Expanded Access Versus Right-to-Try

Expanded Access, also known as compassionate use, has been around for 30 years beginning with access to investigational drugs to treat human immunodeficiency virus (HIV). The program was designed to provide patients who have exhausted all approved treatment options and do not qualify for a clinical trial a way to access investigational drugs. Over the years, the US Food and Drug Administration (FDA) has streamlined the process to improve access, by reducing the size of the application and decreasing the time needed for a decision. Expanded Access for a drug requires a 2-page form, submitted by a physician and approved by an institutional review board (IRB). Over the past 5 years, there have been 9000 Expanded Access Program applications; 99% were approved and 75% were approved in a few days. Manufacturers are permitted to charge patients an FDA-approved price for the investigational drug.¹

New recommendations issued by the FDA in March 2019 sought to increase the inclusion of patient populations who had been underrepresented in oncology clinical trials. Patient populations included in these recommendations include pediatric patients and patients with HIV, hepatitis B and hepatitis C virus infections, brain metastases, prior or concurrent malignancies, or organ dysfunction.²

In June 2019, the FDA initiated a pilot program, called Project Facilitate, to help oncologists request investigational cancer treatments for patients who are not eligible for a clinical trial and who have exhausted currently approved treatment options. Project Facilitate has a call center that provides help in submitting requests to FDA staff. The call center is a single point of contact for oncologists to request an experimental drug. Before Project Facilitate, calls came into multiple offices of the FDA. Now all calls requesting expanded access for an oncology product go through one location.³ The FDA created Project Facilitate because of criticism that the process to request a drug through an expanded access program was too burdensome.³ The FDA decided to pilot enhanced help to access investigational drugs in oncology first. A pharmaceutical manufacturer still has to approve access for the patient, but if access is denied, the FDA will inquire as to why it was not granted.⁴

Because of the perception of the difficulty in accessing investigational drugs, some states began implementing Right-to-Try laws allowing physicians to request access to an investigational drug on behalf of a patient.³ Federal Right-to-Try legislation was passed in May 2018. So, what is the difference between Right-to-Try and Expanded Access? Both programs are for patients with a life-threatening illness who have exhausted treatment options and are not eligible for a clinical trial or are too far away from a trial site. Right-to-Try is a request straight to the manufacturer without the FDA’s approval or oversight. But like Expanded Access, the drug company can reject a Right-to-Try request.⁵ The pharmaceutical company is allowed to charge for providing the drug through the Right-to-Try program.

Like Expanded Access, insurance companies will not pay for the investigational drug or nondrug medical costs associated with treatment with either program. Manufactures may be reluctant to participate because it could decrease the potential clinical trials pool or there may not be a large enough drug supply to treat patients outside of clinical trials. Patients may also prefer knowing they will get a drug rather than taking the chance they would be randomized to placebo in a trial. The drug sponsors may also consider that a negative result or major safety concern could adversely affect the drug perception by patients or investors. Despite the opportunity to recoup costs with both Expanded Access and Right-to-Try, manufacturers may be hesitant to charge for a drug because it may affect the perception of the price set after approval.⁶

Right-to-Try has no FDA oversight of the treatment or treatment process. The program also does not require approval by an IRB.⁷ A physician makes an inquiry directly to the pharmaceutical company. Currently, it is not clear how the request is made. An informed consent is required, but it has not been defined who will create the risk and benefit description for the document. The pharmaceutical manufacturer must also provide an annual report of patients treated and safety issues.⁸ At least one organization has been set up to promote Right-to-Try access. The group hopes to set up a network of physicians to provide investigational drugs through Right-to-Try.⁷

Formal guidelines for Right-to-Try have not been announced. The FDA has created a Web site to answer some questions. The information covers who would be eligible, the requirements for a drug to be available in the program, and the lack of FDA and IRB oversight. For additional information, patients are advised to talk to their physician and physicians are advised to contact the drug’s sponsor.⁹

Despite the lack of guidance on how to use the Right-to-Try program, two patients have been treated through the program as of August 2019.⁸ The phase II drug ERC1671 (Gliovac from Epitopoietic Research Corporation) became the first drug accessed through Right-to-Try in the fall of 2018. The patient had recurrent glioblastoma and did not qualify for a clinical trial evaluating ERC1671. This patient was not treated under the 2018 Federal law, but under the 2017 California’s Right-to-Try Act.¹⁰ The second patient was treated for amyotrophic lateral sclerosis with mesenchymal stem cell neurotrophic growth factors prepared through a proprietary process (NurOwn from BrainStorm Cell Therapeutics). The company has stated that it does not plan to treat any more patients outside of clinical trials.¹¹

Both programs require a physician to have the time to complete required steps to request an investigational drug. With Project Facilitate, FDA staff complete the paperwork, which allows greater access for patients in rural areas or treated by small clinics.⁶ The US Government Accountability Office reviewed laws, regulations, FDA documents, and a sample of 29 pharmaceutical manufacturers to assess the impact of these initiatives on increasing access to investigational drugs. Information on requesting access to an investigational drug was available on 23 of the manufacturers’ Web sites. While 19 would provide access, four would not and over half would require additional steps such as an FDA or IRB review before approving the request.¹² This suggests that many pharmaceutical manufacturers prefer the FDA Expanded Access process rather than the Right-to-Try process.¹³

To qualify as a drug that can be offered under Right-to-Try, a drug must have completed at least one phase I trial and have an effectiveness trial underway. The patient must have a life-threatening illness, exhausted all approved treatment options, not be eligible for a clinical trial, and provide an informed consent to receive the drug.¹⁴ The criteria for a patient to be eligible to request a drug under Right-to-Try are similar to Expanded Access. But with Expanded Access, the FDA determines whether the drug has the potential for a beneficial effect in a patient and an IRB must review and approve the treatment protocol. There is no oversight beyond the physician and patient in Right-to-Try. When considering the minimum criteria for a drug to be used in Right-to-Try as described earlier, we must ask whether we are providing a safe enough opportunity for our patients. Only 13.8% of drugs completing phase I are eventually approved. When this is broken down to therapeutic categories, only 3.4% of oncology drugs in phase I are approved, whereas other categories range from 15% to 33.4%.¹⁵ So, can we feel confident in providing a drug that has completed a phase I trial? The FDA designed Project Facilitate to provide accelerated access to oncology drugs, as the need of treatment alternatives for this therapeutic category is evident. Having input and review by outside parties for a critical treatment choice through Expanded Access appears to be in the best interest for our patients.