Investigational Drugs: FDA and Drug Manufacturers Have Ongoing Efforts to Facilitate Access for Some Patients

When investigational drugs show promise for treating serious or life-threatening diseases, patients are often interested in obtaining access to them. Congress included a provision in the FDA Reauthorization Act of 2017 for GAO to review actions taken to facilitate access to these drugs.

This report describes (1) actions FDA and drug manufacturers have taken to broaden eligibility criteria for clinical trials, (2) actions FDA has taken to facilitate access to investigational drugs outside of clinical trials, and (3) information drug manufacturers have communicated to patients and physicians about access to investigational drugs outside of clinical trials.

GAO reviewed laws, regulations, FDA documents, and manufacturer policies and interviewed FDA officials and a non-generalizable selection of 10 manufacturers and 14 other stakeholders (including patient advocacy and physician organizations). The manufacturers were developing drugs to treat serious or life-threatening diseases, and were selected for variation in company size. GAO also reviewed information that a non-generalizable selection of 29 manufacturers communicated through their websites about access to investigational drugs outside of clinical trials. GAO selected manufacturers for variation in the type of serious diseases their investigational drugs were intended to treat, company size, and other factors.

HHS provided technical comments on a draft of this report, which GAO incorporated as appropriate.

Individuals may access investigational drugs—those not yet approved for marketing in the United States by the Food and Drug Administration (FDA)—by participating in clinical trials conducted by drug manufacturers to test drug effectiveness and safety. FDA has ongoing efforts to help manufacturers identify the circumstances under which they could broaden clinical trial eligibility criteria to include patients who are commonly excluded, such as pediatric patients and patients with impaired liver and kidney function, without compromising study results.

FDA issued guidance in March 2019 with recommendations on ways manufacturers could broaden eligibility criteria for cancer clinical trials, when clinically appropriate. In June 2019, FDA issued related guidance that applies to a wider range of clinical trials beyond cancer trials.

One of the 10 manufacturers GAO interviewed reported broadening its eligibility criteria to include more patients, such as those with HIV. Another manufacturer has begun reviewing its eligibility criteria and expects to include adolescents, as appropriate, in future studies—a population that has generally been excluded from trials. However, these and two other manufacturers cited challenges in these efforts. One stated that expanding participation to patients who use other medications, for example, could adversely affect a study's ability to identify the effects of the studied drug.

Outside of clinical trials, patients with certain medical conditions, who are unable to enroll in a clinical trial, and have no other comparable medical options, may request to obtain access to investigational drugs. This can occur under FDA's expanded access program, or through a 2018 federal law known as “Right to Try.” Under either pathway, a patient can only access the investigational drug if its manufacturer agrees to the request. FDA has taken steps to facilitate access to investigational drugs outside of clinical trials, and most manufacturers in GAO's review communicated information to patients and physicians through their websites about how to access their investigational drugs outside of clinical trials. For example:

Since 2017, FDA took steps to simplify its expanded access program to make it easier to participate. In addition, to address concerns raised by manufacturers, FDA clarified guidance on how it would review data resulting from the program. Seven of the 10 manufacturers GAO interviewed viewed the guidance as an improvement.

GAO's review of information communicated by 29 manufacturers on their websites found that 23 had policies about accessing investigational drugs outside of clinical trials. At the time of GAO's review, 19 of the 23 stated they would consider individual requests for access, while the other four stated they would not. More than half of the manufacturers stated that if they approve a request, they require additional steps, such as FDA review of the request.

Before drugs or biologics are approved for marketing in the United States  by the Food and Drug Administration (FDA), they are considered  investigational. As part of the drug development process, these  investigational drugs are tested for safety and effectiveness on humans in  clinical trials. When investigational drugs show promise for treating  serious or life-threatening diseases or conditions such as metastatic  cancer, patients and physicians are often interested in obtaining access  to them before they are approved. While some patients may obtain  access to these drugs by participating in clinical trials, not all patients are  able to participate—for example, because they do not meet the eligibility  criteria that manufacturers have established for enrolling in a study.

Questions have been raised in recent years about whether clinical trial  eligibility criteria are too narrow and exclude patients who are likely to be  treated once a drug is approved, and FDA has historically provided  guidance to manufacturers to help them consider the circumstances  under which they could broaden these criteria without compromising  study results or raising ethical issues.

Outside of clinical trials, patients who are unable to participate in the  trials, and who have certain medical conditions, such as life-threatening  conditions, and no comparable medical options, can seek access to  investigational drugs through two pathways: 1) FDA’s expanded access  program and 2) the federal Right to Try Act (federal RTT Act). Under  either of these two pathways, access to the investigational drug can only  occur if the drug manufacturer agrees to provide access.

Requests to obtain access to investigational drugs through FDA’s  expanded access program must be reviewed by both FDA and an  institutional review board (IRB) in addition to being agreed upon by the  drug manufacturer. Some stakeholders—including physician and patient  advocacy groups—have criticized FDA’s program for being too complex  and burdensome to entities involved, which they contend could pose a  barrier to individual patients’ access to these drugs. However, others  argue that FDA is not a barrier because it allows most requests for  expanded access to proceed and because factors beyond FDA’s  program—such as a manufacturer’s approval—prevent patients from  obtaining access. In 2017, we found that FDA allowed 99 percent of the  requests under its expanded access program to proceed. We also found  that the agency and other stakeholders had taken steps to simplify and  improve the expanded access process. For example, FDA shortened the  form required for individual patient requests, and it partnered with the  Reagan-Udall Foundation to develop a website—referred to as the  Expanded Access Navigator—to help physicians and patients locate drug  manufacturers’ expanded access policies.

The other pathway for obtaining investigational drugs outside of clinical  trials—the federal RTT Act—was established by law in May 2018. This  provided another pathway for individuals with life-threatening diseases or  conditions to seek access to investigational drugs without a requirement  for FDA or IRB involvement. Some stakeholders, including some  physicians and medical ethicists, have questioned whether patient safety  could be compromised by allowing access to investigational drugs without  FDA and IRB review and whether the new pathway will improve access  for patients because it does not compel manufacturers to allow access to  their investigational drugs.

The FDA Reauthorization Act of 2017 (FDARA) included a provision for  us to describe actions taken by FDA and drug manufacturers to facilitate  individual access to investigational drugs. This report examines  1.  actions FDA and drug manufacturers have taken to broaden patient  eligibility criteria for clinical trials,  2.  actions FDA has taken to help facilitate access to investigational  drugs outside of clinical trials, and  3.  information drug manufacturers have communicated to patients and  physicians about access to their investigational drugs outside of  clinical trials.

To describe what actions FDA and drug manufacturers have taken to  broaden patient eligibility criteria for clinical trials, we reviewed FDA  guidance, reports and other related documents and interviewed  knowledgeable FDA officials about the agency’s ongoing or planned  actions on this topic. We also analyzed information collected through  interviews with, or written responses to, questions from a non- generalizable selection of 10 drug manufacturers about any ongoing or  planned actions they had to broaden the eligibility criteria for their clinical  trials, challenges associated with broader criteria, and other efforts to  increase participation in clinical trials. We selected the drug  manufacturers to achieve variation in company size and because they  were developing drugs or biologics to treat serious or life-threatening  diseases or conditions.

To describe what actions FDA has taken to help facilitate access to  investigational drugs outside of clinical trials, we reviewed laws, FDA  regulations and guidance, and FDA’s website and other related  documents about FDA’s expanded access program and the federal RTT  pathway. We also interviewed knowledgeable FDA officials about the  agency’s ongoing and planned actions related to this topic and a non- generalizable selection of 24 stakeholder organizations to obtain their  views on FDA’s actions. The organizations included the 10 selected  manufacturers noted above; three trade groups representing  manufacturers; three patient advocacy organizations; two physician  organizations; two public policy research organizations; two organizations  that work with manufacturers to facilitate access outside of clinical trials;  one organization focused on improving access to investigational drugs  through clinical trials; and one physician representing a research  organization. We selected patient advocacy and physician organizations  that broadly represented the views of patients and physicians, including  those stating they have experience in seeking access to investigational  drugs outside of clinical trials. In addition, we selected organizations to  provide a range of perspectives regarding FDA’s expanded access  program and the federal RTT pathway.

To describe what information drug manufacturers have communicated to  patients and physicians about access to their investigational drugs  outside of clinical trials, we reviewed the websites of a non-generalizable  selection of 29 drug manufacturers. We first selected 21 drug  manufacturers that were developing investigational drugs or biologics  intended to treat 10 serious diseases to achieve variation across several  factors. These factors included company size, participation in the  Expanded Access Navigator, and whether the manufacturer had an  investigational drug or biologic that FDA designated as a breakthrough  therapy, fast track product, or regenerative medicine advanced therapy in  fiscal year 2018. Two of these 21 manufacturers were among the 10 we  interviewed. In addition, we reviewed the websites of the other eight drug  manufacturers we interviewed. We conducted our review of manufacturer  websites between January 31, 2019, and March 12, 2019, by using a  data collection instrument that included a standard set of questions for  collecting information on the availability of information, procedures for  making a request for access to investigational drugs, and the factors that  the manufacturer would consider in evaluating requests. For  manufacturers that we determined had not communicated information on  their websites about access to investigational drugs at the time of our  review, we contacted them to verify this. To supplement our analysis, we  reviewed additional information that manufacturers communicated on  their websites, such as whether they provided information about access  to specific investigational drugs.

We conducted this performance audit from August 2018 to September  2019 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.

When patients are seeking access to investigational drugs, their first  option is to consider whether they can obtain them through participation in  a clinical trial. Clinical trials are a step in the drug development process  through which a drug manufacturer assesses the safety and effectiveness  of its investigational drug through human testing. A clinical trial can take  place in a variety of settings (e.g., research hospitals, universities, and  community clinics) and geographic locations, and is led by a principal  investigator that is typically a physician.

Manufacturers establish clinical trial eligibility criteria to define the patient  population to be studied, and only patients who meet those criteria can  participate. These criteria can vary depending on the drug being studied  and its intended use. Patient eligibility criteria consist of both inclusion  and exclusion criteria. Inclusion criteria specify the characteristics of the  patient that are required for participation, such as the stage or  characteristics of a disease, and typically identify a patient population in  which it is expected that the manufacturer can demonstrate the effect of  an investigational drug. In comparison, exclusion criteria specify the  characteristics that disqualify patients from clinical trial participation and  can include factors that could mask the effect of an investigational drug,  such as the presence of comorbidities or simultaneous use of other  drugs. Certain patient populations, such as children and pregnant  women, may also be excluded from clinical trial participation because of  ethical reasons.

Drug manufacturers, FDA, and IRBs each have responsibilities as part of  the clinical trial process. In order to test an investigational drug on human  volunteers in clinical trials, a manufacturer must first submit an  investigational new drug application (IND) to FDA. FDA is responsible for  reviewing the IND, which includes various components such as the  clinical trial protocol that describes the patient eligibility criteria, the  medications and dosages to be studied, and other details. In turn, an IRB  is responsible for reviewing and approving the clinical trial protocol as well  as reviewing the informed consent form for the study. In general, clinical  trials that involve human volunteers can begin after FDA has reviewed  and allowed the IND to proceed and the IRB has given its approval.

An investigational drug typically goes through three 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 clinical trials or suspend  the ongoing clinical trials. When a proposed or ongoing study is placed on  a complete clinical hold, the investigational drug cannot be administered  to any human volunteers. Traditionally, the three clinical trial phases are  the following:

Phase I: This clinical trial phase generally tests 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: This clinical trial phase assesses the drug’s safety and  effectiveness on people who have a certain disease or condition, and  typically the assessment is conducted on a few dozen to hundreds of  volunteers. Generally, 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: This clinical trial phase generally involves several hundreds  to thousands of volunteers who have a certain disease or condition  and gathers more information about the drug’s safety and  effectiveness, 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. When seeking FDA’s approval  to market a drug in the United States, the manufacturer submits an  application to FDA that includes the data from the safety and efficacy  clinical trials for FDA to review. Safety data include clinical trial results  about a drug’s toxicity (e.g., the highest tolerable dose) and adverse  events that may result from exposure to the drug. Efficacy data include  information on whether the drug demonstrated a health benefit over a  placebo. FDA reviews the information in the application to either approve  or not approve the drug.

If a patient seeking access to an investigational drug is not able to  participate in the drug’s clinical trial (e.g., because of the study’s eligibility  criteria or geographic location), another pathway to potentially obtain  access to the drug outside of a clinical trial is through FDA’s expanded  access program. Under the program, a licensed physician can submit a  request for access to an investigational drug for treatment use on behalf  of a patient and may do so during or after phase I, II, or III of clinical trials.  To allow access to an investigational drug under the program, FDA must  determine that a patient has a serious or immediately life-threatening  disease or condition and has no other comparable medical options,  among other criteria.

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. FDA is responsible for  determining whether to allow individual requests to proceed to treatment  once the manufacturer has agreed to provide access. If FDA allows the  request to proceed, an IRB must approve the clinical treatment plan that  is submitted as part of the individual request and review the informed  consent form. The licensed physician treating a patient under expanded  access would be required to report to FDA any unexpected serious  adverse reactions that occur during treatment for which there is a  reasonable possibility that the drug caused the reaction.

In 2018 the federal RTT Act established another pathway through which  patients may potentially obtain access to investigational drugs outside of  clinical trials. To be eligible under the law, a patient must have been  diagnosed with a life-threatening disease or condition, have exhausted  approved treatment options, and be unable to participate in a clinical trial  involving the investigational drug. Obtaining access to investigational  drugs through the federal RTT Act primarily requires the involvement of  the manufacturer and treating physician. Similar to FDA’s expanded  access program, treatment can only proceed if the drug manufacturer  allows the patient access to its drug. Under the federal RTT Act, the  manufacturer is responsible for providing to FDA an annual summary of  any use of its drugs under this pathway that includes information on any  known serious adverse events. The treating physician is responsible for  requesting access to the investigational drug for the patient and for  obtaining written informed consent from or on behalf of the patient if the  manufacturer agrees to provide access. Eligibility of an investigational  drug for patient use through this pathway is based on certain criteria,  including that the drug has completed phase I clinical trials, the  manufacturer has not discontinued clinical development of the drug, and  the drug has not been placed on a clinical hold. Unlike FDA’s expanded  access program, the federal RTT Act does not require the FDA or an IRB  to review individual requests for access.

Figure 1 shows a summary of the three pathways through which patients  may obtain access to investigational drugs.

FDA Issued Guidance to Help Manufacturers Broaden Clinical Trial Eligibility Criteria and Two Manufacturers We Interviewed Took Steps to Broaden Their Criteria

Some patients, such as those with compromised liver and kidney  function, have traditionally been excluded from clinical trials. FDA has  ongoing efforts to help drug manufacturers identify the circumstances  under which they could broaden their eligibility criteria to include such  patients without compromising study results. These efforts include issuing  recent guidance with recommendations for including certain patients in  clinical trials for cancer drugs. Officials from one of the 10 drug  manufacturers we interviewed told us they had broadened their eligibility  criteria and another one was taking steps to do so, but these officials and  others noted challenges to broadening eligibility criteria.

FDA public workshop on broadening eligibility criteria. In April 2018,  FDA held a public workshop with stakeholders—including drug  manufacturers, patient advocacy groups, and government agencies—to  discuss ways drug manufacturers and other investigators could safely  broaden eligibility criteria for clinical trials and to inform FDA guidance on  this topic. In July 2018 FDA publicly released a report summarizing the  workshop, in accordance with FDARA. According to the report,  stakeholders at the meeting emphasized the importance of broadening  clinical trial eligibility, when appropriate, to include more patients who will  likely use the drug if it is approved. Stakeholders recommended that  investigators ensure that the eligibility criteria for each of their clinical  trials are scientifically justifiable, rather than, for example, “copying and  pasting” a narrow set of criteria from a prior study without considering if  the exclusions are valid for scientific reasons. According to the report, this  practice can unnecessarily limit eligibility for certain patients. While  stakeholders commented that assessing whether eligibility criteria are  scientifically justifiable may require additional time and resources, they  emphasized it could lead to the removal of unnecessarily restrictive  eligibility criteria and thereby increase participation among patient  populations that have been typically excluded from clinical trials, such as  pediatric patients and patients with compromised liver and kidney  function.

FDA guidance on eligibility criteria. In March 2019, FDA issued four  new draft guidance documents and finalized one guidance document with  recommendations for drug manufacturers to broaden clinical trial eligibility  criteria for drugs that treat cancer. The guidance recommends that  manufacturers include certain patient populations that have typically been  excluded from participation. The patient populations are adolescents;  pediatrics (children and adolescents); patients with human  immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus  (HCV) infections; patients with brain metastases (i.e., cancer that has  spread to the brain); and patients with compromised kidney, heart, or liver  function, or who have a history of (or concurrent) cancer. According to  FDA, the guidance documents are intended to help drug manufacturers  and other investigators broaden cancer trial eligibility criteria. This will  help improve patient access to investigational drugs and ensure that the  results from the clinical trials are generalizable to patients likely to use the  drugs once they are approved. In addition, FDA officials have noted that  including broader patient populations in clinical trials can lead to new  information in a drug’s labeling, which will help communicate the safe and  effective use of these drugs. Table 1 provides a summary of each of the  five guidance documents.

In June 2019, FDA issued draft guidance for manufacturers on  broadening clinical trial eligibility criteria, in accordance with FDARA.  The guidance applies to a wider range of clinical trials beyond cancer  trials and includes recommendations to broaden eligibility criteria and  considerations for the use of clinical trial designs and other  methodologies to help facilitate patient participation. For example, FDA  recommends that manufacturers examine each exclusion criterion to  determine if it is needed to help assure the safety of trial participants or to  achieve the study’s objectives. If not, the manufacturer should consider  eliminating or modifying the criterion to expand the study population as  well as tailoring the exclusion criteria as narrowly as possible to avoid  unnecessary restrictions to the study population.

Two manufacturers’ efforts to broaden eligibility criteria. Officials  from one of the 10 drug manufacturers we interviewed told us they  broadened their clinical trial eligibility criteria and another manufacturer  we interviewed reported that it was taking steps to do so. These two  manufacturers told us they were taking these steps in part because both  believe it will facilitate the drug approval process. Officials from one  manufacturer stated that they broadened their eligibility criteria by  removing exclusions after determining they were not critical to clinical trial  designs, including exclusions related to liver function, infections (e.g.,  HIV), and the use of other medications (e.g., steroids). The officials  explained that, since 2015, they have systematically evaluated their  eligibility criteria to ensure that they do not unnecessarily exclude patient  populations from their clinical trials. Officials from the second  manufacturer told us they have begun evaluating whether to remove  certain exclusion criteria that they typically use in clinical trials, and added  that their efforts are partially in response to FDA’s 2018 public workshop  report, as described above. For example, the manufacturer is reviewing  its exclusion of adolescents in prior clinical trials and officials told us they  will likely include adolescents in an upcoming study if they determine that  patient safety would not be compromised.

Officials from both manufacturers stated that broader eligibility criteria will  allow more patients to access investigational drugs through clinical trial  participation. It can also, officials said, help them obtain FDA approval for  a drug that extends to a wider range of patients, if the drug is found to be  safe and effective. Further, officials from one of the two manufacturers  noted that broader eligibility criteria, such as criteria that include patients  with infections, could help streamline the process for conducting clinical  trials—for example, by eliminating the need to conduct clinical testing to  screen for the presence of infections.

Although most drug manufacturers in our review did not report efforts to  broaden their eligibility criteria, many noted efforts to address other  barriers to clinical trial participation. For example, to address geographic  barriers, officials from six of the 10 manufacturers told us they help cover  costs for patients to travel to clinical trial sites, such as by reimbursing  transportation and hotel costs for patients who travel long distances. In  addition, officials from one manufacturer said they completed a pilot  clinical trial on diabetes in 2019 that used decentralized trial locations in  three states, such as retail health clinics and patients’ homes, to help  patients overcome challenges with obtaining transportation to trial sites.  Similarly, within the next 2 years, another manufacturer is planning to  conduct a pilot clinical trial that is fully remote and expects the design to  improve patient participation in rural communities.

To address the lack of information about upcoming and ongoing clinical  trials that is available to and tailored to patients, two manufacturers  launched clinical trial registries in 2015 and 2016, respectively. Officials  from one of the manufacturers stated they designed their registry to  bridge the gap between the information that patients want about clinical  trials (e.g., information targeted to medical conditions that uses basic  terminology), and what is available in ClinicalTrials.gov, a federal  database that includes information on privately and publicly funded  clinical trial studies. Officials explained that ClinicalTrials.gov is, in  general, more targeted to physicians.

In addition, to address barriers associated with the mistrust of research  stemming from historical events among African-Americans and other  communities, one manufacturer has several ongoing efforts to increase  the participation of racially and ethnically diverse populations in its clinical  trials. For example, the manufacturer conducts workshops to train  minority investigators who conduct clinical trials and requires certain  clinical trial sites to be located in areas with minority patient populations of  more than 25 percent.

Challenges with broadening eligibility criteria. Officials from four of  the 10 drug manufacturers we interviewed—including the two taking steps  to broaden their clinical trial eligibility criteria—told us broadening  eligibility criteria is challenging. They stated that broader criteria must be  carefully balanced with the need to collect evidence from a well-defined  population. Officials from one manufacturer explained that removing  standard exclusion criteria, such as excluding patients who use other  medications, could interfere with the success of their clinical trial if those  medications make it difficult to identify the effects of the studied drug. In  addition, officials from another manufacturer emphasized that determining  whether to remove exclusion criteria takes time and resources because it  involves additional study, which could slow down the clinical development  of a drug.

FDA Took Several Recent Actions to Facilitate Access to Investigational Drugs Outside of Clinical Trials

FDA Simplified the Institutional Review Board Process and Launched a Pilot Program to Facilitate Access to Investigational Drugs Outside of Clinical Trials

To facilitate access to investigational drugs outside of clinical trials, FDA  has simplified its expanded access program’s IRB review requirements  for individual patient requests. FDA made this change in October 2017,  in accordance with a provision in FDARA. This provision addressed  concerns that FDA’s requirement to convene a full IRB to review an  expanded access request could result in delays of approvals because full  IRBs may not meet regularly. Under the revised process, FDA now allows  for a waiver of the requirement for full IRB review when concurrence is  obtained by the IRB chair or another designated member. According to  FDA officials, the updated process will help reduce the potential burden  for physicians, who are responsible for obtaining IRB approval, while still  protecting patients.

In addition, to further simplify its expanded access process for individual  patient requests, in June 2019 FDA launched a pilot program called  Project Facilitate for oncologists and other health care professionals that  treat patients with cancer. According to FDA officials, the pilot program  is focused on oncology because the agency receives a large number of  individual expanded access requests from oncologists. Under the pilot  program, FDA established a new call center that provides a single point of  contact where FDA staff are available to answer questions, assist in filling  out appropriate paperwork, and facilitate the overall process for  requesting and obtaining access to investigational drugs. For example,  FDA officials told us that FDA staff may assist oncologists in locating an  IRB, if needed. As part of the pilot program, FDA will follow up on  individual requests and gather data, such as how many patients received  investigational drugs, and if not, why the requests were denied by  manufacturers. According to FDA, the agency can use these data to  determine how the process is benefiting patients.

Twenty of the stakeholders we interviewed were familiar with FDA’s  simplified IRB review requirements, and of those, 18 told us these  updates were helpful for physicians and patients. For example, officials  from one drug manufacturer commented that the new IRB review  requirements reduce the amount of time it takes for patients to obtain  access to investigational drugs, which is especially important for patients  who are very sick. In addition, we spoke to 12 stakeholders about FDA’s  plans for its pilot program, and of those, nine generally had positive views  of the agency’s planned activities. Officials from one manufacturer  explained that the pilot program could help reduce the burden on  oncologists seeking access to investigational drugs for their patients  through the expanded access program. On the other hand, the officials  from this same manufacturer raised concerns about the potential for FDA  to intentionally or unintentionally pressure companies to make their  investigational drugs available to patients, should FDA have increased  involvement with drug manufacturers as part of the pilot program.

FDA Increased Communication about the Expanded Access Program and the Federal RTT Act to Facilitate Access to Investigational Drugs Outside of Clinical Trials

FDA has also taken recent actions to facilitate access to investigational  drugs outside of clinical trials by increasing its communication about the  expanded access program and the federal RTT Act.

FDA’s increased communication about the expanded access  program. In November 2018, FDA updated the web pages for its  expanded access program in response to findings from an external  assessment that the web pages were difficult to navigate and contained  unclear information. FDA created separate web pages for patients,  physicians, and drug manufacturers, and tailored information about the  expanded access process to each of these stakeholders. In addition, FDA  added a new web page with information that is commonly requested by  physicians and patients, such as the instructions for completing the form  for submitting individual requests and definitions of keywords associated  with the expanded access process (e.g., IRB, informed consent).

In addition, in October 2017, in response to a recommendation in our July  2017 report, FDA clarified its guidance for drug manufacturers on how the  agency reviews adverse events that occur under FDA’s expanded access  program. In the 2017 report, we found that some drug manufacturers  were concerned that use of adverse event data may influence FDA in  making final approval decisions, and that this possibility could contribute  to a manufacturer deciding not to grant patients access to their drugs  through the expanded access program. In response, we recommended  that FDA clearly communicate how the agency will use adverse event  data from expanded access use when reviewing drugs and biologics for  approval.

FDA’s updated guidance states that FDA is not aware of instances in  which adverse event information prevented the agency from approving a  drug, and that it is very rare for FDA to place a clinical hold on an  investigational drug due to adverse events observed during expanded  access treatment. The guidance also explains that several factors make  it difficult for FDA to link an adverse event to the expanded use of a drug  being considered for approval. For example, the guidance acknowledges  that the use of investigational drugs though the expanded access  program generally occurs outside of a controlled clinical trial setting and  patients receiving such drugs may be sicker than patients participating in  a clinical trial, making it more difficult to determine whether the use of the  investigational drug has led to the adverse event.

In responding to questions about increased FDA communication about  the expanded access program, 19 of the stakeholders we interviewed  were familiar with FDA’s updated expanded access web pages, and of  those, 16 told us they were an improvement. Officials from one  physician organization stated that the updated web pages were easier to  navigate than the previous web pages and presented information about  the process more clearly.

Among the 10 manufacturers we interviewed, we found varying views of  FDA’s updated guidance on the use of adverse event data.

Officials from seven of the 10 manufacturers viewed the updated  guidance as an improvement. Officials from one of the seven  explained that it contributed to their company’s decision to allow  access to investigational drugs, when appropriate.

Officials from two of the 10 manufacturers did not view the guidance  as an improvement. Officials from both manufacturers stated that they  still had significant concerns about the potential use of adverse event  data by FDA to adversely affect the development of their  investigational drugs, such as being used to issue a clinical hold. An  official from one of the two manufacturers commented that these  concerns remained despite FDA’s statement in the guidance that it is  difficult for FDA to link expanded access use to a particular adverse  event. In addition, officials from two other manufacturers who viewed  the guidance as an improvement similarly expressed remaining  concerns that adverse events could negatively affect the development  of their investigational drugs.

One manufacturer was unfamiliar with the updated guidance.

Further, officials from four of the 10 drug manufacturers we interviewed,  including two who viewed the updated guidance as an improvement, said  they believed that manufacturers’ concerns about this issue may never be  fully resolved even with additional FDA guidance.

In other comments related to FDA’s communication on its use of adverse  events data from the expanded access program, some drug  manufacturers we interviewed noted the merits of using efficacy and  safety data from the expanded access program to inform FDA’s drug  approval decisions. Officials from two of the 10 manufacturers told us  they believe that FDA’s potential use of adverse event data from  expanded access use, but not efficacy data, would be unfair. Officials  from one of these two manufacturers cited FDA’s updated guidance on  adverse events as contributing to their view, referring to FDA’s statement  that it is unlikely that FDA’s program would yield data that is useful to  FDA in considering an investigational drug’s effectiveness.

However, FDA officials told us that efficacy and safety data from the  expanded access program have been used to support drug approvals in  several instances. For example, in January 2018 FDA approved the drug  Lutathera to treat rare tumors in the pancreas and gastrointestinal tract  using efficacy and safety data the manufacturer submitted to FDA from a  subset of the roughly 1,200 patients who received the drug through the  expanded access program. Officials from four of the 10 manufacturers  expressed interest in discussing further with FDA how the agency would  evaluate efficacy and safety data from the expanded access program and  use these data to help support a drug’s approval and other regulatory  decisions.

FDA’s communication about the federal RTT Act. In November 2018,  FDA launched a new federal RTT web page that outlines both the  eligibility requirements for patients interested in seeking access to  investigational drugs and the criteria that must be met for an  investigational drug to be eligible for use through this pathway. For  example, the web page states that patients must be diagnosed with a life- threatening disease or condition to be eligible to access investigational  drugs under the federal RTT pathway. Further, the agency plans to issue  proposed regulations in September 2019 to implement the federal RTT  Act requirement for manufacturers to submit an annual summary to FDA  on any use of their investigational drugs under this pathway. The  regulations will include a due date for manufacturers to submit the annual  summaries as well as information on what they are to contain, according  to FDA.

Fourteen of the stakeholders we interviewed were familiar with FDA’s  new web page on the federal RTT Act, and among those, eight stated  that it communicated useful and balanced information for physicians and  patients. Officials from the remaining six stakeholders told us they did  not find it helpful for physicians or patients. For example, officials from  two stakeholders (including one drug manufacturer) commented at the  time of our review that the web page could be misleading to some  patients if they interpret the federal RTT Act to mean that manufacturers must provide access to their investigational drugs. Both added that FDA  should more clearly communicate on the web page that there is no such  requirement. In addition, officials from another stakeholder stated at the  time of our review that FDA should explain on the web page the agency’s  role in implementing the federal RTT Act. In May 2019 FDA clarified on its  web page that the federal RTT Act does not require manufacturers to  provide patients access to their investigational drugs and that FDA’s role  includes posting a consolidated annual summary report on the use of  investigational drugs through the federal RTT pathway.

Most Selected Manufacturers Communicated Whether They Consider Requests for Access to Investigational Drugs Outside of Clinical Trials and Conditions for Approval

Most of the 29 drug manufacturers in our review used their websites to  communicate to patients and physicians whether they would consider  individual requests for access to their investigational drugs outside of  clinical trials. Among those that would consider requests, most also  communicated the conditions under which they would review requests  and grant access.

Manufacturers’ consideration of requests for access. Our review of  drug manufacturers’ websites between January 31, 2019, and March 12,  2019, found that 23 of the 29 manufacturers in our review used their  websites to communicate whether they considered individual requests for  access to investigational drugs outside of clinical trials. In  communicating this information, 19 of the 23 manufacturers stated they  were willing to consider requests, while the other four stated they were  not considering requests. The remaining six of the 29 manufacturers did  not communicate information about whether they would consider requests  for access to investigational drugs outside of clinical trials at the time of  our review, but officials from all six told us they were in the process of  developing content on this topic that they intended to post on their  websites.

Information communicated by manufacturers that consider  requests. Among the 19 manufacturers willing to consider requests for  access to investigational drugs outside of clinical trials, all communicated  on their websites that they required physicians to submit requests on  behalf of their patients and provided information on how physicians  should submit these requests. In addition, 18 manufacturers  communicated an estimated time frame within which they would respond  to requests. The manufacturers provided additional information,  including the following:

Eighteen communicated information about the type of patient for  whom they would consider granting access.

Eighteen stated that patients must have a serious or life- threatening disease or condition; have no comparable or  satisfactory alternative therapies available; and be unable to  participate in a clinical trial to be eligible to obtain access.

In addition, 17 stated that the treating physician must determine  for the patient seeking access that the risk of taking the  investigational drug is not greater than the anticipated benefit.

Fifteen communicated other factors they would take into account  during their review of requests. These factors included the following:

Ten stated that the supply of their investigational drugs was a  consideration. That is, a manufacturer must have a sufficient  supply of the investigational drug to support the drug’s clinical  development before granting access to patients outside of clinical  trials.

Five referred to specific drugs to which they would consider  granting access when describing the conditions under which they  would consider reviewing requests. For example, one  manufacturer stated that it would consider requests to access  three of its investigational drugs (intended to treat bladder cancer,  influenza, and HIV).

One manufacturer communicated that after its initial review of  individual requests, it uses an external advisory committee to further  evaluate certain requests and ensure they are evaluated in an ethical  and fair manner. The committee, which includes bioethical experts,  physicians and patient representatives, makes recommendations to  the manufacturer about providing access to individual patients.

Many of the 19 manufacturers that communicated they were willing to  consider individual requests for access stated that after they have  approved a request they also required external entities to review the  request. These included the following:

Thirteen stated they require the relevant regulatory authority to  review requests. Of these, six specified that they require FDA to  review requests for access in the United States. One of these six  explained that it required a review by FDA to ensure all available  safety data for the investigational drug were considered, and  added that FDA is uniquely aware of such safety data.

Five stated they require the review of a research ethics committee  or an IRB.

Information communicated by manufacturers that do not consider  requests. Among the four manufacturers that communicated on their  websites they were not considering requests for access to investigational  drugs outside of clinical trials at the time of our review, two provided  reasons for their decision. Both cited safety concerns; for example, one  explained that it wanted to ensure its investigational drugs were  administered to patients only through clinical trials where safety could be  closely monitored. One also cited limited resources, stating that it chose  to focus its resources solely on conducting clinical trials. Both of the  manufacturers that provided reasons for not considering requests for  access communicated that they will periodically re-evaluate their policies.

We provided a draft of this report to HHS for comment and HHS provided  technical comments, which we incorporated as appropriate.

We are sending copies of this report to the appropriate congressional  committees, the Secretary of the Department of Health and 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 staff have any questions about this report, please contact  me at (202) 512-7114 or dickenj@gao.gov. Contact points for 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 I.

Appendix I: GAO Contact and Staff Acknowledgments

John E. Dicken at (202) 512-7114 or dickenj@gao.gov  In addition to the contact named above, Gerardine Brennan, Assistant  Director; Pamela Dooley, Analyst-in-Charge; Craig Gertsch; Gay Hee  Lee; and Moira Lenox made key contributions to this report. Also  contributing were George Bogart, Laurie Pachter, and Ethiene Salgado- Rodriguez.

Can patients with life-threatening diseases get access to an unapproved drug if they can't participate in a drug study?

If the drug manufacturer agrees, patients may access an unapproved drug through FDA’s expanded access program or through the federal Right-to-Try law.

Most of the drug manufacturers in our review were willing to consider individual requests from patients to access their unapproved drugs, according to the policies posted on their websites. While some manufacturers were unwilling to consider requests because of safety concerns, they said they would periodically reassess their policies.