Varuna Srinivasan, National Center for Health Research: August 7, 2018
Thank you for the opportunity to speak today. My name is Dr. Varuna Srinivasan. I am a physician with a Master’s in Public Health from Johns Hopkins University. I am a Senior Fellow at the National Center for Health Research, which analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.
I have strong concerns about the safety and efficacy of the drug in question today – Amikacin liposome inhalation suspension (ALIS), a product sponsored by pharmaceutical company Insmed Inc. for use in patients with nontubercuolous mycobacterial (NTM) lung disease. I will briefly describe those concerns.
#1: There are several problems with the clinical trials and the sponsors’ emphasis on culture conversion. In one of their key clinical studies, patients are excluded from the study after 6 months if they do not convert to a negative culture. They are then given the option to re-enroll into a secondary study. The drug takes quite a while to be effective, and 6 months is too short to accurately test the relapse and recurrence rates of MAC in these patients. Both relapse and recurrence are more likely to occur after 6 months than within 6 months.
In addition, the pivotal trial is an open label study without a placebo control. Even the primary endpoint could be affected by the knowledge that one is taking a new drug. The secondary endpoint, the 6-minute walk test, can be dramatically affected by motivation in an open label trial. If a patient knows they are taking a new drug, they may be more motivated to see how well it is working, and thus not give up as easily. This knowledge and the act of taking the drug or the placebo could affect adverse event reporting.
#2: None of the endpoints provides useful information about how the drug affects patients’ lives. A MAC infection causes severe respiratory problems, but the endpoints do not measure clinical symptoms but they should.
#3. The studies also lacked diversity. Almost all the patients were white. Very few were Black Asian or Hispanic. Very few were over 65.
In other words, many of the patients who would be interested in treatment for MAC would have no information about safety or effectiveness of ALIS for patients like themselves.
In addition to demographic differences, the safety and efficacy of ALIS may be affected by the patients’ underlying conditions. ALIS may interact with other drugs that the patients in these studies might be taking. Unfortunately, the sponsor did not report whether the patients were taking other drugs.
#4. ALIS also has several side effects. Systemic side effects such as nausea, diarrhea, tinnitus and vomiting were present even though patients were taking an inhaled form of Amikacin. That makes us concerned about the safety of ALIS and the long-term side effects. No information is provided about drug interactions for these patients, and there is a worrisome lack of information about the patient profiles and the individual diseases they suffer from.
In all of these studies, patients have respiratory symptoms, that in some cases seem to be getting worse rather than better with ALIS.
The bottom line: Patients need treatments that are safe and effective. ALIS may be safe and effective for a specific patient population, but the sponsors are yet to identify that population. If there is a specific population for whom the benefits of ALIS outweigh the risks, that population needs to be part of the indication before the FDA should approve this drug.
The US FDA’s Antimicrobial Drugs Advisory Committee voted 12-2 against the pharmaceutical company, Insmed Inc. request for accelerated approval in adults with NTM caused by MAC without regard to line of treatment. The drug was tested only in refractory patients and did not provide adequate information about indications for use in broader populations. Safety and efficacy of the drug for use in adults with NTM in combination with a multi drug regimen was approved with narrow indications in patients with limited or no treatment. The committee also voted 8-6 to approve the company’s surrogate endpoint of culture conversion as an endpoint to prove clinical benefit in patients. You can find more here