Regarding the FDA warning letter to Mylan

Dear Members of our Food Allergy Community,

The media is reporting on an FDA warning letter issued to Meridian Medical Technologies (a Pfizer Company), the manufacturer of EpiPens (both Mylan-branded and ‘Mylan-authorized’ generic devices). The letter cites deficiencies in good manufacturing process requirements and inadequate investigation of patient-reported problems with some devices.

This is all over the news and many of the headlines seem pretty scary. Mylan is waiting for the manufacturer to release a full statement but recently released their own.

We have been in contact with the Mylan. As of 9/8/17, they tell us that the FDA letter is a follow up to the inspection that resulted in the recall in March and solely regarding issues with the lines already recalled. In their statement they say, “Mylan is confident in the safety and efficacy of the EpiPen® products being produced at the site.”

The FDA has also stated that they are ‘not aware of defective EpiPens currently on the market.’ Details of the patient complaints have not been released, but it’s worth bearing in mind that the patient complaints reported may not be due solely to malfunctioning of the device, but also likely include human error.

We are currently advising families as follows:

1. Confirm that you don’t have a device that was previously recalled (http://www.mylan.com/en/epipenrecall)

2. Get comfortable with the auto-injector device that you have been prescribed and know how to use it. Practice with a trainer and, especially with the younger children, hold them in a way that while administering the auto-injector they can’t grab the device or pull away.

3. Also remember that having 2 available auto-injectors can be reassuring as in the event that the first was not administered or malfunctioned, then there is the second available.

4. If you want a substitution or feel any lack confidence or trust, the available options are Auvi-Q or Adrenaclick, which we are happy to call in for you.

Response to recent news about oral immunotherapy

We have received several recent inquiries about the follow up study on Dr. Mimi Tang’s peanut oral immunotherapy with probiotics trial (PPOIT), first published in 2014 (https://tinyurl.com/y83eg5an). This seems like a good opportunity to review with all of you, our patient community, where we think things stand regarding interventions for people with food allergies.

Immunotherapy Background
The first attempts to apply immunotherapy for the treatment of allergy are as old as the application of vaccinations to infectious disease, reaching back more than a century. As applied to allergy, immunotherapy refers to an intervention, for those with established allergy, designed to induce a new immune response to the targeted allergen that protects from subsequent reactions. At this point, there have been dozens of studies of immunotherapy to treat food allergy, most by giving initially tiny and gradually increasing doses of the allergen every day for many months. Most have been small single-center trials, including two here at MGH, but the field has slowly matured to the point that there are now two multi-center industry-sponsored phase 3 clinical trials of immunotherapy for peanut allergy as well as a multi-center phase 2 trial for milk allergy. FDA approval appears to be likely for these treatments of peanut allergy as soon as 2018. In parallel to the progress in clinical trials, though despite current recommendations by professional societies and the NIH, more and more practitioners, including allergists, are offering oral immunotherapy in clinical practice.

Immunotherapy Outcomes
There is more than one way to think about success in the context of immunotherapy treatment. Most patients and parents are less interested in being able to eat the food they are allergic to ad lib (remission) as they are in reducing the risk of a serious accidental reaction (protection) — though that can vary depending upon the food allergen (e.g., milk versus peanut). What the numerous studies have shown is that most individuals can tolerate the therapy, but will only achieve short lived protection. For these patients (roughly 75 percent), they must regularly eat the allergen (the usual recommendation is daily) to maintain protection. It is more challenging to study remission, as it is difficult to define in a time-limited study. Even protection that lasts over a few weeks or months of post treatment avoidance — the longest typically looked at in a research design — might eventually wane. Research shows that only about one quarter to one third of patients will achieve the desired outcome of a more durable benefit.

The PPOIT Study
In Dr. Tang’s study, 56 patients who had been evenly divided between receiving either placebo or a combination of peanut OIT with probiotics were contacted about 4 years after completing the initial trial. The goal was to see how many were still eating peanut. Of the original 56, 48 individuals participated in this follow up, and of those, 16 of the 24 who received active treatment were eating peanut. Only 1 of the 24 who received placebo treatment was eating peanut. To get a sense of how stable their tolerance is (protection versus remission), the 16 individuals eating peanut were invited to once again strictly avoid peanut for 8 weeks and then undergo a food challenge test. Of the 12 who agreed, 7 could fully tolerate peanut after the 8 weeks of avoidance. Research is voluntary, of course, and people can have all sorts of reasons for not participating. However, the most rigorous and appropriate way to evaluate the results of a clinical trial is a sort of worst-case scenario called intention-to-treat analysis (https://tinyurl.com/jqtxzo9). Because a very important reason people may not participate is that they did not do well, this analysis assumes that when the data are missing, the treatment failed. By this conservative approach to analysis, the results of the PPOIT study are essentially the same as we have seen from other OIT studies generally: 16 out of 28 participants (~60%) achieved protection and 7 of 28 (25%) achieved remission. Even if we assumed the most generous assessment, that 16 out of 24 (66%) achieve at least temporary protection, this is hardly what we would consider a ‘cure’, despite numerous headlines (e.g., https://tinyurl.com/ycgbfp3t).

Another way to evaluate the efficacy of this trial is to ask whether allergic reactions were prevented. In PPOIT, the results were that for over the more than 4-year follow-up period, 4 patients treated with PPOIT experienced 11 reactions and 6 patients treated with placebo experienced 9 reactions.

Importantly, this study did not include a treatment arm of peanut oral immunotherapy alone, without the addition of probiotics, which unfortunately leaves us unable to say whether the additional probiotics had any impact on outcomes.

Immunotherapy Hype
Most of my colleagues from around the country and I believe that oral immunotherapy is and will be helpful for many individuals, but we also worry that through the lens of sharing stories on social media and by way of often over-exuberant news media, this therapy enjoys an undeserved shine. There are many reasons for us to want to treat OIT as more than it is. We each have a natural bias toward positive stories, and there is much over diagnosis of food allergy —and subsequent “curing”—among people who are not truly allergic. Those of us who see patients with allergies also worry that many people overestimate the risk and burden of managing food allergies by avoidance, while at the same time underestimating the risk and burden of receiving oral immunotherapy treatment. It is inherently difficult to make a choice that feels passive and wait for more definitive answers when we want to be pro-active. An active treatment like immunotherapy satisfies that desire.

Immunotherapy at MGH
Since the Food Allergy Center was established at MGH in 2010, we have supported the current recommendations regarding immunotherapy. Specifically, that more research was needed before immunotherapy should be regarded as a justifiable option for use in every day clinical practice. Now, in 2017, the paradigm is shifting, the use of immunotherapy is supported by more evidence and we believe that outpatient practice is a more justifiable option for patient management. Despite the reservations articulated above, and as more studies have demonstrated at least limited efficacy, we recognize that patients and their families can, should and are weighing the benefits and risks of OIT and deciding for themselves.

Though we anticipate FDA-approved options for the treatment of peanut in the next 1-2 years, we acknowledge that it will take many more years for approval of each major allergen treatment and that many patients have multiple allergies. Furthermore, the willingness on the part of many insurers to now cover this service has lowered financial barriers for our patients and families. Given our extensive experience in conducting oral immunotherapy trials since 2010, we believe that the FAC@MGH is in a strong position to offer this therapy safely, supported by rigorous pretreatment diagnosis and appropriate education about the benefits risks and burdens associated with this treatment modality.

If you would like to join that discussion to offer your perspective, we invite you to do so by emailing us at foodallergy@mgh.harvard.edu. Please follow us here for updates on our plans to offer immunotherapy and educational programs around it in the coming months.

Mylan recall advice from our nurses

One of our nurses (Rose) did some homework to find out how to obtain replacement injectors due to the recent recall. Please see below:

Parents are being asked to call Stericycle to receive a code number which can then be brought to the pharmacy to exchange their Epipens.
However, one of our patients said the Stericycle phone number is automated and the wait time is impossible. (I called it myself and she is right.  I could not get through)  and another one of our parents went to the pharmacy and the pharmacist did not know what to do for her.
I then called the Mylan Customer Relations line to see what the wait time would be, identified myself as a nurse from MGH, and was immediately connected to Zach, a rep there.  I hope parents will be connected directly the way I was.  Zach said parents need to provide the following to Stericycle, the company managing the recall:
Their name
Child’s name
Address
Ph #
Email
Lot# and NDC number.
Stericycle will take this info, provide an email voucher with instructions on how to return to product for an exchange.  Mylan wants the product returned so they can check the devices. I was assured by the rep that we have had no issues in the US.  Parents are anxious about the turnaround time, given that the school nurses are calling everybody with recalled Epipens.
Rose

 

CoFAR 3.0

This past Thursday and Friday, Drs. Sarita Patil, Yamini Virkud, Perdita Permaul and I represented our Food Allergy Center at the first steering committee meeting for the third iteration of the NIAID-sponsored Consortium for Food Allergy Research (CoFAR) that formally began March 1, 2017.

This is the first time that a Boston center has been part of CoFAR and it comes about as a result of our successful application  to a call for responses from individual medical centers made by NIAID last year. The other six centers around the country are Johns Hopkins, UNC, Mount Sinai, Stanford, Univ of Arkansas, and National Jewish. All of the centers except MGH/Partners and Stanford have been part of CoFAR in the first two rounds.

The NIH, almost entirely through NIAID, funds more than 30 million per year in food allergy research and much more additional basic research on mechanisms of the allergic immune response that may ultimately provide insight into food allergies.

This is not enough, for sure, and other forms of support are also critical — particularly for those higher risk sorts of projects that may lack the preliminary data or challenge existing dogma and often do not fare as well with peer review. However, it is the single greatest source of funding for food allergy research as it is for so many areas of health research.

We are proud to be joining CoFAR and extremely grateful to the US public for supporting NIH and other publically funded research.