The voice of the patient has a role in the drug development AND approval process. In fact, recent legislation mandates an increased emphasis on incorporating the patient perspective into the regulatory process.

Currently, there are no treatments that the FDA has approved specifically for bronchiectasis. On January 11^th, 2018 the FDA convened a meeting of the Antimicrobial Drugs Advisory Committee to review the potential new treatment, Linhaliq, made by Aradigm, and make a recommendation to the FDA on whether or not to approve it for the treatment of non-cystic fibrosis bronchiectasis (NCFBE) patients with Pseudomonas aeruginosa lung infections. Linhaliq is an inhaled version of ciprofloxacin that has undergone several clinical trials to evaluate if it extends the time to the first exacerbation compared to a placebo treatment.

This was the second recent Advisory Committee meeting for a potential bronchiectasis therapy coming after a November meeting where the Committee reviewed and did not recommend another version of ciprofloxacin made by Bayer. The discussion and vote at the Linhaliq meeting were based on a specific and narrowly defined question about whether Aradigm had met the standards of safety and efficacy for the drug’s intended outcome, which was time to first exacerbation. Like the Bayer meeting, the committee voted that Aradigm had not met those standards, however the Advisory Committee only provides recommendations for the FDA to consider. The FDA then makes the final decision. However, an approval after a negative committee vote is very rare.

In this case, the process and the discussions that occurred at the meetings do not adequately reflect the needs, priorities and preferences of the patient community. We are asking you to take the time to read the below background information and use the bullet point template as a guide to share your perspective with the FDA as they enter this critical period of determining whether to approve the applications for inhaled ciprofloxacin.

What were the core issues at the Antimicrobial Advisory Committee Meeting?

• The primary outcome that the FDA and the pharmaceutical companies used was time to first exacerbation which measured whether there was more time until the patient taking the treatment had an exacerbation as compared to those taking the placebo.
• Time to first exacerbation is not felt to be the most appropriate outcome to use for the bronchiectasis population as it may not adequately reflect whether patients truly do better and feel better on the new treatment. The Advisory Committee even acknowledged this during their discussion.
• The Committee, the FDA, the pharmaceutical companies, clinicians and patients have acknowledged that frequency of exacerbations is the better outcome measure.
• The companies also collected data on whether the treatment lowered the frequency of exacerbations, however the Advisory Committee was not allowed to consider this data when deciding whether to recommend approval of the treatment because of the design of the trial and related regulatory review.
• During the discussion, the Committee members placed a heavy emphasis on potential antibiotic resistance risk and some suggested that studies should be as long as 10 years in order to determine if the treatment effect is reduced over time which disregards the urgent nature of preventing even one more exacerbation and the need to lower existing systemic antibiotic use.
• Most of the Committee members expressed a desire to recommend approval for the drug if they were voting on whether it met the evidence for the frequency of exacerbation, or if they were voting to approve it for use in those with frequent exacerbations, and suggested that if a different question had been posed, they would have voted differently.
• Here is some of what you told us in the survey:

• We asked you to rank different outcomes to better understand how important they are to the community. Overall lung function received the highest ranking, followed closely by the number of exacerbations each year. The overall amount of oral and IV antibiotics used ranked third.
• You ranked the time in between each exacerbation last in the survey of 287 patients. The outcome used in the Linhaliq trial was extending the time until the first exacerbation after the treatment started. This was the closest outcome we could list to the Linhaliq trial, since it only applies to starting a new treatment.
• Many of you reported having enormous systemic antibiotic use and multiple exacerbations per year with side effects of great concern.  Individuals reported a wide variety of antibiotics used during exacerbations.
• About a quarter of respondents said they use another type of inhaled antibiotics that are not approved specifically for bronchiectasis, but many also said the available treatments were not options for them.

What it means for you:

If the FDA decides not to approve either of the recent treatments that the Committee reviewed, the companies will need to decide whether or not to try again after collecting more data or working to resolve whatever issues raised in the FDA response letters to the companies.

The Committee process uncovered several important areas where the patient voice is needed. First, we must emphasize to the FDA that an outcome of time to first exacerbation doesn't reflect the priorities of the patients. The way patients feel is directly related to their overall lung function which is highly related to the number of exacerbations each year and the presence of pseudomonas, among other issues.

Second, we must show the FDA that there is urgent unmet need and that the patient community is just as, if not more, concerned about the side effects of the massive amounts of systemic antibiotics used currently. Suggesting that long term studies should be done prior to approving a treatment, just to identify potential waning treatment effect, shows that the committee doesn't understand the urgent implications of each exacerbation and the cumulative effects of current systemic antibiotic use, something of great concern to patients.

Finally, we must show the FDA that there is an empowered and engaged patient community that stands ready to partner with the FDA and with the companies willing to invest and study treatments to meet the needs of rare disease communities.

Ready to write a letter to the FDA? The FDA will review the Aradigm application for Linhaliq (inhaled ciprofloxacin) in the next few days. We've provided some key points to incorporate below, and you can click here for some tips to think about when writing. If you would like any assistance or would like to pass your draft by us, please email Bronchiectasiscomments@copdfoundation.org and a member of the NTMir or COPD Foundation team will get back to you within 24 hours. After you have written your letter, you can email it to the FDA using the instructions below.

• Identify yourself (are you a patient or caregiver plus any details that may be relevant like age range and/or whether you are retired vs still in the workforce).
• Indicate if you specifically have bronchiectasis with the presence of Pseudomonas aeruginosa and other diagnoses.
• Indicate if you participated in the clinical trials for either potential bronchiectasis treatment or whether you have any kind of relationship with the sponsor companies.
• Explain that you are concerned about the lack of patient focus in the recent Advisory Committee decisions on treatments specifically for non-cystic fibrosis bronchiectasis.
• Focus on your experience with bronchiectasis, pseudomonas and NTM, when you were diagnosed, and how the symptoms impact daily living.
• If you have used large amounts of systemic (oral/iv) antibiotics in order to treat your bronchiectasis and related infections, describe this in the letter and explain why you are concerned. Have you had side effects of antibiotic use that could be minimized if you were taking inhaled antibiotics?
• Talk about how you manage your disease now and what burden the treatments place on you.
• Use numbers/data as much as possible.  For example, how often you have exacerbations, hospitalizations or other disease impacts like use of IV antibiotics.
• Describe what outcomes matter most to you. Why do issues like overall lung function and the number of exacerbations you have each year matter to you. Does having frequent exacerbations impact your lung function overall and when your lung function goes down, how does that impact your life?
• Describe how reducing the number of exacerbations you have each year would impact your life.
• If you have participated in a study of inhaled ciprofloxacin, describe the impact you experienced when on the drug.
• Remember, you are the expert on YOUR EXPERIENCE with the condition and its treatment- there are no right or wrong statements.

The review deadline set by the FDA is January 26th. We do not know at this time whether the date will be extended, so please send your letter as soon as possible.

How to send your letter

1. Address the letter to:

   Dr. Sumathi Nambiar

   Director, Division of Anti-Infective Products

   U.S. Food and Drug Administration

   10903 New Hampshire Ave. Bldg. W022, Rm. 6236

   Silver Spring, MD 20993

   2. Send your letter as an attachment via email to the following:

   a.  Sumathi.Nambiar@fda.hhs.gov 

   3. In the CC field of your email enter the following addresses

   a. CommissionerFDA@fda.hhs.gov 

   b. Janet.Woodcock@fda.hhs.gov

   c. Edward.Cox@fda.hhs.gov

   d. John.Farley@fda.hhs.gov

   e. Badrul.Chowdhury@fda.hhs.gov

   f. Lydia.GilbertMcClain@fda.hhs.gov 

    4. In the body of your email you can write a simple note like the following: 

   Dear Dr. Nambiar,

   As a patient with bronchiectasis I respectfully submit the attached letter for your consideration. I would be happy to discuss my concerns with you and appreciate your time in thoroughly considering the patient perspective in your decision making.

   Regards,

   XXXX