Expanded access

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Expanded access (also known as compassionate use) refers to the use of an investigational new drug (IND) outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. Outside the US, such access is allowed through Named patient programs. In the US this type of access may be available, in accordance with United States Food and Drug Administration (FDA) regulations, when it is clear that patients may benefit from the treatment, the therapy can be given safely outside the clinical trial setting, no other alternative therapy is available, and the drug developer agrees to provide access to the drug. The FDA refers to such a program as an expanded access program (EAP).[1] EAPs can be leveraged in a wide range of therapeutic areas including HIV/AIDS and other infectious diseases, cancer, rare diseases, and cardiovascular diseases, to name a few.

There are several types of EAPs allowed in the United States. Treatment protocols and treatment INDs provide large numbers of patients access to investigational drugs. A single-patient IND is a request from a physician to the FDA that an individual patient be allowed access to an investigational drug on an emergency or compassionate use basis.[2] When the FDA receives a significant number of requests (~10 to 100) for individual patient expanded access to an investigational drug for the same use, they may ask the trial sponsor to consolidate these requests, creating an intermediate-size group.[3] “Compassionate use” is a more colloquial term that is not generally used by the FDA.

FDA regulations[edit]

Since 1987, the FDA has had rules in place that have enabled patients, under specific circumstances, to access drugs or biologics that are still in development for treatment purposes. These expanded access program rules were amended in 2009 by the FDA to ensure “broad and equitable access to investigational drugs for treatment.”[4]

The regulations include the following:[4]

  • Criteria that must be met in order to authorize the expanded access use
  • Requirements for expanded access submissions
  • Safeguards to protect patients and the clinical trial process

The regulations also include general criteria for granting expanded access:[3]

  • The patient must have a serious condition or disease for which there is no comparable alternative therapy available
  • The patient must be unable to participate in a clinical trial
  • The potential benefit must outweigh the potential risk of using the treatment
  • There should be no impact on the completion of the clinical trial or the drug’s approval

Despite the updated regulations, debate remains over key elements of expanded access:

  • Deciding at what point in the clinical trial process access should be given. Some stakeholders support expanded access programs after phase I testing in clinical trials. The FDA has stated that most drugs should not be eligible until some point during phase III when efficacy data have been obtained, unless compelling phase II data on safety and efficacy are available.[3][5]
  • Weighing risks to the patient against the potential benefits. The FDA requires that a physician and an institutional review board (IRB) determine that a treatment will not pose undue risk to the patient, relative to the condition he or she is suffering from.[6] However, the FDA maintains the right to overrule the physician and IRB.[3]
  • Determining who should get access. The FDA states that expanded access should only be considered for patients with a serious disease or condition, but the FDA’s rules do not provide a definition of “serious”; instead it provides examples of diseases and conditions that fall into this category.[3] In the case of a cancer drug, the sponsor of an expanded access program must define exactly which patients will get access. Most often, access is limited to those patients with the same type of cancer the drug is being tested for.[7]

A number of challenges can exist when patients seek access to investigational drugs:

  • Obtaining an IRB review. Finding time on an IRB’s schedule can be difficult, particularly for doctors who are not based at research centers where IRBs are readily available. The fee for the review may pose a problem as well. It may be unclear who is responsible for the cost of the IRB review, which can be as much as $2,000. Many IRBs conduct reviews pro bono but others that charge will often only waive their fees for research done in their hospital.[6][8]
  • Protecting physicians against liability risk. Currently, physicians may be concerned that they could face a liability risk for investigational drugs that they recommend to patients or help them gain access to, potentially discouraging them from doing so. The FDA does not have jurisdiction over this issue but there is a bill in Congress, the Compassionate Access Act of 2010 (H.R. 4732), that would address the situation.[6][8][9]
  • Paying for the drug. While the FDA allows drug companies to recover the costs of providing a treatment through an EAP, many companies may hesitate to do so because it requires disclosing the cost of their drug, which is often a closely guarded secret. In addition, many insurance companies won’t cover the costs of experimental treatment so access could be limited to patients with the means to pay for it.[6][8]
  • Assessing the potential impact of adverse events on drug development. Adverse events (AEs) that result from expanded access programs must be reported to the FDA in the same way AEs are reported in the case of a clinical trial. The FDA states that, to their knowledge, no drug candidate has been turned down for approval because of an adverse event that appeared in an expanded access program.[3][6]

State law[edit]

In 2013 and 2014, Colorado, Missouri, and Louisiana passed “right-to-try” laws that permit manufactures to provide experimental medicines to terminally ill patients without US FDA authorization.[10]

Outside the United States[edit]

Outside the U.S., programs that enable access to drugs in the pre-approval and pre-launch phase are referred to by a variety of names including “named patient programs,” “named patient supply” and “temporary authorization for use.”[11] In the EU, named patient programs also allow patients to access drugs in the time period between centralized European Medicines Agency (EMEA) approval and launch in their home countries which can range from one year to eighteen months.[12]

Ethical guidelines[edit]

Weighing risks to the patient against the potential benefits is one of the specified FDA regulations, as it is also the case in medical practice in general. In questions concerning expanded access this is particularly difficult, however, because treatments by new drugs (or unapproved dosages of known drugs) bear unknown risks. How should then a doctor decide (to treat or not) if he or she cannot know the success probability of the treatment for a given patient? For a single decision to take, this question is not meaningful. The situation is different if the doctor has several requests of different patients and therefore a possibiity of sequential learning of the effect of the treatment. If the first treatments were all unsuccessful the conscientious doctor may try to convince the other patients not to take the treatment, but as soon as a treatment is successful then it can be seen as an encouragement to go on. Note that if the physician were a prophet in the sense of being able to recognize the last successful treatment in the series then he or she would stop and would have with this last success all successes in the series and would spare the others from useless pain. Since the physician is no prophet, an ethically valuable strategy is to maximize the probability to stop with a last successful treatment. The solution to this optimization problem is provided by the odds algorithm where the odds are sequentially updated with each new observation.[13][14]


  1. ^ US National Cancer Institute - Access to Investigational Drugs accessed April 22, 2007
  2. ^ FDA Final Rules for Expanded Access to Investigational Drugs for Treatment Use and Charging for Investigational Drugs
  3. ^ a b c d e f Final FDA Rules on Expanded Access to Investigational Drugs for Treatment Use
  4. ^ a b FDA website
  5. ^ Expanded Access to Investigational Drugs Genetic Engineering & Biotechnology News, January 15, 2010.
  6. ^ a b c d e Access to Investigational Drugs Remains Challenge Despite New FDA Rules ‘’The Pink Sheet’’
  7. ^ Managing Access to Drugs Prior to Approval and Launch ‘’Life Science Leader’’[dead link]
  8. ^ a b c FDA webinar accessed May 5, 2010
  9. ^ FDA Law Blog accessed May 5, 2010
  10. ^ Darrow JJ, et al. Practical, legal, and ethical issues in expanded access to investigational drugs. N Engl J Med. 2015 Jan 15;372(3):279-86. PMID 25587952
  11. ^ Helene S (2010). "EU Compassionate Use Programmes (CUPs): Regulatory Framework and Points to Consider before CUP Implementation". Pharm Med 24 (4): 223–229. doi:10.1007/bf03256820. 
  12. ^ [Ericson, M., Harrison, K., Laure, N. & De Crémiers, F., Compassionate Use Requirements in the Enlarged European Union. RAJ Pharma, May 2005: 83.
  13. ^ F. Thomas Bruss, Sum the odds to one and stop, Annals of Probability, Vol. 38, No 3, 1384-1391,(2000)
  14. ^ Rémi Dendievel, New develpoments of the odds-theorem, arXiv:1212.1391v1 (2013)

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