Proposed FDA “Conditional Approval”- More Details

A Q&A with Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY. Marty Tenenbaum, PhD, Founder and Chair, Cancer Commons, Los Altos, CA

Originally published May 10, 2017

Q: Your April 5, 2017 blog post that proposed a new “Conditional” category for FDA drug approval elicited a number of positive and negative responses. Please explain the proposal in more detail to enable better reader understanding.

A: In Response to “Conditional Approval: Right Solution for the Wrong Problem” by
Shannon Brownlee:

We appreciate Ms. Brownlee’s comments on our recent blog post, but think she missed our key points—perhaps we weren’t clear enough:

  • Conditional approval isn’t intended for cancers that have other options—like some types of breast cancer—but rather for the invariably fatal cancers like glioblastoma multiforme (GBM), for which there aren’t any good FDA-approved options.
  • Conditional approval requires not just evidence of safety, but evidence that the drug has promise, at least in some patients.
  • Using the registry is just a different way of collecting the data that traditionally is collected in clinical trials. Instead of a traditional trial in which only highly selected patients participate and relatively few doctors collect the data, we will be collecting data on the entire range of patients from many doctors.

Having many doctors and patients participate removes a lot of the bias inherent in clinical trials. For example, consider a doctor using an experimental treatment on “thousands” of brain tumor patients in 100 clinical trials in which only a handful of doctors are collecting all of the data. All of the doctors involved have a major financial interest in the outcome. We still have no idea if this treatment helps or hurts—and it has been going on for 40 years. With our system, we would know in a year if it helps or hurts.

Moreover, Ms. Brownlee’s arguments extolling the virtues of randomized clinical trials (RCTs) may reflect an unfamiliarity with the cost-effectiveness of “registry trials,” especially when coupled with modern Bayesian designs.

With the traditional approach, we have been lucky to get 3 or 4 treatments approved in the last 40 years. With our approach, we can expect at least 3–6 new treatments conditionally approved each year, as the cost to get approval would be on the order of 1–2% of the cost using the current traditional approach.

  • As Ms. Brownlee states, “It took more than a decade to accumulate enough patients” in an RCT to demonstrate the ineffectiveness of autologous bone marrow transplant (ABMT) in breast cancer. Further, “A few patients may actually have been helped by the Avastin, but there is no way to predict ahead of time whether patients would be helped or harmed.” These points demonstrate the limitations of classical RCTs versus Bayesian point-of-care trials that can be run on top of a registry.
  • The big challenge and opportunity regarding investigational treatments that show promise in some patients is to identify and continuously refine the cohort for whom an intervention is effective, as efficiently as possible. This requires a Bayesian approach, which can rapidly replicate successes and discard failures, not accruing a large trial to test a specific hypothesis, which is likely to be wrong.
  • A registry that captures biomarkers, treatments, and outcomes from patients undergoing a variety of interventions can provide rigorous cross-controls, which are every bit as valid as those provided by randomization.

Using Ms. Brownlee’s example of ABMT, in our system, the registry would have quickly picked up that it was not as good as standard chemotherapy. The current system allowed 41,000 women to use a treatment whose effectiveness was unknown because nobody was tracking it. An RCT took 10 years to find an answer that our registry may have had in as little as 1 year, saving many lives.

Ms. Brownlee states that the registry can’t show efficacy. We disagree. If you have the majority of patients being tracked in the registry, you can use all of the patients who are NOT taking the treatment as the control group. Comparing to the old historic control is useless for brain cancer—almost everyone died and we did not collect the necessary biomic data to correctly match them with current patients.

The comparison that needs to be made is which of many possible new treatments and combinations works the best. Some patients would probably stick with the old standard of care—we would be encouraging them to participate as well—so we can see if the current standard is better than any of the new treatments.

We are talking about using conditional approval only in cases where there really is no acceptable standard of care. And we ARE looking for new drugs and combinations that have extraordinary power to improve outcomes, not looking for something that extends life by weeks. We agree it wouldn’t make sense in a disease where the standard treatments offer hope.

In summary, our proposal is not to minimize the research, it is to maximize the amount of research done to a drug, just in a different time period—after phase 1 instead of before the end of phase 3.

As to picking up idiosyncratic reactions, by definition, these are rare and do require a large group of patients being tracked to identify how frequently they occur. With our registry, it is simple to analyze the data and get an early warning. Having the genomic data would allow us to try to figure out which patients are most likely to have such a problem. With traditional trials, which usually only allow a select population to be tested, a reaction that only occurs in the elderly or in minorities—which are underrepresented— may never be found. Once a drug is approved and underrepresented groups use it, side effects are not tracked as closely as they would be in our registry.

For more reference, please read “Rapid Learning for Precision Oncology” published in Nature on Jan 21, 2014. We include a free PDF download. Please see below for a 3-minute video showing how the Bayesian approach can be applied to medical research in a new method called Global Cumulative Treatment Analysis (GCTA).



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Conditional Approval: Right Solution for the Wrong Problem

A Q&A with Shannon Brownlee, MS, Senior Vice President of the Lown Institute, a think tank in Boston. She is also co-founder of the Right Care Alliance, a social movement for transforming health care.

Originally published April 26, 2017

Q: Musella and Tenenbaum recently proposed a new way, called conditional approval, for the American FDA to move potentially useful drugs to a patient market. They wrote that safety would be covered and efficacy assessed by a registry. What do you think of that idea?

A: Imagine if there were a way to speed up the discovery and testing of drugs for cancer. Al Musella and Marty Tenenbaum, founders of two cancer patient advocacy organizations, think they have just such a plan.

They have proposed giving new cancer drugs conditional approval, allowing them on the market after Phase I (safety) trials in as few as 50 patients. Patients and their doctors would be free to use the new, and unproven products, provided all patients enroll in a registry. The patient’s (de-identified) clinical information (pathology reports and biomarkers, for example) would be included in the registry. This would allow the FDA and researchers to determine, by the end of a pre-set conditional period, whether or not the drug is safe and effective when used on a larger population.

Sounds like a great idea, doesn’t it? It eliminates Phase III efficacy trials, which are slow to complete, expensive to conduct, and drive up drug prices. Musella and Tenenbaum’s plan would give patients ready access to potentially life-saving treatments, speed up approval, reduce the burden on the FDA, bring down the cost of drug development, and create a registry for cancer patients that would open up research avenues. What’s more, Japan, Canada, and South Korea have conditional pathways for new cancer treatments. Why not us?

Because it’s a bad idea that will waste a lot of money and hurt patients. Have we all forgotten the recent history of ineffective and harmful cancer treatments? Autologous bone marrow transplant, or ABMT, and Avastin (bevacizumab) are two that come to mind.

ABMT was developed in the 1980s and was used on at least 41,000 women with metastatic breast cancer. Oncologists, transplanters, and the press embraced the treatment enthusiastically on the basis of a single study comparing it to historical controls. It took more than a decade to accumulate enough patients in randomized controlled trials (RCTs), which showed in 1999 that ABMT was worse than standard chemotherapy—it killed about 10 percent of patients. Insurers paid more than $3.4 billion over the course of the decade for a treatment that actively harmed patients.

A decade after that, Avastin was approved for breast cancer on a fast track in 2008, based on “time to progression.” While there wasn’t any proof that time that progression directly affects how long patients live or their quality of life, Genentech, the manufacturer, argued that it was a good marker of improved patient outcomes. By 2010, worldwide sales of Avastin had hit $6.8 billion.

But once again, it took an RCT to show that the drug caused significant side effects and offered no survival benefit. A few patients may actually have been helped by the drug, but there is no way to predict ahead of time whether patients would be helped or harmed. The FDA withdrew Avastin’s approval for breast cancer treatment in 2011.

Imagine Avastin under a conditional approval plan. Women on the drug would have enrolled in a registry, and that registry might have turned up the side effects that emerged in the actual post-marketing trial. But it could not have shown lack of efficacy.

There are several reasons for this, the main one being that outcomes for people on a registry have to be compared to something. That something would be historical controls–similar patients who have had other treatments. The benefits of most cancer treatments are modest at best, and it’s very easy to be fooled by historical controls unless a new drug has extraordinary power to extend life or cure the disease.

There are other ways to solve the problems of high drug prices and slow development of truly innovative drugs for rare cancers, which Musella and Tenenbaum cite as their motivation for recommending conditional approval for cancer drugs. Congress could let Medicare negotiate drug prices. It could increase the FDA’s budget to speed up approvals. (FYI, the FDA already approves drugs faster than any regulator in the world.) Insurance companies could be required to cover treatment for patients in randomized controlled trials.

Even though Musella and Tenebaum’s registry is a bad replacement for RCTs, it’s still a great idea. Manufacturers can track defects in cars and toasters better than the US tracks outcomes and safety of new medical products. Registries should be required for every patient who receives an implantable device or a new drug for any condition. Let’s use registries for what they’re good at, which is spotting harms once a product is used in a large population. Don’t erode the approval process for the sake of speedy access to drugs of uncertain benefit.

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A Proposed New FDA Drug Approval Pathway: “Conditional”

A Q&A with Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY. Marty Tenenbaum, PhD, Founder and Chair, Cancer Commons, Los Altos, CA

Originally published April 5, 2017

Q: The delay time from discovery/observation, through validation to approval and distribution/use of new cancer treatments remains excessive. With promising experimental treatments, advanced computer technology and biostatistics, creative alternatives to traditional randomized clinical trials, and a government seeking efficiencies, might it now be time for the FDA to issue: “Conditional Approvals”?

A: The first advances in oncology occurred at a time when there were no regulations. Doctors had ideas, and put them to work immediately. They adjusted and combined treatments as needed until they were optimized and became standard treatments. Many types of cancer were cured by this work.

Unfortunately, for patients, with glioblastoma, pancreatic cancer and other rarer cancers, the prognosis remains dire: average survival with currently approved treatments is less than 2 years. These patients can’t afford to wait a decade or more for new drugs to be approved.

The good news is that the oncology drug development pipeline is full of promising targeted- and immuno-therapies that have already demonstrated safety and at least some evidence of effectiveness. However, under current regulations, it will take years before the average patient can get access to these potentially life-saving treatments. Moreover, it is likely that a cure will involve intelligent combinations of treatments. Under current regulations, combination testing cannot even begin until these drugs are approved. And what if a new treatment was not effective as a monotherapy, but could be an essential component of a multi-drug cocktail, say to block a resistance pathway. Catch 22. Under current regulations, many good ideas will never get to patients, and those that do get approved have to be priced so high that many patients cannot afford them.

We would like to propose a new pathway to FDA approval – the “Conditional Approval” – that addresses these issues. It would allow the FDA to approve a treatment that shows safety and a biological effect in a small group of patients. (Click HERE for more details). The twist is that it would require patients using these drugs to participate in a registry where their doctors submit details on the treatments they use, side effects and outcomes.

Conditional approval would be granted to treatments that have been proven safe in a clinical trial(s) with at least 25 patients, and have demonstrated biologic activity: an improvement in a biomarker, brain scan, progression free survival or overall survival.

Once approved, the treatment could be offered as if it had a standard approval, and could not be denied by insurance as being “experimental”. However, all patients who use a conditional treatment would be required to participate in a registry for the duration of the conditional approval period, and to sign a consent form acknowledging and agreeing to the risks inherent in undergoing a treatment whose safety and efficacy have not been fully tested.

The FDA would conduct periodic reviews of this registry data, with three possible determinations: 1) If the safety is questionable or if the results look worse than the standard treatments, conditional approval would be withdrawn, and the manufacturer could continue on the standard paths of approval. However, the FDA could not use these results against the standard approval tracks, as the patient population was not controlled and patients were combining other treatments with it; 2) If the results look at least 20% better than the standard treatments, in the first 50 patients over a predetermined period of time, full approval is granted; or 3) If the results are similar to standard treatments, the conditional approval is maintained until the review shows either the treatment is good enough for full approval or bad enough to withdraw approval.

The decision to try a conditionally approved drug, alone or in combination, would be up to treating physicians, who could consult with peers through a network linked to the registry or use a decision support app that exploits the registry as a database (e.g., show me all treatments and combinations that have been tried on similar patients, sorted by most effective, most cost effective, best risk / benefit ratio, cost, or least side effects.) Such apps could also support low cost point-of-care ‘registry trials,’ whereby patients are dynamically assigned to treatment arms based on expert recommendations and clinical outcomes for similar patients.

It is painfully obvious that the way to cure our currently incurable cancers is to use a combinational approach. We may well have the necessary tools available today—but we are not allowed to use them. When faced with certain death, we believe it is acceptable to not have 100% proven safety and efficacy. We will be approaching the FDA with a request to pilot conditional approval in brain cancer – because life and death decisions should not be made based on regulations – they should be based on what is best for the patient, as determined by the patient and his/her doctors.

We have been working on this plan for a while, but we think now is the time for it to actually be approved. Everything is coming together – like the perfect storm:

  1. We finally have a few experimental treatments in the pipeline that look really good.
  2. The new President is slashing regulations and calling for faster FDA approvals and for slashing drug prices.
  3. Computer technology and biostatistics have reached the point where our plan for a registry trial can be just as reliable as traditional phase 3 trials – maybe more so.

IF this proposal is put into effect, it could lead to rapid advances in the treatment of brain tumors, and the possibility of a breakthrough cure in a few years, instead of the decades it would take on the current path.

We need your support and will be reaching out in a few weeks for help with writing letters and making phone calls. Meanwhile, we welcome your thoughts.

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How to Tell a Patient Their Cancer Has Spread

A Q&A with crisis communication expert Lisa Dinhofer, MA, CT

Q. As a counselor and communicator, you are expert and experienced in managing serious situational difficulties up to and including coping with sudden unexpected death. How would you think it best to approach a person with cancer who is being told, “your cancer has spread”?

A: I’ll answer this question by posing another—how did you discuss the diagnosis initially? Did you jointly establish expectations for addressing this illness going forward?

How a diagnosis is delivered plays a critical role in future conversations around how the illness is responding—or not—to treatment. This initial conversation is the foundation for many more that could go in various directions dependent on disease progression, regression, and patient tolerance.

It’s about process and setting the expectation that you are partnering with the patient in their care, which will include honest and compassionate discussion about options as they become available or diminish. How individuals view a diagnosis changes over time. What can’t be imagined initially may become preferred eventually. Leave room for the unknown.

Initial communication principles that include, “As we address this illness, as we see how your illness is responding, we can continue to make decisions based on what we’re seeing,” set a stage for gentle openers and segues if the need to relay unwanted news becomes necessary. Referencing the illness’s response versus the patient’s, “failure” to respond to treatment rests on the disease not the person.

Strive for balance between optimism, hope, and acknowledgement of the situation’s seriousness. Hope and honesty are not binary. Neither are pragmatism and sensitivity. When allowed, hope’s definition can change in meaning resonant with fluid situations.

A talented artist friend battling lung cancer that had spread to her brain remarked that “hope had become a leash” used by family to drag her from coping and conversing honestly in a way she so desperately needed and wanted in her remaining time. She became more prolific as her illness progressed, enough for a successful gallery show, and used her work to “break through” to her family. Her hope transformed from being cured to preparing her young daughter and husband for what lay ahead. We met in pottery class where she made the urn for her cremains.

The following phrasing suggestions incorporate points above with basics for giving bad news:

  1. “(Patient’s name), we need to discuss your latest test results. Honestly, they are disappointing.” (Pause). This is a “warning shot,” giving the patient an opportunity to psychologically “suit up.”
  2. “The tests reveal the illness has spread to ________.  (Pause for a few beats to sink in. Rushing on increases the likelihood they won’t hear anything else.) I’m so sorry, (name.)” (This is an apology for their circumstances, not your failure).
  3. “What this means is _______________.”
  4. “Here are options for us to consider_____________.”

If a terminal condition, that does not mean there are no options; it means there are different options than before. The goals of your care might change from treatment to palliative, dependent on a patient’s perspective.

The most important principles for delivering difficult news are preparation, controlling beforehand any personal discomfort so as to completely focus on them rather than rushing to end the conversation, telling what you know when it is known to be true, and remembering that this is about them, not you.

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Why the 21st Century Cures Act is a Good Thing

A Q&A with Mary Woolley, President and CEO of Research!America

Originally published Feb. 8, 2017

Q: You attended the December signing by President Obama of the 21st Century Cures Act and are recognized to be a strong supporter. Yet harsh criticism of it has quickly appeared in JAMA, BMJ, a variety of other venues, as well as on these pages. Please tell our readers why this is good legislation and how the public health will be protected from exploitation in this very different regulatory world.

A: The bi-partisan 21st Century Cures Act is grounded in a commitment to assuring that our nation’s research ecosystem has the capacity to accelerate the pace at which safe and effective medical advances reach patients. The Act will expand the efficiency, reach and impact of medical discovery in a manner that sustains crucial safeguards against unsafe or ineffective products. The law finances more research, helps to reduce the administrative cost surrounding basic research, and takes additional steps to overcome challenges the Food and Drug Administration (FDA) faces. Patient groups, health care professionals, academic leaders, industry leaders and the FDA and the National Institutes of Health (NIH) were frequently consulted regarding provisions of this bipartisan bill, and their insights were incorporated. We at Research!America were closely involved throughout development of the bill, and are pleased that it crossed the finish line last December.

After years of automatic spending cuts and flat-funding, researchers have been stressed as they work to find solutions to deadly and complex diseases. The 21st Century Cures provides some relief in that regard with an initial $352 million in FY17 to support the NIH Precision MedicineBRAIN, and Cancer Moonshot initiatives. Congress recognizes that these dollars are targeted and temporary; they do not supplant the need to grow NIH’s annual budget. As reflected in surveys that Research!America commissions regularly, Americans recognize the importance of federally-funded research and support streamlining the pursuit of medical research and innovation.

The FDA, which has for years been underfunded, will also receive new funding with an initial $20 million in FY17 to improve efficiencies in the R&D pipeline. This new funding, in combination with other provisions of the law, is particularly meaningful as it will give the FDA more flexibility to recruit additional experts needed to assure that our regulatory system can properly evaluate rapidly evolving science in areas such as immunology and regenerative medicine.

One important example of rapidly evolving science is the potential to diversify the evidence base used to evaluate the safety and efficacy of medical advances by leveraging “real world evidence” (RWE). The Cures Act defines real world evidence as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” While concerns have been raised that the RWE provisions would force the FDA to relax critical safety and efficacy standards, these provisions were developed with agency input. This section of the law is designed to empower, not require, the FDA to capitalize on real world data. Real world data will be used when — and only when — it is appropriate to do so.

Faster medical progress saves lives. The 21st Century Cures Act will fuel faster progress. It’s incumbent upon research advocates to engage elected officials to build on the Cures Act, and ensure that adequate funding is provided to make the promise of science and innovation a reality in our lifetime.

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How I Survive Cancer

A Q&A with Erin Maloney: Intrepid explorer, Amateur photographer, Aspiring leader; Toronto, ON


Originally published Nov. 1, 2017


Q: You have recently disclosed that you have had a diagnosis of cancer and described your experience in some detail on Medium. What does it mean to you to be a “Cancer Survivor”?

A: Calling myself a survivor sometimes feels like an exaggeration. In 2016, I was diagnosed with Stage 1A2 squamous cell carcinoma of the cervix. It began with a routine pap smear and led to a robotic laparoscopic radical trachelectomy seven months later. Every procedure was challenging, and surgery was particularly arduous. However, I did not have to endure radiation, brachytherapy, or chemotherapy. I got to keep my hair, didn’t have to cope with nausea or worry about the lifelong maintenance required after radiation. So, in many ways, calling myself a survivor feels fraudulent. I have it too easy.

The physical recovery was relatively smooth but there is no preparation available for the mental toll of the Big C diagnosis. After the gynecologist shared the news, everything moved quickly. Within 10 days I had an MRI and was in consultation at Princess Margaret Cancer Hospital. It did not leave much room for preparation. In a very brief timeframe, I went from being a healthy 32-year old with no plans to have children to being a 33-year old who might not have a say in the matter.

People expect others to react in a binary way to that kind of news. There is a belief that one can choose to be optimistic or pessimistic, but that is a false dichotomy. Some days optimism abounds; most days, the fear brews below the surface unacknowledged. I mentally created a list of unanswerable questions (Would a hysterectomy be better? Would I feel like less of a woman? What if it comes back? How do I cope with this forever? Is this what kills me?). I researched and armed myself with information – a coping mechanism that allowed me to ignore my own terror.

I am not the same person I was a year ago. Prior to this, I was entrenched in the pitfalls of my Type A personality: a planner and organizer, domineering and determined, opinionated and unwilling to compromise. I had big ambitions and undaunted confidence. But our best-laid plans can be laid waste by a simple two-word sentence: “It’s cancer.” I wished I believed that this was part of some larger plan but it wasn’t. Instead, what it meant for me was that I had to change. My attitude needed to be different if I was going to come out the other side not completely broken.

Cancer took away my control. I could think of little else. Administrative inefficiencies rendered me powerless. I couldn’t get the answers I was seeking faster than they were willing to give them. For example, making decisions for myself was challenging when I needed answers from a busy surgeon. If I tried to use the same approach as I normally would, I would probably have ended up insane. So, I made the decision to adapt. I had to learn patience, to be more open to spontaneity, flexibility, and work on being able to ‘go with the flow.’ I try to allow humour and positivity to flow into impossible situations. I practice kindness and thoughtfulness as often as I can. I strive to think of others and notice their needs. Above all else, I try to treat people the way I want to be treated; to be more open and to deliver honesty without being cruel or callous.

There are many days when I fail at most of those things. Self-improvement is never easy. Imposed self-improvement as a survival mechanism is even more difficult. Finding and maintaining true positivity in the face of overwhelming terror has been the hardest task of all.

The depression that surfaced during recovery was different; it was borne out of a deep desire to live and the constant fear that I might not. I still don’t have certainty. The fear that surrounds each appointment will never abate. In a strange way, that has been inspiring. I want to live. I want a full, vibrant life that is technicolour. It doesn’t mean every day, and it doesn’t mean I get to tick off all those dreams immediately. Ultimately it means that I want to live better and that’s what makes me a survivor.

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.