On August 13, 2009, the Food and Drug Administration (FDA or the Agency) issued two final rules that expand and clarify the ability of patients to gain access to investigational new drugs and biologics when other therapeutic options are not available.  In an attempt to improve consistency in expanded access decisions, the first rule sets forth criteria and submission requirements that must be met before the FDA will authorize an expanded access use. The second rule clarifies the types of costs that drug manufacturers can recover when an investigational drug is used in a clinical trial or for expanded access, as well as the circumstances in which charging for such drugs is appropriate.  The rules also fulfill a statutory mandate that FDA develop a mechanism for ineligible patients to gain access to an approved drug with a Risk Evaluation and Mitigation Strategy (REMS) that restricts distribution of the product. 

Rule on Expanded Access to Investigational Drugs

The criteria required to be met for all expanded access uses are that the patient or patients must have an immediately life-threatening condition or a serious disease or condition (whether or not they would currently be considered seriously ill) and that there is no comparable or satisfactory alternative therapy available to treat, diagnose, or monitor the disease; the potential benefits must justify the potential risks of the treatment use and those potential risks may not be unreasonable in the context of the disease or condition being treated; and expanded access does not interfere with clinical studies that could support marketing approval or otherwise compromise potential development of the expanded access use.  FDA is responsible for determining whether those general criteria have been met.  The rule also specifies additional criteria that must be met for each of the different types of expanded access. 

“Serious disease or condition” has been defined to mean a disease or condition associated with morbidity that has substantial impact on day-to-day functioning, to be determined using clinical judgment based on several factors.  FDA added this definition as a result of several comments that criticized the lack of a definition in the proposed rule, but the Agency notes in the final rule that it “intends to be flexible” in interpreting the phrase.  Consistent with its commitment to flexibility, FDA explicitly refused to establish a minimum amount of clinical data necessary to support expanded access, in response to comments that recommended limiting expanded access until after the completion of phase 2 testing of the investigational product (among other comments).

Before FDA’s promulgation of this expanded access rule, an individual patient could obtain an unapproved drug for the treatment of life-threatening or severely debilitating illnesses through an individual patient investigational new drug application (IND), an emergency use IND, or a compassionate use IND, while a broader patient population could obtain access through a treatment IND (also known as a treatment protocol).  The new expanded access rule retains those pathways but expands the eligible patient populations and creates a novel mechanism for “intermediate-size patient populations” when the FDA receives “a significant number of requests for individual patient expanded access to an investigational drug for the same use.”  There are three possible intermediate-size population access scenarios that are based on the product’s stage of development: when a drug is being developed, when a drug is not being developed, and when an approved drug is not available through marketing channels.

Licensed physicians who secure an individual IND to treat a patient with an investigational drug must comply with certain safeguards, such as obtaining Institutional Review Board approval, monitoring the patient, submitting adverse event reports to the FDA, and making annual reports to the Agency if the IND lasts longer than one year.  FDA recognized that physicians may not be familiar with such regulatory requirements (which normally are the responsibility of the clinical trial’s commercial sponsor), but concluded that many of the requirements are consistent with routine clinical practice and/or the protection of human subjects and, therefore, are not unduly burdensome.

Rule on Charging for Investigational Drugs

While FDA cannot compel drug manufacturers to make investigational drugs and biologics available for treatment use, the second rule on charging for the investigational products is in part intended to create a financial incentive for companies to make those products available under expanded access programs.  Sponsors who wish to charge patients for an investigational drug – whether in a clinical trial or for expanded access – must obtain prior written authorization from the FDA to do so after justifying the need to charge and the amount to be charged.  Importantly for industry, the revised charging rule allows sponsors who are using an approved drug manufactured by a third party for an approved indication in a clinical trial (as an active control, for example) to charge patients for that drug without prior FDA approval. 

If it is appropriate to charge patients for an investigational drug, the charging rule limits recoverable costs to those that can be specifically and exclusively attributed to making the drug available.  In other words, direct costs are recoverable but indirect costs are not.  Direct costs include the costs per unit to manufacture the drug and the direct costs of shipping and storing the drug.  Indirect costs include research and development, labor, and administrative costs that would be incurred even in the absence of the clinical trial or expanded access use.  When a sponsor makes an investigational product available for expanded use in intermediate-size and large populations, however, the FDA permits the direct administrative costs of those programs to be recovered (e.g., patient monitoring costs) in addition to the direct costs that are recoverable for investigational drugs more generally.  

The bulk of the expanded access regulations are codified in new Subpart I of Part 312 in Title 21 of the Code of Federal Regulations, while the rule regarding charging patients for investigational drugs is codified at 21 C.F.R. § 312.8.

Finally, as part of its initiative to make options and information readily available to patients, FDA also launched a new consumer-oriented Web site that focuses on expanded access to investigational drugs.  

If you have any questions about the new rules regarding treatment use of investigational drugs or about clinical trial regulations more generally, please do not hesitate to contact the author or any other member of the Arent Fox Food and Drug Practice.

Joanne S. Hawana
hawana.joanne@arentfox.com
202.715.8591