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Newsletter Fall 2018 - word

 

Fall 2018

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Insights for Translating Life Sciences into Solutions

 

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By Thomas Seoh

President and Chief Executive Officer

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Dear Friends of Kinexum, 

Welcome to the Fall 2018 Kinexum Newsletter!   

Featured here are four Kinexum experts: (i) Brian Harvey, MD, PhD, former director of FDA's Gastroenterology Division and former US Regulatory Vice President for Pfizer and for Sanofi, discusses the hot topic of clinical development issues in nonalcoholic steatohepatitis (NASH)... Read more

 

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By Brian E. Harvey, MD, PhD

Clinical Development, Kinexum

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Background

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world [1]. The phenotypes of the disease extend from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), the latter of which progresses to liver fibrosis and end-stage cirrhosis [2]... Read more

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By Grant Williams, MD

Clinical Development, Kinexum

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Let’s pretend I am a cancer drug sponsor with an immune-stimulating drug (Drug A) for the treatment of a refractory cancer. I plan to study Drug A in combination with an approved immunotherapy drug (Drug B), such as a PD1 inhibitor... Read more

 

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By Michael Sharp, PhD

Regulatory Affairs, Kinexum

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What is a 510(k)?

I still get asked this question 40 years after the Food, Drug and Cosmetic Act (FDCA) implemented the Medical Device Amendment (MDA)... Read more

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By Dean E. Calcagni, MD

Defense and National Security Practice, Kinexum

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Not counting the NIH, the U.S. Federal government spends more than $1.5 billion each year on medical research and development... Read more

 

 

Note from Kinexum CEO... (cont.)

 

(ii) Grant Williams, MD, former Deputy Director of the FDA Oncology Division, reflects on considerations regarding accelerated approval of oncology drug combinations; (iii) Michael Sharp, PhD, expert in medical device regulatory strategy, explains 510(k) clearances for medical devices; and (iv) Dean Calcagni, MD, Head of Kinexum's Defense and National Security Practice, outlines the numerous federal grant and funding opportunities beyond the NIH. 

Please mark your calendars for the next Kinexum public webcast on Friday, October 26, 2017, from 11 a.m. to noon, EST, by Nir Barzilai, MD, Director of the Institute for Aging Research at the Albert Einstein College of Medicine, and Steve Kritchevsky, MD, of Wake Forest, who are co-PI's of the groundbreaking Targeting Aging with MEtformin (TAME) clinical trial that will examine the effect of metformin on various markers of aging and its potential to delay multiple diseases of aging (a primer for which can be found here).

By the way, we've posted videos of the following webcasts from earlier this year here: Zan's interview of Stanford neuroimmunologist Larry Steinman; Michael Zemel on targeting metabolism for anti-aging; Rob Claar on fast track regulatory pathways for advanced therapies in Japan; and Bart van der Schueren's personal take on EMA.

Zan and other Kinexum consultants will be in attendance at the upcoming European Association for the Study of Diabetes annual meeting in Berlin from October 1-5, 2018 and would be very pleased to meet with anyone to discuss any help we may be able to provide regarding metabolic product strategy and development issues.  

Also, please email me any feedback on my Forbes blog article,AI in Startups.

Wishing you a productive, healthy and rewarding fall season!

 

Cheers,

Thomas

 

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A Perspective on How to Development Treatments for NASH, Our Next Epidemic... (cont.)

NASH is also associated with an increased risk of cardiovascular (CV) morbidity and mortality, as well as metabolic diseases such as Type 2 diabetes mellitus (T2D) [3]. Cirrhosis associated with NASH increases the risk of hepatocellular carcinoma. Currently, liver biopsy is the only generally acceptable method to diagnose NASH and to accurately assess progression to cirrhosis [4]. There are currently no FDA-approved treatments for NASH [5].

FDA Regulatory Environment

With nearly 100 companies interested in developing NASH treatments, the FDA is faced with not only the challenge of promoting the development of such treatments by providing advice to drug Sponsors, but also the challenge of protecting patients from committing to long-term clinical trials that could potentially treat NASH less effectively. 

Industry leaders in this field have provided the FDA with a robust package of studies on their products for NASH treatment. They have provided animal studies that support the mechanism of action of their products, as well as pre-clinical data that support first-in-human (FIH) studies, Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) studies, Phase 2a Dose Ranging studies, and Phase 2b studies with NASH endpoints (e.g., liver biopsy and corresponding MRI-based measurements at either 24 or 36 weeks).

The FDA has advised Sponsors to submit certain data in order to allow their clinical trials to progress to Phase 3 and beyond. As one example, the FDA staff who have attended recent academic hepatology and liver-related meetings stated that compelling liver biopsy evidence of drug effect is necessary at the Phase 2b stage. Providing this evidence would allow clinical trials regulated under an Investigational New Drug (IND) Application [6] by the FDA to proceed to Phase 3. 

In addition, many Sponsors reported that the FDA GI Division has advised them to submit data from the “Full Chronic Toxicology Package under GLP” for review prior to enrolling patients into Phase 3.

The agency has also encouraged Sponsors to “roll over the Phase 2b patients into long-term extension trials” in order to increase the size of the Safety Database with an adequate number of patients exposed at 12 months, 24 months, and beyond.

Lastly, the FDA has asked NASH Sponsors with Phase 2 patient data containing both liver biopsy and corresponding MRI-based measurements to submit this data to the agency early. This early submission would allow for an informal validation “pilot” of the MRI-based NASH endpoints and the degree of correlation with liver biopsy across Sponsors. This agency analysis of pooled Sponsor Phase 2 data could potentially hasten the acceptance of MRI “biomarkers” and remove the requirement for liver-biopsy-based clinical trials for FDA drug approval.   

Despite these advisements from the FDA, there continues to be no official agency guidance document for NASH treatment development. However, the FDA has been active at conferences in providing detailed advice on designing clinical trials that would have an increased chance of generating data that would support agency approval of a drug or biologic product. For example, during the FDA presentation on NASH at a recent “Liver Forum,” a public/private/academic partnership formed to promote the exchange of ideas regarding clinical trials in liver disease [7], the FDA representative stated that the critical aspect of such a development program is the choice of endpoints for the proposed pivotal clinical trial. There are several potential pathways that can be used, which involve traditional clinical endpoints, intermediate clinical endpoints, and surrogate endpoints reasonably likely to predict clinical benefit in patients [8].

At this Liver Forum, FDA’s Dr. Dimick-Santos provided examples endpoints. Traditional clinical endpoints include a “reduction in all-cause mortality,” “prevention of liver transplantation” (e.g., model for end-stage liver disease [MELD] score increase from ≤12 [listing for liver transplant] to 15), and a “reduction of decompensation events” [9]. The FDA examples for potential surrogate endpoints for NASH are a “complete resolution of steatohepatitis,” “no worsening of liver fibrosis,” “at least 1 point improvement in fibrosis using the Brunt/Kleiner Scale” [10], and “no worsening of steatohepatitis, defined as no increase in ballooning or inflammation on NAS (NAFLD Activity Score) Score” [11]. A surrogate reasonably likely to predict clinical benefit could be used as the basis of an Accelerated Approval by the FDA. However, the Accelerated Approval must be followed by a Verification Trial with a traditional clinical endpoint. An alternative for verification is a “seamless” Phase 3/4 design where patients are rolled over at the end of Phase 3 into a Phase 4 verification trial. 

The FDA also advised Sponsors on whether to conduct one or two pivotal trials to support product approval. In order for one Phase 3 trial to be persuasive, the FDA Guidance “Providing Clinical Evidence and Effectiveness for Human Drug and Biologic Products” states that such a trial is “generally limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and conformation of the results in a second trial would be practically or ethically impossible” [12]. Specifically, this should be a large, multicenter trial, with internal consistency across study site, evidence of an effect on multiple endpoints, and statistically persuasive efficacy results (i.e., a “robust p-value”).   

Alternatively, if a Sponsor plans for two seamless Phase 3/4 trials for the Accelerated Approval pathway, then the Sponsor must control the alpha (α) level to be ≤0.05 for each of the Phase 3/4 trials. For example, if α=0.01 for Phase 3 (using liver histology-based endpoints), then α must be <0.04 for Phase 4 (using traditional clinical endpoints). However, if the Sponsor plans only one seamless Phase 3/4 Trial to submit for FDA Approval, then the overall α must be <0.05 and split between Phase 3 (α << 0.05) and Phase 4 (α << 0.05) [13].  

Current examples of Sponsors conducting development programs for NASH treatments can be found on ClinicalTrials.gov:

  • REGENERATE (Intercept Pharmaceuticals)
  • RESOLVE-IT (Genfit)
  • Phase 2 Study of MGL-3196 in Patients with NASH (Madrigal Pharmaceuticals, Inc.)
  • STELLAR-3 (Gilead Sciences)
  • A Study of BMS-986036 in Subjects with NASH (Bristol-Myers Squibb)
  • AURORA (Tobira Therapeutics, Inc.)

Unanswered Questions, Potential Challenges, & Hope for the Future

Although there are significant resources focused on developing NASH treatments, unknowns regarding disease pathophysiology, long-term health benefits from improving short-term aspects of NASH, and the potentially negative impact of chronic use of these medications still remain. For example:

·         The natural history of NASH is unclear (e.g., percentage of progression to cirrhosis).

·         Mechanisms underlying NASH include the accumulation of fat in liver, inflammation, and progress to cirrhosis. How will regulators judge treatments if treatments target only one or two mechanisms, but not all aspects of disease?

·         Liver biopsy is currently the only generally acceptable method to diagnose NASH and to accurately assess progression to cirrhosis. Increased screening (e.g., FibroScan, MRI, biomarkers) for liver disease in populations at increased risk for NASH, such as those with T2D, obesity, hyperlipidemia, and abnormal Liver Function Tests (LFTs), could identify potential patients and refer them for liver biopsy. This could potentially increase the number of patients available for NASH trials.    

·         The FDA has expressed a willingness to consider the liver biopsy endpoint as part of an Accelerated Approval, which would then be verified with traditional clinical endpoints in a “Verification Trial” as part of a Phase 4 Post-Approval Commitment by the Sponsor.  Despite FDA approval for NASH treatments, will “Payers” wait until there is patient outcomes data from these confirmatory clinical trials before committing to reimbursement for these important medications, as they did and continue to do in some patients with hepatitis C? 

Reports from the hepatology community note that as the number of hepatitis C patients who undergo liver transplant decreases, the percentage of NASH-related cirrhosis events leading to liver transplant continues to increase. The hope is with the identification of the significant public health impact of this disease, as well as focused efforts to find safe and effective treatments, overall healthcare costs can be reduced by reducing liver transplants, which could drive positive reimbursement decisions. The missing piece of this puzzle is a rational, integrated healthcare marketplace, where patient savings downstream can be shared with those who pay to treat disease at the earlier stages. Meanwhile, positive clinical trial results from a growing number of Sponsors continue to provide hope for the future.

Written by Brian E. Harvey, MD, PhD, Kinexum Clinical Development

     

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Evidentiary Standards in the Accelerated Approval of Cancer Drugs... (cont.)

I have recently seen many oncology drugs approved based on overall response rate (ORR) in a single-arm trial (SAT). I want the FDA to grant accelerated approval (AA) for my drug given in combination (Drug A + Drug B) based on ORR. What are the regulatory issues involved with this proposal? In the following discussion, I will shed light on these issues.

Accelerated approval in oncology

In the 1980s, the FDA usually required a survival benefit to support the approval of cancer drugs. In the early 1990s, the FDA stated that large effects on tumor endpoints may be viewed as a clinical benefit and could support drug approval. In 1992, the AA regulations were enacted, providing a path for drug approval based on a surrogate endpoint “reasonably likely to predict benefit.” The drug must also show a meaningful advantage over available therapy. Post-approval confirmatory studies were required to assess the clinical benefit of the drug. 

Advantage over available therapy

For the first AA requirement of a surrogate endpoint “reasonably likely to predict benefit” for oncology drugs, the FDA determined that a meaningful ORR with an acceptable response duration sufficed for many tumors. The evidentiary standard for demonstrating this effect will be discussed in a later section.

The second AA requirement was to show a meaningful advantage over available therapy. The usual regulatory approach of showing an advantage of one drug over another is to perform a randomized controlled trial (RCT). The FDA facilitated this process for oncology drugs by allowing the use of SATs for AA. The regulatory rationale for this practice was that for patients with refractory disease, in which no available therapy was effective for long, any meaningful benefit represented an advantage over available therapy. The paradigm for AA based on ORR in SAT in the refractory cancer setting was used many times in the ensuing years. The FDA reported that in the 25 years following the enactment of the AA regulations, 67 oncology drugs were approved based on ORR demonstrated in SATs (Beaver et al. 2018Johnson et al. 2003).

With the advent of new cancer drugs yielding high ORRs, the FDA has also granted AA based on ORR in SATs in non-refractory disease settings. In such cases, advantages over available therapy was established based on cross-study comparisons of the ORRs of investigational drugs to the ORRs of available therapies. These studies were typically designed to demonstrate that the lower range of the 95% confidence interval of the investigational drug ORR excluded the point estimate of ORR of available therapy, which was often determined by a meta-analysis.

An example of this use of historical data as a basis for comparison is described in the FDA review of blinatumomab, which received AA in 2014 for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). Historical ORR data were evaluated from a meta-analysis of clinical study results and by a model-based comparison of historical individual patient data. The FDA statistical review of this BLA provides an explanation of FDA’s position that the observed 30% complete response rate was better than what would be expected with available therapy.

Thereare other ways to show an advantage over available therapy besides demonstrating better efficacy. According to the FDA Guidance on Expedited Programs for Serious Conditions, examples include providing comparable efficacy with less toxicity and providing an important increase in compliance. It is important to note that neither regulations nor guidance describes a clear evidentiary standard for meeting the requirement to establish an advantage over available therapy; regulatory determination seems to involve regulatory and clinical judgement instead.

Substantial evidence of an effect

Did this new tradition of granting AA based on ORR replace the longstanding FDA efficacy standards for new drug approval? Though it is tempting to consider a SAT an uncontrolled study, the FDA believes otherwise. The FDA approves drugs based on the mandate of substantial evidence of efficacy from adequate and well-controlled clinical studies.

SATs are considered to be historically well-controlled studies with respect to the endpoint of ORR. The FDA and the oncology community have widely accepted that the historical ORR in patients with refractory cancer is less than 5%, if not 0%. Thus, if an investigational drug demonstrated a clinically meaningful ORR in a reasonably sized study (usually about 100 patients), this would represent substantial evidence of efficacy on ORR. The FDA considered duration of response a key supporting measure in demonstrating clinical meaning. I dwell on the term “substantial evidence of efficacy” because I believe many sponsors may be unaware of the special nature of ORR in a SAT that has allowed the FDA to rely on this evidence to support the approval of cancer monotherapy regimens.  

Several sources confirm that the FDA still believes that “substantial evidence of efficacy” is a relevant standard, even in the AA setting. One example took place during the Oncologic Drugs Advisory Committee (ODAC) discussion of apaziquone, a treatment for superficial bladder cancer. In this discussion, the FDA clearly noted that substantial evidence of efficacy is a requirement for AA. The apaziquone application proposed to pool the results of two large controlled studies and sought AA based on the combined analysis. The pivotal question for ODAC to support AA for apaziquone was, “Has substantial evidence of a treatment effect for apaziquone over placebo been demonstrated?” Another example can found in the current FDA template for NDA/BLA reviews. The executive summary review template has a section header entitled “1.2 Conclusions on the Substantial Evidence of Effectiveness.” This paragraph is used both for regular approvals and AAs (e.g., acalabrutinib approval in October 2017). Lastly, the FDA Guidance on Expedited Programs for Serious Conditions categorically states that the standard for efficacy under accelerated approval is “substantial evidence based on adequate and well-controlled clinical investigations.”

Substantial evidence in the drug combination setting

Let’s return to our example of the proposed trial design of Drug A + Drug B to support AA. I have frequently encountered sponsors who propose to use this SAT design to support AA of their investigational drug in combination with a standard therapy. In most cases, however, I believe this design is not likely to fulfill regulatory requirements for efficacy. When developing a drug given in combination with another approved active drug, we can no longer assume that the ORR observed in a SAT represents substantial evidence of an effect of either drug. We can no longer refer to a widely accepted historical rate of nearly zero as the comparator. If we seek approval of Drug A given in combination with Drug B, we need to show substantial evidence of the efficacy of Drug A. This would require comparing the ORR of the combination regimen to historical data on the ORR of Drug B. We would need to claim that these results represent substantial evidence of efficacy of Drug A demonstrated in an adequate and well-controlled study. I am not aware of any AA to date in which such ORR evidence has been accepted as the evidentiary basis for efficacy supporting AA. 

Two different evidentiary standards

The point of this short article is to convince you that a different standard of evidence is required for two of the key requirements for AA. What constitutes an advantage over available therapy is summarized in the FDA Guidance on Expedited Programs for Serious Conditions. Although there are many potential bases for claiming an advantage, neither regulation nor guidance provides clear standards for how such an improvement over available therapy must be demonstrated. On the other hand, the expedited therapy guidance clearly states that the standard for efficacy is the same for both accelerated and traditional approval: “substantial evidence of efficacy based on adequate and well-controlled studies.”

Conclusion

The FDA has used AA as a means to make promising cancer drugs available to patients. The FDA practice of granting AA based on ORR in SAT to date has been limited to drugs approved as monotherapy treatments. Currently, many new therapies are being studied as combinations of an investigational drug (Drug A) in combination with an approved drug (Drug B). This is particularly true for immunotherapies, in which the investigational drug may be an immunostimulant intended for use in combination with a PD1 inhibitor. Such immune-stimulating investigational drugs are not expected to be as effective as monotherapies. In these settings, sponsors may propose that promising ORRs observed from the drug combinations (Drug A + Drug B) should support AA.

The ORRs demonstrated in these SATs may be encouraging compared to ORR results reported for the standard drug partner alone, and the combination may appear to provide an advantage over available therapy based on cross-study comparisons of ORRs. However, it is important to consider and discuss with the FDA whether the trial design also meets FDA requirements in demonstrating substantial evidence of efficacy. If the efficacy of the new drug combination is extreme compared to the results from the monotherapy drug partner alone, then perhaps this approach is feasible. In any event, it may be prudent to understand the potentially precedent-setting nature of this approach when discussing this design with FDA.

Written by Grant Williams, MD, Kinexum Clinical Development  

 

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A Crash Course on 510(k) Clearances… (cont.)

 

Although the answer is more confusing than may be expected, it is important for understanding the regulatory status of medical devices.

As legislators and congressional staff fleshed out the MDA, they recognized – thanks to the efforts of a legion of special interests and lobbyists – that medical devices would need different regulation from that of pharmaceuticals. The diversity of medical devices, ranging from urine specimen collection bottles to intraocular lenses, lasers, MRI imaging, and other high-tech modalities, was a starting place to think about this overall regulatory approach. Using a risk-management approach, the outcome was three risk categories: Class I, Class II, and Class III devices.

Class I devices are low-risk devices. They require general controls, such as Good Manufacturing Practice, to ensure safety. These devices do not require FDA clearance prior to marketing.

Class II devices are higher-risk devices and may be more complex. They require general and special controls to ensure safety and effectiveness. Examples of special controls are mandatory performance standards, patient registries for implantable devices, and post-market surveillance. In addition, Class II devices require FDA clearance prior to marketing, unless specifically exempted. Clearance is obtained by demonstrating substantial equivalence to a predicate device that has been cleared under the 510(k) process. Interestingly, the FDA does not “approve” devices through the 510(k) process, but instead “clears” the product for sale in the US.

Class III devices are defined as those that are life-sustaining, life-supporting, or pose significant potential risks to patients. These devices require general controls, special controls, and pre-market approval. Most cases also require a clinical trial.

Having established the paradigm for risk-based regulation, the FDA created classification panels with experts in a wide variety of devices and  therapeutic areas to evaluate devices for risk assignment. This process established product categories for different devices.

The 510(k) approach

We now have an idea of how the FDA’s process of bringing new devices to market works, but what the 510(k) exactly is remains an open question. In truth, there is no such “thing” as a 510(k). Technically, the term 510(k) describes Section 510(k) of the FDCA: device manufacturers must notify the FDA at least 90 days in advance of their intent to market a medical device, which is called a Premarket Notification. Over time, the regulatory community has adopted “510(k)” as shorthand for the actual citation. Both regulators and sponsors use the term “510(k)” as a noun.

Since the promulgation of the device regulations, these regulations have evolved. Not only do we have the “traditional 510(k),” which is the fallback approach for most devices, but also the abbreviated 510(k). The abbreviated 510(k) is used when the following conditions exist: there are is an FDA guidance for the product type; a special control already has been established; and the FDA has recognized a relevant consensus standard. Additionally, there is the special 510(k), which may be used if a new 510(k) is required for a device modification that does not affect the device’s intended use nor alter its fundamental scientific technology.

Even with this information, there remains confusion about the 510(k). For example, when to use which format? Is there an available predicate device? Can the predicate be convincingly shown to be substantially equivalent to the new device?

When we follow the 510(k) crumbs into the regulatory forest, it turns out to be just as dark and confusing as we fear. But wait, there is a light in the forest! It is not the gingerbread house, but the library of FDA guidance documents. There is a guidance for the contents and format of all the types of 510(k) submissions. There is also a document that helps determine when a new submission is required, as well as another to assist with questions regarding substantial equivalence. There are also copies of 510(k) summaries for previously cleared 510(k)s, which are, of course, not the full submissions, but are nonetheless helpful sources of information. The most helpful document is the Acceptance Checklist for 510(k)s, in which the FDA provides the criteria their reviewers use in determining whether a device will be accepted for filing.

Concern about the 510(k) Process

The 510(k) process has been criticized in the last several years, fueled by recalls and law suits involving cleared devices, such as surgical mesh or metal-on-metal orthopedic prosthesis. As a result, the Institute of Medicine (IOM) reviewed the process in 2011, and the IOM panel found the 510(k) approval process flawed. In their report, the committee noted that the 510(k) approval process “cannot be transformed into a premarket evaluation of safety and effectiveness as long as the standard for clearance is substantial equivalence to any previously cleared device.” The committee was not suggesting, however, that medical devices cleared through the 510(k) process and currently on the market were unsafe or ineffective. In response to these concerns, the FDA issued a “Plan of Action for Implementation of 510(k) and Science Recommendations.”

There are certainly problems with the 510(k), and the FDA has initiated an evaluation of the available options in order to both improve patient safety and maintain an efficient regulatory review process. In any discussion of “510(k) reforms or improvements,” however, one must recognize the difficulty in getting filings accepted. In the data available from the FDA, one third of all submissions are for Class II devices, and only one percent of those are PMA. The remaining two thirds of submissions are Class I devices exempt from review. Any change to the 510(k) process that would increase the need for reviewer resources would make timely clearance difficult and would likely result in longer review times for both Class II and Class III devices.

Written by Michael Sharp, PhD, Kinexum Regulatory Affairs  

    

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Beyond the NIH – Other Federal Medical R&D... (cont.)

 

 

The lion’s share of this funding is in the U.S. Department of Defense (DOD), and the lion’s share of DOD funding is in the U.S. Army Medical Research and Materiel Command (USAMRMC).

The USAMRMC is located in Ft. Detrick (Frederick), Maryland. The USAMRMC is primarily involved in medical research and development, but it also performs medical information management, medical logistics management, and health facility planning.

Before diving into a review of the USAMRMC’s research programs, it is important to recognize that the USAMRMC (and all federal R&D organizations) take much longer to develop a relationship with than the commercial sector. However, once a relationship is firmly established, it can be a long-lasting one.

USAMRMC Research Programs

Military Infectious Diseases Research Program: Protect the U.S. military against naturally occurring infectious diseases by developing FDA-approved vaccines, drugs, and diagnostic assays, as well as EPA-approved vector control protection systems (to prevent the transmission of infections by insects, ticks, etc.).

Combat Casualty Care Research Program:Reduce mortality and morbidity resulting from battlefield injuries by developing new life-saving strategies, new surgical techniques, biological and mechanical products, and the timely use of remote physiological monitoring.

Blast Injury Research Coordinating Office: Addresses critical medical research gaps in blast-related injuries, especially in traumatic brain injury and post-traumatic stress disorder. The program is addressing the new concept of "reset" for Warfighters in redeployment, ensuring return-to-duty readiness (or healthy return to civilian life for citizen Soldiers). One of the program's major areas of focus is to improve battlefield medical treatment capabilities to mitigate neurotrauma and hemorrhage.

Military Operational Medicine Research Program:Develop effective countermeasures against stressors and to maximize health, performance, and fitness. The program’s mission is to protect the Soldier from head to toe, inside and out, at home, and on the battlefield.

Clinical and Rehabilitative Medicine Research Program:Implement long-term strategies to develop knowledge and materiel products to reconstruct, rehabilitate, and provide definitive care for injured Service Members. The ultimate goal is to return the Service Member to duty and restore their quality of life.

Medical Chemical and Biological Research:Support the mission of DOD’s Chemical and Biological Defense Program to provide chemical and biological defense capabilities in support of national military strategies.

Medical Simulation & Information Sciences Research Program: Coordinate emerging military medical simulation and health information technologies/informatics research across all stakeholder communities, as well as transfer research solutions and knowledge to meet Military Health System goals.

Congressionally Directed Medical Research Programs (CDMRP)

Congress has entrusted the USAMRMC to manage and execute appropriated funds for Congressional special interest (CSI) medical research, development, test and evaluation efforts, and procurement activities. The CSI appropriations are not requested by the DoD, but are added to the DOD budget by Congress. From 1990 through 2015, the USAMRMC has executed CSI program appropriations totaling over $14.8 billion.

Currently Funded CDMRP Programs

  • Alcohol and Substance Abuse Disorders
  • Amyotrophic Lateral Sclerosis
  • Autism
  • Bone Marrow Failure
  • Breast Cancer
  • Duchenne Muscular Dystrophy
  • Epilepsy
  • Gulf War Illness
  • Hearing Restoration 
  • Joint Warfighter Medical 
  • Kidney Cancer 
  • Lung Cancer
  • Lupus
  • Military Burn
  • Multiple Sclerosis
  • Neurofibromatosis
  • Orthotics and Prosthetics Outcomes
  • Ovarian Cancer
  • Parkinson's Disease
  • Peer Reviewed Alzheimer's
  • Peer Reviewed Cancer
  • Peer Reviewed Medical
  • Peer Reviewed Orthopedic
  • Prostate Cancer
  • Reconstructive Transplant Research
  • Spinal Cord Injury
  • Tick-Borne Disease
  • Tuberous Sclerosis Complex
  • Vision

Advanced Development at USAMRMC

The advanced development process takes promising technology from USAMRMC laboratories, the industrial base, academia, and other government agencies to U.S. Forces. The process encompasses the testing required for FDA approval or licensing, as well as the fielding of the finished product.

Product/Project Managers (PMs) guide the advanced development of medical products for the U.S. Army Medical Department (AMEDD), other U.S. Services, the Joint Staff, the Office of the Secretary of Defense, and the U.S. Special Forces community. PMs address critical readiness issues identified in user-requirement documents to meet cost, schedule, and performance objectives. Tailored procurement, rapid prototyping, and a variety of cooperative and contractual arrangements with academia and industry are among the current acquisition procedures used.

 PM Pharmaceutical Systems Project Management Division (PSPMD): Centrally manages the development and acquisition of drugs, vaccines, diagnostics, repellents, blood products, and resuscitative fluids. It fields products for prevention, diagnosis, and treatment of infectious diseases and injuries contracted during military operations.

Other PMs

- PM Medical Support Systems: Manages products supporting field medical treatment facility infrastructure, preventive medicine, pest management, combat casualty care support systems, military operational medicine, and ground and aeromedical casualty evacuation vehicles.

- PM Medical Materiel Solutions:Manages devices in trauma and emergency medical care, medical transport, general surgery, recovery, and general medical care.

Office of Regulated Activities: A multidisciplinary team of regulatory affairs and clinical compliance professionals dedicated to support the mission of developing FDA-regulated medical products for the Warfighter. This office provides full-service oversight and consultation for regulatory, clinical, non-clinical, manufacturing, data management, and biostatistics support for FDA-regulated drug, biologic, medical device, and combination products.

Doing business with USAMRMC

• Broad Agency Announcement (BAA): Solicits extramural research and development ideas. It includes research areas of interest; general information; evaluation and selection criteria; and proposal/application preparation instructions. The USAMRMC BAA is a continuously open announcement; pre-proposals/pre-applications and proposals/applications may be submitted at any time. Work funded through the BAA is generally in the form of a grant or a Cooperative Agreement.

 Small Business Innovation Research (SBIR)/ Small Business Technology Transfer (STTR):Each government department conducting research and development (R&D) must by law set aside several percentages of their program for SBIR/STTR programs. USAMRMC is no exception and makes dozens of SBIR/STTR awards each year.

The SBIR is intended to help certain small businesses conduct research and development. Funding takes the form of contracts or grants. The recipient projects must have the potential for commercialization and must meet specific U.S. Government R&D needs.

Phase I, the startup phase, makes awards of "up to $150,000 for approximately 6 months support [for] exploration of the technical merit or feasibility of an idea or technology."

Phase II awards grant "up to $1 million, for as many as 2 years," in order to facilitate expansion of Phase I results. Research and development work is performed, and the developer evaluates the potential for commercialization. Up to 2014 Phase II grants were awarded exclusively to Phase I award winners in 2014. The DOD, NIH, and U.S. Department of Education are allowed to make "direct to Phase II" awards.

The STTR uses a similar approach to the SBIR program to expand public/private sector partnerships between small businesses and nonprofit U.S. research institutions. The main difference between the SBIR and STTR programs is that the STTR program requires the company be partnered with a non-profit research institution (e.g., university), which must be awarded a minimum of 30% of the total grant funds.

 MTEC: USAMRMC awarded an Other Transaction Agreement (OTA) to the Medical Technology Enterprise Consortium (MTEC). The OTA is a flexible procurement instrument that provides an "enterprise partnership" between the government and a consortium of technology developers/providers in a specific medical research and development domain. This agreement is designed to facilitate mutually beneficial collaborative research and development activities for medical prototype development between the government and industry/academia. It is also intended to attract nontraditional defense contractors. 

OTA organizations are exempt from Federal Acquisition Regulations (FAR), which maintains an arms-length relationship between the government and industry. The OTA consortia model allows for the government and industry to work more as partners in advancing technologies of mutual interest. With this type of OTA organization, the following do not apply: Competition in Contracting Act; Bayh-Dole and Rights in Technical Data; Contract Disputes Act; Procurement Protest System; FAR; DFARS; Department of Defense Grants and Agreements Regulations (DODGARS); and others. 

• FedBizOps: Opportunities solicited through Broad Agency Announcements (BAAs), Request for Proposals (RFPs) and Request for Quotes (RFQs) can be found on FedBizOpps. When conducting a search, be sure to use USAMRAA DODAAC- W81XWH. 

Solicitations for contract actions expected to exceed $15,000, but not expected to exceed $25,000,000, are issued on FedBizOpps. 

• Tech Transfer Office: The USAMRMC Office of Research and Technology Applications (ORTA), otherwise known as the Technology Transfer Office, coordinates all intellectual property licensing on behalf of all USAMRMC's subordinate laboratories from the federal sector to nonfederal parties. The ORTA office at each subordinate laboratory coordinates Cooperative Research and Development Agreements (CRADAs), Material Transfer Agreements (MTAs), Interagency Agreements (IAAs), Nondisclosure agreements (NDAs), and other technology transfer transactions.

Final Thought

The process of interacting with USAMRMC can be daunting. Kinexum’s Defense and National Security Practice section can assist you in developing a long-term relationship with USAMRMC that will be mutually rewarding both for you and the USAMRMC.

Written by Dean E. Calcagni, MD, Kinexum Defense and National Security Practice

 

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