Expanded Access Policy Disclosure
On December 13, 2016, the 21st Century Cures Act established (and the 2017 Food and Drug Administration Reauthorization Act later amended) a requirement that sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) make publicly available their policy for evaluating and responding to requests for expanded access for individual patients. Although these requirements were rolled out over time, they have now come into full effect.
Many emerging drug and biologic companies may be unaware of this new requirement and recently, journalists have begun reviewing company websites to identify whether companies required to have policies in place have publicly posted their policies. With this additional attention, companies would be well-served to identify whether they are required to comply with the expanded access policy (EAP) disclosure requirement, and if so, to act quickly to develop, implement, and post their EAPs.
What Is Expanded Access?
Expanded access is the use of an investigational new drug to treat a patient outside of a clinical trial, and the U.S. Food and Drug Administration’s (FDA’s) regulations at 21 C.F.R. §§ 312.300-312.320 have long made expanded access possible. Expanded access is also often referred to as “compassionate use,” “preapproval access,” or “early access.” Critically, sponsors are not required to provide expanded access, but many choose to do so voluntarily. The FDA views expanded access to be an “option of last resort,” and advises patients seeking access to investigational therapies to enroll in clinical trials whenever practicable. There are three categories of expanded access.
|Type of Expanded Access||Evidentiary Requirements|
|Individual Patients, Including for Emergency Use||
The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and
The FDA must determine that the patient cannot obtain the drug under another investigational new drug (IND) or protocol
|Intermediate-Size Patient Populations||
There must be sufficient evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and
Preliminary clinical evidence of effectiveness of the drug or a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population
|Treatment IND or Treatment Protocol||
For a serious disease or condition: There must be sufficient clinical evidence of safety and effectiveness to support the expanded access use, which generally consists of data from Phase 3 trials or compelling data from completed Phase 2 trials
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, which generally consists of clinical data from Phase 3 or Phase 2 trials, but could be based on more preliminary clinical evidence
The FDA generally will grant a request for expanded access if, in addition to the specific requirements for each type of expanded access, the following criteria are met:
- Expanded access is being sought for a serious or immediately life-threatening illness or condition;
- There is no comparable or satisfactory alternative therapy;
- The potential benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease or condition being treated; and
- Providing the drug will not interfere with or compromise development for the expanded access use.
Note that for individual patient expanded access requests, the FDA indicates on its website that it has approved over 99% of the requests it has received, so the question companies must weigh is whether to entertain individual patient expanded access requests, not whether the FDA is likely to approve them.
EAP Requirements and How to Comply
In response to patients and their physicians voicing frustration regarding the limited information available on how to request expanded access from companies developing investigational new drugs or biologics for serious diseases and conditions, Congress added section 561A to the Federal Food, Drug, and Cosmetic Act (FD&C Act). This new section requires drug and biologic companies to make publicly available their EAPs for individual patient access to products intended for serious diseases. Companies developing investigational new drugs or biologics that are not intended for serious diseases or conditions are not required to comply with the EAP requirement.
Although these EAP requirements were gradually phased in, sponsors are now required to make their EAPs publicly available upon the earlier of:
- Initiation of a Phase 2 or Phase 3 study; or
- 15 days after the drug or biologic receives designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy (RMAT).
EAPs must contain the following information:
- Contact information for the sponsor to facilitate communication about requests;
- Procedures for making such requests;
- The general criteria the sponsor will use to evaluate such requests for individual patients, and for responses to such requests;
- The length of time the sponsor anticipates will be necessary to acknowledge receipt of such requests; and
- A hyperlink or other reference to the clinical trial record containing information about the expanded access for such drug (i.e., a link to www.clinicaltrials.gov).
Sponsors therefore should determine how they will handle requests for expanded access to investigational products for individual patients, and establish an internal policy. Even if a sponsor’s internal policy is not to offer expanded access, the sponsor must nonetheless make public its EAP. Sponsors often provide this information on their website under a product candidate page, clinical trials page, or a page dedicated to patients.
Implications and Opportunities
Although section 561A of the FD&C Act does not specify the penalty for noncompliance, it is possible that the FDA could seek to enforce the EAP requirement by issuing untitled letters, warning letters, or other notices of noncompliance. Should journalists continue to investigate company compliance with the EAP disclosure requirement, failure to publicly post an EAP could drive negative publicity for a company, including within the physician and patient communities.
We have helped drug and biologic companies determine whether they are subject to the EAP disclosure requirement and understand the regulatory considerations around development and implementation of their policies. Importantly, expanded access can offer the opportunity for a company to gain a greater understanding of the use of its product in a patient population subset that may be excluded from participation in its enrolling clinical trials. This includes treatment of patients who may be coming to the company’s therapy as a second- or third-line treatment option. Where those patients have been “pre-treated” first-line or second-line with other therapies and the company’s investigational therapy follows thereafter under expanded access, the treatment outcomes in those patients can deepen the company’s knowledge about the profile of its therapy in those patients, including identifying potential combination study strategies or follow-on indications to seek post-approval. These incidental learnings can help inform and even streamline the focus of future clinical development programs for an investigational therapy. In addition, while expanded access may identify a safety signal with a product that could generate a clinical hold, identifying those signals sooner can ensure earlier implementation of protocol and dosing modifications aimed at minimizing the occurrence of similar events in a company’s future studies.
Companies would be well-advised to review whether they are subject to the EAP requirements and, if so, to discuss at the executive management level within the company whether an EAP permitting expanded access presents an opportunity for clinical learnings and the potential for streamlined product development that outweighs any safety signal downside that could come with providing such access. Once alignment is achieved on the company’s strategic approach to offering expanded access, companies can quickly develop their internal expanded access policies and make publicly available compliant EAPs.
On May 30, 2018, President Trump signed into law the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 (Right to Try Act), codified at FD&C Act § 561B. The Right to Try Act establishes an alternative pathway for patients with life-threatening diseases to seek access to investigational drugs outside of participating in a clinical trial. The right-to-try law is the product of years of advocacy, led by the Goldwater Institute. Prior to the federal right-to-try law, 40 states had passed right-to-try laws. It is easy to see how these laws have gained so much traction—it is difficult to oppose the idea that critically ill patients with no other options should be denied access to investigational therapies.
Critics of right-to-try laws have highlighted the FDA’s existing expanded access policies and noted that the FDA authorizes greater than 99% of all requests its receives for individual patient expanded access. These critics argue, in part, that right-to-try laws remove the regulatory oversight that is critical to ensuring the safety of patients receiving investigational drugs outside of the clinical trial context. They also contend that right-to-try may have a larger impact by reducing incentives for patients to participate in clinical trials, where enrollment needs are great, and potentially undermining the FDA’s authority to regulate drugs.
Overview of the Right to Try Act
The Right to Try Act does not guarantee access. Instead, it aims to encourage drug sponsors to offer investigational drugs to patients with life-threatening diseases outside of the clinical trials context by casting aside much of the FDA’s oversight authority and limiting liability for sponsors, manufacturers, prescribers, dispensers, and other entities.
To be eligible for right-to-try access, a patient must be diagnosed with a disease or condition: (a) where the likelihood of death is high unless the course of the disease is interrupted; or (b) with potentially fatal outcomes, where the endpoint of a clinical trial analysis is survival. The patient must also have exhausted approved treatment options and be unable to participate in a clinical trial involving the eligible investigational drug. In addition, the patient must provide written informed consent to their treating physician.
An “eligible investigational drug” is defined as an investigational drug that has completed a Phase 1 clinical trial and has not been approved or licensed. The investigational drug must be the subject of a pending new drug application (NDA) or biologics license application (BLA), or under investigation pursuant to an active IND in a clinical trial that is intended to form the primary basis of a claim of effectiveness in support of an NDA or BLA. The investigational drug must be undergoing active development or ongoing production and may not be discontinued by the manufacturer or placed on clinical hold.
Eligible investigational drugs are exempt from:
|Statute or Regulation||Description|
|FD&C § 502(f)||Adequate directions for use; label warnings|
|FD&C § 503(b)(4)||Misbranding|
|FD&C § 505(a)||Drug approval|
|FD&C § 505(i)||Investigational drug exemption|
|PHSA § 351(a)||Biologics license requirements|
|21 C.F.R. Part 50||Protection of human subjects|
|21 C.F.R. Part 56||Institutional review board oversight|
|21 C.F.R. Part 312||Investigational new drug requirements|
However, sponsors of eligible investigational drugs must comply with:
|21 C.F.R. § 312.6||Labeling of an investigational new drug|
|21 C.F.R. § 312.7||Prohibition on investigational drug promotion|
|21 C.F.R. § 312.8(d)(1)||Charging for investigational drugs under an IND|
Other key provisions include:
- Limits on the FDA’s use of clinical outcomes associated with the use of an eligible investigational drug pursuant to right-to-try;
- Requirements that sponsors submit an annual summary of any right-to-try use (including the number of doses supplied, the number of patients treated, the uses for which the drug was made available, and any known serious adverse events); and
- Removing liability for (a) sponsors and manufactures; and (b) prescribers, dispensers, or other individual entities (other than the sponsor of manufacturer) unless their conduct constitutes reckless or willful misconduct, gross negligence, or an intentional tort under any applicable state law; however, liability is preserved for state or federal product liability, tort, consumer protection, and warranty law causes of action.
Like the FDA’s existing expanded access regulations, the Right to Try Act does not guarantee access to investigational drugs. As a result, it is unclear whether the law will significantly expand such access. Although sponsors may be encouraged by the Right to Try Act’s limits on their potential liability, ultimately, sponsors considering whether to offer their investigational products pursuant to right-to-try face many of the same concerns related to expanded access. These considerations include safety, the impact on ongoing development programs, supply, cost, legal and ethical issues, and the ability to recruit patients for clinical trials. Prior to the Right to Try Act, the 40 state right-to-try laws did not meaningfully increase patient access outside of the FDA’s pre-existing expanded access authorities. While this may have been due to the lack of a similar federal law, it may indicate right-to-try’s inherent limitations.
How and when right-to-try will be implemented is unclear. After the Right to Try Act was signed into law, Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER), issued a statement instructing her staff not to answer questions related to the new law. She urged her staff to direct patients to sponsors and sponsors to refer to the statute. Despite having voiced concerns related to the Senate bill, FDA Commissioner Scott Gottlieb expressed his support and the agency’s commitment to an expeditious implementation when it became law. He also previously indicated that there were opportunities to implement the law to include patient protections.
For now, we expect that sponsors will continue utilizing expanded access, as opposed to right-to-try, as the primary means to provide access to patients with serious and life-threatening diseases outside of clinical trials. Sponsors are aware that the FDA grants over 99% of requests for expanded access. Moreover, expanded access represents a well-established means for sponsors to gain real-world evidence and understand their investigational products outside of the rigorous inclusion/exclusion criteria for their clinical trials.
As drug companies come into compliance with the requirement to publicly post EAPs, they must now do so with an understanding that the Right to Try Act may prompt additional inquiries by patients and providers for access to investigational products. As such, companies would be wise to review their EAPs, factoring in the new right-to-try authorities and consider addressing their approach to right-to-try requests within their EAPs.
 21 C.F.R. § 312.310.
 Id. § 312.315.
 Id. § 312.320.
 Id. § 312.305.
 FD&C Act § 561A(f).
 Id. § 561A(c).
 Id. § 561B(a)(1).
 Id. § 561B(a)(2).
 Id. § 561B(b).
 Id. § 561B(c).
 Id. § 561B(d).
 Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017, §2(b).