Overview: Access to Unapproved Investigational Drugs in the U.S.*

Like you, PPMD has had many questions about the way we can access UNAPPROVED investigational therapies in Duchenne. Expanded access, compassionate use, Right to Try – these are all terms we have probably heard, but what do they mean? What are the pros and cons of each? PPMD’s Advocacy team has worked to put together a comprehensive guide to help answer your questions and clarify some of the confusion around these complex pathways to unapproved therapies.

Jump to:

• Definition
• How it works
• Who is eligible
• Coverage, Cost, and Reimbursement for an Investigational Drug
• Coverage, Cost, and Reimbursement of Routine Costs
• Monitoring Outcomes
• Liability
• Informed Consent
• Role of the Physician

*This chart does not cover off-label/investigational uses of approved drugs. 

Definition

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
Manufacturers enroll patients into clinical trials to obtain data about the drug, which the manufacturer may ultimately submit to FDA in support of an application to market the drug in the U.S. This research is heavily regulated and generally will be done under and IND from the FDA. FDA website	Expanded Access for Individual Patients is used to make experimental new drugs, under review for approval at the U.S. Food and Drug Administration (“FDA”), available to individual patients with serious or life-threatening diseases for which there is no comparable alternative treatment. However, the company that makes the drug (the "manufacturer") is not required to provide these drugs in this manner. FDA website	Expanded Access for Intermediate-Size Patients Populations is used to make experimental new drugs, under review for approval at the FDA, available to small groups of patients with serious or life-threatening diseases for which there is no comparable alternative treatment. However, the manufacturer is not required to provide these drugs in this manner. FDA website	Expanded Access for Widespread Patients Populations is used to make experimental new drugs, under review for approval at the FDA, available to patients with serious or life-threatening diseases for which there is no comparable alternative treatment. However, the manufacturer is not required to provide these drugs in this manner. FDA website	RTT allows seriously ill patients to bypass the FDA and obtain an investigational drug with the approval of the patient's doctor, if the drug manufacturer agrees to supply it. This program does not contain a mechanism that allows the Federal Government to force the manufacturer to provide the drug. The drug must have completed Phase 1 clinical trials and be the subject of an active IND. The text of the RTT Act states that it "is consistent with, and will act as an alternative pathway alongside existing expanded access policies" of the FDA. FDA website

**State laws, regulations, and guidances potentially include additional elements

How it works

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
A patient learns that a clinical trial exists to study a drug for a condition, either from advertisements, their treating physician, or from clinicaltrials.gov, where most studies are required to be listed. The patient, potentially with the help of their physician, which is not necessarily required, contacts the nearest study site and the investigating physician at that study site determines whether the patient is eligible to participate in the study. If the patient is eligible, the patient enrolls in the study and is given either the experimental drug or a placebo drug. Data is collected about the impact of the drug/placebo on the patient's condition. Though attention will be paid to the impact on patient safety, a patient can generally be removed from a clinical trial at any time, if the manufacturer or investigating physician believes it is best for them, or if the study ends.	First, the physician who is willing to oversee the care must confirm that the manufacturer is willing provide the drug. This program does not contain a mechanism that allows FDA to force the manufacturer to provide the drug. If the manufacturer is willing, the next step is for the physician to talk to the FDA. Contact information is available here, under “Key Contact Information.” Individual patients cannot apply for Expanded Access from the FDA; only a licensed physician who is overseeing their care may do so. The FDA website contains extensive information on how to do this (under "How to Submit an Expanded Access Application"). Specifically for individual patient access, physicians must submit a Form FDA 3926 to begin the process for individual patient access. For individual patients, there are three possible pathways: (1): Single Patient Protocol: If an investigational new drug application ("IND") exists for the drug, a Single Patient Protocol can be created, which is only for that specific patient. The Protocol must be approved by an Institutional Review Board ("IRB") and then it must be sent to the FDA. There is no 30-day waiting period before treatment may begin. (2): Single Patient IND: If no IND exists, an IND can be created just for that patient. This is known as a Single Patient IND. It must be approved by the FDA. Unless the FDA indicates that treatment may begin immediately, there is a 30-day waiting period before treatment may begin. (3): Individual Patient Access in an Emergency: There are emergency versions of both of the above approaches, known as an Emergency IND and an Emergency Protocol. If there is not enough time to secure IRB review prior to use, the use must be reported to the IRB within 5 working days after use. Emergency IND: If the situation requires a patient to be treated with the drug before a written submission can be made under a new IND, treatment is initially requested and authorized by phone or other "rapid" means of electronic communication and may start immediately once the FDA approves it. The follow-up written submission for the individual patient expanded access IND must be submitted within 15 business days of the telephone authorization. Emergency Protocol: If the situation requires a patient to be treated with the drug before a written submission can be made under a new protocol under and existing IND, treatment is initially requested and authorized by phone or other "rapid" means of electronic communication and may start immediately once the FDA approves it. The follow-up written submission for the Single-Patient Protocol under the existing IND must be submitted within 15 business days of the telephone authorization. Historically, FDA has approved the vast majority of these requests.	First, the physician who is willing to oversee the care must confirm that the manufacturer is willing provide the drug. This program does not contain a mechanism that allows FDA to force the manufacturer to provide the drug. If the manufacturer is willing, the next step is for the physician to talk to the FDA. Contact information is available here, under “Key Contact Information.” Individual patients or patient groups cannot apply for Expanded Access from the FDA; only a licensed physician who is overseeing their care may do so. The FDA website contains extensive information on how to do this (under "How to Submit an Expanded Access Application"). For intermediate-size patient populations: this is done in one of two ways, below. There is no emergency approach for intermediate-size patient populations. (1): If an IND exists for the drug, an Intermediate-Size Patient Population Expanded Access Protocol can be created, which is only for that specific group of patients. The Protocol must be approved by an IRB and then sent to the FDA. There is no 30-day waiting period before treatment may begin. (2): If no IND exists, an IND can be created just for that specific group of patients. This is known as an Intermediate-Size Patient Population Expanded Access IND. There is a 30-day waiting period before treatment may begin. An intermediate-size patient population protocol may also be requested to allow access to treatment with an approved drug or a related drug that is not available through marketing channels because of failure to meet the conditions of approval or a drug shortage, provided the drug and the patient meet the general criteria for Expanded Access as well as the criteria specific to use in an intermediate-size patient population. Historically, FDA has approved the vast majority of these requests.	First, the physician who is willing to oversee the care must confirm that the manufacturer is willing provide the drug. This program does not contain a mechanism that allows FDA to force the manufacturer to provide the drug. If the manufacturer is willing, the next step is for the physician to talk to the FDA. Contact information is available here, under “Key Contact Information.” Individual patients or patient groups cannot apply for Expanded Access from the FDA; only a licensed physician who is overseeing their care may do so. The FDA website contains extensive information on how to do this (under "How to Submit an Expanded Access Application"). For larger patient populations: this is done in one of two ways, below. There is no emergency approach for larger patient populations. (1): If an IND exists for the drug, a Treatment Protocol can be created, which is only for that specific group of patients. The Protocol must be approved by an IRB and sent to the FDA. There is no 30-day waiting period before treatment may begin. (2): If no IND exists, a Treatment IND can be created just for that specific group of patients and sent to the FDA. There is a 30-day waiting period before treatment may begin. Historically, FDA has approved the vast majority of these requests.	(a): A manufacturer of an investigational drug has the option to make it available to eligible patients under this legislation. Companies already are required to make their Expanded Access policies public on their websites, but it is unclear whether they are also required to make public their RTT policy. Companies may make these policies public as well. (b): The patient, in consultation with their physician, should consider all other treatment options. (c) If the physician decides the treatment is appropriate for the patient, then the patient and physician would contact the manufacturer who would (if they are willing and subject to requirements of their policy), provide the drug for this use. IMPORTANT: The FDA's role in this process (if there is a role for the FDA at all) is somewhat up-in-the-air as of June 20, 2018. One of the RTT Act's primary sponsors in Congress, Senator Ron Johnson, issued a public letter to the FDA stating that the Act was intended to "diminish the FDA's power over people's lives, not increase it...It is not meant to grant the FDA more power or enable the FDA to write new guidance, rules, or regulations." Conversely, the Commissioner of the FDA has stated that the FDA has "convened several agency leaders...to formulate a process for handling" RTT. It is unclear at this time how the FDA will play a role or if a step will be added to the process described here involving the FDA.

**State laws, regulations, and guidances potentially include additional elements

Who is eligible

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
Each study will have its own "eligibility criteria." A patient must meet the eligibility criteria in order to participate in the study.	Eligibility is determined by the patient's physician and the FDA, based on the patient’s specific diagnosis, the location of participating Expanded Access program sites, and inability to participate in a related clinical trial. FDA: (See "If I meet the criteria, will I qualify for Expanded Access/Compassionate Use to a drug?" See also "What does the FDA consider when reviewing my request?")	Eligibility is determined based on the patients' diagnosis, the location of participating Expanded Access program sites, and inability to participate in a related clinical trial. FDA: (See "If I meet the criteria, will I qualify for Expanded Access/Compassionate Use to a drug?" See also "What does the FDA consider when reviewing my request?")	Eligibility is determined based on the patients' diagnosis, the location of participating Expanded Access program sites, and inability to participate in a related clinical trial. FDA: (See "If I meet the criteria, will I qualify for Expanded Access/Compassionate Use to a drug?" See also "What does the FDA consider when reviewing my request?")	Eligibility is determined primarily by the patient's physician. In the text of the RTT Act, an "eligible patient" is a patient "who has been diagnosed with a life threatening disease or condition [as defined by the existing regulations]." The patient must have "exhausted approved treatment options" and be "unable to participate in a clinical trial involving the eligible investigational drug, as certified by a physician."

**State laws, regulations, and guidances potentially include additional elements

Coverage, Cost, and Reimbursement for an Investigational Drug

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
A manufacturer may charge eligible patients for direct costs of the drug (only) if they meet certain criteria outlined in 21 C.F.R. 312.8. Many manufacturers do not charge patients the direct costs because they wish to withhold proprietary cost information or for other reasons. Additionally, third party payers (including private insurers and Medicare) are not required to provide coverage for any of the direct costs charged by the manufacturer. Payers generally do not require an investigational drug itself unless otherwise covered outside of the clinical trial.	The manufacturer may require eligible patients to pay the costs associated with manufacturing the drug; however they must obtain authorization from the FDA. There are no federal requirements for insurance companies to cover an experimental drug. 21 C.F.R. § 312.8(c) and (d)	The manufacturer may require eligible patients to pay the costs associated with the manufacturing the drug; however they must obtain authorization from the FDA. There are no federal requirements for insurance companies to cover an experimental drug. 21 C.F.R. § 312.8(c) and (d)	The manufacturer may require eligible patients to pay the costs associated with the manufacturing the drug; however they must obtain authorization from the FDA. There are no federal requirements for insurance companies to cover an experimental drug. 21 C.F.R. § 312.8(c) and (d)	The manufacturer may require eligible patients to pay specific costs associated with manufacturing the drug. They are not required to obtain authorization from FDA to do so.

**State laws, regulations, and guidances potentially include additional elements

Coverage, Cost, and Reimbursement of Routine Costs

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
Routine costs of a clinical trial that are otherwise covered by the third party payer may be covered. There are different rules that apply to coverage for routine care in clinical trials for Medicare, Medicaid, and private payers. Manufacturers sometimes pay for routine costs provided to an indigent uninsured patient.	Routine costs for INDs under expanded access are likely treated similarly as broader clinical trials and may be covered by the third party payer, unless upon medical management review, the payer finds that the use no longer meets qualifying criteria or jeopardizes the safety or welfare of the enrollee. Different rules apply for Medicare, Medicaid, and private payers.	Routine costs for INDs under expanded access are likely treated similarly as broader clinical trials and may be covered by the third party payer, unless upon medical management review, the payer finds that the use no longer meets qualifying criteria or jeopardizes the safety or welfare of the enrollee. Different rules apply for Medicare, Medicaid, and private payers.	Routine costs for INDs under expanded access are likely treated similarly as broader clinical trials and may be covered by the third party payer, unless upon medical management review, the payer finds that the use no longer meets qualifying criteria or jeopardizes the safety or welfare of the enrollee. Different rules apply for Medicare, Medicaid, and private payers.	Routine costs of a clinical trial that are otherwise covered by the third party payer may be covered (similar to expanded access). Coverage of routine costs may be withdrawn if, upon medical management review, the payer finds that the use no longer meets qualifying criteria or jeopardizes the safety or welfare of the enrollee. Different rules apply for Medicare, Medicaid, and private payers.

**State laws, regulations, and guidances potentially include additional elements

Monitoring Outcomes

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
The IND will contain extensive reporting obligations that the manufacturer/study sponsor must make to the FDA. Ethically, all major regulators place gaining dispositive data over any individual patient’s needs, in hopes that the data gained could help more patients in the future. Therefore, regulators such as the FDA would prefer that patients, if eligible, enroll in a clinical trial, rather than accessing drugs through Expanded Access or RTT mechanisms.	The sponsor (manufacturer or physician) of the relevant IND (either the existing IND under which there is a Single Patient Protocol or the Expanded Access IND) must report all adverse events to the FDA and undertake all other reporting required by the IND.	The sponsor (manufacturer or physician) of the relevant IND (either the existing IND under which there is an Intermediate-Size Patient Protocol or the Expanded Access IND) must report all adverse events to the FDA, and undertake all other reporting required by the IND.	The sponsor (manufacturer or physician) of the relevant IND (either the existing IND under which there is a Treatment Protocol or a Treatment IND) must report all adverse events to the FDA, and undertake all other reporting required by the IND.	RTT provides that “[t]he manufacturer or sponsor of an eligible investigational drug shall submit to the [HHS] Secretary an annual summary of any use of such drug under [RTT]” that 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.” Finally, the Secretary of HHS must post an annual summary report of the use of RTT on the FDA website. Thus, manufacturers will require that physicians provide this information to them.

**State laws, regulations, and guidances potentially include additional elements

Liability

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
Clinical trials can be risky for companies, but they generally undertake that risk because of the potential to market the drug. Generally, if physicians and hospitals follow the study protocol, the manufacturer may indemnify them if they are sued over their participation in a study.	Some manufacturers, hospitals, and/or physicians may be uncomfortable undertaking Expanded Access work, fearing that it could lead to increased liability for them.	Some manufacturers, hospitals, and/or physicians may be uncomfortable undertaking Expanded Access work, fearing that it could lead to increased liability for them.	Some manufacturers, hospitals, and/or physicians may be uncomfortable undertaking Expanded Access work, fearing that it could lead to increased liability for them.	RTT specifies that sponsors, manufacturers, prescribers, dispensers, or other individual entities are not liable for the results of providing these drugs unless their actions rise to the level of reckless or willful misconduct, gross negligence, or an intentional tort. A person could also bring a private suit under state or federal product liability, tort, consumer protection, or warranty law against the parties involved in RTT access to an investigational drug. Manufacturers are not required to provide a drug and no manufacturer can be found liable for deciding not to provide access to a drug. RTT raises a number of questions for manufacturers, especially as it is quite new. Approaches will vary company-by-company. Since companies cannot be compelled to provide drugs if they do not wish to do so, there likely are some that will adopt a policy of not providing drugs through RTT. Link

**State laws, regulations, and guidances potentially include additional elements

Informed Consent

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
Patients must provide informed consent prior to initiating treatment of an experimental drug.	Patients must provide informed consent prior to initiating treatment of an experimental drug. FDA website: "Am I protected from risks?"	Patients must provide informed consent prior to initiating treatment of an experimental drug. FDA website: "Am I protected from risks?"	Patients must provide informed consent prior to initiating treatment of an experimental drug. FDA website: "Am I protected from risks?"	A patient must provide informed consent prior to initiating treatment of the investigational drug; however RTT specifically exempts participation from being covered by IRB regulations.

**State laws, regulations, and guidances potentially include additional elements

Role of the Physician

Participation in Clinical Trials	FDA: Expanded Access for Individual Patients (includes an option for emergency use)	FDA: Expanded Access for Intermediate-Size Patient Populations	FDA: Expanded Access for Widespread Treatment Use	Federal Right To Try Legislation ("RTT")**
The physician is in the role of investigator for the clinical trial. The physician may be the patient's usual, treating physician, who happens to be working on the clinical trial, or the patient may see the investigating physician only for study related treatment, and continue seeing their original doctor for everything else.	Physician is in the role of clinician treating a specific patient.	Physician is in the role of clinician.	Physician is in the role of clinician.	Physician is in the role of clinician.

**State laws, regulations, and guidances potentially include additional elements