A Baker’s Dozen Of US FDA Efficacy Approvals Using Real World Evidence
Executive Summary
Fresenius Kabi’s Omegaven is most recent of 13 approvals, including three with breakthrough therapy designations, where FDA has relied on real world evidence to make a regulatory decision about efficacy.
The exigencies of ultra-orphan drug development have provided the early testing ground for the US FDA’s limited use of real-world evidence (RWE) in approval decisions, resulting in 13 approvals identified by the Pink Sheet that relied on external or historical controls to place single-arm efficacy trials in context or derived data from case reports and expanded access protocols.
FDA’s most recent approval using RWE – the July 27, 2018 clearance of Fresenius Kabi AG’s I.V. lipid emulsion Omegaven (fish oil triglycerides) to provide calories and essential fatty acids for pediatric patients with parenteral nutrition-associated cholestasis – is in many ways typical of the agency’s RWE-based approvals to date.
Omegaven addresses a highly specialized niche market and has long been available under an expanded access protocol, making conventional clinical trials a challenge. FDA’s approval history suggests the agency prefers to bring products out of the expanded access/personal importation gray market and into light of the FDA review process, even if the reviewers have to make do with less-than-ideal data. (Also see "Emflaza's 505(b)(2) Pathway Review: Rare, But With Precedent" - Pink Sheet, 31 Mar, 2017.)
RWE Gets Ready For Prime Time
RWE is expected to make the leap from the ultra-orphan ghetto to more widespread use in regulatory decision making as a result of the last Prescription Drug User Fee Act reauthorization, PDUFA VI, which directs FDA to explore the use of RWE in regulatory decision-making. FDA is working towards a draft guidance for drug development by the end of FY2021. To prepare, the agency has embarked upon rounds of demonstration projects, pilots, publications and stakeholder meetings.
A Real-World Primer
The Pink Sheet has covered FDA's emerging thinking on real-world evidence over many years. Below are links to stories with some key highlights.
FDA’s breakthrough therapy designation (BTD) program, which offers greater interaction with the agency during development, has nurtured three novel agents to approval using RWE. In all three cases, single-arm clinical trial data was compared to historical controls.
One of the BTD products, BioMarin Pharmaceutical Inc.’s Brineura (cerliponase alfa) for late infantile neuronal ceroid lipofuscinosis type 2, fits with the ultra-rare disorder profile of most of CDER’s RWE approvals.
Brineura cleared the agency on April 27, 2017 on the basis of a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group). (Also see "BioMarin's Brineura Approval Shows FDA's Open Door For Orphan Drugs" - Pink Sheet, 2 May, 2017.)
The other two BTD approvals using external controls suggest a higher-profile future for RWE. Amgen Inc.’s Blincyto (blinatumomab) and EMD Serono Inc./Pfizer Inc.’s Bavencio (avelumab) both were initially approved for an orphan indication, but neither product is strictly speaking an orphan drug. Both Blincyto and Bavencio are expected to be blockbuster oncologics – and could play an important role in setting the stage for greater acceptance of RWE.
Importantly, FDA’s accelerated approvals of Bavencio for Merkel cell carcinoma and Blincyto in acute lymphoblastic leukemia have been or will be followed by larger conventional confirmatory trials – Phase III trials that could allay some of the concerns about using RWE in regulatory decisions if similar effect sizes are seen. (See sidebar for related story.)
Companies like Roche, which is heavily invested in informatics through Flatiron Health and Foundation Medicine, are already using RWE-generated external controls in reimbursement discussions, with regulatory use expected in the future. (Also see "Roche’s External Control Arms Show What Real-World Evidence Can Look Like In Practice " - Pink Sheet, 14 Jun, 2018.)
FDA’s Historical Experience With RWE
There is “very little historical use of RW experience in drug regulatory decisions about effectiveness,” CDER Director Janet Woodcock told a September 2017 workshop, although RWE is “currently used extensively for evaluation of safety of marketed products.”
Woodcock identified two sets of circumstances where FDA has relied on RWE to determine efficacy: approvals “based on data from registry-like case series” and approvals where “we have used registry data as external controls.”
Woodcock highlighted four examples of orphan drugs approved with RWE:
- Genzyme Corp.’s alglucosidase alfa for Pompe Disease, approved as Lumizyme in 2010 with reference to survival data from an international registry of infantile-onset disease
Genzyme’s BLA for Lumizyme, or algucosidase alfa manufactured at greater scale than the company’s earlier Myozyme, relied on a placebo-controlled trial, LOTS, in late-onset Pompe disease, supported by clinical outcomes data in infantile-onset patients from the Pompe Registry, which was set up as a post-marketing commitment for the 2006 Myozyme approval. The registry data showed increased survival at 18 months in Lumizyme patients compared with age- and disease-matched historical controls, according to Division of Gastroenterology Products Director Donna Griebel’s summary review. The Myozyme approval also relied on a comparison to a 61-patient historical control group, she observed.
- Recordati Industria Chimica & Farmaceutica SPA/Orphan Europe’s Carbaglu (carglumic acid) for hyperammonemia due to NAGS deficiency, approved in 2010 based on plasma level ammonia reductions in a case series
Carbaglu is indicated to treat hyperammonemia due to NAGS deficiency, an extremely rare disorder with only 50 known cases worldwide, Griebel noted in her summary review. “Retrospective case series summary data submitted in this NDA and the data from 3 patients with NAGS deficiency treated in a prospective trial that investigated the impact of Carbaglu on restoration of ureagenesis provide substantial evidence of efficacy,” she said. The retrospective case series included 23 patients, but only 13 had complete plasma ammonia level data available. Nonetheless, the data established that Carbaglu “was associated with reduction in ammonia levels,” Griebel said. “These data are limited in both quality and quantity, but normalization of plasma ammonia levels would not be expected long-term in untreated patients with NAGS deficiency. Therefore, when compared to natural history data, the effect of Carbaglu appears to be clinically significant.”
- Asklepion Pharmaceuticals LLC’s Cholbam (cholic acid) for bile acid synthesis disorders, approved in 2015 based on data on growth, survival and reduction in abnormal cholestatic markers in a case series
Cholbam was studied under a treatment IND opened in 1992 at Cincinnati Children’s Hospital Medical Center (CCHMC). After Asklepion came on board in 2007, the company retrospectively devised a case report form from chart review of patients in the open-label, single-arm Expanded Access Protocol, review team leader Lara Dimick-Santos reported. The company also conducted a retrospective literature review to construct a historical control, she said.
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BTG PLC’s Voraxaze (glucarpidase) for methotrexate toxicity, which was approved based on data from 22 patients from NIH treatment protocol. The size of the efficacy data set was “less than optimal,” Division of Oncology Products 2 Director Patricia Keegan commented in her summary review, but a larger study was precluded by “the low incidence of the condition and inability to prospectively identify patients at high risk for this condition.” However, “given the extensive data, based on more than 40 years of clinical trials, the methotrexate excretion curves are well-characterized and can be used as an historical control against which the results of this trial can be assessed for efficacy,” she said.
Historical Controls Often Key
Historical controls were also key to the approvals of Wellstat Therapeutics Corp.’s Vistogard (uridine triacetate), approved in 2015 for overdose of 5-FU chemotherapy, and Fresenius Kabi’s recently approved IV lipid emulsion Omegaven.
Vistogard was approved in 2015 on the basis of data from 135 patients in two single-arm, open-access studies. The control arm, Division Director Geoff Kim pointed out in his summary review, was formed by “the collective experience of 25 patients reported in literature to have a documented overdose of fluorouracil and supported by an extensive review of submitted safety reports to the agency concerning fluorouracil overdoses.”
The Omegaven NDA for pediatric PNAC patients rests on two open-label studies with 82 infants who received Omegaven and 41 pair-matched historical control patients who received soybean oil-based IVLE. (Also see "Keeping Track: Shionogi, Fresenius Kabi Join July Approval Parade; Busy August Expected" - Pink Sheet, 5 Aug, 2018.)
The Pink Sheet also identified another product approved on the basis of case reports: Provepharm SAS' ProVay Blue (methylene blue), approved for acquired methemoglobinemia in 2016.
The ProVay Blue NDA was based on retrospective case reports found in a multicenter chart review along with cases found in literature search. Like many of the orphan products approved with RWE, ProVay Blue used the 505(b)(2) NDA pathway, which allows for data not developed by the sponsor to be incorporated in the application.
Mining Available Protocols
Data collected under a treatment IND or expanded access protocol can be considered a form of RWE. In rare disease settings where there is little chance of a prospective trial, FDA has at times relied on such data without a formal historical comparator.
FDA Office of Medical Policy Director Jonathan Jarow mentioned the non-traditional NDA Aegerion Pharmaceuticals Inc.’s Myalept (metreleptin), which was approved in 2014 for lipodystrophy on the basis of open-label, single-arm studies, during an RWE workshop presentation.
Myalept, which moved between a number of corporate sponsors, was largely developed under investigator INDs. The efficacy determination in the BLA rested on data from 72 patients in an NIH protocol and 28 treated under a treatment IND.
The Myalept BLA did not, however, use a historical control. Efficacy analysis focused on changes from baseline in metabolic parameters. However, clinical reviewer Julie Golden observed that the lack of a placebo or historical comparator made it “challenging to interpret some of these findings and accurately estimate the treatment effect.”
Expanded access protocol data was key also to FDA’s approval of Advanced Accelerator Applications SA’s radiopharmaceutical Lutathera for GEP-NET, enabling a broader indication than the trial submitted in the NDA could support. (Also see "Lutathera’s Broad Tumor Indication Aided By Expanded Access Data" - Pink Sheet, 18 May, 2018.)
Post-marketing registry data was key to an expanded indication for Vertex Pharmaceuticals Inc.’s Kalydeco (ivacaftor), which extended its label from 10 cystic fibrosis mutations to 33 on May 17, 2017. The additional CF mutations were added to the indication based on registry data and mechanistic information from lab studies. (Also see "Kalydeco Expands Indication Without Clinical Data; Keytruda Is Latest Bladder Cancer Approval" - Pink Sheet, 21 May, 2017.)