Frances Verter, PhD
The cell therapy community has recently witnessed a heated discussion over how a sponsor should or could run an Expanded Access program that offers advanced cell therapy to children that have a condition with substantial long-term impact on day-to-day functioning and no effective alternative therapy1. This is not the first time there has been controversy about an Expanded Access program that offers a potentially life-altering therapy to vulnerable children, and it probably will not be the last2-4.
For those of us who track clinical trials, this raises some purely statistical questions: Just how common are Expanded Access approvals in the field of advanced cell therapy? Who has them, what diagnoses are covered, how many patients can participate, and are there any other interesting parameters by which we can sort them? The goal of this blog is to look into those questions.
First, a note about terminology: Nowhere in the Code of Federal Regulations or in the FDA regulations is there such a thing as an Expanded Access Program5-7. There is only a pathway for Expanded Access approval of an Investigational New Drug (known as IND). However, in colloquial language, it has become very common for people both inside and outside the drug development community to use the phrase Expanded Access Program or “EAP” to describe a group of patients that are getting a therapy that has not been formally approved. Therefore, in order to be consistent with other writers, we will use the abbreviation “EAP”, even though it is incorrect.
The FDA and health regulatory agencies in other countries have always had a pathway for “compassionate use” of therapies in development. The current format of the FDA’s Expanded Access pathway crystalized during the 1980’s. During the AIDS crisis, over 100,000 patients received antiretroviral drugs under EAPs8. Fast forward 30 years, and by the 2010’s the FDA was receiving over a thousand EAP requests per year, with over 99% of them approved9. One study found that 76% of the drugs available via EAP in 2016 went on to achieve FDA market approval10. On 30 May 2018, President Trump signed a federal Right-to-Try law which provides another access pathway for terminally ill patients11.
Under both the FDA’s Expanded Access pathway and the Right-to-Try legislation, the buck stops with the manufacturer of the product. The manufacturer can deny requests to supply the product, or the manufacturer can charge for the product5-7,12. It has been reported that manufacturers dread getting requests for compassionate use, because it puts them in a no-win situation13. If they deny the request, they can be the target of a social media campaign that makes them look heartless9. If they approve the request and supply the drug for free, they lose money. If they approve the request but charge for the product, they can be the target of a social media campaign that makes them look greedy14. And finally, if they charge a very low price under the EAP, and that price becomes known, the manufacturer may later face difficulty getting payers to accept a marked up commercial price when the drug goes to market13.
Drawing from the archives of CellTrials.org, the table below displays all Expanded Access treatments that were approved in advanced cell therapy from the beginning of 2017 through the middle of 2021. During this time frame of 4.5 years, there were a total of 3471 clinical trials of advanced cell therapy listed on all registries worldwide, among them were 913 trials registered to be conducted in the United States, but there were only 27 Expanded Access approvals listed on ClinicalTrials.gov. It would appear that the number of EAPs is 3% of the total US approvals for Investigational New Drugs (IND) in cell therapy, except we were surprised to discover that a couple of the EAPs are not US-based. Perhaps sponsors in other countries sometimes seek the prestige of being able to say they have an FDA-approved Expanded Access study.
|Year||Trial ID||Country||EAP Size||Current Status||Cell Therapy||Diagnosis||Sponsors|
|2017||NCT03010332||US||unknown||Not Available||virus-specific CTL (CMV)||CMV infection||Atara Biotherapeutics|
|2017||NCT03145545||US||Large||Available||alpha/beta T and CD19+ depleted PBSC||hematological malignancies & immunodeficiencies||Children's Hospital of Philadelphia|
|2017||NCT03153462||US multi-site||Large||Market Approval||CAR-T cells (CD19)||B-cell Lymphomas||Kite, A Gilead Company|
|2017||NCT03203941||US||Individual Patients||Not Available||cord blood HSC, unmanipulated||cerebral palsy||University of Texas Health Science Center|
|2017||NCT03327467||US||Intermediate||Available||cord blood HSC, unmanipulated||various pediatric brain injuries||Duke University|
|2018||NCT03601442||US||Intermediate||Available||CAR-T cells (CD19)||B-ALL, DLBCL||Novartis|
|2018||NCT03639844||US 2 sites||Individual Patients||Not Available||T-cells gene-modified given post HSCT||metabolic disorders||Bellicum Pharmaceuticals|
|2018||NCT03746899||US||Intermediate||Available||placental MSC expanded||Critical Limb Ischemia (CLI)||WideTrial|
|2019||NCT03886506||US||Intermediate & Large||Available||placental MSC expanded||Critical Limb Ischemia (CLI)||Pluristem|
|2019||NCT03914885||US||Individual Patients & Large||Not Available||CAR-T cells (CD30)||Hodgkin’s lymphoma||UNC Lineberger Comprehensive Cancer Center|
|2019||NCT03925649||US||Individual Patients||Not Available||adipose MSC||spinal cord injury||Hope Biosciences / University of Texas Health Science Center|
|2019||NCT04008524||China||unknown||Available||CAR-T||Refractory hematological malignancies||Institute of Hematology & Blood Diseases Hospital/Juventas Cell Therapy|
|2019||NCT04135092||US||Individual Patients||Not Available||TCR-T cells against neoantigens||metastatic prostate cancer||National Institute of Health (NIH)|
|2019||NCT04162756||US multi-site||Large||Market Approval||CAR-T cells (CD19)||B-cell lymphoma||Kite, A Gilead Company|
|2020||NCT04260698||US multi-site||Individual||Available||cord blood MNC expanded||Hematological Malignancies||Gamida Cell|
|2020||NCT04338347||US||Intermediate & Large||Not Available||cardiosphere-derived cells||COVID-19 viral infection||Capricor|
|2020||NCT04366830||US||Intermediate & Large||Not Available||bone marrow MSC||COVID-19 ARDS||Mesoblast|
|2020||NCT04400591||US multi-site||Intermediate||Available||CAR-T cells (CD19)||DLBCL||Juno / Celgene|
|2020||NCT04432545||Colombia||Intermediate||Available||umbilical cord MSC||systemic sclerosis with pulmonary involvement||Universidad de la Sabana / Fundación Neumologica Colombiana, Stem Medicina Regenerativa, CryoHoldco|
|2020||NCT04452994||US||Individual Patients||Not Available||CAR-T cells (BCMA)||Multiple Myeloma||Janssen Research & Development|
|2020||NCT04456439||US||Intermediate||Available||bone marrow MSC||COVID-19 multisystem inflammatory syndrome||Mesoblast|
|2020||NCT04465929||US||Individual Patients||Not Available||Schwann cells||peripheral nerve injury||University of Miami|
|2020||NCT04514952||US||Individual Patients||Not Available||adipose MSC||Amyotrophic Lateral Sclerosis (ALS)||Hope Biosciences|
|2020||NCT04661293||US||Individual Patients||Available||muscle derived cells expanded||various muscle disorders||Cook MyoSite|
|2020||NCT04681118||US multi-site||Intermediate||Available||autologous bone marrow cultured with NurOwn®||Amyotrophic Lateral Sclerosis (ALS)||BrainStorm Cell Therapeutics|
|2021||NCT04771078||US multi-site||Intermediate||Available||CAR-T cells (BCMA)||Multiple Myeloma||Celgene (Bristol Myers Squibb)|
|2021||NCT04772378||US||Individual Patients||Not Available||adipose MSC||Parkinson's disease||Hope Biosciences|
|2021||NCT04855955||US||Individual Patients||Available||adipose MSC||Alzheimer's disease||Celltex Therapeutics|
Because there are only 27 Expanded Access studies in this table, it is hard to run any statistics on this data. Here are some things we noticed.
These 27 EAPs include 6 for CAR-T products. Some gave access to a CAR-T product before its FDA approval, and subsequently closed. Some are ongoing EAP that give access to FDA-approved CAR-T products in cases where the product fails to meet manufacturing specifications. The distribution of trials by diagnosis is that over 80% of the 27 EAPs are accounted for by 10 (37%) for cancer therapy, 8 (30%) for neurologic conditions, 4 (15%) to fight viral diseases including COVID-19.
Expanded Access studies come in three size categories: Individual patients, Intermediate-size groups, and Large Populations. The EAP for individual patients are usually not registered on ClinicalTrials.gov at all, so the list in this table is only the tip of the iceberg. Some sponsors on this list have filed more than one EAP for different applications of the same product, whereas Duke University took a more streamlined approach and filed one EAP to cover multiple neurodevelopmental disorders. The FDA has different reporting requirements for different sizes of EAP, but the border between the intermediate and large size groups is not clearly defined or strictly enforced7.
The sponsors of these EAPs are not all traditional pharmaceutical companies or academic institutions. Some of them appear to be organizations that mix biobanking with clinical treatments.
It is very difficult, but not impossible, to learn whether patients are paying to participate in an EAP. The description of the EAP in ClinicalTrials.gov does not include any financial information. But the EAP sponsor must submit a cost recovery plan to the FDA, and for EAPs that are intermediate or large size that plan can include administrative costs6,7. The information contained in the IND filing to the FDA is supposed to remain confidential. However, once a multi-patient EAP is set up at multiple sites, there is a chance that cost recovery information may be leaked by the administration of a participating site. Plus, there is always the possibility that patients will share what they paid.
To learn more about the business models of EAPs, CellTrials.org interviewed Jess Rabourn. He is the CEO of WideTrial, a company that specializes in running EAPs and which has been one of the sponsors of the annual Expanded Access Summit. Mr. Rabourn acknowledged that cost recovery is a sensitive topic in the EAP community; when manufacturers cannot find a way to pass on costs, they respond by restricting access, and patients lose out. There are numerous potential ways to set up partnerships and campaigns that help to cover the cost of EAPs for vulnerable patients. He also suggested that the FDA management of EAPs could be re-examined. For example, what if broad categories of drugs all received the same cost recovery, so the sponsors do not have to reveal their manufacturing costs? The field of EAP will only grow as more patients seek access to novel therapies, and “we have to find ways of subsidizing this endeavor”.
- Verter F. Parent’s Guide to Duke’s Research and Expanded Access Program of Cord Blood Therapies for Neurodevelopmental Disorders. Parent's Guide to Cord Blood Foundation Newsletter Published 2021-11-15
- Yong J, Moffett M, Lucas S. Implementing a Global Expanded Access Program (EAP) for Infantile-Onset Spinal Muscular Atrophy (Type I): Understanding the Imperative, Impact and Challenges. J Neuromuscular Diseases 2019; 6(2):227-231.
- Kiefer P, Kirschner J, Pechmann A, Langer T. Experiences of caregivers of children with spinal muscular atrophy participating in the expanded access program for nusinersen: a longitudinal qualitative study. J Rare Diseases 2020; 15:194
- Yates N. I have spinal muscular atrophy. Critics of the $2 million new gene therapy are missing the point. STATnews Published 2019-05-31
- Code of Federal Regulations. Charging for investigational drugs under an IND. 21CFR312.8 Updated 2020-04-01
- FDA. Charging for Investigational Drugs Under an IND - Questions and Answers. Guidance for Industry Published 2016-06
- FDA. An Overview of FDA's Expanded Access Process and the New Individual Patient Expanded Access Application. DDI Webinar Accessed 2021-11-01
- Amorosa A, Tebas P. Is It Time to Rethink the Expanded-Access Programs for HIV Infection? J. Infectious Diseases 2007: 196:974–977.
- Moch KI. Ethical Crossroads: Expanded Access, Patient Advocacy, and the #SaveJosh Social Media Campaign. MA@PoC 2017; 1(1):e119-e130.
- Miller JE, Ross JS, Moch KI, Caplan AL. Characterizing expanded access and compassionate use programs for experimental drugs. BMC Research Notes 2017; 10:350.
- Right-to-Try. What is Right to Try? righttotry.org Accessed 2021-11-01
- Walker S. Expanded Access Versus Right-to-Try. Hospital Pharmacy 2020; 55(2):79-81.
- Miseta E. Now That Right To Try Is Law, What Does It Mean To You? Clinical Leader Published 2018-11-29
- Merlan A. A Controversial Autism Treatment Is About to Become a Very Big Business. VICE Published 2021-10-06