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AMBROSE Protocol Rationale

Overview

The Adipose Cell Therapy for Chronic Inflammation (ACT-CI) study is a registry study done under the Texas Right-to-Try Stem Cell Law, House Bill (HB) 810, also known as “Charlie’s Law.” Whereas clinical studies are investigational, registry studies are observational. To put it another way, in a registry study the physician treats the condition according to their clinical judgment—the sponsor is a passive observer; in a clinical study we instruct the investigator to treat the condition in a certain manner—sponsors are active researchers.

In other words, clinical trials are efficacy trials (explanatory trials) to determine whether an intervention produces the expected result under ideal circumstances. Registry studies are effectiveness trials (pragmatic trials) which measure the degree of beneficial effect under “Real-World” clinical settings.[1] [2]

Study Objective

The primary objective of this study is to assess the safety, feasibility and effectiveness of an investigational stem cell treatment of an intravenous infusion of autologous Adipose Derived Regenerative Cells (ADRCs). This may also involve PRP-enriched musculoskeletal injections of purified adipose tissue containing resident ADRCs. Injections are performed under ultrasound guidance into disease-affected tissue for the treatment of chronic inflammation involved with severe chronic conditions, injuries, or illnesses that are treatable but are never completely cured or eliminated and entail significant functional impairment or severe pain.

HB 810 – Purpose

House Bill 810 allows the use of investigational adult stem cell treatments in Texas for patients that have been diagnosed with a terminal illness or severe chronic disease. Under this legislation, patients suffering from terminal illness or severe chronic disease have the opportunity to utilize experimental stem cell therapy within the state of Texas. This is a Right-to-Try Law.

The legislation:

  • Requires that in order for a patient to be eligible, a patient’s physician must recommend this treatment option after all other viable treatment options are exhausted. The patient must also sign an informed consent. If the patient lacks the mental capacity required to do so, a parent, guardian or conservator may provide informed consent on the patient’s behalf.
  • Requires treatment to be administered by a physician who is overseen by an institutional review board (IRB), and the treatments must be provided at a hospital, licensed ambulatory surgical center or a medical school.
  • Requires that each IRB overseeing an investigational stem cell treatment shall keep a record on each person to whom a physician administers the treatment and document in the record the provision of each treatment and the effects of the treatment on the person throughout the period the treatment is being administered.

Study Design

ACT-CI has been designed as a Master Protocol with a basket trial design, as promulgated by the FDA in the New England Journal of Medicine.[3] This is a new and promising approach to evidenced-based medicine. It moves away from the pharmacologic approach of a single drug for a specific DX and instead provides for mechanism-based therapies based on histologic and disease criteria.

Basket Trial Format | AMBROSE Cell TherapyPer the FDA,  “High-quality evidence is what we use to guide medical practice. The standard approach to generating this evidence—a series of clinical trials, each investigating one or two interventions in a single disease—has become ever more expensive and challenging to execute. As a result, important clinical questions go unanswered. The conduct of ‘precision medicine’ trials to evaluate targeted therapies creates challenges in recruiting patients with rare genetic subtypes of a disease. There is also increasing interest in performing mechanism-based trials in which eligibility is based on criteria other than traditional disease definitions. The common denominator is a need to answer more questions more efficiently and in less time.”

The patient population suffering from chronic severe diseases with inflammation being a predominant factor likely has multiple morbidities. They are ideally suited to be included in a basket protocol study.

Registry & Real-World Evidence

We will collect Real-World Evidence in the form of registry data to report to the IRB and a prospective Texas State Registry. The ACT-CI study follow up process and registry will include testing for biomarkers, functional testing and QOL surveys for each of the chronic diseases noted in the patient’s case report.

HB 810, with the oversight of and reporting requirements to an IRB for patient safety and protection, provides a platform to advance the science, safety and effectiveness of adult stem cell therapy while maintaining the patient’s right to try. AMBROSE’s protocol and informed consent includes rigorous follow-up over a 2 year period, including but not limited to biomarker testing, QOL surveys and functional assessments. This will be compiled in a patient registry and reported to the IRB on regular basis.

Real-World evidence (RWE), such as registry data, is increasingly seen as important to the FDA. In a talk on September 19, 2017 to the National Academy of Sciences, Advancing Public Health Opportunities with Real-World Evidence,[4] FDA Commissioner Scott Gottleib stated, We’ve been talking about RWE for a number of years. But let me tell you why RWE matters to me. The more widespread use of RWE can make our medical product development process more efficient and help lower the cost of development. More importantly, it can help make sure doctors and patients are better informed about the clinical use of new products, enabling them to make more effective, efficient medical choices. This will ultimately help us achieve better outcomes, and safer and more efficient use of expensive technology…”

He further explained:The fact is there’s often no single truth standard when it comes to the evidence used to support medical decisions. Clinical choices are made all the time, based on a mosaic of information of various precision and certainty. That continuum includes Real-World evidence, as well as the facts gleaned from rigorous and carefully fashioned trials…and a lot of evidence constructs in between.”

In the past, FDA had used Real-World sources such as registry data, electronic health records and insurance claims for post-marketing safety studies but more recently the agency has promulgated the use of RWE to support new indications or label expansions for drugs. In June 2017, the agency expanded the use of Edwards Lifesciences’ Sapien 3 transcatheter aortic valve based on data gathered from a patient registry.[5]

Study Rationale

Charlie’s law defines a Severe Chronic Disease as, “…a condition, injury or illness that: (A) may be treated; (B) is never cured or eliminated; and (C) entails significant functional impairment or severe pain.” This is a broad and comprehensive definition that fits well within the right to try (RTT) framework of the law and the patient population it is intended to serve.

As background, chronic degenerative diseases have become a pandemic overtaking infectious disease and injury as the leading cause of death.Further to the point, the aging of the US population has brought on a vexing problem that is uniquely suited to be addressed by adult stem cell therapy. Approximately 98.2 million adults in the United States have 2 or more concurrent chronic conditions, defined as “conditions that last a year or more and require ongoing medical attention and/or limit activities of daily living.

An aging population living with multiple chronic conditions creates irksome complexity in patient care and costs. Seniors (65+) see multiple physicians and, on average, take an estimated 7 different medications per day.[6] Further, a recent analysis in the journal Health Affairs by economist Sean P. Keehan et al at the Federal Centers for Medicare and Medicaid Services reported that more than 1 in 4 patients are harmed while in the hospital; more than 12 million serious diagnosis errors occur each year; and finally, that patients experience a positive response rate of just 25% in using the top 10 prescription medications in gross sales.

Multiple Chronic Conditions & Rare Diseases

As just one of many examples, arthritis, which affects approximately 6.5 million Texans, is much more common among people who have other chronic conditions.

  • 49 percent of adults with heart disease have arthritis
  • 47 percent of adults with diabetes have arthritis
  • 44 percent of adults with high blood pressure have arthritis
  • 31 percent of adults who are obese have arthritis
  • One-third of adults with arthritis age 45 and older have either anxiety or depression[7]

In other words, chronic disease cannot be viewed as independent single diseases unrelated to others or unlikely to cause additional morbidities.

Rare diseases (conditions that affect fewer than 200,000 people) fit under the framework of Charlie’s law. According to the Genetic and Rare Disease Information Center (GARD) program of the National Center for Advancing Translational Sciences (NCATS), there may be as many as 7,000 rare diseases. The total number of Americans living with a rare disease is estimated at between 25-30 million. This estimate has been used by the rare disease community for several decades to highlight that while individual diseases may be rare, the total number of people with a rare disease is large. Rare diseases are often referred to as “orphan” diseases as their small patient populations and the complex nature of these diseases make them unattractive for pharmaceutical companies to invest in them.

The complexity, pathophysiology and prevalence rate of rare diseases as a whole make many well-suited for therapeutic targets under Charlie’s Law, assuming it is safe and feasible to do the experimental stem cell treatment as would be determined by the IRB, Principal Investigator and treating physician.

References:

[1]  M Godwin et al. Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol 2003;3:28.

[2] G Gartlehner et al Criteria for Distinguishing Effectiveness From Efficacy Trials in Systematic Reviews. Technical Review 12 (Prepared by the RTI-International–University of North Carolina Evidence-based Practice Center under Contract No. 290-02-0016.) AHRQ Publication No. 06-0046. Rockville, MD: Agency for Healthcare Research and Quality. April 2006.

[3] J Woodcock, M.D. and L. LaVange, Ph.D. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both N Engl J Med 2017;377:62-70.

[4] https://www.fda.gov/NewsEvents/Speeches/ucm576519.htm

[5] http://www.raps.org/Regulatory-Focus/News/2017/06/14/27908/FDA-Used-Real-World-Evidence-in-Heart-Valve-Approval/

[6] http://www.webmd.com/healthy-aging/features/how-many-drugs-are-you-taking#1

[7] http://www.arthritis.org/about-arthritis/understanding-arthritis/arthritis-statistics-facts.php

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