Rapid Access in the US, UK, and France

Timing is everything with these early access programs; although all feature some mechanism that brings a product to market earlier, they differ in what stage of development they should be requested. Two of the programs earlier in the drug development process (fast track and breakthrough therapy designation) feature a “rolling review,” which permits the Agency to review portions of the marketing authorization before the complete application is submitted—so long as the preliminary clinical data show the product may be effective. In essence, this allows patients to access a therapy more rapidly if earlier phases show great promise in specific populations.

These 2 programs have other benefits besides rolling review:

• Fast track: frequent interactions with the FDA for the manufacturer (pre-IND, end of phase 1/end of phase 2 meetings) to discuss data that will be required for approval
• Breakthrough therapy: intensive guidance from the FDA on the manufacturer’s drug development program (as early as phase 1); use of more senior reviewers; eligibility for priority review

The priority review designation comes much later in the drug development process, after phase 3 trials have been completed. Priority review provides a shortened 6 months for a product’s FDA review instead of the typical 10, which decreases the time it takes for meaningful technologies to reach the patient.

The accelerated approval pathway is another program aimed to encourage development for drugs targeting serious diseases, but it is an alternative pathway for access, not a designation as the other 3 programs are. Under the accelerated approval pathway, the applicant would gain approval based on an early surrogate or intermediate endpoint. This approval does come with additional safeguards:

1. all promotional materials must be submitted to the FDA for review
2. the sponsor must conduct confirmatory trials; and
3. approval may be withdrawn if evidence no longer supports approval or if the manufacturer does not follow through with its commitments.

Key: BLA – Biologics License Application; FDA – Food and Drug Administration; IND – Investigational New Drug Application; NDA – New Drug Application.

To be eligible for the expedited access programs, specific criteria unique to each scheme must be met. All 4 programs share a common criterion—that the drug in development is intended to treat a serious condition. As for the additional qualifying criteria:

There is an additional mechanism to receive a priority review from the Priority Review Voucher Program (PRVP), which specifically targets diseases where there is a high patient burden and unmet need: tropical diseases,² rare pediatric diseases,³ and the Zika virus.⁴ The PRVP provides a voucher to manufacturers that develop products for these specific diseases. This voucher can be used at the time of another product’s New Drug Application (NDA) or Biologics License Application (BLA) submission to earn a priority review, shortening the review time by 4 months. Or, the voucher can be sold to another manufacturer, which can be quite lucrative as well—in 2015, United Therapeutics sold its voucher for $350 million. This program has become more popular since the inclusion of rare pediatric diseases, with 6 of the 10 vouchers awarded in the program’s 7-year history being granted in the last 2 years for pediatric conditions.⁵

So how do early access programs outside the US—namely the UK’s Early Access to Medicines Scheme (EAMS)⁶ and France’s Autorisation Temporaire d’Utilisation (ATU, Temporary Use Authorization)—compare? These schemes, for the most part, operate differently than the early access programs in US; however, they have the same objective: granting faster access to innovative new treatments for patients suffering from diseases with high unmet needs.

Launched in 2014, the UK’s EAMS allows doctors to prescribe unlicensed, potentially life-saving treatments while final clinical trials are underway and until the marketing authorization (MA) is granted. To be eligible for early prescribing, the product must earn a positive scientific opinion (SO), though the process is relatively swift: an interim disclosure of a positive SO is possible by day 45 of the dossier submission, and the decision can be adopted by the National Health Service (NHS) within 75–90 days. Approximately 500 patients have benefitted from 8 SOs granted since inception.⁷ While EAMS is, in some ways, comparable to the accelerated approval pathway in the US, it differs in that EAMS-approved medicines are not paid for by the NHS, requiring manufacturers to bear the costs until MA. On the upside, EAMS approval may bring downstream benefits such as accelerated regulatory and Health Technology Assessment (HTA) approval. Nevertheless, because the scheme is unfunded, larger manufacturers have an advantage over smaller companies, which may harm the stated goal of promoting unfettered innovation. Accelerated access in the UK may be changing quickly, however—the UK government is currently engaged in a comprehensive systemic review of 3 key areas for reform: regulation, reimbursement, and uptake.⁸ This review, the Accelerated Access Review (AAR), will produce a report in September 2016 that aims to create a consolidated pathway for accelerating patients’ access to innovative medicines, devices, and diagnostics.

In France, the ATU scheme is administered by l’agence nationale de sécurité du medicament et des produits de santé (ANSM). Unlike the EAMS, the ATU pays for new products (typically 10–12 months prior to MA and until 7 months after MA) that treat rare or severe diseases lacking alternative therapeutic options in France. In this sense, the ATU process is also somewhat similar to the accelerated approval pathway in the US. There are 2 types of ATU: a “nominative” ATU scheme⁹ intended for an individual named patient; and a “cohort” ATU scheme¹⁰ which targets a specific group of patients. Manufacturers are able to freely price their products when applying for the ATU; however, there is a provision to clawback any difference between the set price and the price approved by the Comité Economique des Produits de Santé (CEPS) during the HTA process. The ATU scheme has thus far been a success; it has significantly decreased the time to access medicines for patients.¹¹ However, the scheme is currently under heightened scrutiny given the increased pressure on healthcare resources from free-pricing of medicines.

Clearly there is substantial interest in accelerated access, and, based on the programs available in the US, UK, and France, there are benefits to patient populations with high unmet need in having a drug approved early. Nevertheless, with the ever-changing nature of access barriers, it is critical to understand the requirements that may offer more rapid access to therapies.

The article should be referenced as follows: 

Clark R, Agashe V, Arvin-Berod C. Rapid Access in the US, UK, and France: How Do the US Expedited Programs for Serious Conditions Compare to EAMS and the ATU? HTA Quarterly. Fall 2016. October 13, 2016.

Sources:

1. FDA Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
2. FDA Guidance for Industry: Tropical Disease Priority Review Vouchers.
3. FDA Guidance for Industry: Rare Pediatric Disease Priority Review Vouchers.
4. https://www.govtrack.us/congress/bills/114/s2512
5. https://faculty.fuqua.duke.edu/~dbr1/voucher/
6. EAMS – Operational Guidance
7. EAMS – Independent Review by PwC
8. AAR Interim Report, October 2015
9. Article 5—Directive 2001/83/CE
10. Article 83—Regulation no. 276/2004/CE
11. Degrassat-Théas A, Paubel P, Parent de Curzon O, Le Pen C, Sinègre M. Temporary authorization for use: does the French patient access programme for unlicensed medicines impact market access after formal licensing? Pharmacoeconomics. 2013;31(4):335-343.