Posts

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part Three


A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc.Partner at Pharma Initiatives; mshapiro@xcures.com. This is the final installment in a three-part series in which Dr. Shapiro has shared his thoughts on the question below. Read part 1 and part 2.
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: In clinical research, agreements between the research sponsor and the treating institution define what aspects of a study protocol are charged as research or related administrative costs, and what items are considered standard-of-care; that is, eligible for billing to insurance. This is made by a coverage review at the institution. While the sponsors provide the study drug freely to the site and patients, they expect to receive valuable data in exchange. In expanded access, which is treatment rather than research—but stills follows a protocol approved by the U.S. Food and Drug Administration (FDA)— sponsors pay the required administrative costs and the free provision of the investigational drug. The drugs are expensive, and the sponsor incurs additional compliance costs when they make an investigational drug available. So, expanded access is largely a charitable act on behalf of the sponsor. While there are regulations allowing sponsors to recoup their costs under expanded access, these are rarely used. Most sponsors, especially larger companies, deliberately plan for expanded access when planning manufacturing campaigns during oncology drug development. In fact, large sponsors report that they approve about 95% of the expanded-access requests that they receive.
Recently, the FDA commissioned a study by McKinsey & Company on their processes for expanded access and has been busy implementing several recommendations to streamline the administrative barriers. In that report, it was estimated that it takes a physician and their support staff an average of 30 hours to prepare a single-patient expanded-access request, so the FDA introduced a plan to prepare the requisite forms for single-patient expanded-access requests for doctors who request it. The cost of expanded access then is partly borne by the patient’s doctor, who must invest significant extra time to request the drug and comply with the additional responsibilities associated with using it.
These programs are for the primary purpose of treatment, not research. Nonetheless, ethicists have made it clear that there is an ethical imperative to learn from treatment provided under expanded access. Therefore, at xCures we try to learn as much as we can in the least burdensome way possible while helping to meet regulatory requirements for reporting on safety and patient outcome by using real-world data to further reduce the administrative burden for sponsors and physicians participating in expanded-access programs.
Under the Right to Try Act, the patient does not have a “right to try,” but they do have a “right to ask.” Specifically, they can ask their doctor, who, if suitably licensed to practice medicine, can ask a sponsor to make an experimental drug available. That is no different than expanded access—there is a right to ask. In both cases, the sponsor is under no obligation to provide the drug. The difference is that with Right to Try, a health insurer is not required to pay for care associated with the treatment, which contrasts with the coverage determination for clinical trials, including expanded access, conducted under an Investigational New Drug authorization.
The law does provide clarification about liability, which is another aspect of medical costs. The physician, their institution, and manufacturer are explicitly shielded from liability related to a drug administered under Right to Try for anything other than reckless or willful misconduct, gross negligence, or an intentional tort. I think this may reduce barriers to access, but in my experience, expanded access is not typically inhibited by insurance coverage, and only rarely does language around indemnification in compassionate use agreements become a contentious point of negotiation between sponsors and hospitals. In clinical trials, the consent must disclose who is responsible for costs in the event of a trial-related injury. Often that risk is insurable since adverse experiences that occur during a clinical trial are treated and billed normally. Under Right to Try, the costs of treating any adverse drug effects are likely to be billed entirely to the patient.
So, under Right to Try, the patient will bear the costs of medical care, and unlike an insurer with market power to negotiate discounted rates, they will likely pay the chargemaster rates. They may end up paying for the cost of the drug as well, since the Right to Try Act waives the application of sections in 505 and 351 prohibiting commercialization of unapproved drugs. Only those who are wealthy enough to completely self-pay their healthcare could reasonably access treatments under Right to Try, which could easily run into the hundreds of thousands of dollars (perhaps more). With expanded access, the cost is spread across the sponsor, insurer, institution, and patient, making it more accessible for now.
***
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part Two

A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc.Partner at Pharma Initiatives; mshapiro@xcures.com. Last week, Dr. Shapiro shared his initial thoughts on the question below. Today, he discusses issues of cost and equitable access to care.
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: In late-stage cancer care, treatment is very expensive. While there is a great deal of focus on the cost of the drugs, many other costs are involved, including the cost of care, the cost of the facility, and the cost of laboratory and other tests. When you add clinical research on top of care, there are additional tasks, but it is normally the research sponsor that pays for those administrative and research costs, which are incurred by physicians and the institutions conducting the clinical trial.
Insurance companies also pay for at least some of the associated costs of care. In fact, sponsors of cancer trials strive to design studies that follow existing standards of care to minimize the additional costs of non-standard procedures. The Affordable Care Act (ACA) specified that standard-of-care procedures delivered during a clinical trial could be charged to insurance for studies conducted under an Investigational New Drug application. Before the ACA, insurers in many states did not cover procedures performed when the patient was in a clinical trial, so the passage of the ACA can be credited with the increase of access to and enrollment in cancer clinical trials in the past few years. Patients also bear many of the costs of their cancer care, even when they are in clinical trials, because they are responsible for insurance copays and deductibles.
The new company xCures is working with Cancer Commons to help cancer patients who cannot participate in clinical trials—either because they are too sick, otherwise don’t qualify, or don’t live near enough to a center conducting a suitable trial. To help these patients gain access to medically logical therapy, we create a bridge between the research sponsor’s companies, physicians, and patients to facilitate expanded access. We are focused on reducing the administrative burdens and barriers that inhibit these stakeholders from providing expanded-access treatments.
Right to Try has a similar set of requirements as expanded access but removes some of the administrative time and cost involved, such as oversight from an institutional review board and the U.S. Food and Drug Administration (FDA) or following a formal treatment protocol that defines the safe use of the treatment. It also removes the need to notify the FDA of serious and unexpected adverse drug reactions altogether. That caused ethicists some concern since it is important to learn whether a patient was helped or harmed and share that information with other patients or doctors. It also makes assessing the effects of the law difficult for policymakers.
While the FDA has been clear that expanded access can help and rarely hurts research sponsors, some companies are reluctant to offer expanded access out of fear that they will learn something that might harm their chances for a drug approval. A review of hundreds of non-disclosure agreements and tens of thousands of patients treated under expanded access had laid this fear to rest. But, a clear advantage for sponsors is that under Right to Try, the law disallows the use of outcomes from Right to Try patients to adversely affect the review of the product by FDA. This type of clarification would certainly help encourage expanded access but risks creating a problem of unreported results even as new legal requirements for registration and reporting of clinical trials were implemented under 42 U.S.C. § 282(j)(5)(B).
So, Right to Try is a new tool in the toolkit for seriously ill patients, but the pathway for expanded access is better defined and may be less expensive to implement for most stakeholders, points I will discuss in part three of this series.
***
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.
Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part One


A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc.Partner at Pharma Initiatives; mshapiro@xcures.com
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: Incorporating clinical research into the clinical care of cancer patients may provide more options, and better outcomes, but participation is quite low. In 2004, only about 3% of American cancer patients participated in clinical trials.
More recent data suggest that the number may now be about 5%, although it is lower for women, children, minorities, and patients in community settings. The low figure should be of concern for a couple of reasons. First, patients are the scarcest resource in cancer research. Low participation in clinical trials represents a lost opportunity to learn and improve care. If every patient were part of systematic research, we could greatly accelerate the pace of cancer research findings. Second, most cancer treatment guidelines recommend a clinical trial as the standard-of-care at some stage in the course of disease. So, with current levels of participation, as many as 95% of American cancer patients are NOT receiving standard-of-care treatment at some point in their care. This deficit is partially attributed to the presence of comorbidities or poor function. Recent research suggests that liberalizing inclusion and exclusion criteria in clinical trials could increase enrollment by about 45%. In the study of common cancers, enrollment of patients with solid tumors could be increased from about 7% to 11%.
In my work at xCures, in partnership with Cancer Commons, we recently had a patient who traveled out of state to be screened for enrollment into a targeted-therapy clinical trial at an academic center. At screening, the patient was deemed ineligible because the disease had not yet progressed. A few months later, that patient began to progress, made another trip out of state, was re-screened and found eligible for the trial, but developed an acute and disqualifying comorbid condition the night before starting treatment. This illustrates a common challenge to enrolling patients in cancer clinical trials: The need to thread the needle during a window where the patient is “sick enough but not too sick.” This period can be days or weeks in diseases like glioblastoma and pancreatic adenocarcinoma. We would like to see more use of the U.S. Food and Drug Administration (FDA)’s expanded access programs for the 90% to 95% of cancer patients who can’t participate in a trial. Of course, the results of such participation would have to be reported so as to increase shared knowledge. Expanded access is a mechanism for doctors to access investigational treatments outside of a clinical trial for patients who have serious or life-threatening conditions without satisfactory therapeutic options.
Recently, the national Right to Try Act became law in May of 2018 (Public Law 115-176) following the passage of right-to-try laws in 40 states. The first patient treated under the federal Right to Try Act was in California last year. The sponsor, ERC-USA, notified the FDA that it would make their brain cancer vaccine available in June, shortly after the passage of the law, and treated a patient in November. While the stated goal was to move quickly, the time to treatment was longer than what we typically see for glioma patients with expanded access. However, this is a new alternative for treatment of cancer patients with an investigational therapy and may supplement clinical trials and expanded access programs as options for those patients who lack other treatment options.
All three of these approaches to treatment—clinical trials, expanded access, and Right to Try—raise issues of both cost and equitable access to care, which I’ll discuss next week in part two of this Q&A.
***
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.
Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Options to Treat a Glioblastoma

A Q&A with Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY; email: musella@virtualtrials.com, phone: 888-295-4740
Q: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with a glioblastoma multiforme (GBM)?
A: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me—a newly diagnosed GBM in an adult in otherwise good shape. There are several choices.

  1. Standard of care: Surgery, radiation, Temozolomide. Chance of 5 year survival is about 5%.
  2. Standard of care PLUS Optune. Bumps my chance of 5 year survival up to 24.9% (if used over 90% of the time) with no added toxicity.
  3. Phase 3 Clinical trials: There are now about nine phase 3 trials for newly diagnosed GBM. Some have impressive phase 1 and phase 2 data. By the time a treatment gets to phase 3, it has shown enough promise in earlier trials that the sponsor is willing to risk a lot of money to test in a phase 3 trial. Most have two big downsides: 1) Most have a control group of patients who receive the old standard of care so that some of the participants do not get the experimental treatment. 2) Most do not allow you to use Optune, so you are trading a known benefit for a chance at an unknown benefit.
  4. Phase 1 or 2 trials: There are about 75 of these trials in the USA. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials, which are much better than those seen with standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not (under the current system) have the ongoing results of these trials—we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments.
  5. Off label use of drugs approved for other diseases. There are many choices here and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.
  6. Cocktail approach involving experimental and approved treatments. Right now, this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments tried, and the outcomes so we can learn from every patient.

Getting Access to Experimental Therapies
There are a few pathways to getting experimental therapies. Currently, none are really practical on a large scale. I have tried to get expanded access/compassionate use/right-to-try access on the most promising experimental treatments and it is very hard. Last year, fewer than 1,000 patients were able to get FDA approval to try experimental drugs under the FDA’s expanded access program for all types of cancer. Getting multiple drugs this way for a cocktail is just about impossible. We had high hopes for the Right To Try act which was passed this year, but it turned out not to help at all. Drug companies are not willing to use this pathway for brain tumor patients. However, even if we could get them, without tracking the results, we are not learning and are doomed to repeating the same failures.
Marty Tenenbaum and I previously wrote about our ideas for solving this problem. See https://virtualtrials.com/fda2017.cfm
So – bottom line: What would I do?

  1. Surgery—trying for maximal safe resection, possibly using Gliolan (a dye that helps surgeons see small clusters of GBM cells) to increase chances of maximal resection, and insertion of Gliadel wafer (intraoperative chemotherapy) if the resection cavity is not up against the ventricles (and we are not planning on entering a trial that excludes prior use of Gliadel).
  2. Radiation—standard radiation or possibly proton beam radiation. Possibly followed by some type of boost. Possibly try adding a radiation enhancer like Trans Sodium Crocetinate, especially if there is residual tumor.
  3. Temozolomide—during and after radiation. Only if the tumor sample has methylated MGMT. If the tumor is unmethylated, I would try to get Val-083 either in a trial or on compassionate use/right to try. The length of time to use 3. temozolomide is controversial. There is finally a phase 3 trial comparing 6 months versus 12 months of temozolomide, but right now we really do not know which is best. Some doctors use it for as long as needed.
  4. There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine and gene therapy trials have tails of 20% or more of patients living over 5 years and with minimal or no side effects. I would try to get one (or maybe two) of these. The polio vaccine trial (PVSRIPO) is getting a lot of hype on “60 minutes” with some very impressive results on a small number of patients. I know the first patient in the trial, and she is doing great and tumor free 5 years after the treatment. [Disclaimer: I am on the patient advisory board of the brain tumor center at Duke, and helped fund the PVSRIPO Trial].
  5. Optune. We are put into a very tricky situation here. Many trials will disqualify you if you use Optune, but Optune has the highest survival rates in large trials. So as I said before, you are being asked to gamble a known benefit for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. The results with Optune alone are still not good enough. The results shown above were for newly diagnosed GBMs. For recurrent GBMs, they are not nearly as good so it is important to use it early in the course of the disease. Ideally I would combine Optune with one of the immunotherapy treatments in phase 2 or 3, but that is not possible yet. We really need to fix that. Why should I be allowed to die just to appease an archaic tradition of requiring standard phase 2 and 3 trials?

What would you do?
Al Musella’s contact info is included in the author affiliations at the top of this page.
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.