Research · 12 min read
Expanded Access and Right to Try: What Each Route Actually Requires
There are two written federal routes to a drug that is not approved yet. Both run through a licensed physician and a manufacturer that agrees to supply it, and neither one obliges anybody to say yes.
Key takeaways
- Expanded access aims to facilitate availability of investigational drugs to patients with serious conditions when there is no comparable or satisfactory alternative therapy.
- Serious means morbidity with substantial impact on day-to-day functioning, judged clinically; immediately life-threatening means reasonable likelihood of death within months or likely premature death without early treatment.
- Every expanded access use requires three determinations, one of which weighs the request against the clinical trials that could support approval.
- There are three pathways — individual patient, intermediate-size population, and widespread treatment protocol — with escalating evidence requirements.
- An emergency use can be authorized by telephone, with the written submission due within 15 working days.
- The treating physician becomes an investigator and the submitter becomes a sponsor, each carrying defined regulatory responsibilities.
- Charging requires prior written authorization and is capped at direct costs, supported by documentation an independent certified public accountant has reviewed and approved.
- Right to try is a statutory exemption with four conditions on the drug and three on the patient, including physician certification by someone the manufacturer does not pay to certify.
- The statute carries the direct-cost limit across by cross-reference while exempting the informed consent, review board and investigational drug regulations.
- No provision in either route obliges a manufacturer to supply a drug, and the statute expressly shields a decision not to.
Answer first: two routes, and both need a manufacturer to agree
The first route is the older one, set out in a subpart of the investigational drug regulations. Its stated aim is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy.
The second is a statute added in 2018 that creates an exemption rather than an approval pathway. It exempts an eligible investigational drug provided to an eligible patient from several requirements, on conditions.
Neither one is a request you make to a website. Both start with a licensed physician, and both depend on a manufacturer being willing to supply the drug at all.
The statute is explicit about that last point in its liability provision. No liability lies against a sponsor, manufacturer, prescriber, dispenser or other entity for its determination not to provide access to an eligible investigational drug.
What the older route covers, and the two definitions underneath it
The subpart applies to investigational drugs. It also applies to approved drugs whose availability is limited by a risk evaluation and mitigation strategy, where the primary purpose is to diagnose, monitor or treat a patient's disease or condition.
Two terms are defined at the top and they set the threshold for everything after.
A serious disease or condition means one associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible provided it is persistent or recurrent.
The definition then says who decides. Whether a disease or condition is serious is a matter of clinical judgment. It is based on impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.
An immediately life-threatening disease or condition is defined more narrowly. A stage of disease in which there is reasonable likelihood that death will occur within a matter of months, or in which premature death is likely without early treatment.
Three criteria that apply to every expanded access use
Before any of the specific pathways come into play, the agency has to determine three things.
That the patient or patients have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor or treat it.
That the potential patient benefit justifies the potential risks of the treatment use, and those potential risks are not unreasonable in the context of the disease or condition to be treated.
And the third one is about everybody else. That providing the drug for the requested use will not interfere with clinical investigations that could support marketing approval of the expanded access use. Interference is defined to reach their initiation, conduct or completion, or otherwise compromising the potential development of that use.
That third criterion is the one people find surprising. Access for one patient is weighed against the trial that would establish whether the drug works for everyone.
What a submission has to contain
Expanded access is a paperwork route, and the regulation lists what the paperwork holds.
A cover sheet on the prescribed form. The rationale for the intended use, including a list of available therapeutic options that would ordinarily be tried first, or an explanation of why the investigational drug is preferable to them.
The criteria for patient selection or, for an individual patient, a description of that patient's disease or condition including recent medical history and previous treatments.
The method of administration, dose and duration of therapy. A description of the facility where the drug will be manufactured.
Chemistry, manufacturing and controls information adequate to ensure the proper identification, quality, purity and strength of the drug. Pharmacology and toxicology information adequate to conclude it is reasonably safe at the proposed dose and duration.
And a description of the clinical procedures, laboratory tests or other monitoring necessary to evaluate the drug's effects and minimize its risks.
The submission and its mailing cover have to be plainly marked as an expanded access submission.
Three pathways, sorted by how many people are being treated
The subpart splits into three sections by population size, and each adds its own conditions.
The individual patient pathway lets the agency permit use for one patient by a licensed physician. Two extra determinations apply. The physician must determine that the probable risk to the person from the drug is not greater than the probable risk from the disease or condition. The agency must determine that the patient cannot obtain the drug under another application or protocol.
Treatment there is generally limited to a single course of therapy for a specified duration unless multiple courses or chronic therapy are expressly authorized. At the end, the physician or sponsor must give the agency a written summary of the results including adverse effects.
The intermediate-size pathway covers a population smaller than a widespread treatment protocol. It names three situations where it may be needed. A drug not being developed. A drug being studied where the requesting patients cannot enroll. And an approved drug no longer marketed for safety reasons, or unavailable through marketing.
The widespread route is the treatment protocol. It requires that the drug is being investigated in a controlled trial designed to support a marketing application for that use, or that all trials are complete. It also requires that the sponsor is actively pursuing marketing approval with due diligence.
Its evidence bar differs by severity. For a serious disease or condition there must be sufficient clinical evidence of safety and effectiveness, ordinarily from phase 3 trials but possibly from compelling completed phase 2 data.
The emergency procedure, and the clock it starts
One provision handles the case where there is no time to file anything.
If there is an emergency requiring treatment before a written submission can be made, the agency may authorize the use to begin without one, and the reviewing official may authorize it by telephone.
The request can be made by telephone, facsimile or other electronic means, and the regulation prints the offices and contact points for drugs and for biological products, including an after-hours route.
Then the obligation that follows. The physician or sponsor must explain how the use will meet the applicable requirements, and must agree to submit an expanded access submission within 15 working days of the authorization.
Everything else runs on a slower clock. An expanded access application goes into effect 30 days after the agency receives it, or earlier if the agency notifies that use may begin.
Who is responsible for what
The regulation converts ordinary roles into regulated ones, which is why this is not something a clinic does casually.
A licensed physician under whose immediate direction the drug is administered or dispensed is considered an investigator, and must comply with investigator responsibilities to the extent applicable.
An individual or entity that submits the application or protocol is considered a sponsor, with sponsor responsibilities.
A physician who does both is a sponsor-investigator and carries both sets.
Investigators are responsible in all cases for reporting adverse drug events to the sponsor. They must also ensure the informed consent requirements are met, ensure review board approval is obtained, and maintain accurate case histories and drug disposition records.
Sponsors are responsible in all cases for safety reports and annual reports, and for ensuring physicians are qualified to administer the drug for that use. They must also provide the information needed to minimize risk and maximize potential benefit, including the investigator's brochure where one exists, and maintain drug disposition records.
What a patient can be charged, and why it is not a price
Charging is possible and it is tightly bounded, which is the part most worth understanding.
A sponsor must obtain prior written authorization from the agency to charge for an investigational drug, and must justify the amount.
The ceiling is a category rather than a number. A sponsor may recover only the direct costs of making its investigational drug available.
Direct costs are defined as costs that can be specifically and exclusively attributed to providing the drug for the authorized use. They include per-unit manufacturing costs such as raw materials, labor and nonreusable supplies and equipment, or costs to acquire the drug from another manufacturing source. Direct costs to ship and handle it count too.
Indirect costs are excluded by name. Costs incurred primarily to produce the drug for commercial sale, and research and development, administrative, labor or other costs that would be incurred even if the treatment use had not happened.
Two enforcement features sit around that. The calculation must be supported by documentation accompanied by a statement that an independent certified public accountant has reviewed and approved it. And the agency will withdraw authorization to charge if it determines charging is interfering with development of the drug for approval.
For expanded access for treatment use, authorization to charge runs for one year from the time it is granted unless a shorter period is specified, and reauthorization can be requested.
What the right to try statute actually does
The 2018 statute takes a different shape. It does not create an application; it creates an exemption.
An eligible patient is defined by three conditions. Diagnosed with a life-threatening disease or condition. Has exhausted approved treatment options and is unable to participate in a clinical trial involving the drug. That is certified by a physician in good standing who will not be compensated directly by the manufacturer for so certifying. And has given written informed consent, or had a legally authorized representative give it.
An eligible investigational drug is defined by four. A phase 1 clinical trial has been completed. It has not been approved or licensed for any use. An application has been filed, or it is under investigation in a trial intended to form the primary basis of an effectiveness claim and subject to an active investigational application. And its active development or production is ongoing and has not been discontinued or placed on clinical hold.
The exemption names what is switched off, and it is substantial. Drugs provided in compliance with the section are exempt from several statutory requirements. They are also exempt from the informed consent, review board and investigational drug regulations. The condition is that everyone in the chain complies with three specified regulations, one of which is the direct-cost limit described above.
So the cost ceiling survives the exemption. The parts about review board oversight and the investigational drug framework do not.
What the statute does for the company, and what it reports
Two provisions explain why the statute was written the way it was.
The first protects the development program. The Secretary may not use a clinical outcome associated with use under this section to delay or adversely affect the review or approval of the drug. Two exceptions apply: a determination that the outcome is critical to determining safety, or a request from the sponsor.
That determination has procedure attached. Written notice with a public health justification, made part of the administrative record, and it may not be delegated below the director of the center charged with premarket review.
The second is liability. Take any alleged act or omission concerning an eligible investigational drug provided in compliance with the section. No liability in a cause of action lies against a sponsor or manufacturer. Nor against a prescriber, dispenser or other entity, unless the conduct constitutes reckless or willful misconduct, gross negligence, or an intentional tort under applicable state law.
Reporting is annual and public. The manufacturer or sponsor submits an annual summary of any use. It includes 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. The agency posts an annual summary report on its website.
Why none of this describes buying an unapproved product online
Set the two routes side by side and the shape is the same in the places that matter.
Both require a serious or life-threatening disease. Both require a licensed physician who takes on defined responsibilities and, in the statutory route, certifies the patient's situation without being paid by the manufacturer to do it.
Both require the manufacturer to be a real, identified sponsor with an active development program, and both leave that manufacturer free to decline.
Both cap what can be charged at direct costs, documented and reviewed by an independent accountant in the regulatory route and carried across by cross-reference in the statutory one.
A checkout page is not any of that. Anyone told that a product is available through one of these routes has a short list of checkable questions. Which physician is the investigator. Which company is the sponsor. And what the identified drug's application status is.
What this page does not tell you
Three boundaries, stated where you can see them.
Everything above comes from the text of the expanded access regulations and the right to try statute. No individual case, request or outcome is described, and no company is named.
The regulations and the statute both cross-reference other rules that were not fetched, including the informed consent and review board parts and the general investigational drug requirements. Where those are mentioned, it is because the text points at them, not because their contents are described here.
And nothing here is medical or legal advice about obtaining any drug. Both routes run through a treating physician, which is where a question about a specific situation belongs.
Sources
- 21 CFR Part 312 Subpart I — Expanded Access to Investigational Drugs for Treatment Use, with 21 CFR 312.8Section 312.300(a) for the scope covering investigational new drugs and approved drugs whose availability is limited by a risk evaluation and mitigation strategy where the primary purpose is to diagnose, monitor or treat a patient's disease or condition, and for the stated aim of facilitating availability to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy; 312.300(b) for the definitions of immediately life-threatening disease or condition and of serious disease or condition, including the sentences about short-lived and self-limiting morbidity, morbidity that need not be irreversible provided it is persistent or recurrent, and whether a condition is serious being a matter of clinical judgment based on survival, day-to-day functioning and progression. Section 312.305(a)(1) through (3) for the three criteria applying to all expanded access uses; 312.305(b)(2)(i) through (viii) for the eight submission contents; 312.305(b)(3) for the plainly marked submission and mailing cover; 312.305(c)(1) through (3) for the physician being considered an investigator, the submitter a sponsor, and a physician who does both a sponsor-investigator; 312.305(c)(4) for investigator responsibilities including adverse event reporting to the sponsor, informed consent, review board review and case history and drug disposition records; 312.305(c)(5) for sponsor responsibilities including safety and annual reports, ensuring physicians are qualified, providing the information needed to minimize risk and maximize benefit including the investigator's brochure where one exists, and drug disposition records; 312.305(d)(1) for an expanded access application taking effect 30 days after receipt or on earlier notification. Section 312.310 for the individual patient pathway; 312.310(a)(1) for the physician's probable-risk determination and (a)(2) for the agency's determination that the patient cannot obtain the drug under another application or protocol; 312.310(c)(1) for the general limit to a single course of therapy for a specified duration absent express authorization of multiple courses or chronic therapy; 312.310(c)(2) for the written summary of results including adverse effects at the conclusion of treatment; 312.310(d) for the emergency procedure, authorization by telephone by the reviewing official, requests by telephone, facsimile or other electronic communications, and 312.310(d)(2) for the agreement to submit within 15 working days. Section 312.315 for the intermediate-size population pathway and 312.315(a)(1) through (3) for the three situations in which it may be needed. Section 312.320(a)(1) and (a)(2) for the trial status and marketing status criteria and 312.320(a)(3)(i) for the evidence bar for a serious disease or condition, ordinarily phase 3 data but possibly compelling completed phase 2 data. Section 312.8(a)(3) for prior written authorization to charge, 312.8(a)(2) for justifying the amount, 312.8(a)(4) for withdrawal of authorization where charging interferes with development, 312.8(c)(4) for charging for treatment use running one year unless a shorter period is specified with reauthorization available, 312.8(d)(1)(i) for the definition of direct costs, 312.8(d)(1)(ii) for the excluded indirect costs, and 312.8(d)(3) for supporting documentation accompanied by a statement that an independent certified public accountant has reviewed and approved the calculations.
- 21 U.S.C. 360bbb-0a — Investigational drugs for use by eligible patientsSubsection (a)(1) for the definition of eligible patient, including diagnosis with a life-threatening disease or condition, exhaustion of approved treatment options and inability to participate in a clinical trial as certified by a physician in good standing with the physician's licensing organization or board who will not be compensated directly by the manufacturer for so certifying, and written informed consent by the patient or a legally authorized representative; (a)(2) for the four conditions defining an eligible investigational drug — a completed phase 1 clinical trial, no approval or licensure for any use, a filed application or investigation in a trial intended to form the primary basis of an effectiveness claim under an active investigational application, and ongoing active development or production not discontinued or placed on clinical hold. Subsection (b) for the exemption from the named statutory provisions and from parts 50, 56 and 312 of title 21 of the Code of Federal Regulations, conditioned on compliance with 21 CFR 312.6, 312.7 and 312.8(d)(1). Subsection (c)(1) for the bar on using a clinical outcome associated with such use to delay or adversely affect review or approval unless the Secretary determines the outcome is critical to determining safety or the sponsor requests its use, and (c)(2) for the written notice with a public health justification, its inclusion in the administrative record, and the prohibition on delegating the determination below the director of the reviewing center. Subsection (d)(1) for the annual summary of 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 (d)(2) for the agency posting an annual summary report on its website. The Limitation of Liability note printed with the section, from Pub. L. 115-176, § 2(b), for the absence of liability against a sponsor or manufacturer and against a prescriber, dispenser or other entity absent reckless or willful misconduct, gross negligence or an intentional tort under applicable state law, and for the absence of liability for a determination not to provide access.
Frequently asked questions
What is expanded access?
A set of regulations covering the use of investigational drugs, and of approved drugs whose availability is limited by a risk evaluation and mitigation strategy. It applies where the primary purpose is to diagnose, monitor or treat a patient's disease or condition. The stated aim is to facilitate availability to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy.
What has to be true before the agency can permit it?
Three determinations. That the patient has a serious or immediately life-threatening disease or condition with no comparable or satisfactory alternative therapy. That the potential patient benefit justifies the potential risks and those risks are not unreasonable in context. And that providing the drug will not interfere with the initiation, conduct or completion of clinical investigations that could support approval of that use, or otherwise compromise its development.
How does the individual patient pathway differ from the others?
It adds two determinations and two limits. The physician must determine that the probable risk from the drug is not greater than the probable risk from the disease. The agency must determine the patient cannot obtain the drug under another application or protocol. Treatment is generally limited to a single course for a specified duration, unless multiple courses or chronic therapy are expressly authorized. A written summary of results including adverse effects goes to the agency at the end.
Is there an emergency route?
Yes. Where an emergency requires treatment before a written submission can be made, the agency may authorize use to begin without one, and the reviewing official may authorize it by telephone. The request can come by telephone, facsimile or other electronic means. The physician or sponsor must explain how the use meets the requirements and agree to submit the written expanded access submission within 15 working days of the authorization.
Can a company charge for an investigational drug?
Only with prior written authorization, and only up to direct costs. Direct costs are those specifically and exclusively attributable to providing the drug for the authorized use. They cover per-unit manufacturing costs such as raw materials, labor and nonreusable supplies, or acquisition from another manufacturing source, plus direct shipping and handling. Costs incurred primarily to produce the drug for commercial sale, plus research and development, administrative and other costs that would exist anyway, are excluded. The calculation needs documentation with a statement that an independent certified public accountant reviewed and approved it.
What is right to try, and how is it different?
A 2018 statute that creates an exemption rather than an application pathway. An eligible patient must have a life-threatening disease, have exhausted approved options, and be unable to join a trial. That last point is certified by a physician in good standing who is not compensated directly by the manufacturer for certifying. The patient must also give written informed consent. An eligible investigational drug must have completed a phase 1 trial and not be approved for any use. It must also have an application filed, or be in a trial intended to support approval, and be in ongoing active development.
Does either route force a company to supply the drug?
No. The statute says directly that no liability lies against a sponsor, manufacturer, prescriber, dispenser or other entity for its determination not to provide access to an eligible investigational drug. The regulatory route likewise depends on a sponsor submitting or granting a right of reference to its application. Both routes describe how access can happen, not an entitlement to it.
Does using one of these routes hurt the drug's approval chances?
The statute addresses that directly. The Secretary may not use a clinical outcome associated with use under the section to delay or adversely affect review or approval. The exceptions are a determination that the outcome is critical to determining safety, or a request from the sponsor. Such a determination requires written notice with a public health justification, becomes part of the administrative record, and cannot be delegated below the director of the reviewing center.