-Written by Tiffany Westrich Robertson
In August 2017, IFAA attended a meeting at the Food and Drug Administration (FDA) so that we could speak on behalf of those patients who are running out of treatment options and who may benefit from new therapies that target a different mechanism of action. This article is based on that visit. Note: Each country has its’ own regulatory process to evaluate the safety and efficacy of drugs, which includes a similar format to what is described below.
The need for new treatments
Patients living with autoimmune & autoinflammatory types of arthritis are often treated with biological products that are designed to target specific molecules that block the actions of cells, which in turn, helps control the inflammation associated with these diseases . The first biologics were TNF- inhibitors (Tumor Necrosis Factor) but since they came to market other products have been developed that target different molecules, or have “different mechanisms of action”. Examples include B-cell inhibitors, T-cell inhibitors, Interleukin-6 (IL-6) inhibitors, Interleukin-1 (IL-1) inhibitors, Janus kinase (JAK) inhibitors, and phosphodiesterase 4 (PDE4) inhibitors – and more are currently being tested in clinical trials. But why so many and why are the different targets important to patients?
Disease Individuality. While there are several autoimmune and autoinflammatory diseases where arthritis is a component (“autoimmune arthritis”/”autoinflammatory arthritis”), in a handful of these diseases the arthritis is a major clinical feature – and therefore, these diseases are often treated with the same types of treatments. But even within the same disease class, there is no one-size-fits-all solution, because no two patients have the same percentage of genetic predisposition combined with the same environmental triggers. Therefore, patients with the same diagnosis may respond very differently to treatments. Having different mechanisms of action opens up options to patients, particularly to those who are not responding well to one or more commonly prescribed therapies.
Duration of Efficacy. Biologic treatments typically have a lifespan of 2-3 years before efficacy diminishes (in most patients, not all). But this is one reason why more treatments are needed, as some patients who have been using biologics for some time will eventually run out of options. Additionally, between 30 – 40% of patients fail to respond or become intolerant to anti-TNF therapy. When this happens, the strategy is usually to try another TNF inhibitor or switch to a medication with a different mechanism of action [2, 3].
Disease Progression. In these diseases, structural damage is permanent and irreversible. Therefore, finding the right treatment, and mechanism of action, is necessary to avoid additional disease progression and disability.
The regulatory process (U.S. Food and Drug Administration – FDA)
It takes an average of 8-10 years for a biologic to get to market once the drug is developed and tested in the lab. After initial studies are done in animals, a plan is designed to test the product in humans (via clinical trials) and then submitted to a regulatory agency for review and approval to proceed (See Figure 1). In the United States, this is done at the Food and Drug Administration (FDA). At the end of the second phase clinical trials, the FDA and the pharmaceutical company meet to review findings and to determine how the larger “phase three” trial will be done. After some additional written communications between both parties, and if the trials are approved to move forward, the final phase of testing the product on humans will begin. This last phase of trials will help the pharmaceutical company create product safety and efficacy treatment profiles and determine recommended dosage.
When the clinical trials are completed, the pharmaceutical company applies to present their data to the FDA – in what is called an Investigational New Drug (IND) Review (Figure 1 – red circle). In the United States, the information is first presented to an Arthritis Advisory Committee (AAC) , who convenes to review all submitted data and offer their professional opinions regarding safety and efficacy of the proposed drug prior to the final FDA ruling. In August of 2017, IFAA attended one of these Investigational New Drug (IND) Reviews, both to better understand the process and to speak on behalf of patients who need access to new treatments. This following information is a summary of that experience.
Investigational New Drug (IND) Review
IFAA was interested in attending this meeting so that we could speak on behalf of those patients who are running out of treatment options and who may benefit from new therapies that target a different mechanism of action. To do this, we first had to find funding to get to the FDA; once secured, we registered online to reserve a ten minute time slot during the Public Comments segment of the meeting. The particular drug under review was tested to treat Rheumatoid Arthritis (RA), so we then reached out to fellow RA patients to ask why they want – or need – more therapeutic options. Their responses were used to help formulate our presentation.
The meeting began promptly at 8am, with the AAC seated in the center of the room, the pharmaceutical company representatives to their left, and the FDA and media to their right. As a registered speaker, I sat in the audience near the center aisle, so I could easily access the podium when it was my time to speak. After brief introductions of the AAC members, it was time to begin.
The pharmaceutical company presented information about the product, the method of application (injection form with a syringe), and how it was different from – or similar to – other biologics currently on market. Then they proceeded to review each individual clinical trial and the outcomes that were tested. Outcomes included:
- Testing efficacy based on the ACR 20/50/70 – which refers to the American College of Rheumatology rating on disease improvement. 20 = you are 20% improved, 50 = you are 50% improved, 70 = you are 70% improved. The main target in these trials was to achieve an ACR 50.
- Testing the drug in patients “of unmet need”, particularly those who have failed more than one other biologic agent prior to the trial.
- Quality of life measures – specifically how the drug impacted a patient’s daily experience with symptoms, such as fatigue and mental clarity.
The FDA then reviewed issues they felt were of particular importance regarding safety and efficacy. When both parties were finished, the AAC members were invited to ask “clarifying questions”. For each question, the correlating slide that was shown during the presentations was brought back up on the large screen. Once all questions were answered, we broke for lunch.
When the meeting resumed, it was time for Public Comments. At this time IFAA was called to the podium to testify on behalf of RA patients.
Excerpt from our testimony:
“While many patients do have success using existing treatments available, a significant percentage do not. This is especially important given the progressive nature of the disease and the potential for permanent and irreversible damage that can happen if the right treatment is not applied. RA is not a one-size-fits all disease; therefore, what works for one patient may not work for another. Many patients either do not respond initially or stop responding when a treatment loses efficacy over time.
“Over the past years, IFAA has had the opportunity to speak with 100’s of patients who have tried and failed 3, 4, 5, 6 – and, in some cases, who have exhausted or are near to exhausting all treatment options. While they all have unique stories, one similar sentiment unites them: “I’m scared. What if I fail again? What am I going to do?”
“In a patient population where the disease is so varied per individual, access to new mechanisms of action are necessary so a greater percentage of patients can achieve clinical improvements and an acceptable quality of life. The longer patients have to wait for the right mechanism of action that will work best for them, the more irreversible damage and unnecessary disability is possible. This will only lead to higher long term complications and a larger financial burden to our healthcare system.”
The AAC Discussion
Once Public Comments concluded, the AAC began deliberating about efficacy findings, safety findings, and the overall benefit-risk profile of the drug for treatment in patients with RA. Below were specific topics for discussion:
- Discuss the safety findings in the Phase 3 trial.
- Discuss the dose selection for the Phase 3 trial.
- Discuss the design of the placebo-controlled study and consider what optimal study design should be when assessing radiographic progression in rheumatoid arthritis.
- Did the data provide substantial evidence that the drug provides a clinically meaningful benefit in the treatment of rheumatoid arthritis?
- Is the safety profile adequate to support approval in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more disease modifying anti-rheumatic drugs (DMARDs)?
- Do you recommend approval at the proposed dose?
At the end of an intense discussion, the AAC members were asked to vote first on the efficacy of the proposed drug, then on safety. They each had a voting device with two buttons, one for yes and one for no. Once the vote was generated electronically, the results appeared on the screen behind the panel. Then the Moderator asked each AAC member how they voted; at this time, they had the opportunity to disclose their rationale for voting as they did. The committee unanimously agreed that the drug was efficacious in treating RA. However, in the vote on its’ safety profile, there were still too many unanswered questions for the committee to give their full support.
What Happens Next?
While the FDA is not bound by the committee’s recommendation, it does take its advice into consideration. The pharmaceutical company will continue their discussions with the FDA, which will include providing any additional information necessary so a decision regarding the safety of this drug can be established. At that time, if the FDA determines the drug can be released for market, it will become another therapeutic option for treating RA. It is also under review in other countries by their regulatory agencies.
Approving new treatments that are safe and effective for patients who rely on biologic therapies to prevent permanent, irreversible damage is necessary. IFAA is glad to have had this opportunity to speak out on behalf of those who need it most. We will continue following this, and all potential therapeutic options, as they find their way to market.
Did you know YOU can get involved in this process, too?
It’s true! Not only can you attend FDA meetings (FOR FREE) in person, you also have opportunities to submit your comments online – which then become part of the official records used by the FDA to make their final decisions on whether or not a product goes to market.
To get started, subscribe to the ‘new’ FDA patient newsletter. It will notify you when and how you can get more involved, in addition to alerting you about important safety warnings and product approvals.
Make Sure to Submit Your Comments Online When it Matters to YOU! In just a couple of clicks you can tell the FDA why you believe a drug should – or shouldn’t – be considered for market. All you have to do is subscribe to the newsletter and when a public meeting – like the one we told you about in this post – is happening, you have until the day prior to write your comments and submit them for the record. You can even attach photos!
Apply to be a Patient or Caregiver Advisor. In 2017, the FDA created the first advisory committee made up solely of patients and caregivers, who can provide advice on complex issues related to medical devices. They also developed the Patient Representative Program. This program brings patients – and their caregivers – and the extraordinary breadth of knowledge and personal experience in more than 300 diseases and conditions they possess, directly into the regulatory medical product development and review process. They serve on 47 FDA Advisory Committees and panels to advise on drugs, devices and biologics currently being considered for approval or clearance. Learn more.
Patient Focused Drug Development (PFDD). Efforts to further patient engagement at the FDA have expanded, including this major initiative that started in 2012. The PFDD heavily relies on Patient Centered Outcomes Research (PCOR) to provide information about what outcomes are most important for patients.
In September 2017, a meeting for lupus patients is convening and IFAA will be there. If you are a lupus patient (any type) you can register to be there in person (you would have to pay your own expenses) OR PARTICIPATE ONLINE. Patients who participate will have the opportunity to answer questions via live polls and those responses will be used to help the FDA better understand the treatment needs in patients living with lupus. Both options have limited seating, so RSVP now! There was one for Psoriatic Disease in March 2016 (IFAA was there too!) You can view the archives here.
Get Involved Outside of the US
In Europe? Learn more about your regulatory process and how you can get involved as a Patient Advisor: European Medicines Agency (EMA)
In Canada? Learn more about your regulatory process.
Other Locations: You can find a list of all regulatory agencies, by country, HERE. Then search their website to learn more about how you can get involved! (Please let IFAA know if you do this and if/how you get involved!)
IFAA works hard to be patients who are “at the table” – and aim to bring those experiences to you through this blog, Systemically Connected. Thank you for your continued support, which enables us to continue attending conference, events, & meetings that help advance care for our community and enable YOU to get more involved in your own healthcare.
 the next phase to our award-winning project that advances patient involvement in research
 Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther 2012;91:30-43.
 Smolen, JS and Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheum. 2015; 11: 276–289.