Two federal statutes—one overseen by the FDA and the other not—could help to facilitate more rapid access to investigational medical products meant to treat COVID-19. But as interest in the programs expands, so too will the pressure on regulators and companies to deliver both results and products to patients. There are significant trade-offs to consider.
Executive IQ Brief
- How things work now: There are three main pathways through which a patient might access an investigational drug: They could enroll in a clinical trial, they could ask the FDA to allow them to join a trial under “Compassionate Use” conditions, or they could ask a company directly to allow them to access a drug. These latter two options, known respectively as the Expanded Access pathway and Right to Try, generally allow patients to obtain access to an investigational drug in cases where they would ordinarily not qualify for the clinical trial testing it.
- What’s new: The FDA is under intense pressure to identify and allow distribution of treatments, vaccines, and diagnostic products for COVID-19. Emergency use authorizations are already in effect for some diagnostic products. As clinical trials for potential treatments begin, the FDA has stated that it will consider deploying its Expanded Access authority to ensure quick access to treatments. Patients might also leverage “Right to Try” legislation to obtain access to investigational drugs.
- Impact: While Expanded Access may help patients obtain faster access to investigational drugs, manufacturers face several key challenges: Providing enough supply of a drug to their trials, protecting patients, shielding themselves from legal liabilities, and ensuring their products get FDA approval as soon as possible. Companies will need to prepare their Expanded Access policies and post them on their website under the terms of a 2017 law, and recent case studies indicate many will soon be under intense scrutiny to accelerate access to investigational drugs.
Regulatory Background and Context
Under normal circumstances, the FDA takes one year to review a new drug, including 2 months of administrative review and 10 months to review the data supporting the drug’s safety and efficacy. In some circumstances, this timeline may be accelerated, such as for drugs granted priority review (8 months) or subject to other accelerated measures like the Real-Time Review pilot program for oncology drugs.
Because the FDA’s review process is generally predictable (and the US sales market is lucrative), many drug manufacturers choose to get their drug approved in the US first or seek simultaneous approval in other countries in addition to the US.
However, individual patients and small populations regularly request access to unapproved therapies, especially those who are unlikely to survive until full approval is granted.
However, seriously or terminally ill patients may be unable to enroll in a clinical trial. Many trials set eligibility criteria that prevent patients who are seriously or terminally ill from enrolling, since deaths, illness or organ failure associated with illness may make it difficult to determine if a drug is generally safe and effective. For example, it could be difficult to determine if an adverse event if caused by the drug or by the natural progression of the illness. A patient might also have a different disease than the one the investigational drug is being tested against in the trial.
To address this challenge, the FDA’s Expanded Access program (also known as “Compassionate Use”) can provide patients with serious or life-threatening illnesses with access to an investigational drug.
In addition, in 2018 Congress established a new access pathway known as “Right to Try.” Under this authority, patients who meet certain criteria can request access to drugs that have passed a Phase 1 clinical trial directly from the manufacturer without the FDA acting as an intermediary.
Both pathways may become increasingly important as public pressure on the FDA increases due to the COVID-19 pandemic.
How Things Work Now
The FDA has offered Expanded Access (EA) for investigational treatments since the 1970s. The FDA has authority (21 CFR 312.305) under this program to allow certain patients to access investigational drugs and biologics, even if the product has not yet demonstrated safety and efficacy.
There are three types of Expanded Access for drugs and biologics:
- Individual Patient Investigational New Drug (IND) Application, which is intended for use with single patients. The FDA also has the power to expedite these requests in emergency situations (312.310);
- Intermediate-size Patient Population IND, in which an investigational drug can be used for “a patient population smaller than that typical of a treatment IND or treatment protocol,” and is generally used when many patients have the same request for individual access to a drug (312.315); and
- Treatment IND (312.320), in which the FDA “may permit an investigational drug to be used for widespread treatment use.”
Each of these types may also use a “treatment protocol” instead of a “treatment IND,” in which an existing trial would be amended to allow treatment by a broader variety of patients.
Each of these population levels must meet certain criteria, including the presence of “serious illness” and a risk profile that could see higher potential benefit than risk in using an experimental treatment. Serious illness and life-threatening disease are defined in statute as “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning,” and a disease where “there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment,” respectively.
Expanded Access is only available for drugs under an active Investigational New Drug application (used to initiate clinical trials) or treatment protocol (used to expand a clinical trial). As part of the submission process, the FDA requires EA sponsors—which may differ from the clinical trial sponsors—to complete Form FDA 3962 for Individual Use and Forms FDA 1571 and 1572 for Intermediate and Treatment Use. Individuals are typically sponsored by physicians, while larger populations tend to have industry sponsors. Granted EAs are intended to be used to diagnose, treat or monitor seriously ill patients.
Critically, companies are not obligated to allow use of their drug under this program, even if the FDA has granted the request. A company may not wish to grant access to a drug if, for example, if believes the drug to be unsafe, if it does not believe it has sufficient supply of a drug to make it available to both trial participants and Expanded Access requests, or if it believes that supporting Expanded Access requests would be too expensive for it to handle. While companies may charge patients for access to an investigational therapy under Expanded Access, it may only cover a portion of its costs, not including staff costs.
Already, Expanded Access is being used to address COVID-19.
On Tuesday, March 10, Centers for Disease Control and Prevention Director Dr. Robert Redfield discussed how expanded access was being used in Washington state to address the disease associated with the novel coronavirus, COVID-19. At a hearing with the House Appropriations Subcommittee on Labor, HHS, Education, and Related Agencies, Dr. Redfield noted that Gilead Sciences’ remdesivir—an antiviral agent originally developed for MERS-CoV—has been used under the expanded access authority in one of the most disproportionately affected states in the US.
Right to Try
As an alternative to Expanded Access, “Right to Try” was established in 2018 by Congress. The law lays out specific criteria for eligibility for both patients and investigational products and is unlikely to apply to large populations.
In practice, the Right to Try program allows patients to bypass the FDA, allowing a critically ill patient to request use of an investigational drug directly from a manufacturer. As with the expanded access program, however, the manufacturer is not obligated to grant such a request. In essence, “Right to Try” is more analogous to “Right to Ask to Try.”
There are some key differences between Expanded Access and Right-to-Try, however.
The only products eligible for access under the RTT program are those that have completed Phase 1 trials and are undergoing active development or production. Under RTT, a physician must certify that a patient has exhausted all treatment options. However, RTT also includes legal liability protections for companies and a legal requirement that the FDA not use data from the use of a drug dispensed under RTT against a future drug application for approval.
To date, very few patients have obtained access to investigational drugs under RTT.
The global outbreak of a novel coronavirus (SARS-CoV-2) and its associated disease (COVID-19) have continued to put significant pressure on health care infrastructure in the United States, and on the FDA as a regulatory body. Currently, there is no approved therapeutic or vaccine to treat or prevent COVID-19, though Phase 1 clinical trials have begun on early vaccine and drug candidates for COVID-19.
As cases of COVID-19 continue to mount, the FDA is under intense pressure from the White House, as well as the American public, to authorize treatment and prevention measures. It is unlikely that any potential treatment or vaccine would be approved through the typical, albeit time-consuming, process.
In February, the Secretary of HHS declared the COVID-19 outbreak a Public Health Emergency. Under this authority, the FDA has granted several Emergency Use Authorizations (EUAs), which grant market authorization—not approval—to certain diagnostic devices intended for use in identifying the virus in individual patients. It has not yet granted Emergency Use Authorization to any drugs or vaccine products.
Impact of Expanded Access
As clinical trials for potential therapeutics for COVID-19 begin, patients (or their physicians) may seek access to therapies through Expanded Access or Right-to-Try.
The FDA may feel pressure to authorize Treatment INDs covering a large number of patients to facilitate access to investigational drugs. However, this could have significant implications for the pharmaceutical, biologic, and medical device industries, as well as patients.
At a White House Coronavirus Task Force press conference on March 19, FDA Commissioner Dr. Stephen Hahn noted that individual expanded access requests for use of remdesivir in seriously ill patients were available, citing the FDA’s rapid turnaround ability on these requests. The US Army Medical Research and Development Command has already been approved for expanded access use of remdesivir for Department of Defense-affiliated personnel, setting precedent for additional intermediate populations or widespread treatment approval. Although remdesivir is currently in Phase 1 clinical trials for COVID-19, the FDA has stated that about 250 patients have received the drug for treatment of the disease through expanded access.
According to a statement from the agency, “the data collected from the expanded access program may contribute to the agency’s understanding of the drug.”
However, the FDA has still indicated the need for controlled clinical trials to collect robust data. The data collected through Expanded Access is not as robust or comprehensive as data collected through a controlled clinical trial, as it promotes access at the expense of controlling for certain variables.
Typically, the EA pathway for any population size does not provide legal protection (note: the Right to Try Act does) to the sponsor; however, the Public Readiness and Emergency Preparedness (PREP) Act does afford these protections to certain products when a declaration of emergency use has been made. HHS issued this declaration on March 12, 2020, creating a strong incentive for companies to develop drugs, biologics and devices for COVID-19 as Covered Countermeasures by immunizing sponsors from liability and creating an injury fund for any potential claims.
The coming weeks are likely to see significant action from manufacturers and the FDA as the life sciences industry continues its breakneck pace in trying to identify treatments for the novel coronavirus. Under mounting pressure from the White House and the American public, the FDA is expected to give significant regulatory flexibility to manufacturers with products that could treat, prevent or cure COVID-19.
Moderna’s SARS-CoV-2 vaccine candidate, created in partnership with the National Institutes of Health, is an mRNA-based vaccine that has moved on to Phase 1 trials. It is currently eligible for expanded access, as are a number of other investigational therapies that AgencyIQ is tracking.
Vaccines are generally not good candidates for Right to Try or Expanded Access, however, given the legislative criteria that an eligible person be out of available options and have serious health issues. A vaccine is generally intended to avoid the onset of side effects, not treat patients once they have a disease.
The Executive Branch is working aggressively to marshal every possible federal resource to expedite efficiency in the production and delivery of drugs and devices.
One immediate step drug companies should take to prepare for increased interest in Expanded Access is to publish their Expanded Access policy online, which is required under the FDA Reauthorization Act of 2017. Interest in those policies is likely to be extraordinarily high.
Companies will also have to contend with their ability to manufacture products in sufficient quantity to satisfy the needs of both their clinical trials and interest by patients seeking expanded access. Most drug production during clinical phases involves small-scale production at laboratory facilities—not large-scale production by factories. Companies may not be able to increase production in time even if they wanted to do so.
They should also consider the potential public relations aspects of Expanded Access. The company Chimeric was pilloried in the media several years ago for not granting expanded access to its experimental drug to a young boy, Josh Hardy. The company’s executive eventually resigned, and the boy received the drug. Companies may be under greatly amplified public pressure to obtain access to their drugs, and regulatory affairs staff may be placed in the crosshairs of unsympathetic patients, legislators and media.
Final FDA approval of any medical substance is unlikely to occur soon. Many vaccines and therapeutics will not begin clinical testing until the summer at earliest, and the FDA has stated that it remains committed to ensuring any treatments are backed by evidence before obtaining full approval.
However, there are many steps the FDA can take to advance product availability short of full approval, including Expanded Access and Emergency Use Authorization. Expect the FDA to leverage those flexibilities to full effect.