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Latest From HNFA

Dear supporters,

We have some exciting news to report! As you may recall, Hope NOW (HNFA) met with the FDA for the fourth time in late August and proposed a clinical study concept that incorporated predictive algorithms, more-sensitive and faster “adaptive trials” as an alternative to the current slow and less-sensitive “population mean comparison” trials, and crossover of patients from the placebo control arm to the active drug. The FDA expressed support and suggested we might want to work directly with the researchers – and we have! So far, two biopharmaceutical companies are on board. We connected them with a leading data analytics firm so that impending trials can be designed far more efficiently with faster and more meaningful results. This could pave the way for a drug or treatment to be given faster consideration for Accelerated Approval (AAP) – or even full approval (registration) – as the evidence of efficacy will be stronger. All the components of our proposed study concept have the potential to foster ALS trials that are smaller, faster, smarter and more ethical.

Hope NOW (HNFA) has also completed filing a 501(C)(3) nonprofit application and created a Board which recently held its first official meeting. Robert Hebron was elected Chair, Jehad Majed Vice Chair, and Linda Clark Secretary.

Other board members include Nick Grillo, Eric Valor, Jay Smith, and Stephen Finger. An advisory committee will also be created and officer positions filled as necessary. These will be announced and shown on our website so keep coming back!

Several members of the HNFA board are actively serving on committees for the ALS Association’s FDA Guidance Document. This involvement has been critically important. Our members have already played a significant role shaping the direction of this project.

Looking ahead to 2016 we expect to lead more public events to campaign for smarter trials and faster drug approvals. We still to tackle the FDA’s resistance to utilizing real clinical endpoints in ALS for Accelerated Approvals (e.g. FVC). The swift progression of ALS should not require the use of surrogate endpoints to measure the statistical effects of a therapy. The FDA has granted AAP for the treatment of cancers, HIV, and made ZMAPP available for Ebola patients – but rejects the same consideration for treatments aimed at ALS. Not many fatal diseases move as quickly as ALS, have no treatment, and affect so many people at any age. With your help we will keep up the pressure for swift and compassionate action.

Hope Now for ALS is focused on two objectives:

  • Establishing a pathway for Accelerated Approval (AAP) for all safe and promising therapies for ALS,

and

  •  Modernizing the clinical trial process to bring it into the 21st century.
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Terminally Ill Denied Treatment – that Healthy People are Paid to Try

In Phase 1 trials, healthy people, often students, are offered money to test new drugs for safety.  In a Phase 2 trial, people with the targeted disease are enrolled and may experience benefits – only to be denied access at the end of the trial.  For terminal diseases like ALS that is a death sentence!

 

Hope NOW has launched a new Change.org petition at www.change.org/hopenow

featuring Amanda Bernier, https://www.facebook.com/AmandasAngelsALS. Amanda is the young mother and former firefighter who learned she had ALS at age 29, just weeks after becoming pregnant. We are petitioning Congress and the FDA to grant terminally ill people the right to try investigational therapies by utilizing the Accelerated Approval Program (AAP) the way it was intended.  In 1992, in response to HIV/AIDS activism, the FDA adopted the Accelerated Approval Program (AAP) – a conditional approval to treat this fatal disease. Later AAP was applied to treatments for heart failure and cancers.  So why isn’t it being applied to ALS and other rapidly fatal diseases!

Hope NOW  is currently focused on two initiatives:
 
#1: “21st Century Patient Rights”  
We continue our political effort to pressure Congress and the FDA for the “right to try” investigational therapies and to apply the 1992 Accelerated Approval Program (AAP) as it was intended, so that all citizens, regardless of their socio-economic status, have genuine access through their health insurance.
 
The PROBLEM:  The FDA will not grant Accelerated Approval (AAP) to any ALS treatment because they claim the disease needs to have a validated “surrogate endpoint”.  FDASIA passed in 2012 by Congress clearly states that actual “clinical endpoints” can be used. The FDA’s position appears to be in violation of  FDASIA and willful resistance to using AAP which allows a conditional approval prior to Phase 3 trials.  Hope NOW is calling out the FDA for not following the will of Congress and the American people.  It is our position that patients, in consultation with their doctors, have the “right to try” investigational therapies.
 
#2:  21st Century Trials
We have been meeting with the FDA since May 12, 2015 to share the “state of the science” and urge the FDA to accept and adopt faster, smarter, and more humane clinical trials. Our 4th meeting with the FDA took place Aug 24, 2015.
 
The PROBLEM:

The FDA still adheres to a 1962 clinical trial protocol that is fixated on an arbitrary statistical number.  This outdated protocol has created a multi-billion dollar clinical trial industry and approvals that takes an average of 12 years at a cost of up to $1 billion for a new treatment.  The FDA has not uniformly adopted current state-of-the-art science applications for trials.  Unlike 1962, today we have computers to analyze large databases, strategically populate trials, utilize complex predictive algorithms, and detect small changes and patterns in clinical data.

*A surrogate endpoint is typically a biomarker intended to substitute for a clinical endpoint to save time and money.  It is  most useful in slow-moving diseases where measuring the progression of clinical endpoints (e.g. patient function or survival) could take years. The ALS research community has not yet concluded there is a verifiable biomarker for ALS. However, forced vital capacity (FVC), can and should be regarded as both a clinical and a surrogate endpoint.

Amyotrophic Lateral Sclerosis (ALS) or Motor Neuron Disease (MND) is a degenerative neurological disease that affects neurons in both the brain and spinal cord, causing voluntary muscles throughout the body to wither. It is always fatal, on average within 3 years. It afflicts people of all races, genders and ages.  People with ALS (PALS) lose the ability to eat, drink, speak, walk, use their arms and hands, and ultimately breathe. Up to 6,000 U.S. citizens are diagnosed with ALS each year, and up to 35,000 have the disease at any given time.

There are experimental drugs showing promise that may improve quality of life, and slow or even stop the progression of this horrific disease – BUT WE ARE DENIED ACCESS TO THEM UNDER OUR CURRENT SYSTEM.

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No Accelerated Approvals (AAP) for ALS!

1) Call to Action (details below)

2)  Hope NOW will be issuing a new CHANGE.ORG petition that focuses on our current goals.
Please watch for it in your email: “Terminally Ill Patients Denied Treatment” and please sign it right away.

We continue to make progress in our negotiations with the FDA for smarter, faster, and more humane clinical trials. The FDA has expressed support for the study design proposed by Hope NOW and we are now scheduling meetings with researchers and drug companies to expedite its implementation.

However, we have also learned the FDA will not utilize the 1992 Accelerated Approval Program (AAP) due to a technicality called “surrogate endpoints”. This strict interpretation of AAP is closing the door to fatal diseases like ALS which do not have a verified “surrogate endpoint”. ALS treatments need AAP, a “conditional approval” that allows PALS access to promising treatments after a Phase 2 trial.
Please take a few minutes and write to your congress person using the sample letter below. We’ve also listed all the representatives below to make it easier for you.

Thank you for your courage and continuing to fight for the lives of those battling this cruel disease. Together we are creating positive change that will give PALS Hope Now.

Please remember to sign our next petition: “Terminally Ill Denied Treatment” Nick, Jehad, Eric, and Linda (co-founders of Hope NOW for ALS)

CALL TO ACTION:
Congress is back in session and it’s time to remind them this fight isn’t over. Please send the following message to members of Congress and copy your media contacts:
——
Honorable [member of Congress],
Your terminally ill constituents need your help.
HopeNowforALS.org has learned in its FDA meetings that the FDA will not utilize the Accelerated Approval Program (AAP) for ALS based on a little-known technicality called “surrogate endpoints”. With a fast moving fatal disease there is no need for surrogate endpoints to measure the statistical effects of a therapy. Real clinical endpoints (manifestations of the disease) can be used due to the swift progression of ALS.

The FDA’s strict interpretation of the 1992 AAP produces unintended and dire consequences to those with an imminent death sentence. The FDA has granted AAP for the treatment of cancers, HIV, and made ZMAPP available for Ebola patients – but rejects the same consideration for treatments aimed at ALS and other fatal diseases.

Right to Try (RTT) laws are being passed in state after state, but without new federal legislation there is no guarantee terminally ill patients will have access to safe and promising therapies that are still in clinical trials.The FDA likes to tout “Expanded Access” (EAP or compassionate use) as the solution, but “Expanded Access” has many barriers. Only a few people with significant education, wealth, and medical resources are likely to realize any benefit from EAP.

Furthermore, drug developers are often unwilling to provide the treatment for a host of reasons:
• risks to future FDA approval,
• inadequate resources to manufacture and distribute the drug free of charge, or
• a desire to shelter the true manufacturing cost to avoid jeopardizing future market value.

HopeNowforALS.org has conducted four meetings since May 12, 2015 with Janet Woodcock and other senior staff at the FDA. We are focused on two objectives:
• Establishing a pathway for accelerated approval (AAP) for all safe and promising therapies for ALS, and
• Modernizing the clinical trial process bringing it into the 21st century.
California is poised to become the 25th State to adopt Right to Try (RTT) legislation. It’s a step in the right direction but – we need Congress to enact new legislation that ensures terminally ill patients will have genuine access. AAP is a “conditional approval” that allows the FDA to withdraw approval if the treatment fails to perform as expected.

We strongly urge Congress to:

1. Modify the FDA’s authorizing laws to require that all expedited drug development tools, including AAP – with or without “surrogate endpoints,” are utilized for fatal diseases, and
2. Make it clear to the FDA that terms like “expedited” and “accelerated” do in fact mean what they imply – speed.

[Your name and contact info]
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Hope Now for ALS – 21st Century Trial Design original proposal to FDA

ALS is a progressive neurological disorder that has always resulted in progressive deterioration and death.  There is no cure and the only approved treatment extends life on average 2-3 months.  80% of ALS patients die within 5 years of diagnosis and 90% within ten years.  ALS is an extremely heterogeneous disease, where patients progress at vastly different rates and often in non-linear fashion.  More than 20 different genetic mutations are associated with it but only explain 25% of total cases.  These facts make it very hard for a drug to pass a series of clinical trials and be approved using a traditional randomized double blind placebo test protocol.  Differences in the underlying progression rates between randomly selected placebo and non-placebo groups reduce the signal to noise ratio of observed changes in the primary endpoint during the trial period, producing significant statistical noise and limiting the ability to reach a standard of confidence of p<.05, or in other words a probability of less than 1 in 20 that a random event has proven the trial hypothesis rather than actual drug efficacy.

Once a standard for efficacy has been preselected (e.g. 10% less decline in FVC on treated v. placebo group) and trial size has been determined, utilization of the p<.05 standard makes analyzing trial results virtually a mathematical exercise removing all judgment and discretion from consideration by the regulator.  While this, along with the longstanding use of the standard to date, gives the regulator extreme comfort in not being second guessed that they approved a drug that they shouldn’t approve, it does little for the patient community that is seeking treatment for a disease that is always fatal and has no treatment.  The reason for this conflict is quite apparent – in the use of this same standard in all situations one group’s desire for life is diametrically opposed by the other’s desire to avoid criticism.  Unfortunately, the latter controls all of the decision points.  We accept that defining a primary desired endpoint will determine desired trial size, i.e. a more dramatically predicted change in an endpoint requires a smaller number of trial participants to test efficacy.  However, we take the position that also letting a historical p value standard remain a tyrannical rule of the game virtually eliminates the ability of the regulator to employ judgment in allowing approval of a drug/treatment and fails to reflect the societal evaluation of situational risk both in how a trial is conducted and how the results are evaluated.

Historically a standard of p<.05 came from social and behavioral science research. There is nothing magical about .05. It is more a historical standard than anything else.  Whatever P-value is chosen to be used to judge the results of a clinical trial should reflect the risk assumption or aversion desires of society at large with respect to that effort.  (See: Ronald Thisted, PhD “What is a 0P-Value” 2/14/2010 University of Chicago Department of Statistics and Health Studies.) For a drug that has serious side effects that is being used to treat a non-life threatening or life altering disease, a very low P-value as a standard makes sense.  On the other hand, we feel that in the case of a drug, where safety has already been demonstrated in Phase1 and/or Phase 2 trials, that is being used to treat an always fatal disease that has no currently available treatment alternative should either reflect a less stringent P-value standard or allow discretion and judgment to take into account other experimental observations and statistical analysis in determining trial outcome.  We do not seek elimination of statistical analysis but we sincerely recommend that a one size fits all P-value standard not be the only basis of evaluation, and not be employed in a vacuum, and recommend that judgment employed also reflect the severity of the disease and the level of unmet need for treatment.

Congress has very clearly taken the position that judgment and discretion is a critical part of the drug approval process and that the FDA has broad discretion in defining efficacy, a fact that the FDA has agreed with in our prior discussions.    We believe ALS presents a very clear case for employing that judgment and discretion.  That being said, we do not take the position that all aspects of current trial protocol should be abandoned.

To that effect, we strongly believe that advances in statistical analysis as well as advances in science are a necessary prerequisite to getting an effective treatment into the clinic.  Advanced data processing, statistical modeling and machine learning techniques have been developed and significantly enhanced over the last decade.  In combination with large patient data sets involving ALS, such as PRO-ACT or ALS-TDI’s Precision Medicine Program database that is now under development, these statistical techniques can be applied to help accelerate the development of treatments and cures for ALS.  Patient predictive models for ALS created recently can now adapt to the unique characteristics of individual patients to accurately predict each patient’s future disease state, through measures such as ALSFRS-R score, FVC and survival likelihood.

The use of predictive algorithms for ALS progression offers multiple opportunities to reduce statistical noise in ALS drug trials.

The first use for such an algorithm would be in selecting trial participants that will tend to progress at similar pace so as to better ensure that the placebo and non-placebo groups in a trial are more homogeneous than what would occur through typical exclusion/inclusion criteria and randomization.  This would better assure that noise created by mixing fast and slow progressors did not skew in different directions in comparing the treated and placebo groups, a fact that is especially important if improvement in disease progression for the treated group is the primary endpoint of the trial. Similarly, the drug/treatment effect can be made more obvious, particularly in small size clinical trials.

The second use for the algorithm is that it creates a virtual third arm for assessing trial results.  If at the start of the trial the algorithm produces a predictive result for each patient, that predictive result can be compared to the actual result as well as using the placebo group as a point of comparison to the treatment group.  By comparing the predictive result to the actual for the treated group you eliminate the heterogeneous nature of the disease as a source of statistical confusion as the virtual arm placebo group is made up of the same exact patients as the treated group.  In other words, the predicted rate of progression for the treatment group that would have occurred had they not received treatment provides a direct same patient specific control for comparison, allowing for smaller, faster, smarter studies to produce a result that can support a regulatory decision.

Finally, conducting a trial this way, allows for even further learning from the results.  You can compare the placebo group results to the virtual trial arm predictive placebo results.  If the placebo group has been populated using the progression algorithm to create maximum homogeneity, then this comparison should give a clear picture of the viability of the algorithm and its use in creating a virtual control arm.  If that result is a positive one it strengthens the learning gained from the second proposed use of the algorithm. In addition, one can then give the placebo group the drug and add the results on them to the treated group and compare to the original placebo arm and the virtual arm in order to power up the trial statistically at a much lower cost and in less time.  It also solves a recruiting objection of patients who object to an algorithm determining whether they are place in a treated or placebo group as everyone is ultimately treated unless safety becomes a concern or the drug is conclusively shown to have no positive effect.

In addition to the above, we propose that a confirmatory trial of this type:

(1) include 20-100 patients with 50% in the treated arm,

(2)  collection of clinical data (e.g. FVC; ALSFSR) on each patient going back 1-3 months;

(3) using change in FVC as a primary endpoint and change in  ALSFSR as a secondary endpoint to help judge any ambiguous results not merely as a disqualifying factor to re-judge demonstrated efficacy using FVC,

(4) using possible biomarkers as an exploratory secondary endpoint for the same purpose, and

(5) a three-month post treatment observation point in assessing first phase trial results followed by a crossover for the placebo group combining them with the treatment group and using the predictive algorithm to reconstitute a virtual placebo arm.

In summary, we strongly believe that trial design in the case of ALS needs to reflect two propositions:

(1) recognition of advances in biostatistics allowing the use of predictive progression                  algorithms in ALS trials; combined with

(2) appropriate use of discretion in selecting  and interpreting P-value significance

Doing so will allow for quicker, less costly confirmatory studies in the area of ALS, hopefully leading to drug/treatment approval, whether on a normal or accelerated basis, and ultimately bring good proven treatments to the clinic and patient community in a faster more efficient way, resolving the quagmire created by rigid adherence to traditional time honored drug trial protocols.

In making these suggestions we understand completely that complications may be being added to the trial process but we firmly believe that generating more and better data and better employing clinician and scientific judgment in analyzing results will produce a far better outcome than what has occurred to date.  We look forward to a productive dialogue and a statement of the FDA’s position on each of these issues.

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Hope Now for ALS in the news!

Taking page from early AIDS activists, ALS patients push for access to experimental drug

Ron Leuty Reporter- San Francisco Business Times

A one-time tech security specialist, “Mike” now calls himself an amateur chemist and neurologist, seeking out new drugs to treat the deadly muscle-wasting disease known as amyotrophic lateral sclerosis.

It’s not a hobby; it’s his life.

Diagnosed in October 2013 with ALS — or Lou Gehrig’s disease — the 55-year-old Massachusetts resident believes he’s found hope in an experimental drug under development by a small Palo Alto company. Lab tests showed that Mike has the same makeup of biomarkers, or disease characteristics, as ALS patients who responded in a 2012 study of Neuraltus Pharmaceuticals Inc.’s drug.

If only Mike and other ALS patients could get “compassionate use” access to Neuraltus’ drug, they wouldn’t have to wait for a formal clinical trial to see if the compound slows ALS from progressively robbing them of the ability to walk, touch, swallow, speak and, finally, breathe. In the process, these one-person studies would help Neuraltus understand more about the drug.

There is the rub that exposes some of the cruel realities of the drug-development business: As Neuraltus plans to start a mid-stage study later this year, it literally and figuratively can’t afford to give away the drug to desperate patients in search of a ray of hope.

“If I were a patient, I’d be the same way,” Neuraltus CEO Rich Casey said. “I’d want to get the drug as soon as possible.”

Yet a grassroots band of ALS patients and caregivers — under the banner of Hope Now for ALS— are pressing Casey, the FDA and others, invoking a give-it-to-me-now strategy that AIDS activists used to win early access in the 1980s and 1990s to experimental HIV-fighting drugs. Ultimately, they hope to convince someone to cover Neuraltus’ costs for compassionate use or an expanded access program in parallel with a clinical trial.

“A large expanded access arm would benefit ALS research and help (patients),” Mike wrote in an email to Casey last month. “It is also important that long-term access to the drug should be ensured for those participants that benefit from it.”

It is, Mike admitted, an uphill battle.

“Big Pharma companies were sponsoring (HIV) clinical trials and provided stuff for free,” said Mike, who asked that his name not be used because his elderly parents don’t know about his ALS diagnosis. “With ALS, this is not happening because these are tiny biotech companies working on these (drugs). The big boys have been scared off by the disease and a 20-year history of failure.”

The ALS Association — the organization that last year raised close to $100 million via the “Ice Bucket Challenge” social media phenomenon— last month awarded a $1.5 million grant to help pay for a Phase II study led by Dr. Robert G. Miller at Sutter Health’s California Pacific Medical Center in San Francisco. Overall, the study will enroll 60 ALS patients in eight centers, Casey said, and privately held Neuraltus will contribute another $1.2 million or so.

It is a big step forward for a company with little cash and a promising drug, called NP-001.

But, in a way, patients like Mike may have stood a better chance of receiving NP-001 if Neuraltus wasn’t moving forward with its study. A well-controlled trial requires that researchers give the drug to some patients while others receive a placebo in order to provide as close to an apples-to-apples comparison to statistically quantify a drug’s safety and effectiveness.

“If everyone gets compassionate use, you wouldn’t want to go into a trial where you could get a placebo,” Casey said.
Various legislation has tried to find a work-around solution. The Goldwater Institute, for example, has pushed for “Right to Try” laws in various states, including California, but those are toothless because they can’t require a company to provide access to experimental drugs for terminally ill patients.

For now, companies must make a tough short-term decision, Casey said, with a longer-term benefit in mind.

“(Patients are) desperate and I can’t say, ‘OK, I’ll send you some drug,’ ” Casey said. “My first obligation is to develop NP-001 for all patients through a well-controlled study.”

Neuraltus’ latest trial, which could start enrolling patients in November and may produce data by this time next year, could lead to another Phase II study in about 300 patients. An even larger late-stage trial could set the stage for Food and Drug Administration approval. But that would be years away, assuming no scientific bumps along the way and Neuraltus lining up additional funding.

“We still have to prove the drug works,” Casey said.

The timeline doesn’t serve many of the roughly 400,000 ALS patients worldwide, including about 30,000 in the United States. About 5,000 people are diagnosed with the disease every year, and most will die within three to five years after diagnosis.

It has been a long, arduous road for ALS patients and Neuraltus.

For one, researchers haven’t even nailed down what causes ALS, let alone found a drug that can attack the disease rather than its symptoms. (South San Francisco’s Cytokinetics Inc., for example, is starting a Phase III trial focused on improving ALS patients’ breathing.) Many patients and researchers see NP-001 as one of the few compounds that could get to a root of the disease.

Researchers believe NP-001 works by regulating macrophages, a type of white blood cell that typically acts as the central nervous system’s garbage disposal by clearing away dead or damaged cells. In ALS, however, macrophages are thought to be stuck in the “on” position, causing inflammation that may contribute to the disease’s progression.

“This seems to be the only treatment that has shown promise,” said Mike’s wife, Alla. “The doctors don’t know if it’s safe enough, but there is nothing more dangerous than ALS. It doesn’t just kill you, but it takes everything from you that matters to you.”

The fact that five-person Neuraltus has been a one-product company with little to fall back on if NP-001 fails — and the drug’s potential intellectual property issues — is another red flag for potential investors. What’s more, many investors don’t have the patience to see Neuraltus through years of studies to confirm the biomarkers it saw in a subset of patients in its 2012 trial and followup studies.

Other companies haven’t helped, either. Trial failures in ALS and Alzheimer’s, for example, have made venture capital firms and other investors wary to pony up cash for another experimental neurological drug.

Even other companies’ supposed successes can pose problems. For example, some ALS patients this spring pushed the FDA to accelerate approval of a drug from a mom-and-pop Pasadena company, called Genervon Biopharmaceuticals LLC, after a 12-patient study seemed to indicate that patients who received the drug could swallow milliliters more liquid.

Genervon hadn’t actually filed for accelerated approval, though, and the FDA hasn’t budged without more evidence of the drug’s safety and efficacy for ALS patients. Still, a Change.org petition, urging the agency to approve Genervon’s drug, has collected nearly 800,000 signatures.

Girded by that social media success, members of Hope Now for ALS started firing off form letters to Casey, the ALS Association and the FDA. Their pleas aren’t falling on deaf ears, Casey said.

Still, clinical trials cost millions of dollars — Neuraltus’ potential 300-patient mid-stage study, for example, could cost as much as $30 million — and there is little room for error over the five to 10 years a drug is in development.

That is time that Mike and other ALS patients don’t have to give.

“If someone told me to chain myself to the FDA tomorrow, I’d do it. But just going by myself is not going to do it,” said Alla, Mike’s wife.

“We have a good life together and we’re trying to hold on to what we have now,” she said. “And every day it gets worse.”

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Hope Now for ALS update: Summary of July 6th call

Dear Hope Now for ALS (HNFA) supporters,

We apologize for the delayed update. We have been trying to schedule the next meeting so we could report that in this update. After our July 6 meeting, we submitted a detailed proposal to the FDA and requested a timely response, but it appears the FDA is stalling. They suddenly want to invite other “stakeholders” to our meeting. We believe this is a tactic to bring people and organizations into the discussion that will defend the status quo and to convert the role of actual PALS and CALS into a minority voice. With much regret, we need to report that after three meetings we see little evidence that the FDA is willing to be flexible with respect to clinical study designs and data analysis approaches that could accelerate the development and delivery of safe and effective medicines for ALS. WE WILL NOT ACCEPT THIS!

Please write the FDA today and copy members of Congress and the media expressing your outrage that ALS is still not being treated with urgency. Demand that the FDA respond immediately to Hope Now for ALS (HNFA) in a substantive and meaningful way as they promised they would. State that you regard Hope Now for ALS as your representative for this process and that you expect the FDA to continue timely, direct discussions with HNFA on expedited and modernized development and approval pathways for ALS treatments – a 21st Century Approval Process!

Please email Dr. Woodcock at the FDA: janet.woodcock@fda.hhs.gov
and copy the people below and your representatives and media contacts
druginfo@fda.hhs.gov
richard.moscicki@fda.hhs.gov
william.dunn@fda.hhs.gov
stephen.ostroff@fda.hhs.gov
john.jenkins@fda.hhs.gov
eric.bastings@fda.hhs.gov
ronald.farkas@fda.hhs.gov
nicholas.kozauer@fda.hhs.gov
brad_grantz@toomey.senate.gov
Grace_Stuntz@help.senate.gov
josephine_eckert@murray.senate.gov

Summary of the July 6th conference call

Our third meeting with Janet Woodcock and her staff focused on finding common ground; specifically, balancing the need for faster, less costly, more conclusive trials and the FDA’s desire to keep ineffective treatments off the market. We were able to agree on FVC (change) as a primary endpoint, and ALSFRS (change) as a secondary endpoint. The ensuing discussion focused on topics fundamental to designing quick confirmatory studies that could lead to approvals for drugs/treatments that have demonstrated safety and preliminary evidence of efficacy in Phase 1 or 2 trials. Two principal topics that emerged from this discussion were (1) use of a patient-specific ALS progression predictive algorithm to construct a virtual and homogeneous placebo trial arm designed to reduce statistical noise in trials caused by the heterogeneity of ALS; and (2) understanding where and how the FDA can show some flexibility in the use of its statistical significance standard based on calculation of a p value as the standard for establishing “efficacy.” Achieving a p-value of < 0.05 in a trial where measuring a modest improvement in ALS progression is the primary endpoint necessarily increases trial size to substantiate positive outcome, adding time, cost and other complications that function as disincentives for companies to pursue approval of new medicines for ALS. However, by incorporating progression prediction models and patient-specific data, a 21st century approach to trial design, we would be more likely accurately measure the effect of the drug, improving the chances for recognizing of success when it occurs. We also advocated for the collection of secondary data in trials especially investigational biomarkers, and stratification of patients to better discern evidence of “efficacy” and to identify subsets of patients who benefit from a drug when efficacy is not seen in a majority of the patients. Unfortunately, as with our previous in-person meeting and our prior teleconference with FDA, we did not receive clear, actionable responses from FDA, and on some critical points of discussion, we encountered firm resistance to any form of new thinking in how drugs for ALS are developed and approved.

Detailed Notes of the July 6th Conference Call

On June 6, 2015, Hope Now for ALS held its third meeting with the FDA to discuss creation of an expedited development and approval pathway for new ALS treatments.

We opened the meeting with some sad news, informing the FDA that a member of our leadership team, Dr. David Huntley (husband of Linda Clark – also on our leadership team) lost his battle with ALS on July 4th. We informed the FDA of his passing at Linda’s request to remind everyone that making and delivering progress for ALS is a matter of extreme urgency. FDA responded with an expression of sorrow and a statement that they understand and share the urgency felt by the patient community.

Bob Hebron led the meeting for Hope Now for ALS (HNFA). The primary participants for FDA were Drs. Janet Woodcock and Ronald Farkas, although most of the FDA participants from the prior call also attended.

HNFA introduced the concept of using a predictive algorithm to select patients for a study, and then to serve as a second control arm alongside an actual control arm with the objective of reducing the statistical noise caused variability in the rates and characteristics of progression among PALS. The predictive algorithm approach was then discussed in some detail, including input from experts developing a predictive algorithm for ALS using existing patient data. It was explained that the algorithm accurately predicts decline in ALSFRS and can be adapted to predict other measurement endpoints, such as FVC.

HNFA then proposed that a clinical study designed to test for a slowing of progression could be conducted by using the predictive algorithm to select fast-progressing patients (termed “enrichment” by FDA) that could fill the study with “like” patients in terms of rate of progression. A positive effect on fast progressors might be seen more quickly (statistically), and in a smaller study population, than trying to discern the same effect in a population of mixed rate progressors. FDA indicated that enriching the study with fast progressors might be acceptable to them, and they expressed an openness to using the predictive algorithm for that purpose; however, they noted that if the study were populated only with fast progressors, the results might not be as generalizable to the larger ALS population as it would be if the study were run in a broader population of PALS (i.e., fast and slower progressing PALS).

HNFA then proposed that the study could perhaps be stratified (meaning looking at subgroups within the population) to learn more from the study, and to try to further reduce the statistical noise generated by the variability in the progression rates and types of motor functions lost as the disease progresses, seen at the individual patient level. FDA responded that attempting to stratify a study prospectively would complicate study design, lengthen the time needed for enrollment and cause the study to have to be larger (i.e., FDA would be looking for a much larger, longer study with each subgroup large enough to have adequate statistical power if the sponsor intended to draw conclusions regarding drug effect based on any subgroup analysis). FDA then said that retrospective analysis could be conducted on the study results to try to understand what happened, but the implication was that retrospective analysis would likely not support an approval.

HNFA then made the point that the patient community is looking for an agreement with FDA on smaller, smarter studies to keep the cost down and speed up the entire process. FDA’s response was entirely statistics-based and summarized below:

  • A study can be small if there is a huge treatment effect
  • A small study risks statistically missing a small treatment effect
  • FDA reported that some Breakthrough drugs approved based on early data didn’t show a large treatment effect in later confirmatory studies.
  • FDA advised that once an expected treatment effect is estimated (e.g., how much more slowly a drug might cause ALS to progress in the study population), cut it in half and design the study to be large enough to detect the smaller treatment effect to a level of statistical significance.

FDA did not directly respond to our statement regarding an agreement on smaller, smarter studies.

[Explanation – not from the FDA. What FDA actually said here is that they expect any entity trying to develop a new drug for ALS to do conduct the same large, time-consuming. randomized controlled studies today that the agency would have required 10, 20 or even 30 years ago. The FDA’s response is rooted in its long-standing its adherence to a purely statistical approach to designing studies and evaluating study results, and is based on the results of at least one, and preferably two, randomized controlled studies producing positive results at a measure of statistical significance, called a p-value, of 0.05 or less. Setting the p-value requirement at 0.05 or less means (in simplified terms) that the chance the results seen in the study happened because of chance (and not because of the drug) is 5 percent or less. FDA was explaining that an acceptable p-value can result from a large treatment effect in a small population of patients; however, to detect a small slowing of progression to a level of statistical significance acceptable to the FDA (p = 0.05 or less), a much larger, longer, more expensive study would need to be run. This convention, which has been relied on by FDA for decades as its standard for approving new drugs (since the 1960s), creates a reality in which getting a modestly effective drug approved by FDA takes much longer, costs much more and is much more uncertain for sponsors, than getting a highly effective drug approved. Given the current state of the medical science for ALS, all the drugs currently in the pipeline appear to have the potential for causing modest positive effects on disease progression and symptoms; thus, the FDA’s position on study size and statistical significance creates a financial and technical barrier to sponsors who might otherwise be interested in trying to navigate the agency’s development and approval process if a more creative and financially-feasible pathway was available. It also creates an obvious problem for the current and future generations of PALS and CALS who are faced with a drug development and approval process that makes approval of a new drug in a timeframe meaningful to them, all but impossible. HNFA is attempting to negotiate a more reasonable and productive development and approval path for ALS treatments with the FDA. So far, it appears that FDA has no interest in joining us in thinking outside the traditional statistical box.]

HNFA raised the concept of using the predictive algorithm to analyze the study results as a second control arm (run alongside an actual control arm with patients receiving a placebo) that might be a better way to control a study because of the algorithm’s potential to reduce statistical noise associated with variability among patients and the accuracy/precision noise known to be associated with measures like the ALSFRS and FVC. FDA replied that they would not object to looking at its use as a control arm, and that the usefulness of the algorithm could be evaluated by comparing the control outcomes predicted by the algorithm with the outcomes from the actual control arm. FDA described use of the algorithm for this purpose as exploratory, and appeared to be disinclined to rely on anything learned from its use to interpret the study results.

HNFA then asked: What is different about the input we are receiving from FDA today from what we would have heard 5, 10, 15 or even 20 years ago? FDA responded that the difference is they are talking to us about it – something they would not have done in the past. FDA did not offer any other explanation of differences between the advice they are offering us now versus what they would have advised in the past. HNFA then proposed that the study should include a cross-over provision (to the active drug) for patients randomized to the placebo control group, if after an appropriate period of following the patients in their respective groups (treatment and control), the drug appeared to be having a positive effect for some patients. FDA responded that they thought we were talking about a delayed start trial where some patients would start on a placebo, then be switched to the active drug. We responded that we were actually proposing a more traditional randomization to treatment or placebo at the start, with cross-over at the end of the monitoring period, and that if some of the patients who crossed over to the active drug then responded to treatment (for example by seeing their progression slowed), those responses should be considered favorable and could be compared to the predicted rate of progression using the algorithm. FDA did not provide a clear response to this concept but seemed to be discouraging it, and we raised the question regarding why FDA had never developed a way to consider patient responses observed after cross-over from the control to the treatment group as evidence supporting efficacy of the drug being tested? FDA responded that they were talking about these kinds of concepts at a high level but had not begun applying them at the study design and review level.

HNFA expressed its growing frustration that we do not seem to be getting clear and actionable responses from FDA. In response FDA asked that we submit a list of things the FDA had expressed “openness” about so they could confirm or clarify their position.

FDA reiterated its concerns about trying to use biomarkers as supporting evidence in an ALS study, stating that they had been burned by biomarkers too many times. (We did not pursue this discussion further since based on previous discussions, use of biomarkers at this time appears to be off the table with FDA. It seems they have no objection to collecting biomarker data – but they are not open to using them for purposes of regulatory decision-making regarding an ALS treatment.)

On endpoints, FDA stated that they think there is significant variability in ALSFRS and FVC measurements, and stated that if FVC is selected as the primary endpoint, it would not be evaluated in a vacuum. They would be looking for concordance in other measures (e.g., they would want to see ALSFRS and other patient outcome measures generally go in a positive direction if FVC outcomes were statistically positive).

During the meeting, HNFA expressed the following to FDA and FDA provided the following responses:

  • We have made clear to FDA the ALS community’s perception of risks versus benefits, and that the community considers the risks of the disease to substantially outweigh the risks of investigational treatments that, based on early data, indicate they may provide some benefit.
  • FDA responded that they understand that the ALS community supports approval of treatments with adverse side effects if the drugs also provide some benefit.
  • HNFA clarified that the community extends their position on risk to FDA being open to approving drugs in an expedited manner based on limited data, and then relying on post-approval studies and registries to learn more, faster about the safety and efficacy of the treatment and how to optimize its use, even if granting the early approval might result in some treatments ultimately being found less safe or effective than originally thought, requiring re-labeling or even withdrawal from the market. Presently, PALS have almost nothing available to them and the pipeline is thin in part because of the high regulatory hurdles for ALS treatments; problems that can only be addressed through a stream-lined and expedited development and approval path. A specific recommendation that was made during the meeting was that FDA should be more flexible with its statistical significance standard (p = 0.05) for diseases like ALS with an extreme unmet medical need, which would allow for smaller, faster studies that, if positive at a lower level of statistical significance, could lead to a conditional approval (which is what accelerated approval already is), supported in the post-approval space by continued study.

FDA responded in a noticeably rigid manner that it must meet its statutory standard in the Food Drug and Cosmetic Act (FDCA), and that if the ALS community wanted the standard changed, they should pursue that with Congress.

[Explanation – not from FDA . The standard for approval in the FDCA is generally worded and allows broad discretion to FDA in deciding what the standard for approval should be for any drug intended to treat any disease. Congress has directed FDA to be more flexible when setting the standards for new medicines intended to treat serious and life-threatening diseases with unmet needs. ALS is among the most serious of all known diseases, and is almost universally fatal within 2 to 5 years) In our case, FDA has firmly indicated that they do not intend to be flexible.]

HNFA responded that FDA has broad discretion in interpreting and applying the approval standards in the FDCA, and that Congress had already instructed them to use that discretion for new medicines intended to treat diseases like ALS.

HNFA explained to FDA that our goal is to complete these discussions regarding a streamlined development and approval path for ALS drugs in a few additional weeks, then move to the next stage of proposing the pathway to sponsors for comment and potential use in starting registration clinical studies within the next few months, with the goal of completing the data collection portion of those studies by the end of this year, and that we expected FDA to partner with us in achieving this goal.

In follow up communications between HNFA and FDA since the July 6th meeting, HNFA has opted to submit a conceptual study design to FDA, and FDA agreed to provide feedback within approximately one week. The conceptual study design was provided to FDA and we expected a response this week. Instead, we received an e-mail from FDA stating that they would “…like to broaden the participants so more members of the ALS community can participate and provide input.” This decision by FDA, which was made unilaterally without consultation with HNFA, appears to mean that they do not intend to respond to our proposal in a timely manner. It also means that the pace of discussions with FDA regarding the modernization and acceleration of new drug development programs for ALS will be substantially slowed, and will lose focus as “stakeholders” with goals that differ significantly from the urgent needs of PALS and CALS are selected by FDA and brought into the process.

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Sick kids, desperate parents, and the battle for experimental drugs

The complex world of compassionate use drugs and who gets access to them.

JENN MCNARY KNOWS ANGER. It has overcome her often, and with the ravaging might that only a mother knows when her child is dying. Except in her case, it’s not one son but two who face a death sentence.

At 34, McNary’s face still has the glow of youth, and it lights up when she talks about all four of her kids, although she knows she has given most of her life, her energy, and all of her fight to her two oldest. As McNary sits in the kitchen of her modest apartment in Pembroke, her eyes harden as she remembers the moment a few years back when she realized there was something worse than knowing both of her children would die — knowing there was something out there that could help them, but that only one of them could have.

That something was an experimental drug, made by Sarepta Therapeutics, a company in Cambridge. The worlds of a young New England mom and the high-stakes multibillion-dollar biotech industry were about to collide in what seemed like anything but a fair fight.

AUSTIN AND MAX, AGES 16 AND 13, were born with a rare, cruel genetic disease called Duchenne muscular dystrophy. It robs children of their muscle function, so they lose the ability to walk, then move, until their breathing muscles and their hearts start to give out. Survival into adulthood is rare, and there is no cure.

McNary’s younger son Max was 9 when he qualified for a small clinical trial of Sarepta’s drug, called eteplirsen, for boys with a certain mutation causing the disease. When the trial started, Max was having difficulty walking, as is typical for boys that age with Duchenne. But within 16 weeks of taking the medicine, McNary saw him begin to improve.

She was elated. Naturally, she immediately saw hope for Austin. At 12 and already in a wheelchair, he had not qualified for the Sarepta clinical trial. McNary assumed — naively, she now says — that she would just ask the company to provide the drug to Austin via a program known as “expanded access,” also commonly called “compassionate use.” The program was established by the Food and Drug Administration in the late 1980s, during the days of the AIDS epidemic, after HIV patients implored the agency for access to promising experimental drugs (though the agency made some therapies available as early as the 1970s).

Via compassionate use, patients who are deathly ill, have no other treatment alternative, and do not qualify for clinical trials are able to gain access to experimental drugs as long as the drug maker is willing to provide them and the FDA approves the request.

Austin’s neurologist reached out to the company, requesting eteplirsen on a compassionate-use basis. But the company denied the request. The doctor tried again, and the company again said no. Then McNary saw Chris Garabedian, Sarepta’s CEO at the time, at a conference on Duchenne muscular dystrophy, and she had the chance to ask him, in person, the one question on her mind: Why couldn’t Austin get the drug?

Garabedian gave her more than one reason. The company, called AVI BioPharma then, was small and cash-strapped. It had barely enough drug supply for the 12 kids in the clinical trial, let alone compassionate use. Garabedian said it would not be fair to pick one child, even if it was the sibling of a child in the trial, to begin taking his drug.

That explanation didn’t satisfy McNary, at least not at the time. “I was furious,” she says. “How could he put a dollar amount on my kid’s life?”

She went home, ready to do anything in her power to get the drug for Austin. But as she pondered options that involved, as she put it, “raising a huge stink,” Austin asked her a question she would never forget. “He said, ‘I have some friends who are worse than I am. Are you going to get them on the drug too?’ ” McNary recalls.

Realizing that “the world is bigger than my family,” McNary shifted gears. “The conclusion that we came to was that compassionate use wasn’t going to work,” she says. “I thought: OK, new plan. Get drugs for everybody.”

JENN MCNARY JOINED FORCES with several highly vocal parents within the Duchenne community, putting pressure on the FDA to consider eteplirsen for what’s known as accelerated approval, a program that allows drugs to be approved based on scientific indications that a drug is working, pending confirmation from larger or longer studies.

The switch in strategy was due in great part, McNary says, to having felt that the company was trying to listen and had reached out to her and other parents to explain its position. She was plenty upset when Sarepta denied compassionate use, she says, but Chris Garabedian “educated me,” she adds. “If he had ignored me, I probably would have gotten a lot angrier.”

When it comes to compassionate use, educating parents and patients hasn’t been the norm, and it’s been the industry’s biggest mistake. Patients with no time to lose have faced companies offering little support navigating the compassionate-use process — often because the companies themselves don’t know how to handle it. They “get surprised or even nervous” when press releases are posted with clinical trial results and patient requests start pouring in, says Henri Termeer, the former CEO of Cambridge-based Genzyme Corp. During his tenure at Genzyme, Termeer oversaw multiple compassionate-use requests for the company’s rare-disease drugs. “It doesn’t go away because you wish it to go away,” he says. “You have to be part of the solution.”

Compassionate use is developing into “a major issue for the industry to grapple with,” adds Garabedian, who left Sarepta in April. “With the therapeutics that we see emerging, many of them from the Boston-based companies, you will be able to see signals very early on in a patient or two, and then the entire community is going to say, ‘There is nothing else out there, we want this drug.’ ”

Indeed, compassionate-use requests to the FDA are exploding. In fiscal 2014 the agency received 1,882 compassionate-use requests, a 93 percent increase over the 977 requests in 2013, and the highest number since the agency started publishing these figures in 2010. The vast majority of the requests, 1,809, were filed by doctors on behalf of individual patients, and a little more than 1,000 of those were emergency requests filed when death is imminent — a huge increase over the 317 filed in 2013.

That’s not the total number of patient requests for compassionate use — those are just the petitions that the FDA sees. An unknown, presumably much higher number of requests never reach the FDA because the companies deny them first. The way the system works, doctors first petition a company for compassionate use, and only if a company agrees can the doctor file a request with the FDA. The chatter in industry meetings and boardrooms is that compassionate-use requests are going up, but that’s not the main concern.

There’s growing unrest with the realization that when a company denies a request, patient voices are getting louder. The power of the Internet and especially social media has allowed patients and their families to take their plea to the masses and, in some cases, see their story go viral.

“What began during the AIDS epidemic as social protest has evolved into social media protest,” biotechnology executive Kenneth Moch recently told the audience of the MassBio Patient Advocacy Summit. Cancer patients Andrea Sloan and Nick Auden, both lawyers, famously took their pleas for experimental drugs to Twitter, Facebook, YouTube, and Change.org, amassing the support of hundreds of thousands to challenge drug companies’ denials of their petitions.

KENNETH MOCH has been at the epicenter of one of those battles. His case was the stuff of movies, a fast-moving saga that featured one boy’s family begging for a drug, a CEO who would not budge, an aggressive patient advocate who masterfully choreographed a PR siege against the company, and legions of online supporters who elevated the family’s plight to deafening levels.

In early 2014, 7-year-old Josh Hardy developed an aggressive viral infection after a bone marrow transplant. The only approved drug sent him into kidney failure. An alternative drug was under development at Chimerix, the small biotechnology company in Durham, North Carolina, where Moch was CEO. Josh’s doctors pleaded with the company to release the drug, called CMX001, via compassionate use.

Chimerix had run a compassionate-use program of CMX001, and more than 400 patients had received the drug, including several, like Josh, with adenovirus infections. There were a few published case reports of patients with the same infection as Josh, and some showed patients getting better. But the program was shut down in 2012 — a “difficult decision,” according to the company, so it could focus its resources on getting CMX001 approved. Chimerix’s answer to Josh’s doctors was a polite but steadfast no.

By March 5, 2014, Josh’s doctors told his family he had about a week to live. With nothing to lose, his family took to social media. Thursday, March 6, 2014, marked the first post on the Facebook page of Josh’s mom, Aimee Hardy. “The drug company has refused to release the drug for compassionate care because they are trying to take it to market. Basically they are not going to save a child’s life for money,” her post stated.

She triggered an avalanche. The next day, employees and board members of Chimerix received hundreds of phone calls and e-mails in support of Josh, including a call from a US congressman, says Moch.

The family was introduced to Richard Plotkin, a former litigation lawyer who heads the Max Cure Foundation, which he founded after his grandson was diagnosed with lymphoma. With the same relentless energy once deployed in the courtroom, Plotkin plunged headlong into the Hardy cause, directing its PR campaign. “Josh was akin to my grandson, and if Chimerix withheld the drug, Moch and Chimerix became my enemies,” Plotkin says.

Plotkin helped arrange interviews with CNN, Fox & Friends, and CBS. Aimee Hardy’s first major appearance was on a Sunday night with CNN’s Elizabeth Cohen. “The fact that they say that we can’t have it is absolutely infuriating to me,” she told CNN of Chimerix and CMX001.

Moch tried to explain why Chimerix denied Josh the medicine. Based on the hundreds of requests for compassionate use of CMX001 that Chimerix received the year before, Moch knew that granting Josh’s request would have meant hundreds more “Joshes” would come knocking at the company’s door, arguing they were as deserving of a chance, which the company didn’t have the resources to handle. As Moch explained to CNN: “If this were just one patient wanting this drug, then this would be a very different question. But it’s yes to all or no to all.”

Plotkin asked Erica Bailey, the social media expert at the Max Cure Foundation, to reach out to supporters. “I was up for 48 hours straight,” Bailey says. “I probably took a nap an hour here or there, but I was constantly communicating on Twitter and Facebook and getting updates.”

Within several days, the SaveJosh Facebook page had reached more than 1 million views, and #SaveJosh trended in the Twitter national top five. Social media posts and comments teemed with frustration. A lot of the anger was directed at Moch: “Your CEO is #heartless.” “There is no excuse not to save a life where you can when you can. No one should have the right to say no.” “Hey Mr. CEO, what if Josh was your baby? That would change your mind. Where is your humanity if you won’t save a child?”

One commenter on the SaveJosh Facebook page posted Moch’s home address and phone number. (Moch would receive death threats, deemed serious enough by the FBI that he and his wife had to spend five nights in a hotel under an assumed name, with armed protection.)

Not known to Josh’s supporters was that Chimerix had been working with the FDA to create a clinical trial through which Josh could get the drug. By Tuesday afternoon, five days after Hardy’s initial Facebook post and with the social media firestorm in full swing, CMX001 was on its way to Josh.

At the time, Moch couldn’t talk about the behind-the-scenes negotiations because of patient privacy rules. Chimerix, a public company, also had to be careful about making premature announcements. “The press and social media were demonizing and threatening me and Chimerix, and there was nothing we could publicly do or say to stop the body blows,” Moch recalls.

Late on Tuesday, March 11, the news broke, and quickly went viral, that Josh would get the drug. “We changed our entire tone. We changed our hashtag from #SaveJosh to #SavedJosh,” Bailey says. “It was political, it was romantic, it was social media wrapped up in a little bow.”

Shortly after taking the medicine, Josh started to improve. He went home a few weeks later and is today recovering at home. Moch was fired a few weeks after Josh got the drug.

THE HARDY SAGA laid bare questions about fairness and equality of access to a scarce resource in an era where social media can amplify the voices of some patients over others. “Should an experimental product be made available to an individual patient who is more vocal, more sophisticated in the use of media, more knowledgeable about the system, more adept at electronic searches?” wrote Arthur Caplan, director of the Division of Medical Ethics at the NYU Langone Medical Center, in a Health Affairs Blog piece titled “Rescue Me: The Challenge of Compassionate Use in the Social Media Era.”

According to Caplan, the Josh Hardy case was the trigger for the creation in early 2014 of the NYU Working Group on Compassionate Use and Pre-Approval Access, which is working with companies, regulators, and patient advocates to reform the compassionate-use process.

One of the advisers to the group is Richard Plotkin, the man who helped vilify Chimerix and Moch. In a fantastic turnaround, Plotkin now calls Moch a hero. Today the former enemies consider each other friends and have appeared at patient advocacy events recounting their experiences.

Plotkin speaks of having evolved in his understanding of the complexities of compassionate use, including the potential negative impact to the company if the drug had failed to save Josh. “In hindsight, I can now say that if I were CEO of Chimerix, I would have taken the same position as that taken by Ken Moch — not allowing my subjective emotions to control what was the more reasonable position, namely, not derail what Chimerix was doing to save hundreds, if not thousands, of Joshes’ lives.”

In fact, the most widely misunderstood learning from the Chimerix saga was that, in the end, it was a victory for the traditional clinical trial path toward approval. The flurry of celebratory headlines implied that Chimerix had reversed its position in giving the drug to Josh. But that’s not true. Chimerix never caved. It did not provide the drug via compassionate use. What saved Josh Hardy was Chimerix and the FDA moving faster to create a clinical trial, of which Josh was the first patient. More than 100 patients have been enrolled, and early results seem encouraging.

Thus, one warrior mom and an army of advocates helped expedite the creation of a study that might very well help get CMX001 approved. Multiple lives have been saved through the new study, and with a greater purpose, because the information gleaned would have been lost had the patients received the drug via compassionate use.

THIS IS WHERE THE STORIES of Chimerix and Sarepta and the lives of Jenn McNary and Aimee Hardy intersect in a crucial way. They are examples of extremely vocal families pushing the FDA to pay attention. Even if CMX001 saved Josh Hardy and McNary thinks eteplirsen is helping her sons, the only way to know for sure if the drugs are efficacious is to do the proper studies. In the eteplirsen case, following patient pressure, the agency allowed the creation of a more flexible clinical trial in which McNary’s son Austin and several other boys who are no longer able to walk were enrolled. In both cases, the result has been to enhance and possibly expedite the approval process by enrolling patients into new trials, opening the treatment door to those whose only prior option was to ask for compassionate use.

“Patients have demanded and have taken a place at the table,” says Richard Moscicki, deputy center director for science operations at FDA’s Center for Drug Evaluation and Research. “So we recognize that, and we are committed to trying to figure out how to incorporate that into our own internal thinking.”

Compassionate use has been a hot topic for the agency, as patient frustration with the current system seems to have reached a tipping point. While it’s true the FDA grants 99 percent of the compassionate-use requests it gets, patients have complained that the application process itself is too cumbersome, involving forms that the typical doctor, working on behalf of a desperate patient, would find difficult to navigate. “We’re talking hours and hours and hours of work” by doctors, nurses, and other hospital staff, says Charles Levenback, an oncologist in Houston at MD Anderson Cancer Center. Levenback was Andrea Sloan’s main physician during her high-profile campaign to obtain an experimental cancer drug from a company called BioMarin.

It is this mounting sense of frustration with the FDA that has triggered the proliferation of so-called “Right to Try” laws. Now passed in 21 states and under consideration in many others, the laws allow terminally ill patients who have exhausted all treatment options, including clinical trials, to directly obtain from companies — and without needing the FDA’s consent — unapproved drugs that have advanced past phase I testing, which evaluates safety in a small number of people.

The impact of these laws remains to be seen. They don’t force companies to make their drugs available, and it’s hard to envision manufacturers willing to bypass the authority of the very agency that eventually approves their products.

But the laws have been a major wake-up call for the agency. In February, the FDA announced the creation of a single form to be filled out for compassionate-use requests, which should take about 45 minutes to complete.

WE ALL SHARE THE INSTINCT to rescue those in need. That’s what makes it so hard to grasp that an act that seems so benign — at the very least it offers hope, at its best it saves a life — could have negative consequences for the patients themselves and, even worse, for others.

There is a subconscious bias to believe, especially when a loved one is dying, that experimental drugs are miracle cures. “When we talk about experimental treatments, the doctor is frequently talking about a response rate, not a cure, but the patient is hearing cure,” says Charles Levenback.

In reality, very few of the phase I and II drugs in companies’ pipelines are likely to help patients, and could even cause harm from unknown side effects. In cancer, most drugs in phase I never make it to the market, and a significant percentage of those that make it to phase III, the larger studies used to determine a drug’s efficacy, still fail. In other therapeutic areas, like Alzheimer’s, the track record is, sadly, still worse.

Even some of the drugs showing early promise and that are fast-tracked for approval by the FDA end up failing.

Meanwhile, there is an ever-growing tsunami of information, with results from clinical trials constantly posted in press releases and on websites, where the slightest indication of hope takes on a new meaning in the hands of the desperately ill. There is little doubt among experts that, as the flow of information expands, so will requests for compassionate use.

Until now, the industry dealt with this challenge in an ad hoc, haphazard way that has left many patients feeling confused and ignored. Some companies have compassionate use programs but don’t advertise them; others don’t have the programs at all and do not intend to. There isn’t a directory where patients can easily find this type of information — it’s not something companies systematically put on their websites.

Increasing transparency would be a major step forward in making the process more patient-friendly. The 21st Century Cures Act, overwhelmingly passed by the US House on July 10, has a provision that would require manufacturers to make publicly available their policies on compassionate use, including the posting of contact information for patients desiring to make requests.

For Henri Termeer, the former Genzyme CEO, transparency is the only way to deal with this growing challenge. “We create the dilemma by making something available that is enormously desirable. So we need to give guidance, the best possible guidance we can give, to clarify how this works.”

There are reasons companies are reluctant to adopt compassionate use programs. They can cost millions to establish. While the programs’ intentions are noble, a dollar spent underwriting the compassionate use of a drug is a dollar diverted from developing the drug for future patients — a choice favoring one individual over others.

Companies also assume significant risks, many of which the public is unaware of, with expanded access programs. The FDA wants to be informed of all serious side effects thought to be linked to a drug provided via compassionate use. On the other hand, any hints that the drug works are not taken into account during review.

This makes sense, since efficacy needs to be measured carefully in clinical trials. Still, it’s hard to imagine any other industry where a manufacturer is willing (or pressured) to release a prototype in an uncontrolled setting, knowing that its regulators are closely watching for instances where that product causes harm.

If major side effects surface via compassionate use, it’s much harder to understand why the side effects occurred, since these patients tend to be much sicker. And this can mean trouble with the FDA.

That’s what happened last year to Los Angeles-based oncology drug company CytRx Corp. after the death of a patient who had obtained the company’s cancer drug via compassionate use. The FDA ordered all of the company’s clinical trials of the drug to be stopped. The hold, which only meant new patients could not be enrolled, lasted two months.

Patient advocates complain that all too often the industry hides behind this fear of surprise side effects as a reason for not wanting to establish more compassionate-use programs. While the impact of a clinical-trial hold can’t be underestimated for a company, such holds do seem to be extremely rare. A preliminary look at some 5,000 compassionate-use cases has only produced two examples where side effects led to some FDA action, says Richard Moscicki. The flip side of that, he says, is that compassionate use can help flag promising drugs at his agency. “I can tell you that in the short two years that I have been here I have actually seen a compassionate-use case really turn the review division around in its thinking, seeing evidence that a drug really was having value.”

THE GOALS OF COMPASSIONATE USE are mostly incompatible with those of drug development. So perhaps the enterprise would function better overseen by an independent third party.

That’s the experiment being done by pharmaceutical giant Johnson & Johnson, which in May embarked on a novel partnership with NYU’s Arthur Caplan. He will lead an independent panel of 10 experts (to include doctors, bioethicists, and patient representatives) that will review the compassionate-use requests that Johnson & Johnson receives.

There’s increasing recognition that a mechanism to take the economic burden off companies, especially smaller ones, could greatly motivate the creation of more programs. “You’ve got to put money aside to pay for the access,” Caplan says. “Society needs to decide if they want to put money into this.”

Many questions remain open for discussion, and most defy a single, simple answer. Should phase I drugs even be considered for compassionate use, given that so little is known about their safety and efficacy? Where should society draw the line when defining a disease as “life threatening” for the purpose of qualifying for compassionate use? Should children be given special consideration for these programs because they rarely qualify for clinical trials?

A solution that caters to the sickest patients while doing what’s best for the general public will no doubt prove elusive. There are no better words than those of a mother to capture this predicament. When Aimee Hardy was asked what she would say to Kenneth Moch if she saw him today, this was her answer: “I would tell him that I hope and pray that his family and himself are doing very well, and again I am sorry the situation had to be so public and difficult. But I would do it all over again if I had to. Josh is not just any Josh. He is my Josh.”

Sylvia Pagan Westphal, who has a Ph.D. in genetics from Harvard Medical School, is a health care writer who has contributed to the Globe’s opinion pages. Send comments to magazine@globe.com.

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Please Email Congress Before Friday, July 6

Dear supporters of Hope NOW for ALS,

Please email Congress before Friday to ask for their continued support. Due to the upcoming recess, this week is our only opportunity to request their support before our next teleconference with the FDA on July 6.
On June 17, we conducted a teleconference with the FDA and we can report some progress, but also some concerns.

The good news is the FDA agrees that:

1) FVC is a valid clinical endpoint,
2) trials can be populated with “fast progressors,” and
3) an ALS therapy could be approved after a Phase II study if it resulted in a clinically significant, positive effect on FVC decline.

FDA described what they meant by clinically significant as “compelling, convincing evidence” between the treated group and the control (placebo) group.

The FDA’s position on potential ALS biomarkers is that none have been validated and, therefore, none can be used as surrogates to support an accelerated approval, but they did assure us that collecting data on potential biomarkers would not be used as evidence against approval of an ALS drug if a correlation between the marker and the primary endpoint (for example FVC) is not seen. Also, FDA agreed that measurement of potential biomarkers could be included in a study to enhance understanding of their relationship to ALS. FDA provided some general responses on how an ALS biomarker could be validated, but did not progress to details.
We proposed the concept that small clinical studies can produce sufficient evidence of efficacy to support an approval, especially if progression prediction models are employed to appropriately select the trial population or to establish individual patient baselines. The FDA expressed openness to learning more about predictive algorithms.

During discussions of some of the potential biomarkers for ALS, it appeared that the FDA’s Division of Neurology Products (DNP) medical review officers (Drs. Eric Bastings and Ronald Farkas) were unfamiliar with the state of biomarker science in ALS. We hope this is not the case, and we intend to explore and build their knowledge of the state of medical science with respect to ALS during our ongoing communications.

Based on our discussions during the meeting, we are also concerned that the FDA is employing a very narrow, rigid and outdated view of the circumstances in which the Accelerated Approval pathway should be available to drug companies trying to bring new medicines to market. Dr. Woodcock made the FDA’s position on Accelerated Approval very clear by stating that in FDA’s mind there is nothing fast about Accelerated Approval, and they wish they hadn’t called it that. Her position on the Congressional intent of Accelerated Approval seems to be at odds with the directions FDA received from Congress in the 2012 FDASIA legislation, which made it clear that FDA is to apply new thinking, flexibility and an expanded set of evidentiary tools to speed new medicines to patients who need them for diseases like ALS.

This issue will be discussed again at the next meeting since Accelerated Approval is clearly intended for diseases like ALS for which there is no effective treatment.

We are also concerned with the subjectivity the FDA maintains in determining what constitutes efficacy and “convincing evidence.” We intend to press the FDA for a clear definition of efficacy for a given trial design that could result in quickly accepting a new drug application (NDA). This is particularly relevant to GM604 in order to define a small, confirmatory study that could result in its approval if the results meet the definition of efficacy. We also believe this will create a template for future ALS treatment options.

As mentioned earlier in this update our next conference call is scheduled on July 6 and this call should determine if the Dr. Woodcock and the FDA will bend and be reasonable. Using the template below please email your congress before Friday and request their continued support.

Remember, the best way to follow breaking news items that affect our campaign is to follow us on Facebook: https://www.facebook.com/gm604forals

We’re in this together,

Jehad Majed (jmajed@mac.com), Matthew Bellina, Nick Grillo (gm6nick@gmail.com), and the Torrino Family

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