Investigational New Drugs: FDA Has Taken Steps to Improve the Expanded Access Program but Should Further Clarify How Adverse Events Data Are Used
Published: 2017-07-11T00:00:00

Fast Facts:
FDA's expanded access program allows patients with serious or life threatening illnesses access to certain drugs before it has approved them. FDA also requires that manufacturers submit data about adverse reactions to these drugs.
While FDA has provided some guidance to manufacturers, FDA does not fully explain the few instances when it would use these data on adverse reactions. This may influence manufacturers' decisions to give these drugs to patients due to concerns that adverse reactions will result in FDA placing a hold on their drug.
We recommended that FDA clearly communicate how it uses these data in its drug approval process.

Highlights:
section_title: Why GAO Did This Study
paragraphs: FDA's goal for the expanded access program is to allow patients with immediately life-threatening and serious ailments access to investigational drugs when appropriate. Stakeholders have raised concerns that FDA's process is confusing or burdensome, particularly for the entities that have roles in the process—such as physicians, manufacturers, and institutional review boards.
GAO was asked to examine the expanded access program. Among other objectives, GAO examined 1) what is known about the number, type, and time frames of expanded access requests received by FDA; 2) what actions FDA and other stakeholders have taken to improve expanded access; and 3) how FDA uses data from expanded access in the drug approval process.
GAO reviewed regulations and FDA documents and analyzed FDA data on the numbers and types of expanded access requests it received from FY2012 through 2015, the most recent at the time of the review. GAO also interviewed FDA officials and other stakeholders including nine manufacturers—selected to represent large and small companies—and patient and physician representatives.
section_title: What GAO Found
paragraphs: Under the Food and Drug Administration's (FDA) expanded access program, patients with serious or life threatening ailments and no other comparable medical options can obtain access to investigational drugs outside of a clinical trial. Expanded access requests must be submitted to FDA but manufacturers must also grant permission for patients to access their investigational drugs. Of the nearly 5,800 expanded access requests that were submitted to FDA from fiscal year 2012 through 2015, FDA allowed 99 percent to proceed. Almost 96 percent of these requests were for single patients (either emergency or non-emergency). FDA's review process for expanded access requests is designed such that all requests are either allowed or not allowed to proceed within 30 days of receiving each request. FDA typically responded to emergency single-patient requests within hours and other types of requests within the allotted 30 days.
FDA and other stakeholders, including a non-profit organization and a drug manufacturer, have taken steps to improve the expanded access process and patient access to drugs. For example, in response to concerns that the process to request expanded access to drugs was complex and cumbersome, FDA simplified its website, guidance, and the forms required for the most common types of requests. Efforts by other stakeholders include a project to educate and streamline the process by which institutional review boards approve treatment plans for expanded access drug use and a pilot advisory group to help a drug manufacturer manage expanded access requests. Some states have also enacted “Right-to-Try” laws to facilitate patient access to investigational drugs. These laws provide liability and licensing protections for manufacturers and providers under state law if an adverse event—such as an adverse reaction to the drug—occurs with patients who were allowed access to investigational drugs. However, some stakeholders GAO interviewed cited concerns that these laws may not help patients access drugs, in part because they do not compel a manufacturer to provide access.
Manufacturers sponsoring clinical trials must submit safety reports to FDA that include adverse events data resulting from clinical trials and any expanded access use, to be used in assessing the safety of a drug within the drug approval process. FDA reported using these data from expanded access use in a few cases during the drug approval process but not more widely, because its use does not have the same controls as clinical trials. FDA officials reported that they communicate with manufacturers on how they will use expanded access adverse events data. However, GAO's review of documents FDA uses to communicate with drug manufacturers about the expanded access program found that only one included a reference to its use of these data, and it did not include specific examples of how the data might be used. Further, some of the manufacturers told GAO the guidance was unclear. These manufacturers noted that the lack of clear information can influence their decision whether to give patients access to their drugs because of their concerns that an adverse event will result in FDA placing a clinical hold on their drug, which could delay its development. This could impact FDA's goal of facilitating expanded access to drugs for treatment use by patients with serious or life-threatening diseases or conditions, when appropriate.
section_title: What GAO Recommends
paragraphs: FDA should clearly communicate how it uses adverse events data from expanded access use in the drug approval process. FDA agreed with the recommendation.

section_title: Letter
paragraphs: Through the Food and Drug Administration’s (FDA) expanded access  program, patients with serious or immediately life-threatening ailments  and no other FDA-approved therapeutic options may potentially obtain  investigational drugs or biologics as a last resort for treatment. In these  instances, FDA may allow access to treatments using drugs still in the  development process—and, therefore, not yet approved by FDA for  marketing in the United States—when certain criteria are met. In addition  to FDA—which receives and reviews expanded access requests and  determines whether to allow them to proceed—other entities have roles in  the process. For example, manufacturers decide whether to give patients  access to their investigational drugs. In addition, institutional review  boards (IRB) must approve patients’ expanded access treatment plans,  and physicians treat the patients with the investigational drugs and  monitor their progress.
FDA has reported that it allows nearly all of the expanded access  requests it receives to proceed; however, little is known about the number  of requests denied by manufacturers and, therefore, never submitted to  FDA. In addition, little is known about the time it takes FDA to review  expanded access requests—although, in most cases, expanded access  use may begin 30 days after the request is received by FDA, unless the  agency acts to expedite or disallow the request from proceeding.
FDA’s expanded access program has been criticized by some physician  and patient advocacy groups for being too burdensome and confusing to  the entities involved, which could pose a barrier to individuals’ access to  investigational drugs. Additionally, manufacturers have raised concerns  about how FDA might use data from expanded access use in its process  for approving the drug for marketing in the United States. However,  stakeholders, including physicians, patients, and patient advocates, have  also highlighted steps FDA and other stakeholders have taken to improve  the program.
You asked us to review various aspects of FDA’s expanded access  program. This report examines  1.  what is known about the number, type, and time frames of expanded  access requests that are allowed to proceed by selected drug  manufacturers and by FDA;  2.  what factors selected drug manufacturers and FDA consider when  reviewing expanded access requests;  3.  what actions FDA and other stakeholders have taken to improve  4.  how, if at all, FDA has used data from expanded access use in its  drug approval process.
To determine what is known about the number, type, and time frames of  expanded access requests that are allowed to proceed, we analyzed  information collected through interviews or written responses to questions  from a non-generalizable selection of nine drug manufacturers on their  experiences with the expanded access program. The manufacturers were  selected to include large and small manufacturers based on the number  of FDA approved products they were marketing as well as other factors,  such as whether they had experience with the expanded access  program. Additionally, we obtained and analyzed data from FDA on the  number, type, and time frames of expanded access requests reviewed by the agency from fiscal year 2012 through fiscal year 2015. To assess the  reliability of FDA’s data, we interviewed knowledgeable agency officials,  conducted quality checks to identify any obvious errors, and compared  the detailed data FDA provided to us with summary data that FDA had  publicly reported on its website. We determined these data were  sufficiently reliable for the purposes of our reporting objective.
To describe the factors that manufacturers and FDA take into account  when reviewing expanded access requests, we analyzed information  collected through interviews or written responses from the nine selected  manufacturers. Additionally, we reviewed FDA regulations pertaining to  expanded access to investigational drugs and interviewed knowledgeable  FDA officials.
To determine the actions that FDA and other stakeholders have taken to  improve expanded access, we reviewed FDA regulations and guidance  related to expanded access and interviewed knowledgeable FDA officials.  We also analyzed information collected through interviews with or written  responses from the 9 manufacturers and a non-generalizable selection of  14 other stakeholders, including patient and physician advocacy groups,  and analyzed publically available proposals and reports regarding efforts  to improve expanded access.
To evaluate how FDA has used data from expanded access use in its  drug approval process, we analyzed information from interviews with FDA  and the stakeholders. Lastly, we assessed FDA’s communication with  manufacturers on the agency’s use of expanded access data against the  federal internal control standards related to information and  communication. The forms of communication we reviewed included  FDA’s regulations, guidance documents, and website and other forms of  communication with manufacturers regarding expanded access, such as  letters acknowledging the receipt of expanded access requests.
We conducted this performance audit from March 2016 to June 2017 in  accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings and conclusions based on our audit objectives. We believe that  the evidence obtained provides a reasonable basis for our findings and  conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: FDA is responsible for assessing the safety, efficacy, and quality of drugs  marketed in the United States. As part of this role, it oversees the drug  development process and is responsible for approving new drugs for  marketing. Patients with serious or immediately life-threatening illnesses  and no other FDA-approved therapeutic options may be able to access  treatments still in the development process through FDA’s expanded  access program.
subsections: section_title: Drug Development and Approval Process
paragraphs: The process by which a drug or biologic is developed and considered for  approval for marketing in the United States involves a number of steps  that include the clinical testing of the drug’s safety and effectiveness on  human volunteers. Before a drug can be tested on humans, it is first  tested for toxicity on animals. Following such testing, a manufacturer  must submit an investigational new drug application (IND) to FDA in order  to test the drug on humans. FDA’s decision of whether or not to allow the  human testing to proceed is based, in part, on evidence and analysis  regarding the drug’s toxicity in animals and the availability of human  volunteers. Additional information about the typical process for human  testing and FDA’s review processes is described below and depicted in  figure 1.
subsections: section_title: Pre-clinical Testing
paragraphs: Before a drug or biologic can be tested on humans, it is tested for toxicity  on animals. These tests are also used to gather basic information on the  safety and efficacy of the drug or biologic. FDA may decide whether or  not to allow the investigational drug to be tested on humans, based in part  on results of the drug being tested on animals.
section_title: Investigational New Drug Application
paragraphs: A manufacturer that wants to test an investigational drug or biologic on  humans must first submit an IND to FDA for the agency to review, and  FDA must allow the IND to proceed before testing on humans can  begin. The IND includes various components, such as the clinical  treatment plan, which provides the detailed procedure for how humans  will be tested, and Form FDA 1571, which contains a number of  administrative elements pertaining to the request. See appendix I for a  copy of this form.
Clinical trials on humans can only begin after FDA has reviewed and  allowed the application to proceed and an IRB has reviewed and  approved the clinical treatment plan and reviewed the patient’s informed  consent form. After receiving this approval, the manufacturer is  considered the sponsor of an existing IND, and clinical trials that involve  human volunteers can begin. Once in effect, the sponsor of the existing  IND may amend its research plan as needed, such as to expand or  otherwise change patient eligibility criteria. Testing under an amended  treatment plan may only begin after the changes have been submitted to  FDA and approved by an IRB.
section_title: Clinical Trials
paragraphs: An investigational drug typically goes through three phases of clinical  trials before it is submitted to FDA for marketing approval. According to  FDA officials, in some cases when a new drug is being tested for a life- threatening ailment, the drug development process may be expedited by  going through only one or two phases of clinical trials before an  application is submitted to FDA for marketing approval. At any point  during the clinical trials, FDA could issue a clinical hold on the existing  IND that would delay the proposed or ongoing clinical trials. When a  drug undergoing clinical trials is placed on clinical hold, it cannot be  administered to any human volunteers. This includes volunteers already  in a clinical trial, and no new volunteers may be recruited to clinical trials.  If the drug completes a clinical trial phase and is not on clinical hold, FDA  allows it to proceed to the next phase. The three clinical trial phases are  detailed below:
Phase I: Phase I clinical trials generally test the safety of the drug on  about 20 to 80 healthy volunteers. The goal of this phase is to  determine the drug’s most frequent side effects and how it is  metabolized and excreted. If the drug does not show unacceptable  toxicity in the phase I clinical trials, it may move on to phase II.
Phase II: Phase II clinical trials assess the drug’s safety and  effectiveness on people who have a certain disease or condition and  typically are conducted on a few dozen to hundreds of volunteers.  During this phase some volunteers receive the drug and others  receive a control, such as a placebo. If there is evidence that the drug  is effective in the phase II clinical trials, it may move on to phase III.
Phase III: Phase III clinical trials generally involve several hundreds to  thousands of volunteers and gather more information about the drug’s  safety and effectiveness on different patient populations and at  different dosages, again while being compared to a control. If phase  III clinical trials are successfully completed, the drug may move on to  FDA’s review and approval process.
section_title: Review and Approval Process
paragraphs: When seeking FDA’s approval to market and sell a drug in the United  States, the manufacturer submits an application to FDA. Included in  these submissions are the data from the safety and efficacy clinical trials  for FDA to review. FDA uses the information in the application to either  approve or not approve the drug. Based on a study looking at 10 years of  data, among the drugs that enter Phase I clinical trials, on average, 9.6  percent were ultimately approved for marketing in the United States. For  example, if 100 investigational drugs entered Phase I clinical trials,  approximately 63 (63.2%) would advance to Phase II clinical trials, with  19 of those (30.7%) advancing to Phase III clinical trials. Of those 19  drugs, 11 (58.1%) would advance to the new drug application process,  and, ultimately, 10 of those (85.3%) would be approved for marketing and  sale in the United States.
section_title: Expanded Access Program
paragraphs: Through FDA’s expanded access program, licensed physicians, on behalf  of their patients with serious or immediately life-threatening ailments, who  have no other comparable medical options, and who are unable to  participate in a clinical trial, can request and possibly access  investigational drugs for treatment of the patients, if the patients meet  certain eligibility requirements. FDA’s goals for the program are to  facilitate the availability of investigational drugs when appropriate, ensure  patient safety, and preserve the clinical trial development process. All  expanded access requests must be submitted to FDA, and once received  take effect within a designated time unless the agency acts to expedite or  disallow them from proceeding. The expanded access process also  requires the involvement of other entities, including the manufacturer that  is developing the drug and must provide access to it, an IRB that must  approve the expanded access treatment plan and review the patient’s  informed consent form, and a physician who administers the drug. FDA  categorizes expanded access requests into two broad categories— protocol requests and IND requests—and the roles and responsibilities of  each of these entities within the process can vary depending on the  category of the request.
subsections: section_title: Expanded Access Protocol Requests
paragraphs: An expanded access protocol request aims to provide access to an  investigational drug outside of a clinical trial when the sponsor of an  existing IND submits a treatment plan for expanded access in an  amendment to that existing IND. The manufacturer typically makes these  requests and is, therefore, the sponsor of the expanded access request.  The manufacturer must submit the expanded access treatment plan using  a new Form FDA 1571 notifying FDA that the manufacturer is amending  its existing IND to provide the investigational drug to one or more patients  outside of the clinical trial. An expanded access protocol may be  submitted to provide access to a single patient or to more than one  patient. A manufacturer may decide to open an expanded access protocol  because it has received requests for a drug that is still in clinical trials— for example, requests for terminal patients with no other options—or  because it has a drug that has completed clinical trials and wants to make  the drug available to patients who have no other comparable treatment  options while waiting for FDA’s new drug approval response. For  expanded access protocol requests sponsored by manufacturers, the  roles and responsibilities of the various entities involved in the process  typically are as follows:
The manufacturer: In addition to submitting the request for the  expanded access protocol to FDA, the manufacturer, as the sponsor  of the request, is responsible for the collection and submission of data  to FDA on any adverse events that occurred from administering the  drug to patients who received it under the expanded access protocol.
These data are included with the manufacturer’s regular adverse  event data reporting to FDA under the existing IND.
The physician: The patient’s physician administers the  investigational drug to the patient and must report any serious  adverse events to the manufacturer sponsoring the expanded access  protocol.
The IRB: A designated IRB must approve the clinical treatment plan  that is submitted as part of the expanded access protocol application  (similar to its review of the original clinical treatment plan) and review  the patient’s informed consent form. FDA generally requires that all  IRB reviews be completed by a full IRB—meaning the majority of  members of the board participate in the review process—and FDA  makes no specific exception for expanded access.
section_title: Expanded Access IND Requests
paragraphs: An expanded access IND request aims to provide access to an  investigational drug outside of a clinical trial and under a new IND. The  vast majority of expanded access IND requests are opened to provide  access to a single patient. A patient’s physician typically submits these  single-patient requests and is, therefore, the sponsor of these requests  and must submit to FDA the Individual Patient Expanded Access  Application, using Form FDA 3926 or Form FDA 1571. See appendix II  and appendix I for copies of these forms. In general, physicians would  pursue expanded access IND requests when they learn of a drug being  developed and think the benefit of giving their patient expanded access  outweighs the risks. For expanded access IND requests sponsored by  physicians, the roles and responsibilities of the various entities involved in  the process typically are as follows:
The physician: The physician first obtains a letter of authorization  from the manufacturer that documents it will allow the physician to  reference its existing IND information. After receiving this letter, the  physician submits an expanded access request to FDA. If FDA allows  the request to proceed to treatment, the physician must provide FDA  with a written summary of the results at the conclusion of treatment.
The manufacturer: The manufacturer decides whether it will allow  the patient (or patients) access to the drug. If the manufacturer  decides to give the patient (or patients) access to the drug, it gives the  physician a letter of authorization.
The IRB: The IRB must approve the clinical treatment plan that is  submitted as part of the expanded access IND application and review  a patient’s informed consent form. FDA generally requires that all  IRB reviews be completed by a full IRB—meaning the majority of the  members of the board participate in the review process—and FDA  makes no specific exception for expanded access.
Beyond these broad categories, FDA further categorizes expanded  access requests (whether protocol or IND requests) by the number of  patients treated and the type of situation. The agency reports data  separately on four categories of expanded access requests that FDA  defines as follows:  1.  Single-patient.  2.  Single-patient emergency, for example, for a patient who is not  expected to live long enough for FDA and an IRB to review a typical  single-patient expanded access request.  3.  Intermediate-size generally for two patients to potentially hundreds of  patients.  4.  Treatment for larger widespread populations.
Where the drug is at in the drug development process can affect the type  of expanded access request that may be submitted to FDA. (See figure  2.)
Figures 3 and 4 illustrate two common examples of situations in which  expanded access requests may be submitted to FDA and the roles and  responsibilities of various stakeholders for each example. They include an  example of an expanded access treatment protocol request submitted by  a manufacturer late in the drug development process, and an expanded  access single-patient IND request submitted by a physician earlier in the  process.
Within FDA, the centers that oversee the pre-clinical and clinical testing of  drugs and biologics, the Center for Drug Evaluation and Research  (CDER) and the Center for Biologics Evaluation and Research (CBER),  also review and determine whether an expanded access request for a  drug or biologic is allowed to proceed.
section_title: Selected Drug Manufacturers Reported Different Experiences with Expanded Access Requests, and FDA Allowed Nearly All Requests to Proceed from Fiscal Year 2012 through 2015
subsections: section_title: Selected Drug Manufacturers Reported Different Experiences with the Number and Types of Expanded Access Requests They Received
paragraphs: Each of the nine selected manufacturers from whom we obtained  information reported having experiences with the expanded access  program, but the extent of the experiences, and with what type of request,  varied. Specifically, one manufacturer reported only having experience with expanded  three manufacturers reported only having experience with expanded  access protocol requests; and  five manufacturers reported having experience with both types of  requests.
Of those manufacturers that had experience with expanded access IND  requests, all of the requests were sponsored by physicians and were for  single patients, including both emergency and non-emergency requests.  Most of these manufacturers said that expanded access INDs can  happen at any phase of a drug’s development, but, based upon the  availability of safety and efficacy data, manufacturers are more likely to  approve these requests at later phases of drug development. The  numbers of single-patient IND requests these manufacturers reported  receiving ranged from 39 to approximately 800. Additionally, some  manufacturers reporting experience with expanded access IND requests  said that they may decide to establish an expanded access protocol  instead of separately considering single-patient expanded access IND  requests. For example, one manufacturer reported that, once it receives  an expanded access IND request for a single patient, it will proactively  evaluate whether there is the potential for additional requests, and, if so, it  will work to establish an expanded access protocol to cover a group of  patients for FDA’s review. Another manufacturer said that it has three  pathways for patients to access investigational drugs—clinical trials,  expanded access protocols, and expanded access INDs—and that it will  first evaluate whether a patient is eligible for its clinical trial or an  expanded access protocol it has established before it will consider  providing access to the drug through an expanded access IND request.
Three of the nine selected manufacturers reported that their only  experience with the expanded access program was with expanded  access protocol requests. These manufacturers cited the following  reasons for establishing expanded access protocols. One reason cited by  two manufacturers was that expanded access protocols allowed them to  give groups of patients access to their drugs subsequent to completion of  their phase III clinical trials, pending approval of their drug for marketing.  Another manufacturer said that it had already built late-phase expanded  access into its overall drug development plans. Among these  manufacturers, the reported numbers of patients covered under their  expanded access protocols varied—ranging from 18 patients to 800  patients.
section_title: FDA Allowed 99 Percent of Nearly 5,800 Expanded Access Requests to Proceed During Fiscal Years 2012 through 2015
paragraphs: From fiscal year 2012 through 2015, FDA reviewed nearly 5,800  expanded access requests and allowed nearly all of them to proceed.  Specifically, of the 5,753 expanded access requests the agency  reviewed, it allowed 5,697 (99 percent) to proceed. (See table 1.)  According to a study using FDA data, in the rare cases when FDA did not  allow a request to proceed, the most common reasons were incomplete  applications, unsafe dosing, the requested drug’s demonstrated lack of  efficacy for its intended use, the availability of adequate alternative  therapies, and inadequate information provided in the application on  which to base a decision.
Nearly all of the expanded access requests FDA received and reviewed  (approximately 96 percent) were for single patients (including both  emergency and non-emergency requests). However, because  intermediate-size and treatment requests expand access to groups of  patients, more patients may have gained expanded access to drugs  through these types of requests. For example, one of the selected  manufacturers reported that 400 patients received its drug through an  expanded access treatment protocol and anticipated further growth in the  number of patients treated under that protocol by the end of 2016.  Another manufacturer reported that over 1,500 patients had requested  access to its treatment protocol since November 2015. FDA officials said  that the agency does not keep data on the number of patients treated  under intermediate-size or treatment expanded access requests.
We analyzed data from the FDA divisions and offices that reviewed  expanded access requests and found that most requests were  concentrated among a few divisions and offices. For example, among the  16 CDER divisions that review these requests, four divisions—Anti- infective, Antiviral, Hematology, and Oncology 2—reviewed over 3,700  requests, accounting for 74 percent of all requests that CDER received  from fiscal year 2012 through 2015. In contrast, during that same time  period 9 other divisions reviewed a combined total of 201 requests,  accounting for 4 percent of all requests received. (See table 2.)
Similarly, for requests reviewed by CBER, one of its three offices—the  Office of Tissues and Advanced Therapies—reviewed 484 of the 692 total  requests, which accounted for approximately 70 percent of the requests  reviewed by that center. (See table 3.)
section_title: FDA Typically Responded to Emergency Expanded Access Requests in Less than 1 Day and Responded to All Other Requests within the Allotted 30-day Time Frame
paragraphs: FDA officials told us that it only tracks response times for expanded  access IND requests (not protocol requests), and, from fiscal years 2012  through 2015, the agency typically responded to emergency expanded  access IND requests in less than 1 day, according to FDA data. These  data also show that the agency responded to all other expanded access  IND requests within the 30 days allotted to the agency, as established in  regulation. FDA officials reported that, given the nature of emergency  expanded access IND requests, they try to respond to these requests  within hours of receiving them. From fiscal years 2012 through 2015, of  the more than 2,300 emergency expanded access IND requests that  were submitted, FDA’s median response time was within less than a day.  (See table 4.)
For non-emergency single-patient IND requests that were allowed to  proceed, the median number of days to review the requests among the  two centers ranged from 3 days to 19 days, and was 30 days for both  intermediate-size and treatment requests. Under FDA’s rules, unless a  request is not allowed to proceed, an expanded access IND request goes  into effect 30 days after FDA receives it or on earlier notification by FDA  that the expanded access use may begin.
FDA officials told us that the agency does not track the time it takes to  respond to expanded access protocol requests for various reasons. First,  because there are so few protocol requests compared to expanded  access IND requests, FDA officials said that the data on time frames for  protocols are less meaningful. Second, because expanded access  protocol requests are associated with existing INDs that have previously  approved treatment plans, all expanded access protocol requests are  allowed to proceed as soon as FDA receives the request, except for the  treatment category of expanded access protocol requests (i.e., for large  sized or widespread patient groups). FDA imposes a 30-day review  period on expanded access treatment protocol requests due to the  potential for exposing large groups of patients to an investigational drug.  If FDA has not otherwise responded to an expanded access treatment  protocol request within 30 days, the request is automatically allowed to  proceed.
section_title: Selected Manufacturers and FDA Consider a Number of Factors in Reviewing Expanded Access Requests
paragraphs: The nine selected manufacturers from whom we obtained information  reported that they consider a wide range of factors when reviewing  expanded access requests. The factors ranged from those related to the  specific patients who would receive a drug to how expanded access  might affect the drug development process. Specific factors that were  commonly reported as used in reviews by the manufacturers we spoke  with included patient factors and drug development factors.
Patient factors that were commonly reported included the following:
The patient’s condition and treatment history. For example, one  manufacturer told us that the patient must have a disease that is  “serious” or “life-threatening” and have no comparable or satisfactory  alternative treatment available to the patient.
The patient’s eligibility for a clinical trial. For example, one  manufacturer said that it assesses whether the patient is ineligible to  enroll in a clinical trial for a medically valid reason or meets eligibility  criteria for an ongoing trial but seeks treatment in a location without  access to that trial.
Whether the potential benefits of treatment outweigh the  potential risks to the patient. For example, one manufacturer  reported that providing investigational drugs with limited safety data in  an uncontrolled setting could increase the potential for significant  adverse events to occur.
The bioethical implications of providing drugs through expanded  access. For example, one manufacturer said that it considers whether  providing its drug through expanded access for one patient ethically  obligates it to provide its drug to all patients who request it.
Drug development factors that were commonly reported included the  following:
Reducing participation in clinical trials by approving expanded  access requests. For example, one manufacturer said that as  patients become increasingly aware of the availability of an  investigational drug through expanded access, manufacturers may  face challenges enrolling a sufficient number of patients for clinical  trial studies because patients receiving the drug through expanded  access are guaranteed the investigational drug (as opposed to  participants in a clinical trial who can have a chance of receiving a  placebo).
The risk that adverse events experienced by patients using an  unapproved drug through the expanded access program could  compromise the drug development process. For example, some  manufacturers raised concerns that, because an investigational drug  is administered in an uncontrolled setting under expanded access,  any data reported from such adverse events could complicate the  safety findings for that drug during FDA’s review of those data and  contribute to a decision to not approve the drug.
The potential public backlash that could arise against the  manufacturer should an expanded access request be denied. For  example, one manufacturer told us that denying an expanded access  request could lead to negative publicity through social media. This  negative publicity could, in turn, deter potential investors from funding  the drug’s development.
The requested drug’s availability. For example, one manufacturer  said that it evaluates whether it has enough supply of its drug  available to successfully administer its clinical trial, as well as to  provide the drug to expanded access patients. Another manufacturer  said that this is a particular concern early in the drug development  process, as manufacturers typically only produce the amount of drug  needed to support each clinical trial phase. Generally, the drug’s  supply is low in the early clinical phases and increases in the later  clinical phases.
The financial and administrative resources required to fulfill the  request. Manufacturers said that resource requirements could  particularly impact smaller manufacturers that have fewer resources  available to process expanded access requests and administer  clinical trials simultaneously.
FDA officials told us that the factors they consider when reviewing  expanded access requests to determine whether that request should be  allowed to proceed are based on criteria in regulation. Specifically, upon  receipt of an expanded access request, FDA officials said that they  review that request against the following four general criteria established  in regulation:  1.  The patient has a serious or immediately life-threatening disease or  condition.  2.  There is no comparable or satisfactory alternative therapy.  3.  The potential benefit justifies the potential risks of the treatment, and  those potential risks are not unreasonable in the context of the  disease or condition to be treated.  4.  Providing the drug will not interfere with clinical investigations that  could support marketing approval of the drug or otherwise  compromise development of the expanded access use for that drug.
In addition to these general criteria applicable to all expanded access  requests, FDA officials reported that they consider additional criteria in  regulation that apply to specific types of expanded access.
Single-patient requests: The physician must determine that the  probable risk to the patient from the investigational drug is not greater  than the probable risk from the disease or condition and FDA must  determine that the patient cannot obtain the drug under another IND  or protocol.
Intermediate-size populations: FDA must determine that 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 it under  expanded access. In addition, there must be preliminary clinical  evidence of effectiveness of the drug or a plausible pharmacological  effect of the drug to make expanded access use a reasonable  therapeutic option in the anticipated patient population.
Treatment INDs or protocols: FDA must determine that the drug is  being investigated in a controlled clinical trial (or that all clinical trials  of the drug have been completed) and that the IND sponsor is actively  pursuing marketing approval of the drug for the expanded access use  with due diligence. Additionally, when expanded access use is for a  serious disease or condition, FDA must determine that there is  sufficient clinical evidence of safety and effectiveness to support the  expanded access use. When expanded access use is for an  immediately life-threatening disease or condition, the available  scientific evidence, taken as a whole, must provide 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.
FDA officials told us that, in addition to these criteria, agency reviewers  will also consider whether submitted requests have provided sufficient  information to allow FDA to make an informed decision on the request.
section_title: FDA and Others Have Taken Steps to Improve the Expanded Access Program and Patient Access to Investigational Drugs, but Stakeholders Continue to Cite Concerns
subsections: section_title: FDA Continues to Undertake Efforts to Improve the Expanded Access Program
paragraphs: According to FDA officials and stakeholders, FDA has undertaken efforts  to improve the expanded access program. These efforts include  publishing a simplified application form, finalizing existing guidance and  making changes to its website for single-patient expanded access IND  requests, and working with the Reagan-Udall Foundation—a non-profit  established by Congress to assist FDA—to develop a website to help  patients and physicians navigate the expanded access process.
subsections: section_title: Simplified Application Form, Guidance, and Website
paragraphs: In response to concerns raised by patients and physicians that the  process for physicians trying to request expanded access to drugs for  single patients was complex and cumbersome, FDA issued a new  simplified, alternative application form for these requests (Form FDA  3926) in June 2016, finalized its related guidance, and made changes to  its website. According to FDA, prior to these changes physicians who  wanted expanded access for a single patient had to complete and submit  the same form that manufacturers complete when establishing clinical  trials (Form FDA 1571). According to FDA officials, the new form requires  the physician to complete 11 elements of information, far fewer than the  26 elements identified on Form FDA 1571. FDA officials estimate that the  new application will take physicians, on average, 45 minutes to complete.
In addition to the new application, FDA finalized another guidance  document which provided more details on the implementation of FDA  expanded access regulations, to further assist physicians in the expanded  access process. FDA has also redesigned its expanded access website  pages to explain the new form and guidance document in detail.
Most stakeholders, including physicians, spoke positively about the new  application and some said the new application is easier and takes less  time to complete compared to Form FDA 1571. However, even with these  changes, a few of the stakeholders that we spoke with said the revised  website and forms may still be hard to understand, particularly for  physicians and patients who have no prior experience with expanded  access requests.
section_title: Website to Help Physicians and Patients
paragraphs: In response to concerns from patients and patient advocates that it is  difficult to locate and understand information about single-patient  expanded access IND requests, FDA asked the Reagan-Udall  Foundation to develop a website—referred to as the Expanded Access  Navigator—that will help physicians and patients find relevant information  about the process. According to the foundation’s proposal, the  Navigator will include a directory of manufacturers’ expanded access  policies, procedures, and points of contact. The Navigator will also offer  information on IRBs and reporting requirements for physicians.  Foundation officials also told us that FDA has been helping with this effort  by identifying issues and reviewing the content of the Navigator, and that  the website is expected to launch in June 2017.
Foundation officials noted that key challenges with the website include  determining how to keep its information current and how to get potentially  cautious manufacturers to provide the needed information. Some  stakeholders told us they were skeptical the website could be maintained  with updated information or were concerned that it could be a duplication  of the information found on ClinicalTrials.gov. However, the proposal for  the Navigator website states that it would not duplicate the information on  ClinicalTrials.gov. Other stakeholders told us that the Navigator could  help patients quickly and efficiently obtain information on drug  manufacturers’ expanded access policies and information. This type of  website appears to complement a provision in the recently enacted 21st  Century Cures Act, which requires manufacturers to make their expanded  access policies publically available.
section_title: Other Stakeholders Are Working to Improve the Expanded Access Process and Increase Patient Access to Drugs
paragraphs: Some stakeholder groups are taking steps to improve the expanded  access process through efforts to streamline the IRB process, help  manufacturers manage expanded access requests for drugs, and  increase patient access through legislative changes.
subsections: section_title: Streamlining the IRB Process
paragraphs: In response to concerns raised by stakeholders, including manufacturers  and patient advocacy groups, that IRB involvement in the expanded  access process increases the time it takes for patients to obtain access to  drugs in single-patient IND situations and that IRBs lack a full  understanding of the expanded access program, the WCG Foundation is  developing a project to streamline the IRB process and educate IRBs.  According to the foundation officials, the timeliness of IRB reviews is  hindered by the IRB’s unfamiliarity with the expanded access review  process, which may occur only once every few years for some IRBs. In  addition, foundation officials said that even though FDA has developed  the abbreviated Form FDA 3926 for physicians to use for single-patient  expanded access IND requests, some IRBs continue to require the use of  the longer form (Form FDA 1571) as the basis for their review of the  application, which could slow the process further. See appendix I for a  copy of Form FDA 1571 and appendix II for a copy of Form FDA 3926.
The foundation’s project aims to overcome these obstacles by working  with IRBs to meet and respond to a physician single-patient IND request  within 72 hours from the date the request was received. In addition, they  must agree to adopt FDA’s simplified application (Form FDA 3926) for  single-patient IND requests. Some of the intended outcomes for the  project include establishing a core group of IRBs with expanded access  experience, streamlining the IRB process by providing the IRB community  with a standard form for reviewing expanded access requests, and  educating the broader national IRB community on using a streamlined  IRB process. FDA officials said the agency supports WCG’s efforts and is  meeting with foundation officials on a regular basis. Some of the  stakeholders that we spoke with noted that more education and guidance  for IRBs on how to handle expanded access requests is needed.
section_title: Pilot to Help Drug Manufacturers Manage Expanded Access Requests
paragraphs: To address concerns that drug manufacturers’ decisions on expanded  access requests could be biased or unfair, the drug manufacturer  Janssen Pharmaceuticals Companies of Johnson & Johnson is piloting a  process through which it receives recommendations about which patients  should receive expanded access from a third party group. Specifically,  in May 2015, Johnson & Johnson announced a partnership between  Janssen and the Compassionate Use Advisory Committee (CompAC) at  the New York University (NYU) School of Medicine’s Division of Medical  Ethics. At the time the committee was established, Janssen was receiving  numerous expanded access requests for a drug it was developing to treat  a form of cancer, but the drug had not yet been approved for marketing  by FDA. According to officials from Janssen and NYU CompAC, Janssen  decided it needed help with allocating the drug fairly and transparently to  patients outside of clinical trials. The committee, which consists of  medical experts, bioethicists, and patient representatives, meets weekly  to review anonymized expanded access requests submitted to Janssen,  evaluate each request against a set of criteria the committee developed,  and provide Janssen with a suggested approach for each request.  Between July 1 and December 31, 2015, the committee recommended  that Janssen approve 60 of 76 requests that it reviewed. Janssen  reported that it approved all 60 of these requests recommended by the  committee, and, based on the positive experience with the pilot, the  manufacturer is planning to expand the program to additional  investigational drugs.
section_title: Efforts to Increase Access to Drugs through State Legislative Changes
paragraphs: In an effort to help facilitate patient access to investigational drugs, the  Goldwater Institute—a public policy research organization—developed  model legislation for states. The institute’s model legislation, which is  referred to as Right-to-Try, would place limitations under state law on  liability lawsuits and licensing actions against individuals or entities  involved in the care of individuals seeking expanded access. The institute  officials stated that such legislation would provide incentives for  manufacturers and physicians to provide access to such drugs. According  to the institute’s officials, the model legislation applies only to drugs that  have successfully completed phase I clinical safety trials. According to the  Goldwater Institute, as of June 2017, 37 states had enacted Right-to-Try  laws similar to this model.
The stakeholders we spoke with, including representatives of drug  manufacturers and patient and physician advocacy groups, reported  concerns about these legislative changes:
Some contended that the laws would not help patients gain access to  investigational drugs because they do not compel manufacturers to  give access. As we previously noted, manufacturers have cited  various reasons why they may not give a patient access to their  investigational drug, and it is unclear to what extent these laws would  address these concerns.
Others raised concerns that the laws might give patients false hope  that experimental drugs will cure them. Thus, patients may not fully  consider the risks associated with these drugs, which may not be  effective and which could potentially be more harmful than no  treatment.
section_title: FDA Reported Limited Use of Expanded Access Safety Data in its Drug Approval Process, and Some Manufacturers Have Asked for More Clarity on This Use by FDA
paragraphs: FDA reported using expanded access safety data, specifically adverse  events data, in a few cases in approving new drugs for marketing in the  United States and not more widely because expanded use situations  generally lack controls used in most clinical trials. FDA guidance  specifies that safety data, which include any unexpected adverse events  that are associated with the use of a drug, even during expanded access  use, must be reported along with safety data from clinical trials. Agency  officials noted that these data can contribute important safety information  that might not otherwise be collected in clinical trials and that they take  into account the context of the expanded access situation, such as use in  patients with serious or life-threatening ailments, when reviewing new  drug applications (NDA) and biologics license applications (BLA). For  example, officials said that in some cases adverse events data from  expanded access use can identify rare side effects not detected in clinical  trials, as well as inform FDA reviewers of any safety issues involving  patient populations that were not otherwise included in the drug’s clinical  trials. FDA’s primary goal of the expanded access program is to allow  patients with no other options access to investigational drugs when  appropriate. Data from expanded access use can also help FDA meet its  agency goal of collecting meaningful data about the use of investigational  drugs.
However, several stakeholders we spoke with, including the selected  manufacturers, raised concerns that FDA is not clear about how it uses  expanded access adverse events data in its review of NDAs and BLAs.  Some of the manufacturers noted that use of such data may influence  FDA in making final approval decisions and that this possibility can  contribute to a manufacturer deciding not to grant patients access to their  drug through the expanded access program. Some of the manufacturers  reported that they have concerns about the possibility that FDA’s use of  adverse events data from expanded access requests would result in a  clinical hold on their drug, which would halt all testing on human subjects  and, as a result, delay the drug’s development process. One study  included a review of ten years (2005 through 2014) of expanded access  data to determine how often a clinical hold was put on a drug that was  obtained via expanded access. This review only found two instances in  which adverse events from expanded access use contributed to a  decision to have a clinical hold put on a drug. However, manufacturers  continued to raise concerns about how FDA uses adverse events data  from expanded access use.
FDA briefly mentions its perspective on how adverse events data from  expanded access are viewed in NDAs and BLAs; but, the information is  vague and is not consistently communicated in other documents FDA  uses to communicate with manufacturers on expanded access use.  Specifically, our review of FDA’s regulations and nine related documents  FDA uses to communicate with manufacturers regarding expanded  access use found little information communicating how FDA uses adverse  events data from expanded access in new drug application reviews. Our  review included FDA’s three new guidance documents on expanded  access, four letters of acknowledgement FDA sends to sponsors after  they submit an expanded access request, and two guidance documents  on IND safety reporting (a 2012 final document and 2015 draft of new  guidance). Only one of the documents—its expanded access treatment  use guidance that was issued in June of 2016—refers to how expanded  access data might be used by FDA in the drug approval process.  According to FDA officials, it included this reference in response to  manufacturer’s requests that more clarity be provided on how these data would be used. Although FDA took steps to improve its communication on  this, the information in the document is vague in that it contains few  details and no specific examples. The specific language is as follows:  “…There are a small number of cases in which FDA has used  adverse event information from expanded access in the safety  assessment of a drug. However, FDA reviewers of these adverse  event data understand the context in which the expanded access  use was permitted (e.g., use in patients with serious or  immediately life-threatening diseases or administered in a clinical  setting (not clinical trial)) and will evaluate any adverse event data  obtained from an expanded access submission within that  context….”
According to standards for internal control in the federal government,  management should ensure adequate means of communicating with  external stakeholders who have a significant impact on the agency  achieving its goal. While FDA officials told us that they believe  manufacturers are aware of how the agency uses adverse events data  from expanded access use, some of the manufacturers and other  stakeholders told us they did not think the guidance was clear. Some  manufacturers also noted that the lack of clear information about how  FDA uses these data can influence their decision not to give patients  access to their drugs. This could impact FDA’s goal of facilitating  expanded access to drugs for treatment use by patients with serious or  life-threatening diseases or conditions, when appropriate.
section_title: Conclusions
paragraphs: FDA’s expanded access program was established to facilitate access,  when appropriate, to investigational drugs for certain patients when no  other comparable medical options are available. Although FDA provides  clear guidance on the expanded access data that must be submitted by  physicians and manufacturers and recently took steps to communicate  how it will use these data, the agency’s communication lacks clarity and  specificity. In addition, this information is not consistently communicated  in other documents that FDA uses to communicate with manufacturers  about the program. Manufacturers and other stakeholders expressed  concerns about this lack of clarity, and some noted that, without a better understanding of the how the data will be used, they may be more likely  to deny expanded access requests for fear that any adverse events  associated with these often terminally ill patients may delay the  development of the drug should FDA place a clinical hold due to the  adverse event. Such delays in clinical trials can have a significant impact  on a manufacturer, especially on small companies trying to make a drug  available to a larger patient population. Without clearly communicated  information from FDA on how adverse event data from expanded access  is used, manufacturers do not have the information they need to make  informed decisions about expanded access.
section_title: Recommendation for Executive Action
paragraphs: To help FDA meet its goal of facilitating expanded access to  investigational drugs by patients with serious or life-threatening diseases  or conditions, when appropriate, the Commissioner of FDA should clearly  communicate how the agency will use adverse event data from expanded  access use when reviewing drugs and biologics for approval for  marketing and sale in the United States.
section_title: Agency Comments
paragraphs: We provided a draft of this report to HHS for comment. In its comments,  reproduced in appendix III, HHS concurred with our recommendation.  HHS noted that while there have only been two instances in which  adverse event data have contributed to decisions to temporarily put  development of investigational drugs on partial clinical holds, additional  clarity on how FDA uses such data from expanded access use may allay  manufacturers concerns. HHS also provided technical comments, which  we incorporated as appropriate.
We are sending copies of this report to the congressional addressees, the  Secretary of Health & Human Services, and other interested parties. In  addition, the report is available at no charge on the GAO website at  http://www.gao.gov.
If you or your staffs have any questions about this report, please contact  me at (202) 512-7114 or dickenj@gao.gov. Contact points for our Offices  of Congressional Relations and Public Affairs may be found on the last  page of this report. GAO staff who made key contributions to this report  are listed in appendix IV.
section_title: Appendix I: Form FDA 1571, Investigational New Drug Application
subsections: section_title: Food and Drug Administration’s (FDA) Form FDA 1571 contains a number of administrative elements pertaining to an investigational new drug application. This form is completed and submitted to FDA by manufacturers who seek FDA’s approval to conduct clinical trials of an investigational drug on humans.
section_title: Food and Drug Administration’s (FDA) Individual Patient Expanded Access Application, Form FDA 3926, is to be completed and submitted to FDA by a patient’s physician requesting single-patient expanded access of an investigational drug.
section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Staff Acknowledgments
paragraphs: In addition to the contact named above, Gerardine Brennan, Assistant  Director; Carolyn Garvey, Analyst-in-Charge; Nick Bartine; George  Bogart; Laurie Pachter; Vikki Porter; and Dharani Ranganathan made key  contributions to this report.