Increasingly, patients are demanding access to medication through Early Access Programs (EAPs), which are becoming more acceptable and sophisticated. Here we cover the success factors of employing EAPs in oncology and explain some of the nuances of using them in new areas of oncology development such as immunotherapies, CAR-T, cell and gene therapies.
Does the Situation Call for an EAP?
EAPs provide access to a promising, unapproved medicine to patients with terminal or severely debilitating disease and for whom there is no satisfactory alternative. A manufacturing company can grant access (with regulatory approval) on a named-patient basis or to a cohort of patients meeting specific criteria.
Cohort EAPs are most often used just before product commercialization when a product has had positive Phase II/III results and the company has decided to apply for marketing authorization. During this time, companies often get requests from physicians and patients for early access to a product – especially in an oncology setting where a patient has a poor prognosis and few treatment alternatives.
Physicians also often request access for a specific named patient based on the patient’s rapid progression, lack of treatment options, or biomarker profile. In these cases, regulators often reduce their evidence requirements, and the treating physician and company can determine if the treatment is suitable.
All EAPs should:
- Not threaten enrollment and conduct of controlled clinical trials, for trials are the fastest and best way to a get a product to a patient
- Meet the relevant regulatory requirements for each region (as these are varied, local knowledge is essential)
- Not pose added risk to patient safety
- Ensure that there is sufficient product to meet demand
Often, patients participating in oncology trials continue to benefit from a product well after the data have been analyzed and the report published. In these cases product supply should be maintained. Although such patients can be moved to an EAP, supplies for these patients are often better handled in an open-label extension to the original study; an EPA should be used only if there is a wider need, in which case it should be set up independently from the trial.
The viability of the clinical development program should be protected at all times, and therefore careful consideration should be given to providing early access when there are still active clinical trials. It is also wise to consider potential post-authorization commitments so the open EAP doesn’t hinder the recruitment of patients into a regulatory mandated study. Finally, especially given the recent examples in which products have been approved on limited data, in large global cohort programs, the number of patients can quickly outnumber the patients in the clinical development program. This might not be seen favourably by regulators.
The oncology space is filled with poignant patient stories, and it can be tempting to grant access to patients when there is little or no data to support doing so. In these cases, the wider implications need to be considered given that a precedent will be set. Would access be granted if there were multiple patients in a similar situation? Making a balanced and objective decision requires that physicians within the company and at the hospital scrutinize the available data.
All companies should be able to articulate a public positon on early access so that they can manage expectations and offer patients and physician clear routes to gaining access.
Planning an EAP in Oncology
In planning an EAP, one must consider:
- Costs. For the most part, manufacturers are expected to provide a product free of charge. There are some cases in which they can seek reimbursement, but doing so can be complex and is more common in the rare disease space. Thus, companies need to be fully aware of their potential investment. Unlike clinical trials, where the study can be closed at a set number of patients, EAPs are driven by the number of physician requests and can only be limited in so far as the country selection and inclusion criteria; the final patient number cannot be capped.
- Product Supply. There needs to be an adequate supply of product. Again, given that demand cannot be fully determined up front, this must be planned carefully. Epidemiological data, RWE databases, historical trial data, and early sales forecasts can all help model the likely uptake.
- Evidence Generation. Although the main aim of EAPs should be to provide access, they do provide an opportunity to generate additional evidence to support data gaps. While data cannot be a mandated condition of supply, in most regions high-level data collection is permitted. This can be very valuable as it gives the first real insights into how a product will perform outside a clinical trial. This type of real-world data (RWD) is also becoming more accepted by regulators and payers alike.
- Risk of Adverse Events. The adverse event (AE) profile needs to be well established and reflect an appropriate risk – benefit ratio. In an EAP, there is little control over the product and the management of AEs. Therefore, there must be confidence that the occurrence of AEs will be broadly in line with the clinical trial data, so as not to put the approval at risk. In a launch situation, there are often post-approval strategies such as Risk Evaluation and Mitigation Strategies (REMS) implemented which are more robust than simply asking physicians in EAPs to follow a toxicity management algorithm.
Key Operational Considerations
Once it has been deemed appropriate to conduct an EAP, one must take special care in operationalizing it. As part of their operational framework, EAPs require:
- An End-to-End Solution. This includes an intuitive request platform for physicians with integrated supply and resupply processes. This integrated approach should also include the option to collect and extract data. EAPs are expected to be more cost effective than clinical trials, with reduced project management oversight. A “help desk” can be used to manage issues. How this is operationalized will be slightly different for a big cohort EAP versus a named-patient supply. In large cohort programs, there should be a project manager and a clear project plan, which can be provided by specialist vendors. Named patient, ad hoc requests are usually handled within the company.
- Defined Roles and Responsibilities. These should be clearly articulated between the manufacturing company and the delivery vendor (if applicable) as well as between the company and treating physicians. Companies often take a hands-off approach, and the main responsibility lies primarily with the treating physician. This is achieved by asking physicians to sign a declaration outlining the terms under which the product is being given. Unlike in clinical trials, it is physicians’ responsibility to ensure that the appropriate consent and approvals are in place. It is also their responsibility to ensure the product is given as directed by the company.
- An Exit Plan. How and when the EAP will close needs to be planned up front and the expectations around the termination of supply carefully managed with physicians and patients. The anticipated national approval and reimbursement rates all come into play, and as these are moving targets, the plan needs to be flexible.
- A Communication Plan. It is important to think about the right messaging and communication to physicians and the public. This is where medical communications teams can bring insight and offer specialist support. Pricing and market access teams may also be consulted during planning in case EAP reimbursement is possible and can generate an early revenue stream.
The Use of EAPs in Oncology
With about one third of all new product launches being for oncology products, there is fierce competition for drug budgets – a situation that can be helped by EAPs. Although ethical considerations are often the main driver behind EAPs, there is no doubt that EAPs can help prepare the market ahead of approval and be useful in the early stages of product launch. Because EAPs get the product out in use, they create a potential set of positive advocates at launch. As such, due consideration should be given to which countries are included in the program to ensure that first-wave launch markets are covered. Finally, it is useful to consider how the field medical teams can add support and add value to an EAP; without promoting the EAP they can build customer relations and prepare the market for launch.
The “right to try” legislation in the US will likely have an impact on the number of requests for early access sought by physicians and granted by the FDA. However, the US is not a place where we see the need for large cohort EAPs since the approval and reimbursement times are faster than elsewhere. With that said, as insurers move towards evidence- or value-based pricing models, this might lead to protracted discussion and therefore timelines more akin to the EU. In the short term, the “right to try” legislation will be mostly used in a named-patient setting. The same bill requires transparency reporting, which means that any early access given in the US needs to be made public on ww.clincialtrials.gov.
As gene sequencing becomes more accessible, we can be increasingly certain how a specific product might benefit a given patient. The FDA’s approval of the next generation sequence (NGS) panel, Foundation One CDx, is evidence of how gene sequencing and biomarker profiles will continue to drive cancer treatment choices. In addition, with the approval of Keytruda®, we are seeing approvals that are agnostic of tumor type and based purely on biomarker analysis. All of this makes it easier to outline how an unapproved product might benefit a specific patient – again leading to targeted, named patient requests.
Immunotherapy is a massive area of growth in the oncology space. Competition is fierce, and EAPs can be a way to support market adoption. One of the conditions of EAPs is that they are reserved for products that offer benefit over existing treatments. Thus, a fifth-to-market immuno-oncology (IO) is not an EAP candidate unless, for example, it is used in an indication. This approach will give physicians exposure to the product while clinical data for the main indications are being sought.
Finally CAR-T and gene treatments are not likely to be subject to large cohort EAP programs. The high costs and the very tailored nature of their engineering means that the investment for companies is likely to be unsustainable. As such, these treatments are likely to be provided on a named-patient basis.
As we strive to get access to products faster and regulators are more open to the use of unapproved products, early access is emerging as a route for many treatments. Companies should think through their early access policies in advance and consider up front which products will and won’t be given pre-approval. Overall, EAPs are good for patients, as they can offer further treatment options when other approaches are exhausted.
The FDA announced a new expanded access pilot project at this year’s ASCO meeting. Stay tuned for what this means for biopharma companies.