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Clinical Trial Co-operatives: “No Patient Left Behind”

Set up patient-centric, biomarker-driven Clinical Trial Co-operatives where many companies participate & "buy in" with biomarker/drug pairs.

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Focus of Innovation

  • Collaboration
  • Cost reduction
  • Patient-centric or decentralization
  • Patient selection

Focus of Innovation - Other

Efficient screening
Reduced screen-fails
Reduced startup times

Name of applicant

Gavin MacBeath

Title of applicant

Founder and SVP, Head of Translational Medicine

Affiliation of applicant

Merrimack Pharmaceuticals

The promise of precision medicine is that patients will benefit most if they are treated with a drug that is matched to their specific disease. Why, then, are most Phase 1 and Phase 2 cancer trials still performed on unselected patients, even when there is a strong biomarker hypothesis underlying the program? The problem is two-fold. First, most biotech or pharmaceutical companies are reluctant to pre-select patients in Phase 1 and often Phase 2 trials because, even if they know the biomarker, this requires screening many patients to find the few that are “biomarker positive”. If, for example, the biomarker is present at 5% frequency, this means screening 100 patients to find 5, which is slow, inefficient, and expensive. Companies thus resort to running trials in unselected patients, which means that most patients participating in these trials stand very little chance of benefiting from the drug. This is a gross disservice to the patient, but also puts the drug at risk, as lack of responses in early clinical trials frequently leads to discontinuation of entire programs.

Second, the problem is compounded by the very nature of cancer. Unlike other diseases, cancer rapidly evolves. As patients are treated with different agents, their tumors adapt, acquiring new mutations or activating different pathways in order to circumvent each new round of therapy. This means that, in order to match a patient to their ideal therapy, we need to assess their current disease state, not their disease when they were first diagnosed with cancer. This presents a significant challenge in the clinical trial setting. To obtain relevant tissue, patients often need to undergo a core needle biopsy, which is a painful and risky procedure. Although "liquid biopsy" technology (i.e., analyzing cell-free circulating tumor DNA) provides a way around this problem for genetic biomarkers, it is not applicable to non-genetic biomarkers such as proteins and metabolites. Nevertheless, most patients are willing to undergo a biopsy if it means being treated with a promising new therapy. They are not, however, willing to get biopsied if they then stand a 95% chance of not qualifying for the study. To circumvent this problem, most biomarker-selected trials (i.e., precision medicine trials) rely on archived tissue blocks that were obtained by surgery when the patient was first diagnosed with cancer, often 5-10 years earlier, rather than on fresh biopsy material, which is more representative of their current disease.

Both of these problems may be solved through a simple and efficient system that places the patient first, rather than the drug. Currently, biotech/pharma companies each run their own independent clinical trials, incurring substantial costs in both time and money devoted to trial design, startup activities, and advocacy efforts (Figure 1A). At best, these trials run independently and at worst, they compete with each other. As an alternative, Precision Medicine Clinical Trial Co-operatives could be set up in which any organization seeking to develop a drug could participate (Figure 1B). Initially, the co-operatives could be indication-specific, meaning that there would be a separate multi-arm trial for each major type of cancer (breast, colorectal, lung, etc.). Ultimately, if successful, this could be brought under a single umbrella program.

To participate in the co-operative, a company would have to supply a “drug/biomarker pair”: an investigational agent coupled with a fully qualified biomarker assay. A committee would then review the submission and, if appropriate, both the drug and assay would be incorporated into the ongoing multi-arm trial. Any patient consenting to the trial would provide tissue (core needle biopsy), as well as blood and urine for biomarker testing. Their samples would be tested by full genomic profiling, as well as the full suite of company-supplied biomarker assays that are not covered by genomic testing (i.e., protein- or metabolite-based tests). One big advantage of this system is that drugs that do not target genetic abnormalities, but instead focus on the myriad other ways in which tumors can arise, progress, or develop resistance, would receive equal attention, something that is often missed in this increasingly genomic-focused era. The challenge, of course, would be to ensure that all the tests could be run with the available tissue, possibly necessitating the multiplexing of some types of biomarker assays (e.g., immunohistochemistry assays, in-situ hybridization assays, metabolite assays, etc.).

To protect companies’ interests, data on each patient would only be provided to the company supplying the drug for that patient while that drug is being assessed. Companies can “buy in” to the trial at any point and pay for the study on a per-patient basis. This cost structure enables companies to pursue important but rare disease segments, thereby removing a large economic barrier to the development of drugs for orphan indications. Once a pre-specified number of patients enroll for a given drug/biomarker pair, the arm would close and the company would be required to publish their results within a reasonable period of time.

This idea of pay-as-you-go, multi-drug clinical trial co-operatives enables both single arm (Phase 1) and randomized (Phase 2/3) studies. In early stages of drug development (Phase 1), the goal is to obtain safety information on the drug, as well as early signs of efficacy. It is almost unprecedented to run first-in-human dose escalation studies in biomarker-selected patients, yet the concept of clinical trial co-operatives lowers the barrier doing this, ensuring that every patient counts. At the same time, one of the biggest challenges of developing precision medicines is that it is often not known how the status of a new biomarker affects patient prognosis. This means that there are often no reliable historical data to benchmark the performance of a new drug. It is therefore critical to obtain efficacy data on a new drug in comparison to a control arm when working in biomarker-selected populations. Clinical trial co-operatives could be set up to enable the seamless flow from single arm studies (dose escalation and Phase 1 expansions) into randomized studies with appropriate control arms (Phase 2 proof-of-concept). In principle, these co-operatives could even be used to feed enrollment into biomarker-selected Phase 3 registration studies.

The success of this idea depends on widespread participation: the greater the number of companies that participate, the higher the probability that a patient will be matched to an appropriate treatment arm. With enough participation, every patient would be matched to an arm (“no patient left behind”). As an initial test of this idea, Merrimack is currently running a multi-arm, biomarker-selected Phase 1 clinical trial in late-stage colorectal, head and neck, and non-small cell lung cancers (Figure 1C). Every patient entering the trial must submit a fresh core needle biopsy. The biopsy is then assayed for multiple biomarkers, including both genetic and non-genetic biomarkers. Based on the results of these assays, patients are assigned to one of four treatment arms. At this point, only patients that score positive for one type of mutation are excluded from the trial, which means that patients have a >95% chance of qualifying for the study once they consent to the biopsy. This trial is currently sponsored by Merrimack and addresses specific questions around the safety and preliminary efficacy of novel drug combinations. This seed idea, however, could be expanded dramatically and benefit far more patients if it included promising new precision medicines from many different drug companies and if the effort were driven by a neutral third party (such as the Kraft Family Foundation). As a significant additional benefit, trials like this could also promote collaboration between participating companies, particularly in the cases in which patients are found to score positive for more than one of the biomarkers in the panel. This situation presents an exciting opportunity for novel/novel drug combination therapy, which could ultimately move the needle to an even greater degree.

Why would your idea have a significant impact?

Cancer patients are remarkably willing and eager to participate in clinical trials, but want to know that they are getting the best chance at a meaningful result. Currently, the vast majority of targeted therapies are being developed in unselected patients, not just in Phase 1 but also in Phase 2 and 3. Companies rely on retrospective biomarker analyses to test or prove biomarker hypotheses. This is a disservice to patients, most of who are “biomarker-negative” and thus will receive at best no benefit and often harm from interventional agents that are not matched with a biomarker. Setting up clinical trial co-operatives enables (and even forces) companies to prospectively select patients as early as Phase 1. This places the patient first and provides the greatest probability for early success.
In addition, this idea will significantly lower the barrier to developing drugs that target rare indications. Due to the high cost of drug development, companies are often reluctant to target niche indications with small potential markets. By removing the high cost and long startup times associated with screening for patients with rare biomarkers, clinical trial co-operatives enable the development of drugs for orphan indications.

What are the biggest hurdles to implementing your idea?

The two biggest hurdles are (1) buy-in from biotech/pharma companies and (2) the commitment of a neutral third-party to organize and run the effort. First, due to the nature of business, drug development companies view each other primarily as competitors, rather than partners. This idea requires companies that are competing in the same space (a particular cancer indication) to acknowledge that it is better to have a large effect in a well-defined and smaller patient population than to have a smaller effect in a broader population. It also requires companies to commit earlier to a specific biomarker hypothesis, which requires stronger and more in-depth science preceding clinical development.

Second, this idea requires a neutral third party to organize and run the effort. To enable maximum participation, companies need to know that there is no bias underlying the program. The effort would best be run by a philanthropic organization, rather than a specific academic medical center. This is because the effort will only succeed if it is large enough and involves multiple large academic centers. Like companies, academic institutions can also view each other as competitors, rather than partners. This will only succeed in a spirit of cooperation, which would be easier to establish if run by a truly neutral third party.

How difficult will it be to overcome those obstacles?

The first obstacle (buy-in from biotech/pharma companies) can be overcome by achieving critical mass. As a rough estimate, if five companies were to commit to this idea prior to launch, this would establish credibility and it would become much easier for other companies to participate. Early success and positive press are powerful motivations, so tying this to President Obama’s Precision Medicine Initiative could help achieve the necessary critical mass, as would involving the National Cancer Institute. The other critical piece is to obtain a commitment from large, well-recognized academic centers that run clinical trials, such as the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, or Mayo Clinic Cancer Center. These and many other institutes have a powerful vision for Precision Medicine, so commitment from these institutes should be relative straightforward and contribute substantially to securing buy-in from companies.
The second obstacle (having a neutral third party organize and run the effort) is certainly surmountable. There are many people and organizations with the necessary passion and talent to organize this type of endeavor. This initiative does require an initial outlay of capital, which would likely come from philanthropic sources, but once the system is established, ongoing overhead costs can be captured in the per-patient cost of participating in the trials. Because startup, closeout, and advocacy costs are minimized by this system, the overall cost of running trials through this centralized format should still translate into an overall savings for the drug companies.

How would you test for the impact of this idea and how would you quantify the impact?

It is relatively straightforward to quantify the impact of this initiative. All clinical trials in oncology in the United States are posted on http://clinicaltrials.gov and enrollment criteria are publically disclosed. It is therefore possible to quantify how many trials involving molecularly targeted agents are being run in biomarker-selected vs. unselected patient populations. In principle, it is even possible to quantify how many patients are being treated in these trials and hence how many “biomarker negative” patients are being incorrectly treated with targeted agents. Once this idea is implemented, it will be straightforward to see how many new drugs and new treatment arms are added each year to trials run by the Clinical Trial Co-operatives, all of which (by definition) will be run in biomarker-selected patients. Finally, feedback can be obtained from participating companies as to whether or not they would have prospectively selected patients in their trials had the Clinical Trial Co-operative not existed.

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Hi Gavin, I have two questions about your idea.  The first is regarding how this idea would work when multiple companies develop similar drugs.  For example, Merck and BMS may both want to treat the patients with PD-1+ cancers.  How will these patients be distributed between the two competitors?  Why wouldn't they just run their own trials?

Secondly, it seems that to participate in the co-op model, the companies would have to shoulder a fair amount of risk - they're betting the future of their compound that they've accurately identified an appropriate (but untested) biomarker.  If their biomarker predictions are wrong, it may be difficult to resurrect the drug for another attempt.  What motivation does the co-op model provide to companies that would offset this risk?

Very interesting idea, thanks for sharing!

Anne

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