include information adequate to satisfy FDA that the criteria in 312.305(a) and paragraph (a) of this section have been met. The expanded access submission must meet the requirements of 312.305(b).

(c) Safeguard. The sponsor is responsible for monitoring the treatment protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.

(1) A sponsor must meet the applicable requirements in paragraph (b) of this section for charging in a clinical trial or paragraph (c) of this section for charging for expanded access to an investigational drug for treatment use under subpart I of this part, except that sponsors need not fulfill the requirements in this section to charge for an approved drug obtained from another entity not affiliated with the sponsor for use as part of the clinical trial evaluation (e.g., in a clinical trial of a new use of the approved drug, for use of the approved drug as an active control).

(2) A sponsor must justify the amount to be charged in accordance with paragraph (d) of this section.

(3) A sponsor must obtain prior written authorization from FDA to charge for an investigational drug.

(4) FDA will withdraw authorization to charge if it determines that charging is interfering with the development of a drug for marketing approval or that the criteria for the authorization are no longer being met.

(1) Charging for a sponsor’s drug. A sponsor who wishes to charge for its investigational drug, including investigational use of its approved drug, must:

(i) Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the clinical investigations, would provide a significant advantage over available products in the diagnosis, treatment, mitigation, or prevention of a disease or condition;

(ii) Demonstrate that the data to be obtained from the clinical trial would be essential to establishing that the drug is effective or safe for the purpose of obtaining initial approval of a drug, or would support a significant change in the labeling of an approved drug (e.g., new indication, inclusion of comparative safety information); and

(iii) Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor. The cost may be extraordinary due to manufacturing complexity, scarcity of a natural resource, the large quantity of drug needed (e.g., due to the size or duration of the trial), or some combination of these or other extraordinary circumstances (e.g., resources available to a sponsor).

(2) Duration of charging in a clinical trial. Unless FDA specifies a shorter period, charging may continue for the length of the clinical trial.

(1) A sponsor who wishes to charge for expanded access to an investigational drug for treatment use under subpart I of this part must provide reasonable assurance that charging will not interfere with developing the drug for marketing approval.

(2) For expanded access under 312.320 (treatment IND or treatment protocol), such assurance must include:

(i) Evidence of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to reasonably assure FDA that the trial(s) will be successfully completed as planned;

(ii) Evidence of adequate progress in the development of the drug for marketing approval; and

(iii) Information submitted under the general investigational plan (312.23(a)(3)(iv)) specifying the drug development milestones the sponsor plans to meet in the next year.

(3) The authorization to charge is limited to the number of patients authorized to receive the drug under the treatment use, if there is a limitation.

(4) Unless FDA specifies a shorter period, charging for expanded access to an investigational drug for treatment use under subpart I of this part may continue for 1 year from the time of FDA authorization. A sponsor may request that FDA reauthorize charging for additional periods.

(1) A sponsor may recover only the direct costs of making its investigational drug available.

(i) Direct costs are costs incurred by a sponsor that can be specifically and exclusively attributed to providing the drug for the investigational use for which FDA has authorized cost recovery. Direct costs include costs per unit to manufacture the drug (e.g., raw materials, labor, and non-reusable supplies and equipment used to manufacture the quantity of drug needed for the use for which charging is authorized) or costs to acquire the drug from another manufacturing source, and direct costs to ship and handle (e.g., store) the drug.

(ii) Indirect costs include costs incurred primarily to produce the drug for commercial sale (e.g., costs for facilities and equipment used to manufacture the supply of investigational drug, but that are primarily intended to produce large quantities of drug for eventual commercial sale) and research and development, administrative, labor, or other costs that would be incurred even if the clinical trial or treatment use for which charging is authorized did not occur.

(2) For expanded access to an investigational drug for treatment use under 312.315 (intermediate-size patient populations) and 312.320 (treatment IND or treatment protocol), in addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the costs of monitoring the expanded access IND or protocol, complying with IND reporting requirements, and other administrative costs directly associated with the expanded access IND.

(3) To support its calculation for cost recovery, a sponsor must provide supporting documentation to show that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2) of this section. The documentation must be accompanied by a statement that an independent certified public accountant has reviewed and approved the calculations.

[74 FR 40899, Aug. 13, 2009]

The current U.S. system of protection for human research subjects is heavily influenced by the Belmont Report, written in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report outlines the basic ethical principles in research involving human subjects. In 1981, with this report as foundational background, HHS and the Food and Drug Administration revised, and made as compatible as possible under their respective statutory authorities, their existing human subjects regulations. The Federal Policy for the Protection of Human Subjects or the “Common Rule” was published in 1991 and codified in separate regulations by 15 Federal departments and agencies, as listed below. The HHS regulations, 45 CFR part 46, include four subparts: subpart A, also known as the Federal Policy or the “Common Rule”; subpart B, additional protections for pregnant women, human fetuses, and neonates; subpart C, additional protections for prisoners; and subpart D, additional protections for children. Each agency includes in its chapter of the Code of Federal Regulations [CFR] section numbers and language that are identical to those of the HHS codification at 45 CFR part 46, subpart A. For all participating departments and agencies the Common Rule outlines the basic provisions for IRBs, informed consent, and Assurances of Compliance. Human subject research conducted or supported by each federal department/agency is governed by the regulations of that department/agency. The head of that department/agency retains final judgment as to whether a particular activity it conducts or supports is covered by the Common Rule. If an institution seeks guidance on implementation of the Common Rule and other applicable federal regulations, the institution should contact the department/agency conducting or supporting the research.

The FDA’s New Procedures for the Use of Investigational Drugs in Treatment

Frank E. Young, MD, PhD; John A. Norris, JD, MBA; Joseph A. Levitt, JD; Stuart L. Nightingale, MD
First released April 1988 FDA, Office of Health Affairs Printed in JAMA 1988; 259:2267-2270 Transcribed and re-posted in accordance with US 17 U.S.C. Sec. 105
The Food and Drug Administration has established new procedures to make promising investigational drugs available for treatment of patients with immediately life-threatening or serious diseases as early in the drug development process as possible and well before general marketing begins. The purpose of this article is to inform the medical community about these new procedures and to facilitate their implementation. Examples of immediately life-threatening and serious diseases are given and the procedures that physicians should use to obtain a drug under the new regulations are described. The treatment use of zidovudine (Retrovir), while still in the investigational phase, is described as a case study. The article also summarizes the Food and Drug Administration’s new procedures under which drug sponsors can charge for investigational drugs. *** The desperate situation facing patients with acquired immnodeficiency syndrome (AIDS) has highlighted the need to make promising new drugs available as early as possible in the development process. Because of the need to evaluate drugs to treat AIDS rapidly, the Food and Drug Administration (FDA) has created a special 1-AA internal agency designation for AIDS-related drugs to ensure that they receive the highest priority at all stages of the drug review process. Despite these modifications in the review process for therapies for AIDS and other dreaded diseases, we are concerned that everything possible be done to make not only promising AIDS-related drugs, but also other significant therapies, available to the public as soon as we have enough data to make a reasonable judgment that the drug may be effective and that it will not cause unreasonable risk. Therefore, the FDA has recently established procedures to make promising investigational drugs that are not yet generally marketed available for patients with immediately life-threatening or serious diseases. We have taken these steps, which include codification of a “Treatment IND” (treatment investigational new drug application), so that breakthrough drugs that are still undergoing clinical trials can be used for patients when there is no satisfactory alternative treatment. Last year, the FDA formally proposed and made final the new procedures that outline the circumstances for treatment use, outside of a clinical trial of experimental drugs. We expect with these procedures not only to facilitate the availability of promising new drugs to desperately ill patients as early in the drug-development process as possible, but also to obtain additional data on the drugs’ safety and effectiveness. In this article, we will describe the new procedures to assist physicians in brining to their patients important new therapies that are still technically in the investigational stage and provide an overview other regulation. Additionally, we will explain the practical aspects of how and when to make application to either commercial sponsor or, less commonly, the agency itself.
PAST PRECEDENTS FOR TREATMENT USE OF INVESTIGATIONAL DRUGS
In some instances in the past, the FDA has encouraged the use of treatment protocols for promising drugs prior to final approval for marketing. Our new Treatment IND procedures are built on experiences with treatment protocols initiated after the basic studies of a drug were well underway and when early clinical evidence appeared strongly favorable. These procedures enabled patients in some cases to be treated with the drugs outside of the controlled clinical trials. The first class of drugs to arouse interest in treatment protocols was the cardioselective B-blockers. Several thousand patients with bronchospastic lung disease received the drug metoprolol outside of controlled trials well before it was approved in 1976. Similarly, the antiarrhythmic drugs recently approved – tocainide, mexiletine, flecainide, and encainide – were made available to physicians who cared for patients with complex, life-threatening arrhythmias prior to the approval of their New Drug Applications (NDAs). One of these drugs, amiodarone, was approved in late 1985, but before that over 600 cardiologists treated at least 20,000 patients under Treatment INDs. The FDA was able to obtain information from these highly qualified specialists as they treated their patients. I addition, calcium antagonists, offering a new treatment modality for angina, especially for patients with vasospastic angina, were used widely under treatment protocols. Twenty thousand patients ultimately took nifedipine before approval of the NDA, thereby generating significant safety data from follow-up studies. Another calcium antagonist, verapamil, was given to approximately 5000 patients under treatment protocols. Another example where the FDA successfully utilized the Treatment IND approach is that of somatrem (Protopin), a synthetically derived human growth hormone. A Treatment IND for somatrem was needed when it was recognized that the pituitary growth hormone that was previously supplied was contaminated with Creutzfeldt-Jakob virus and had led to the deaths of several individuals who were treated with this particular compound. This Treatment IND was highly significant because it met the urgent public health need of those American children who depended on this therapy and were at risk of developing life-threatening hypoglycemia. Other examples over the past decade where special situations have led to treatment availability of investigational drugs include the Group C cancer drugs (e.g. etoposide, and streptozocin [streptozotocin]); a system of distribution has been in effect since the mid-1970s for anticancer drugs deemed sufficiently promising to be made available to patients with cancer through the National Cancer Institute’s limited distribution system. Similarly, a program for the treatment availability of tetrahydrocannabinol for treating nausea and vomiting secondary to cancer chemotherapy was established, utilizing the same system. More recently, built on the concept of the Treatment IND, a modified Group C procedure was introduced to make interleukin 2 combined with lymphokine-activated killer cells, and interleukin 2 alone, available through experimental studies in comprehensive cancer centers.
CASE STUDY: ZIDOVUDINE
The primary motivation for the codification of the Treatment IND process was the demonstrated need to bring breakthrough drugs to desperately ill patients when no other alternative therapy exists. The extreme plight of people with AIDS clearly exemplifies this need. Thus, zidovudine (Retrovir [formerly called azidothymidine]) illustrates how rapidly an experimental drug can be made available once it appears promising for an immediately life-threatening disease for which there is no effective alternative in early clinical trials. The first phase of human testing for zidovudine, involving only 33 patients with AIDS-related complex, was conducted from July to December 1985. Results of those very limited trials were promising and Phase II trials began in February 1986 to test the drug’s safety and effectiveness. Close to 300 patients with AIDS, most of whom suffered from Pneumocystis carinii pneumonia, were involved in this multi-center trial, which was a randomized comparison of zidovudine and a placebo. In September, the trials were halted early when it was found that 16 patients taking the placebo had died, whereas only one patients taking zidovudine had died. Once these impressive data were submitted to the FDA, it took the agency less than a week to grant a Treatment IND to treat AIDS patients with a history of P carinii pneumonia. The FDA also approved a model informed consent form as part of an overall effort to facilitate availability of the drug. In all, more than 4000 patients with AIDS were treated with zidovudine between the time that the Treatment IND application was field in September 1986, the time that the NDA was filed in December 1986, and the date of the approval of the NDA on March 19, 1987. Therefore, of the total 21 months of clinical evaluations and review, the drug was available to physicians throughout the country through Treatment INDs for a period of six months or about 30% of the time required for clinical evaluation and approval of the NDA.
NEW FDA CRITERIA AND PROCEDURES
In our new Treatment IND procedures, we have explained some of the factors that we believe are important considerations in determining whether treatment use of an experimental drug is appropriate and we have outlined how investigational drugs can be obtained for treatment purposes for serious or immediately life-threatening diseases. It should be emphasized that there are very specific criteria that must be met for the treatment use to be approved by the agency. The initial criteria are that (1) the drug is intended to treat a serious or immediately life-threatening disease; (2) there is no comparable or satisfactory alternative or other therapy to treat that stage of the disease in the intended population; (3) the drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed; an (4) the sponsor for the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence. For drugs intended to treat an immediately life-threatening disease, a request may be denied for treatment use if the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug (1) may be effective for its intended use in its intended patient population or (2) would expose patients who receive the drug to an unreasonable and significant additional risk of illness or injury. In addition, for drugs intended to treat a serious disease, the treatment use request may be denied if there is insufficient evidence of safety and effectiveness to support such use. The FDA will generally consider Treatment INDs for drugs in the latter stages of clinical testing, after a critical nucleus of data has become available (Figure). In the case of an immediately life-threatening disease, a drug may be made available for treatment use earlier than the Phase III investigations, but ordinarily not earlier than Phase II investigations. In the case of a serious disease, a drug ordinarily may be made available for treatment use during Phase III investigations or after all clinical trials have been completed; however, in appropriate circumstances, a drug may be made available for treatment use during Phase II investigations. The treatment use of a drug in these circumstances includes the sue of a drug for diagnostic purposes. Discussion of the phases of clinical testing is provided in the FDA regulations at 21 CFR 312.21. In considering the treatment use of experimental drugs, the stage of a disease is important in determining whether it is immediately life threatening, serious, or not serious. For example, for some diseases such as multiple sclerosis, treatment use of an experimental drug would not be appropriate at early stages of the disease. In applying for an investigational drug for an Treatment IND, the sponsor should define the intended patient population and, in medically appropriate cases, limit treatment use to particular stages of a diseases or to patients with a particular set of symptoms, For example, as described earlier, The Treatment IND for zidovudine was limited to AIDS patients who had a history of P carinii pneumonia. To illustrate the types of diseases or stages of diseases that would normally be considered to be immediately life threatening, the FDA has provided the following examples in its final regulation: advanced cases of AIDS, advanced congestive heart failure (New York Heart Association class IV), recurrent sustained ventricular tachycardia or ventricular fibrillation, herpes simplex encephalitis, most advanced metastatic refractory cancers, far-advanced emphysema, severe combined immunodeficiency syndrome, bacterial endocarditis, and subarachnoid hemorrhage. The following would normally be considered serious diseases or stages of diseases: Alzheimer’s disease, advanced multiple sclerosis, advanced Parkinson’s disease, transient ischemic attacks, progressive ankylosing spondylitis, active advanced systemic lupus erythematosus, certain forms of epilepsy, nonacidotic or hyperosmolar diabetes, and paroxysmal supraventricular tachycardia. These examples are illustrative only and are not intended as a comprehensive list.
HOW TO GET INFORMATION ON WHICH DRUGS ARE AVAILABLE UNDER TREATMENT INDs
The FDA intends to inform physicians when an investigational drug has been approved for treatment use in an immediately life-threatening or serious disease for a patient population for which there is no satisfactory alternative drug or other therapy available. The FDA will utilize the FDA Drug Bulletin, which is mailed without charge to over a million physicians and other health professionals several times a year; the FROM THE GOOD AND DRUG ADMINISTRATION column in JAMA (which appears in the second issue each month); and other vehicles, such as press releases and background papers, as appropriate. In the short period since our new treatment-use procedures were announced, we have received a umber of applications for a Treatment IND, and three have already been approved: cytomegalovirus immune globulin for attenuation of primary cytomegalovirus infection associated with kidney transplantation, ifosfamide and mesna for germ cell carcinoma where first line and salvage therapy have failed, and trimetrexate for P carinii pneumonia in certain AIDS patients. More applications are expected as physicians and pharmaceutical companies become more familiar with our new procedures.
HOW TO APPLY FOR TREATMENT USE OF AN INVESTIGATIONAL DRUG
The goal of the treatment-use procedures for investigational drugs is to make promising drugs available to desperately ill patients earlier than they would otherwise be available, while still enabling the clinical trials to progress. It should be emphasized that the FDA is setting up flexible rather than ridged procedures. The DA will consider the specific situations on a case-by-case basis and the Commissioner will evaluate all evidence as a whole before making a final decision. A physician may follow two pathways to obtain drugs for desperately ill patients. The most efficient and recommended path is through contacting the commercial sponsor of the investigational drug so that the sponsor of a drug within a controlled trial can make the drug available under a treatment protocol, if the sponsor has not already done so. The less-preferred path is for the physician to contact the FDA directly. This will be necessary only when the commercial sponsor of the investigational drug is unwilling to offer a treatment protocol.
Requesting the Drug from a Sponsor
The physician should directly contact the sponsor (most frequently a pharmaceutical company, but occasionally a government agency such as the National Institutes of Health). The sponsor will make available a brochure containing technical information for appropriate use of the drug by the practitioner. The sponsor will also make available to the physician the drug itself. The sponsor will have on file with the FDA information that includes (1) the intended use of the drug; (2) an explanation of the rationale for use of the drug, including, as appropriate, a list of what available regiments ordinarily should be tried before using the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available marketed treatments; (3) a brief description of the criteria for patient selection; (4) the method of administration of the drug and the dosages; (5) a description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk; (6) an informational brochure for supplying to each treating physician; and (7) a commitment by the sponsor to ensure compliance of all participating investigators with the informed consent and Institutional Review Board requirements 21 CFR 50, 56.
Requesting the Treatment IND Directly from the FDA
If a physician wants to obtain an investigational drug subject to controlled clinical trial for a treatment use, the practitioner should first attempt to obtain the drug from the sponsor of the controlled trial under a treatment protocol. If the sponsor of the controlled clinical investigation of the drug has not gained approval for or will not apply for a Treatment IND for the drug, a physician may seek to obtain the drug from the sponsor and personally submit a Treatment IND to the FDA requesting authorization to use the investigational drug for treatment use. A Treatment IND request from a physician must include (1) a signed form FD 1571, the Investigational New Drug Application; (2) a statement of the steps taken by the practitioner to obtain the drug under a treatment protocol from the drug sponsor; (3) a treatment protocol containing (a) the intended use of the drug, (b) an explanation of the rationale for use of the drug, including, as appropriate, a list of what available regimens ordinarily should be tried before using the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available marketed treatments, (c) a brief description of the criteria for patient selection, (d) the method of administration of the drug and the dosages, and (e) a description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk; (4) a statement of the practitioner’s qualifications to use the investigational drug for the intended treatment use; (5) the practitioner’s statement of familiarity with information on the drug’s safety and effectiveness derived from previous clinical and nonclinical experience with the drug; and (6) a statement to the effect that the investigator agrees to report safety information to the FDA in accordance with the FDA’s regulation 312.32. The FDA will review treatment IND applications and respond to the physician within 30 days.
OTHER ASPECTS OF TREATMENT IND USE
To best protect the patient, the FDA is instituting a number of important modifications of current practice. One ensures that drugs distributed under a Treatment ID or treatment protocol are manufactured in adequate facilities to ensure quality control. The FDA will take special precautions to guard against health fraud and any other inappropriate use of a drug that has not completed all phases of evaluation and review. Additionally, the FDA does not want to jeopardize the controlled clinical trials that are under way. Thus, the procedures make authorization of a Treatment IND or treatment protocol contingent on the existence of ongoing clinical trials and on the drug sponsor’s active pursuit of marketing approval. The FDA is committed to ensuring that the Treatment IND process does not create disincentives to the expeditious development and approval for marketing of promising therapies. Obviously, these decisions require the exercise of judgment by the Commissioner on a case-by-case basis. In this context, we emphasize the importance of introducing “orphan drugs’ to the market. The FDA’s Orphan Drug program will continue to emphasize the need to develop and make available orphan drugs for individuals with rare diseases. Efforts will be made to accommodate patients with such diseases within the Treatment IND context. Additionally, physicians should know that the FDA will continue to respond on a case-by-case basis to requests for emergency INDs for individual patients. Need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND. In such a case, the FDA may authorize shipmen to f the drug for a specified use in advance of submission of an IND. A request for such authorization may be transmitted to the FDA by telephone or other rapid means of communication. Except in extraordinary circumstances, such authorization will be conditioned on the sponsor’s submitting an appropriate IND as soon as practicable after receiving the authorization. The GDA’s new procedures contain a number of other important elements. For example, they define conditions under which drug manufacturers may charge for investigational new drug products. These conditions are intended to provide sufficient incentives for drug manufacturers to make investigational new drugs available to patients before general marketing begins, but under sufficient safeguards to prevent commercialization of the product, as well as to ensure the integrity of clinical trials.
CONCLUSION
The FDA has developed a number of innovative procedures in an effort to bring hope to thousands of desperately ill Americans and their families. The FDA plays a critical role in improving the quality of health care in this country. While those in the academic and governmental research communities are engaged in the initial discovery and clinical testing of new therapeutic agents, it is the FDA’s role and responsibility to facilitate the swift transfer of new discoveries from the laboratory into the marketplace. Only then can important new therapies serve their true purpose of helping patients. The GDA has no higher priority than facilitating the timely availability of important, safe, and effective new drug products to treat desperately ill patients.