Patients are frustrated. And their doctors are frustrated that they can’t do more to help. Together they see a blockade in their access to new therapeutics that may have the potential to change the outcomes of people diagnosed with unsolved, quick killer diseases. Now, large sections of the public, aided by new online marketing tools and compelling stories of human need, have brought the early access issue to our attention, perhaps more so in the last eighteen months than seemed imaginable just five years earlier. Elected officials are demanding better answers to why their constituents who battle scourges like stomach cancer, ovarian cancer, and ALS cannot try unproven drugs in the short time they have before dying. So the word is out. Patients and physicians need better access to exploratory medicine.
But the commotion has raised a dust cloud of misunderstanding around the principals and practices of Expanded Access programs (EAPs) in the United States. If drug companies, health care providers, and policy makers fail to speak from the same page on this topic, then the opportunity to improve the treatment landscape for dying patients may be wasted.
So let’s clear up the confusion. What do the regulations allow? What is Expanded Access intended to achieve? What are the historical best practices and how can these humanitarian programs be made economically and operationally feasible?
In the United States, Expanded Access is the treatment-use of an investigational drug; i.e., a new compound or biologic that is undergoing clinical research prior to its first FDA marketing approval. After several negotiated treatment-use programs in the 1960s and 1970s, the FDA wrote, in 1987, its first regulations for centrally coordinated, group level Expanded Access to investigational drugs.1
Since the 1962 amendments to the Act, an Investigational New Drug (IND) exemption must be submitted and then authorized by FDA prior to any U.S. human use of a new drug that is not yet approved for marketing. An IND is required for treating cohorts of patients in research trials of a new drug, and in 1987 the Treatment IND was devised for treating cohorts of patients who were not candidates for the research trials. Added to the new regulations was the Individual Patient or Emergency IND, which, unlike the Treatment IND, is intended for exceptional conditions and is filed one by one, by each patient’s physician. This single-patient channel sometimes goes by the popular name “Compassionate Use”.
These regulations have evolved gradually and now can address small groups of patients (2-100) in what is called the Intermediate Size IND, with easier authorization criteria than the larger Treatment IND. The FDA also allows the sponsor to open an access program by amending its existing IND with a Treatment Protocol, or Intermediate-Size Protocol, if it chooses to do so, instead of submitting a brand new IND.2
FDA requires the following to be the case for any Expanded Access trial in the U.S.:2
1) The drug is intended to treat a serious or life-threatening disease or condition.
2) The potential benefit to the patients outweighs the additional risk to the patients, in consideration of the seriousness of the disease.
3) The access program must not interfere with continued clinical development of the drug toward marketing approval.
4) The primary intent must be treatment. Any research objectives must be secondary.
Number 3 is particularly important. The doctrine of non-interference ensures that addressing the immediate need for treatment options doesn’t defeat the long term need for effective approved drugs. If the issue were ignored, access programs could theoretically entice patients away from placebo controlled research trials. Or drug companies could divert too much time and resources to EAPs, away from the tasks required to advance a product toward marketing approval. But the issue is seldom ignored. Complying with the non-interference doctrine is simply a practice of good program design and management. Tykerb, Gleevec, and Iressa are targeted receptor inhibitor drugs that were considered breakthroughs in treating advanced stage multi-drug resistant cancers. Expanded Access programs for those drugs enrolled 4000, 7000, and 24,000 patients respectively, while Phase 2 research trials of the same drugs rapidly met their enrollment targets.3,4,5 The sponsors achieved this through mutually exclusive inclusion criteria, which has been standard practice in EAPs for the last 25 years. The common narrative of an ethical conflict between the needs of present and future patients rests on the notion that EAPs generally delay research, but the case history does not support this notion.
In addition to the four requirements above, the Individual, Intermediate Size, and Treatment varieties of Expanded Access each have their own specific authorization criteria. Typically, an Expanded Access program can be authorized upon favorable safety and efficacy data from completed Phase 2 trials, but it can sometimes begin earlier, especially in “immediately life threatening” conditions.6
In 1992, AIDS advocacy organizations and the FDA released a “Parallel Track” statement to remind industry that the regulatory mechanism of Expanded Access was intended to permit treatment use of new drugs in *parallel* with clinical development, not merely as a bridge between Phase 3 and marketing approval.
Expanded Access for investigational drugs in the U.S. is often conflated with the business of global “Managed Access”. But there is a big difference. Managed Access programs, or MAPs, are part of a common commercial strategy for international market access. A MAP is sponsored by a drug company that has finished clinical development of its product in one territory (typically the U.S.) and seeks to begin selling that product in additional territories on a pre-registration basis. Post first-approval MAPs are not conducted with experimental-stage products. They are seldom designed in a way that generates any useful data. And due to the drug’s post-research phase of development, there is less of a hazard of delaying clinical development, so inclusion/exclusion criteria of MAPs are often identical to the criteria used in the research trials.
The specialty industry of MAP service providers has gotten into the business of advising the growing field of Expanded Access. But the resulting policies may fall short of the opportunity to make Phase 2/Phase 3 products available to large sets of patients. Respected officers at big pharmaceutical companies have struggled to understand key principals; namely the precedent of large EAPs that are conducted during -not after- clinical development, the broader spectrum of patients that can be enrolled in EAPs, and the opportunity to collect data that may inform the design of more-targeted Phase 3 studies.
Drug developers have been slow to consider Expanded Access strategies that include cost recovery, despite clear provisions that permit multiple parties to share the burden of humanitarian treatment programs. Medical services associated with EAPs can often be billed to Medicare or private payers. And in cases in which patients share the costs of their own exploratory treatment, patient assistance funds can be set up to cover the individuals who are in financial distress.7
In summary, despite clear regulatory code and industry guidance documents, drug development stakeholders continue to show a stunning range of beliefs and perceptions about the practice of Expanded Access. That’s a headwind against collaboration. The good news is that the opportunity remains for modern drug companies to work with health care providers and regulators for meaningful investigational treatment options for patients. The innovators will lead by example.
1. Hutt P, Merrill R, Grossman L. Food and Drug Law, Cases and Materials. 3rd Edition. Foundation Press, 2007
2.Code of Federal Regulations, Title 21, Part 312, Subpart I.
3. Capri G., Chang J., Chen S.C. Conte P., Cwiertka K.,Jerusalem G., Jiang Z., Johnston S., Kaufman B., Link J., Ro11 J.,, Schuttel J.., Oliva C., Parikh R., Preston A., Rosenlund J., Selzer M., D. Zembryki D., De Placido S. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol (2010) 21 (3): 474-480. doi: 10.1093/annonc/mdp373
4. Capdeville R.., Krahnke T., Hatfield A., Ford J.M., Van Hoomissen I., Gathmann I. Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias. Ann Oncol (2008) 19 (7): 1320-1326. doi: 10.1093/annonc/mdn050
5. Stahel R1, Rossi A, Petruzelka L, Kosimidis P, de Braud F, Bernardo MM, Souquet PJ, Parra HS, Gridelli C. Lessons from the (“Iressa” Expanded Access Programme: gefitinib in special non-small-cell lung cancer patient populations. Br J Cancer. Dec 2003; 89(Suppl 2): S19-S23.
6. Department of Health & Human Services; Food and Drug Administration. Guidance for Industry (Draft) Expanded Access to Investigational Drugs for Treatment Use — Q’s & A’s. May 2013
7. Department of Health & Human Services; Food and Drug Administration. Guidance for Industry (Draft) Charging for InvestigationalDrugs Under an IND — Q’s & A’s. May 2013