Life Science Compliance Update

April 21, 2017

Dr. Stossel Corrects a Common Misconception

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Thomas P. Stossel, MD, MD (Hon), is a visiting scholar at the American Enterprise Institute and professor emeritus at Harvard Medical School, who has recently published several articles on how to remove barriers to medical innovation, and how medical innovation actually happens. This article highlights the impressive research by Dr. Stossel, supporting his position that private investment does much more to push the progress of medicine along than people think.

One article, published in the Wall Street Journal on January 5, 2017, addressed the assumption that “the root of all medical innovation is university research, primarily funded by federal grants.” He noted that the assumption is incorrect and that it is the “private economy, not the government,” that “actually discovers and develops most of the insights and products that advance health.”

The article opens with complimenting Congress for passing the 21st Century Cures Act, claiming that it “will promote medical innovation,” while at the same time telling readers to be “wary, however, of the $4 billion budget boost that the law gives to the National Institutes of Health.” In addition to his Wall Street Journal article, Dr. Stossel wrote a more in-depth article in National Affairs, arguing the same points, with more research and information embedded into the article. 

There were few findings in medical science that could significantly improve health until the late 19th and early 20th centuries, with innovation primarily coming from “physicians in universities and research institutes that were supported by philanthropy.” Dr. Stossel notes, however, that things changed after World War II when the National Institutes of Health became the major backer of medical research, changing incentives. Universities that previously lacked research operations started to develop them, and existing programs were largely expanded. As noted in Dr. Stossel’s article in National Affairs, “for decades, Congress allocated generous and growing funds to the NIH that enabled it to provide many research grants to universities. As a result, universities expanded their laboratory facilities and research faculties — and the government-academic biomedical complex, or GABC, was born.”

Since that time, improvements in health have rapidly occurred. Also during that period, funding for the National Institutes of Health has lagged behind the growth of an aging population in need of medical innovation while private investment in medicine has largely kept pace with the aging population and “is the principal engine for advancement.”

In his National Affairs article, Dr. Stossel discussed research papers submitted for publication, noting:

Although revered by academics as a quality filter, “peer review” of research papers submitted for publication (and of grants for research funding) is a flawed enterprise. As scientific journals found success in providing researchers the priority and credit they were looking for, the volume of submissions began to exceed the supply of journals’ publication space. The practice of peer review — having selected experts render opinions regarding the quality of articles submitted to journals — was designed to solve that problem. Today, electronic publication has eliminated the space problem, but a prestige hierarchy of journals has replaced it with a false scarcity. Researchers covet attention in the most prestigious journals, and the high-profile journals sustain their elevated status by arbitrarily rejecting the majority of articles submitted to them. The monopoly power of these journals, fueled by researchers’ vanity, allows indifferent editors to delay decisions about whether to publish research articles until dueling authors and reviewers come to a resolution. The referees of these disputes provide a quality of service that would be expected from the nature of the reviewers: anonymous, unpaid cronies or competitors of a paper’s authors. As a result, research data can languish in obscurity for months or years while authors work their way down the prestige pecking order and finally obtain a place to publish.

According to Dr. Stossel, more than 80% of new drug approvals originate from work solely performed in private companies and such drug approvals come on average 16 years after the beginning of clinical trials, which typically cost $2.5 billion from start to finish. Therefore, it appears even if academics and NIH really wanted to create a new drug, economic reality would get in the way.

The National Affairs article notes that, “achieving innovation requires wanting to innovate more than trying to impress reviewers of research papers or grant applications. It involves trial-and-error efforts that academic-review committees dismiss as “fishing expeditions” and that violate the scholarly premium on ‘hypothesis-driven’ studies. Success in academe also demands sticking to one’s research ‘brand.’ By contrast, innovation usually requires shifting gears to employ different technologies and experimental approaches. Such inconsistency reliably leads grant-application reviewers to discount an applicant’s qualifications.”

Dr. Stossel closes his Wall Street Journal article by stating:

Despite its exaggerated role, basic research in universities does advance human knowledge, train scientists, and contribute to medical advances—albeit uncommonly and inefficiently. But the system is unsustainable. A better approach would be to encourage academics to join with industry, where the financial resources and drive to innovate reside. Unfortunately, the biomedical complex demonizes corporations. If academic institutions stopped demeaning the activities needed to develop medical products, industry might take a greater interest in supporting their research.

Great advances in health care have been made, but there are still important challenges, from obesity to dementia. One step toward addressing them would be for Washington to adopt the right approach to medical innovation—and to stop simply throwing money at the current inefficient system.

April 18, 2017

Will There Be an Uptick in FDA NDA Approvals This Year?

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Late last year, John Jenkins, director of the FDA’s Office of New Drugs told attendees at an event that the decline in new drug approvals (NDAs) was not due to a shift in FDA standards or policies. The number in 2016 (22) is remarkably lower than the total in 2015 (45). Could there be changes in 2017?

Report from event: Uptick in 2017?

Regulatory Focus reported from the Prevision Policy conference, quoting Jenkins directly: “There are fewer applications in front of us to act upon,” Jenkins said, noting that although he cannot discuss individual applications, a handful of the complete response letters (CRLs) issued in 2016 were due to good manufacturing practice (GMP) deficiencies and the need for FDA to conduct inspections. But Jenkins did say that there has been an uptick recently in the number of applications received, meaning the number of approvals could increase in 2017.

Recent news of an FDA approved drug to treat Parkinson’s disease lends some evidence to that claim. The drug, Xadago (safinamide), is an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

MERIT Act

Introduced by Rep. Larry Loudermilk (R., Ga.), the Modern Employment Reform, Improvement, and Transformation (MERIT) Act, H.R. 559, would make it easier to “drain the swamp” by removing federal employees for poor performance or misconduct. The MERIT Act allows for due process: It requires notice in writing to the employee in question from the head of an agency and provides an opportunity to respond with an appeal. The Merit Systems Protection Board is required to issue a decision within 30 days of the appeal. 

The National Review suggests this Act could be quickly applied to the FDA. They argue: “In recent years, in both the formulation of policy and the evaluation of individual products, the FDA has made egregious errors and arbitrarily expanded its authority in extra-statutory ways that have had important consequences. Most of these missteps have been in the direction of excessive risk-aversion or heavy-handed regulation, although a few, such as oversight of herbal dietary supplements and compounding pharmacies, have been marked by laxity, timidity, or outright incompetence.”

It is unclear if this would increase the success rates of NDAs, but indicates the close intersection between the political environment, FDA policy, drug pricing, and even the regulators themselves.

Scott Gottlieb’s Impact?

President Trump’s nomination for FDA Commissioner, Scott Gottlieb, could result in faster approval of drugs as reported by the Hill. Gottlieb could introduce a new regulatory paradigm focused on competition to accelerate innovation, dramatically shorten the time from development to patient access, and sharply reduce the prices for new drugs. Rather than settling for the status quo that rewards delayed access and excessive caution, he can promote early access and fast learning.

April 10, 2017

Modern Drug Development

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In an article published in Science Translation Medicine, Disciplined approach to drug discovery and early development, Robert Plenge of Merck Research Laboratories writes on the best practices for drug discovery. He outlines what is necessary for the highest chances of success. This is important as diminished productivity in therapeutics research and development (R&D) has driven drug costs up while delivering value to patients some consider insufficient.

Plenge’s Argument

Plenge outlines four areas—causal human biology, therapeutic modality, biomarkers of target modulation, and proof of concept (PoC) clinical trials—that have received ample attention. But it is important to link the concepts to test therapies in human trials. He acknowledges this will not end all late-stage R&D failures as drug discovery is an inherently risky venture. But he outlines examples that suggest feasibility. He notes that his principles will improve the R&D portfolio’s chances of success in developing much needed therapies to patients.

He notes that it is important to have evidence from human biology before beginning the process. With careful study of human genetics, you can learn a lot. Using animal models without human tissue or cells is problematic. While this is hard in some disease areas, it underscores his point that it will inherently be challenging to develop therapies in some areas. Furthermore, the target goal is going need to be pragmatic. For example, gain-of-function on an enzyme is rare. So you have to accept the limitations of what the science can do for your ultimate goal.

Plenge calls for insight into biomarkers and stresses they should be as human-related as possible. It may be easier in some cases, like diabetes, but others will be difficult. He describes human genetic studies as “Nature’s randomized clinical trial,” and they offer an increased opportunity to know what a researcher should be looking for to use in a clinical trial.

Finally, in a clinical trial, it should be small, fast, and meaningful as possible to test proof-of-concept. This means that in some cases, there may be diseases that researchers may not wish to consider looking into. It also means picking patients carefully to find those most likely to show a response. If this can be done, and there is a trustworthy biomarker in place, the research is in good shape.

Limitations?

Derek Lowe writes about some of the limitations in this paper. “First and foremost,” he says, “there is an underlying assumption that we have sufficient data from humans to enable the discovery of new therapeutic targets and biomarkers. Validation of this assumption requires an ecosystem to define which sources of human data establish causality; members of the ecosystem must then work systematically toward building such databases that are accessible to all.”

He outlines the example that no resource enables systemic identification of human genetic variants linked to clinical outcomes in large patient populations in a setting appropriate for recall. However, there are efforts to generate these databases. Another problem outlined by Lowe is that one may not have sufficient “experiments of nature,” by mining human genetic diversity. Even if you do, it may not provide adequate information of how to modulate a proposed target.

Furthermore, “clinical trials technologies and designs may not (or not yet) allow for the sort of data collection and biomarkers that you’d like. Even with these complications, I’d say that these criteria are definitely worth aiming for. But even if you have all of them going for you, you can still easily fail in the clinic. Note also that even though many infectious diseases score high by these standards, targets for them can be hard to come by – those projects tend to have high preclinical failure rates, which aren’t addressed here.”

While outlining other problems, Lowe describes the biggest issue as that it is hard to meet all of the rules proposed by Plenge at the same time. “Something’s going to come up short, and judgment calls are going to have to be made about which of those are deal breakers and which aren’t. I’d say that lack of any human biology connection is a deal-breaker, for example, while lack of a really good fast-readout biomarker is just a sign that you’re going to be spending a lot more time and money in the clinic than you want to (not that that’s not a big consideration in itself). But I think that overall, Plenge is correct, that the closer you come to these ideals, the better off you’re going to be. They’re something to shoot for.”

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