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. 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.

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) General criteria for charging

(b) Charging in a (research) clinical trial

(c) Charging for expanded access to investigational drug for treatment use

(d) Costs recoverable when charging for an investigational drug.

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.

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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.

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