The Personalizing Research Project

I had a sort of epiphany on the trip home from the NACFC .  After 5 years as a "normal person" attending this Conference (the vast majority of attendees are: research scientists from academia, biopharma peeps, clinical care team members, investors, and a hundred or so major donors to the CFF), I have built a number of important connections with scientists working on understanding and testing the CFTR protein, or manipulating the gene somehow to correct for mutations.

My Concerns

Currently, the biopharmaceutical industry is holding the reins as the driving force in drug development and innovation for CF.  Of course, the Cystic Fibrosis Foundation carefully selects which projects to invest in, and does an excellent job of promoting competition to drive prices down...eventually.  This is, in no way, a critique of the actions of the CFF. I hope that everyone that reads my blog understands my position on the actions of the Cystic Fibrosis Foundation.  You might even say I am a "superfan."  I have participated in the Strategic Planning Committee for the Foundation, served on the Patient Engagement Advisory Council, worked as the volunteer chair of the Great Strides walk in Spokane for the last 2 years, attended the CFF sponsored NACFC Conference for the last 5 years, and had their "Adding Tomorrows" logo tattooed on my body.  As much as I love what the CFF is doing, they don't possess the power to control big pharma.

I pledge allegiance...

Also, for the record--there is NO DOUBT that partnering with biopharma has resulted in some huge innovations in the treatment of CF.  Note that my only other tattoo is that beautiful Kalydeco molecule on my left foot, reminding me everyday to "Honor the Gift" we have been given with this Vertex developed miracle.

My observation is that we (patients/families) cannot rely on big pharma to put patients before investors, and the CF Foundation has limited power over things such as cost of any successes resulting from their investments (as we have seen painfully with Kalydeco and Orkambi).  I see a number of issues brewing, that could potentially slow down our progress toward better combinations of potentiators and correctors.  Because I know first hand how life-changing these drugs can be...I think that sucks.  I want to do more than line the pockets of executives and investors...we have the power to enhance the lives of patients and get important people considering the patient as a real part of this equation.  

The FDA and Randomized Placebo Trials

Before I launch into this, I want to say that the FDA has been an amazing partner in CF progress.  The passage of the EXPERRT Act in 2012 gave the agency the flexibility it needed to even consider some of the specialized therapies we are bringing their way.  With consideration to Kalydeco and Orkambi, the FDA provided swift, expert review--bringing the drugs to patient hands in the safest, most expedited manner.  When considering expansion of the Kalydeo label to include the R117h mutation, the FDA listened carefully to patient testimonials, and made the right choice to expand access to these patients in the end.  The FDA has been extremely helpful to us, and has shown that it has the potential and desire to evolve. Right now, we are entering some really murky territory with the FDA.  Traditionally, the FDA has required data from large scale, randomized, placebo controlled trials as a means to gain approval for marketing a drug in the U.S.  How would you feel about the following situation? I would sincerely appreciate anyone who would take the time to leave a comment with their thoughts.

Your child has a residual function mutation, and is benefiting from Kalydeco.  A better potentiator is discovered, but enrolling in the clinical trial for this compound would mean a 1/3 possibility of receiving a placebo for up to 20 weeks.  Would you take the chance of going off Kalydeco, and enroll in the trial anyway?

You are an adult with advanced lung disease who has been taking Orkambi for several months.  The initial few weeks were tough, but you are seeing some benefits, as well as some side effects.  Other companies are racing toward clinical trials with alternatives to Orkambi that present with better in vitro CFTR activation, and potentially safer toxicology report.  A few months ago, a hiccup in insurance coverage caused you to miss several days of Orkambi suddenly, and resulted in a serious (and scary) exacerbation.  If you have the chance of getting assigned a placebo, and going back to non-functional CFTR for a portion of this trial...do you enroll?

You are heterozygous, and want to ensure that the most effective potentiators, correctors, and transcriptional read-through agents get approved to treat your specific combination of CF mutaions, but Vertex has the CF community locked down with their combo for heterozygotes--which is furthest along in development, and will reach the market first.  If the majority of eligible patients are accessing this first option that gets to market, who are we going to test better combos on?

Let me stress again that this is not a direct attack on Vertex--they are simply acting like a business. Vertex just happens to be out in the lead of this race to treat/cure CF, and they are playing the game like any other for-profit pharmaceutical company would. Also imporant to note is that I view the research scientists at Vertex in a much different light than I see the executive leadership.  I have completely mixed emotions--reverence mixed with disgust for Vertex--and the situation is anything but black and white. What I am suggesting, rather, is for enriched patient dialog with the FDA, as we may need to change some rules to see our progress take place in a way that encourages innovation.  I want to make sure that the patient is at the center of the business of curing CF, rather than Vertex alone calling the shots.  As I mentioned before, I would appreciate your comments on these important issues.  

In a discussion I attended at the NACFC, I had a bit of a battle with an FDA reviewer. Please take a look through the slides of his presentation, and consider what is at stake here.  I think this is important to be aware of for everyone with CF--whether you are currently taking a CFTR modifier or not.  

This slide clearly mentions the ethical concerns I have been discussing, but the FDA reviewer seemed to play it off as relatively minor.  He did NOT believe that asking patients to come off of Kalydeco or Orkambi to test potentially superior combos would be a formidable problem to trial enrollment...What do you think?

Dr. Durmowicz was asked a question in regard to the ethics of using placebo controlled trials for upcoming CFTR modulators, and pulling patients off of treatments like Kalydeco or Orkambi, that that may exhibit clearly positive benefits, to test potentially better drug combinations.     

Dr. Durmowicz casually remarked that patients wouldn't mind doing it...in the name of progress.  *This is where I begin feeling extremely agitated.  In my experience with Brady missing doses of Kalydeco due to a stomach bug, and accounts that I have heard from others within the CF community--the "rebound effect" can produce some seriously unpleasant side effects, and in worse cases--potentially dangerous exacerbations.  Not to mention the MENTAL sabotage of finally feeling a dream come true in finally being able to breathe with greater ease, and then being asked to go back to a disease+ state of being.  In my opinion, that is So. Not. Cool.

I worry that the best case scenario is that the trials experience significant delays in enrollment. Worse case scenario is that drugs that could have a meaningful effect can't enroll at all, and the projects can't move forward!  Additionally, I think that FDA regulators are underestimating how hard it can be to come off of CFTR modulators. I have seen and heard from many patients that withdrawal from CFTR modulators can induce an exacerbation, and may produce much less meaningful trial data.   As soon as FDA reviewer Dr. Durmowicz made the remark...steam started pouring out of my ears.  I didn't want to do it, but I couldn't help myself. Something gripped me, and I felt myself rise, and walk to the mic.  I had no choice. I introduced myself as a CF mom with a child taking Kalydeco and explained that I "respectfully disagreed" with his opinion before I gave him a mouthful.  I assured him that no one wants progress more than we do, but our mutual goal is going to be extremely hard to achieve if we can't get patients to enroll in trials they might consider to be unsafe and/or unethical by design. My comments to the FDA regulator drew applause from the audience, and several drug manufacturers approached me afterward to cheer my efforts, and remark that they have the same concerns.  The owner of one company in particular, who is developing an alternative drug for homozygous patients, expressed great excitement over his discovery--but worried about the ability to move forward against a "Vertex monopoly."  As a chemist, I fully understand the need to test these drugs with scientific rigor, to ensure a safe and effective product for the patient consumer...but I also think we are entering uncharted territory with personalizing drugs to alter an individual's cellular biology. If the FDA's main concern is SAFETY, I propose that cycling patients off and on CFTR modulators might have some very unsafe consequences and produce less than meaningful data.  We have a responsibility to at least try to minimize the collateral damage as we continue on this very personalized journey to the perfect CFTR modulator cocktail for each patient.  Please share YOUR EXPERIENCES transitioning on and off CFTR modulators in the comments.  I feel like I have heard a lot of anecdotal remarks, but I am increasingly curious to get a greater body of feedback on this issue. If the FDA doesn't understand our concerns--the responsibility rests on our shoulders to educate them.

In our current environment, we would be naive to rely on for-profit pharmaceutical companies to have our best interests at heart. The same is true for Vertex that is true for other virtually any other pharmaceutical company--the investor is their #1 priority.  As much as I love what companies like Vertex have been able to accomplish in drug development--I am absolutely NOT OK with the $$$ amount placed on my child's health every month. The astronomical price of their innovations has led many countries to be delayed or denied access of Kalydeco and Orkambi.  I am NOT OK when families in several countries around the globe write to me in desperation because their loved ones are being denied access to Kalydeco or Orkambi. Watching someone you love deteriorate before your eyes with CF is torture...watching them deteriorate, knowing there is an existing drug that could alter their lives if you could only access it is a special kind of bitter pill that I wouldn't ask anyone to swallow.  There have been access issues here in the U.S. as well, with one woman in Arkansas waiting over 2 years before getting coverage for Kalydeco.   Many CF patients rely on Medicaid or State programs that have limited budgets, and these are some of the most expensive drugs ever marketed...  This situation sickens me because I know precisely how life changing CFTR modulators can be for some patients--patients like my son Brady.  I want to see MORE CF patients benefiting from these drugs RIGHT NOW, and NEW DRUGS come to market to effectively treat MORE PATIENTS in the future.

What Can I Do?

1) Leave a comment for me to share with the CF Foundation, and the FDA.  

*This blog represents my views alone as a CF Mom, and while I do serve as a volunteer, I am not speaking or writing on behalf of the CFF.  I will, however, be sharing feedback on this issue with them, because I feel they are an important ally for the patient population.

2) Subscribe to the PRP--The Personalize Research Project

At the same time we are helping regulatory guidelines evolve, I've discovered another powerful technique where I feel that the patient community might be able to make significant influence.  In my experiences at the NACFC over the last 5 years, the interactions I've had with scientists have been extremely powerful, and in some cases--altered the course of research.  For me, this year's NACFC was a perfect storm of advocacy, science, emotion, connection, influence, and empowerment.  In the grand scheme of using my specific talents to make the greatest impact in advancing our community toward the cure--I have finally crystallized my focus, my calling, and my goal--to not only personalize the delivery of clinical care for CF patients, and to advocate for a system that meets the needs of patients--but to take it even one step further--and advocate for personalizing the research as well.  When I say personalize, it means two things:

1) Personalize research techniques to effectively test and combine compounds to give the greatest benefit to each individual patient.

• Encourage use of techniques utilizing human airway cells, organoids, nasal epithelia, and animal models developed with specific mutations to obtain the richest data to predict in-vivo clinical correlations.  

• Encourage the use of n-of-1 trial design to allow those with rare mutations or combinations to benefit from CFTR modulator therapies.

2) Personalize the research by making it about the patient.  Personalizing as in, making it personal.

Ultimately, the work done in the lab has an enormous effect on real people...like Brady.

For me, coming face-to-face with research scientists gives me the opportunity to enhance their understanding about why individualizing care options is so important. I do everything I can in these interactions to make them actually care a little bit about Brady.  I want them to think about Brady while they are at work in the lab everyday.  I want them to understand that their work is so incredibly important, and that we appreciate the hell out of it.  I want to influence the person actually holding the test tube, and/or developing the new scientific techniques we will use to cure CF. Even industry drug developers got their start in a University lab somewhere, I want them to understand what it means to live with CF.  Allowing these scientists to understand our struggle in a little more personal way injects their research endeavor with infinitely more meaning (beyond just publishing a paper, or getting another graduate student through their program).  I want to bring the patient/family voice directly to the lab bench.  We DO belong at the table along with academia and industry.  I think this is desperately important in the current drug development environment.

Making the Connection
I get a similar reaction every time I put myself face to face with a research scientist.  First of all, they are surprised that I am there, and that I am so knowledgeable about CF science.  I always thank them for making their career about CFTR science, and do my best to convey the details of how deeply chemistry and the understanding of the CFTR protein has impacted Brady and our family.  Many of them are moved to tears, and write to me later that our meeting was the most meaningful part of the Conference for them, and they ask permission to share the story with their grad students and department.

The Ripple
CF will eventually be cured in a lab somewhere, and I want whoever is behind that cure to care about CF patients a little bit (preferably a lot!)--or at the very least feel some sort of ethical awareness of how their work is impacting actual patients living with this awful disease.  Scientists represent the SOURCE of our progress with understanding and treating CF.  I believe that personalizing the lab work (with the presence of the CF patient/family voice) could serve to infinitely magnify the size of the ripple we are able to make in the research arena.

The Evidence
I have witnessed or been a part of these real instances where a patient or parent interacting with a researcher has had a powerful influence.  For privacy, I have left the names and specifics out of the following scenarios, but these represent REAL EVENTS that I have witnessed at NACFC.  Please share comments if you have experienced the power of the patient/scientist connection.

Case #1) CF Mom who is searching for data on the action of her daughter's rare mutation gets seated next to an important research scientist at dinner. By the end of the night, the scientist realizes he has a cell line in the freezer with the daughter's mutation from a former study he had conducted, and agrees to pull it out and perform a few experiments to see whether Kalydeco might offer some benefit.  The tests show potential for benefit and Mom is able to build a case to obtain off-label coverage.  Mom obtains first script of Kalydeco and is able to document benefits.  Patient has now been able to benefit from Kalydeco for several years before she would have otherwise, and the entire research lab now has a personal connection to CF.

Case #2) CF Mom gets seated next to important research scientist at dinner.  She discusses her son's rare mutation, and her efforts to obtain more knowledge about the potential for current therapies to impact the mutation.  Research scientists invites Mom and her son to visit their lab and donate some cells for them to run tests on.  Mom gets more information about her son's mutation, and the entire lab team now understands the implications of their work as they move forward with their experiments.

Case #3) I attended the NACFC for the first time in 2011 and saw the phase 3 trial data for VX-770.  I was also able to get face-to-face with investigators familiar with the  preliminary data on VX-770 in younger kids. As a result, I understood that future expansion to younger children was undeniably on the horizon--more a matter of time to meet regulatory requirements, than concerns over safety in this younger group. Armed with data, I was able to build a case for off-label coverage of Kalydeco, and access the drug more than 2 years before it is "approved" for my child's age group.  *I am not claiming, by any stretch of the imagination, that attending the NACFC guarantees off-label coverage of anything.  Coverage happens on a case by case basis. I am saying, rather, that detailed knowledge of both the mechanism of action of VX-770, paired with data regarding testing in children guided me to at least TRY to access this drug for my child.  I am saying that if I hadn't attended the NACFC, Brady would have waited 2 more years before starting Kalydeco.  Personally, I wouldn't dream of missing the NACFC, because the knowledge I've gained there has had a significant impact on the real life consequences of the disease for my son.  Period.  

I want to clarify that I am not claiming that interactions with scientists are more important that interactions with the care team.  More accurately, the clinical care team tends to have a better understanding of what CF means, and typically have many "personal" connections to patients and families living with CF, due to their regular interactions in clinic and the hospital. Research scientist often have absolutely zero connection with patients or understand how hard it can be to live with CF. I see interacting with scientists as a sphere of opportunity where we are currently absent, where we have the power to exert a large amount of influence.

So What.

In regard to the goal of personalizing research to offer the most benefits and the least risks to every individual--I encourage you to leave comments on this blog as well as sign up as an advocate on the CF Foundation's website. I have no doubt that issues will arise demanding action from advocates as we move forward. The CF Foundation has amazing policy experts, and they allow us to organize our efforts and make the biggest impact. Every year I come home from the NACFC with deeper insight.  I have witnessed so many important ways that the patient voice is missing, or misunderstood. I think that at this point in history, it is extremely important that we continue to advocate for a system and regulations that support our goals.

We can't afford to stop communicating.  The FDA is evolving right along with medicine, and the CF Foundation has truly developed an exemplary relationship with them over the years. When I go to meetings on Capitol Hill requesting increases in FDA funding--I tell the story of how swiftly and expertly the FDA reviewed the Kalydeco application, and how much that meant to my family.  I want the FDA to be able to do the same for every drug we send their way, and they need proper resources to do it!   In my experience in working with the FDA, the patient voice seems to be deeply regarded, and is a powerful tool (as we saw with the impact of patient testimonials in the expansion of Kalydeco to the R117H mutation).  Many on the voting committee remarked that hearing from the patients themselves made a huge impact on the way they voted.  We need to continue working and communicating deeply with the FDA, as the complexity of our research endeavors demand.  I think there is an enormous potential to work together here, and show the world how curing disease is done!

I will be be exploring some of the techniques available today to test individualized therapies in a future blog.  Researchers see potential in testing on human organoids, nasal epithelial cells,and animal models with specific mutation combinations to bring greater precision to testing, and minimize risks to patients.

Organoid studies provide an exciting opportunity to test the effect of drug combinations on individual patients.  

Lastly, I want to share a dream of mine, that I would like to see materialize--Each time I get the opportunity to connect with a CF scientist, I think to myself--"Man, it would be so awesome to be able to visit their lab, and get to have a conversation with everyone who works there."  If someone were to ask me about my "dream vacation," it would be akin to a world CFTR laboratory tour--so I think I should do just that.  If the goal is to personalize research for CF, getting face-to-face with the person holding the test tube is a good way to start.  I know I need to start talking about this dream, to promote some general awareness, which will hopefully lead me to my next step--financing.  In the meantime, I will be following up with every scientist I had the pleasure of visiting with at the NACFC, and exploring invitations I've already received.  It is time to blow the top off of the idea that patients don't have a place at the research bench.  For truly personalized medicine in a disease community with over 2000 disease causing mutations, I argue that patient voices are the missing "secret sauce" that will help usher in the cure we have all been dreaming of, while simultaneously acting to limit the power of big pharma. *Drop Mic*
**IMPORTANT NOTE. This blog is NOT in any way advising against the infection control guidelines outlined by The Cystic Fibrosis Foundation.  They are based on the latest science, and are there for a reason--safety.  I attended the NACFC Conference as a parent, and believe that meaningful connections can also be made using technology to connect patients with researchers.