On May 28, 2015, the FDA approved sirolimus for use in patients with lymphangioleiomyomatosis (LAM), a destructive lung disease that preferentially affects young women, based on a single randomized controlled RDCRN study conducted by the Rare Lung Diseases Consortium (RLDC). The trial, called ‘MILES’ for Multicenter International LAM Efficacy of Sirolimus, was investigator-initiated and sponsored, and although an IND was obtained at the outset (in 2005), there was no intent to pursue an FDA indication for the drug until the results of the study became available in December 2010. The path to approval was somewhat unique, and recounting it may prove useful to other rare disease communities seeking FDA review of their drug.

The MILES study team obtained an IND (Sponsor-FXM) for MILES in December 2005, with permission from Pfizer to cross reference the sirolimus Masterfile (held by Pfizer). Approximately $8 million in funding was received through the 5 year course of the trial from NCATS, the FDA, the Japanese and Canadian governments, the LAM Foundation and the Tuberous Sclerosis Alliance, Cincinnati Children’s Hospital and University of Cincinnati. Pfizer provided study drug and $200,000, but did not play a role in the design or execution of the study. Thirteen sites enrolled participants, including 10 in the U.S., 2 in Japan and 1 in Canada, between December 2007 and August 2009. A new diagnostic biomarker, called serum VEGF-D, was developed during the course of the trial, which obviated the eligibility requirement for biopsy and boosted enrollment from 75 to 89 subjects in the last 6 six months of the study. The last study visit occurred in August 2010 and the final data analysis became available December 1, 2010. Sirolimus was shown to stabilize lung function and improve some measures of functional performance and quality of life. The conclusion of the study that sirolimus is an effective therapy for LAM was published in The New England Journal of Medicine in April 2011.

About the same time, we contacted Pfizer to ask if they would consider pursuing an FDA indication for LAM based on the positive MILES trial result. After about three months of internal deliberations, Pfizer replied in June 2011 that they would not approach the FDA about changing the sirolimus label, in part because the product was already commercially available and the resource demand of a submission would be significant against a limited market potential and expiring patent for sirolimus. We decided instead to file a Citizen’s Petition – an attempt to compel government to change the approved product label in the absence of an application from the manufacturer. Pfizer was fully in favor of this initiative, presumably because if the FDA was receptive, the path to approval could be sufficiently less resource-intensive and potentially attractive to the company.

We contacted the FDA about this approach. After reviewing the matter, based on optimism from the MILES trial publication that sirolimus might be approvable for LAM by a more conventional approach, the FDA decided that the most efficient path would be for Pfizer to submit an application, rather than relying on the Citizen Petition procedure. The FDA then took the initiative to call and actively encourage Pfizer to apply for an indication in May 2012. Shortly thereafter, a meeting between RLDC, the LAM Foundation, and Pfizer occurred at the Pulmonary and Allergy Branch of the FDA. The FDA agreed to an atypical regulatory filing pathway in which the MILES data sets would be directly submitted to the IND application that we had submitted for the MILES Trial, and Pfizer would be permitted to cross-reference the data. Under these conditions, Pfizer agreed to pursue an indication for sirolimus in LAM. An Orphan Drug Designation for sirolimus in LAM (granted October 31, 2012) was filed by the LAM Foundation and then transferred to Pfizer to provide for the waiver of a large filing fee (~ $1 million) that is typically required of companies.

Upon initial review of the MILES datasets, the FDA expressed optimism that MILES might well be sufficient to support approval. The randomized and double-blind trial design, rigorously maintained by the Data Management and Coordinating Center of the RDCRN program and MILES coordinators despite the complexities of central drug level monitoring and dose adjustments, helped to make the case for efficacy. The FDA further offered that an Advisory Committee, extensive post marketing studies, additional audits, or an Integrated Safety Summary would not likely be required, as long as the FDA review of the full datasets confirmed the summary results. The FDA granted Breakthrough Therapy Designation for sirolimus for the treatment of LAM on December 12, 2014 to both the MILES Sponsor (FXM) and to Pfizer, providing the means to accelerate the review process. The FDA reviewed 3 dataset submissions, made requests for refinements, and then gave the green light to submit the application. The Cincinnati MILES team, the RDCRN’s Data Management and Coordinating Center in Florida and several people at Pfizer worked for two years on the 2,562 page MILES Clinical Study Report (CSR) that was required for filing. The final MILES datasets, the CSR and the supplemental New Drug Application (sNDA) were submitted to the FDA on December 24, 2014. Less than six months later, with little activity and few queries, the FDA granted approval.

To summarize what we learned about the process for obtaining approval for a drug for a rare disease: 1) Designing and executing the trial in the most rigorous fashion possible, engaging patient advocates and pharma early, and filing an IND were critical to success; 2)We found the FDA to be a helpful and welcoming partner from the outset. In rare diseases where biological plausibility of the drug and target are high, the FDA is prepared to make a ruling on the basis of a single trial, if the data support it. The FDA proactively encouraged Pfizer to seek an indication, pressured us to complete the CSR and sNDA filing as quickly as possible, and guided us through the shortest regulatory path possible; 3) Having skilled legal advisors who are knowledgeable about the FDA is key; 4) The patient voice at the table in the form of the LAM Foundation was clearly impactful at the FDA meeting; 5) The special processes available for rare diseases at the FDA worked to our advantage. Orphan Drug Designation reduced filing fees and provided for extended exclusivity that enhanced the attractiveness of approval for pharma, and Breakthrough Designation accelerated the approval process and provided access to FDA resources for trial design. In his 2016 NIH Rare Lung Disease Day address, Dr. Francis Collins cited the path to an FDA-approved therapy for LAM as an exemplar of success in rare disease (https://videocast.nih.gov/summary.asp?Live=17929&bhcp).

Was obtaining FDA approval ‘worth it’? Sirolimus is the first drug approved for the treatment of LAM, now used by approximately 40% of LAM patients in the U.S. (based on a recent LAM Foundation poll), and one of only a very few drugs approved for a diffuse parenchymal lung disease. FDA approval is the ultimate endorsement that the ratio of benefit to risk of a therapy is favorable, and physicians are now prescribing the drug with greater confidence. Insurers are more inclined to provide coverage without a struggle. And finally, the FDA ruling has facilitated approvals in other countries where patients have had difficulty obtaining the drug. To date, sirolimus has been approved by the governments of the U.S., Japan, Russia and South Korea, and is under consideration in the European Union, Australia and Brazil.

We hope to conduct another MILES-like trial for LAM called ‘MILED’, Multicenter Interventional LAM Early Disease Trial. The objective of the new randomized controlled trial (RCT) will be to determine if early, low dose sirolimus can prevent progression to more advanced disease in asymptomatic LAM patients with normal function.

by Francis X. McCormack, MD and Bruce Trapnell, MD
Fall 2016

June 05, 2016