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By: Ruth Stevens, Cynthia Phurrough, and Angela Drew

Ruth StevensCindy PhurroughAngela Drew






The recently updated Food and Drug Administration’s (FDA’s) Expanded Access program (commonly referred to as Compassionate Use) has been the subject of several recent news articles and two additional FDA guidances regarding charging for investigational drugs and a new streamlined application form. The timing of the release of the guidances was interpreted as a sign that Sarepta’s eteplirsen product for Duchenne’s muscular dystrophy would not be approved.Earlier, FDA’s announcement that an approval decision would be delayed fueled speculation that the drug may have a better chance of being approved than investors had previously thought. However, when FDA released the guidances describing how a company can charge for drugs provided by the Expanded Access program, Sarepta’s share price plunged because investors assumed FDA was paving the way for patients to receive eteplirsen in the absence of an approval. The following day, Janet Woodcock, head of FDA’s drug division (CDER) clarified that the release of the guidances was not connected to the review of Sarepta’s product. Those familiar with issuance of FDA guidances would have known that the process of changing policy or issuing/updating guidances is unlikely to occur in such a tight timeframe anyway.

What Is Expanded Access and How Do You Get It?

The Expanded Access program allows the use of unapproved or investigational drugs and biologics outside of a clinical trial.* There are three categories of use based on whether access is for a single patient, intermediate, or larger size patient populations.

  • For a single patient, the treating physician submits a single-patient investigational new drug (IND) application, including a protocol, form 3926, and a Letter of Authorization from the product manufacturer. Emergency requests can be made by telephone or Internet with subsequent IND submission within 15 working days.
  • For intermediate or larger-sized populations, the sponsor must submit a new IND or an amendment to an existing IND, along with a protocol amendment, and Form 1571.

In all cases, the manufacturer must agree to provide the drug product to the patient(s), and institutional review board approval of the protocol and patient informed consent are required. There is a 30-day waiting period before treatment may begin unless the sponsor is otherwise notified by FDA.

For all types of expanded access, FDA makes a determination of the risk/benefits of the treatment use with the drug. To approve the expanded access use, FDA must decide:

  1. that the patient has a serious or life-threatening disease or condition and has no other comparable or satisfactory therapeutic options,
  2. that providing expanded access will not interfere with development of the drug for the expanded access use, and
  3. that the patient cannot obtain the drug under another IND or protocol in a clinical study of the drug.

Note that FDA grants more than 99% of Expanded Access requests.

Why Would a Pharmaceutical Company NOT Agree to Provide Expanded Access?

There are several reasons why companies do not always agree to expanded access. The company must bear the costs for manufacture of the drug and administration of the program. This can be a significant burden for small- to medium-sized biotech companies, as supply of the drug is usually limited in the early stages of development.

Additionally, providing Expanded Access may diminish the number of patients available for the company’s clinical trial(s). Although FDA must determine that expanded access to the drug for the requested use will not interfere with clinical studies to support approval, some companies fear competition for recruitment of patients into their clinical studies. While a clinical trial often enrolls some patients randomly into a placebo group, Expanded Access may improve a patient’s chance of receiving treatment with the drug. This could be especially true for patients with serious medical conditions and no good treatment options.

Price may also cause problems after approval of a product supplied by Expanded Access. FDA places restrictions on what a company can charge for their product under expanded access. Increasing the price post-approval can make negotiations with third-party payers more difficult.

The biggest risk, however, is regulatory. Unfavorable safety data arising from use of a company’s product in seriously ill patients in an Expanded Access program can delay or increase the regulatory burden for approval of the product. FDA may request further analyses in certain populations, changes to the inclusion/exclusion criteria, or even extra studies. In a limited patient population, this can create a significant challenge.

CytRx is an example of this, in that their clinical development program for aldoxorubicin, in patients with soft-tissue sarcoma, was placed on partial clinical hold in November 2014 after a patient in the Expanded Access program died. As a result of the partial clinical hold, CytRx amended the protocol’s inclusion and exclusion criteria, bolstered the screening assessments, and added evaluations of serum electrolytes prior to administration of aldoxorubicin. This delayed their overall program. (The phase 3 clinical trial has now been completed and data are expected to be released in July 2016.)

The Good, the Bad, and the Ugly

There is no doubt that Expanded Access provides potentially life-saving options for seriously ill patients with limited or no other options. However, social media can put extreme pressure on drug companies and their employees in cases where Expanded Access is not provided. The “social media storm” that surrounded Chimerix after their Expanded Access program was closed included thousands of phone calls to the CEO, postings on their websites, and death threats to their executives. Within 1–2 weeks, Chimerix and FDA agreed upon a clinical study to enroll 20 patients, including the subject of the social media storm, Josh Hardy. Although the Chimerix phase 2 results for brincidofovir were extremely promising, the drug failed in phase 3 trials.

The Future for Expanded Access

With the introduction of the new guidances, FDA makes it clear that no major changes are intended for the current Expanded Access program, with the exception of the streamlined submission form for single-patient treatment. Many states have passed Right to Try laws that aim to skirt FDA’s Expanded Access program. However, in most cases, FDA is not the reason that access to investigational drugs is hindered.

In May, Senator Ron Johnson introduced the Trickett Wendler Right to Try Act of 2016 to the U.S. Senate. This Act aims (1) to improve access to drugs by reducing liability for manufacturers and physicians prescribing experimental drugs, and (2) to prevent FDA from using data from Expanded Access programs to adversely impact review of drugs being used in Expand Access programs. If this bill passes the Senate and House of Representatives, it may seem like a victory for those in favor of improved access to investigational drugs. However, the reality is that a statute requiring FDA to ignore safety data when reviewing a drug is unlikely to avoid legal challenge.

On a separate note, to encourage objective decision-making, Johnson and Johnson has implemented a pilot program in which an independent Compassionate Use Advisory Committee at New York University vets compassionate use requests for their unapproved cancer drug. The committee consists of a 10-member panel of physicians, bioethicists, patients, and patient advocates from five countries. While this model may be more appropriate for larger companies, it is hoped that all patients will receive ethical and transparent review under this model.

*A program for Expanded Access to medical devices exists but is not covered here.

Ruth Stevens, Ph.D., MBA, has had an integral role in all aspects of drug development for more than 25 years, and brings former FDA team leader experience to her role as chief scientific officer and EVP of Camargo Pharmaceutical Services. She is a pharmacokineticist and an expert in regulatory strategy, and has overseen the development of the full range of regulatory submissions, as well as applications for compassionate use.
Cynthia Phurrough, B.Sc., utilizes more than 30 years of regulatory and clinical development experience in her role at Camargo Pharmaceutical Services as senior director of Clinical Services. She is experienced in clinical study design and oversees clinical study conduct, including developing and executing clinical trial strategies in compliance with ICH GCP regulatory guidelines.
Angela Drew, Ph.D., has experience in medical research, data analysis, and clinical program strategy and implementation. She brings pharmaceutical strategic planning and regulatory experience to her role as a research scientist and product ideation consultant at Camargo Pharmaceutical Services.