Tag: investigational drugs

Bioethics Blogs

Precision Medicine: Using Genomic Data to Predict Drug Side Effects and Benefits

People with type 2 diabetes are at increased risk for heart attacks, stroke, and other forms of cardiovascular disease, and at an earlier age than other people. Several years ago, the Food and Drug Administration (FDA) recommended that drug developers take special care to show that potential drugs to treat diabetes don’t adversely affect the cardiovascular system [1]. The challenge in implementing that laudable exhortation is that a drug’s long-term health risks may not become clear until thousands or even tens of thousands of people have received it over the course of many years, sometimes even decades.

Now, a large international study, partly funded by NIH, offers some good news: proof-of-principle that “Big Data” tools can help to identify a drug’s potential side effects much earlier in the drug development process [2]. The study, which analyzed vast troves of genomic and clinical data collected over many years from more than 50,000 people with and without diabetes, indicates that anti-diabetes therapies that lower glucose by targeting the product of a specific gene, called GLP1R, are unlikely to boost the risk of cardiovascular disease. In fact, the evidence suggests that such drugs might even offer some protection against heart disease.

Genetic approaches have increasingly been used to identify potentially promising new drug targets. In the study reported in Science Translational Medicine, researchers led by Robert Scott and Nick Wareham from the University of Cambridge, England, and Dawn Waterworth from GlaxoSmithKline, King of Prussia, PA, also wanted to explore whether genomic data could yield important clues about the potential side effects of drugs targeting particular genes.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Right to Try Laws and the Power of Stories

I appreciate the response by Lisa Kearns and Arthur Caplan to my commentary in the Hastings Center Report on right to try laws. Besides presenting a cogent summary of problems with right to try laws, the response allows me to clarify a point that I tried to make in the commentary.

I said that in focusing on abstract science and policy arguments against right to try laws, experts (and here I meant to include ethics experts) have neglected the power of stories.

Patients’ stories are the currency of right to try advocates. But the stories advocates tell fail to convey the full range of patient experiences with relatively untested drugs. In my view, right to try critics would be more persuasive if they told patients’ stories, too. Legislators and the public should hear stories about the burdens and disappointment that can follow a resort to last-chance drugs. I referred to one such story in my column and describe more of them in a June 2015 Texas Law Review article, “The Right to Try Investigational Drugs: Science and Stories in the Access Debate.”

Twenty-four states in the nation have right to try laws. I congratulate Kearns and Caplan on persuading New York and Connecticut legislators to take a careful look at right to try proposals in their states. Adding patient stories to the discussion could help right to try critics accelerate this trend. 

Rebecca Dresser is a professor at Washington University in St. Louis and the author of When Science Offers Salvation: Patient Advocacy and Research Ethics.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

If I Only Had a Brain? Tissue Chips Predict Neurotoxicity

Caption: 3D neural tissue chips contain neurons (green), glial cells (red), and nuclei (blue). To take this confocal micrograph, developing neural tissue was removed from a chip and placed on a glass-bottom Petri dish.
Credit: Michael Schwartz, Dept.  of Bioengineering, University of Wisconsin-Madison

A lot of time, money, and effort are devoted to developing new drugs. Yet only one of every 10 drug candidates entering human clinical trials successfully goes on to receive approval from the Food and Drug Administration (FDA) [1]. Many would-be drugs fall by the wayside because they prove toxic to the brain, liver, kidneys, or other organs—toxicity that, unfortunately, isn’t always detected in preclinical studies using mice, rats, or other animal models. That explains why scientists are working so hard to devise technologies that can do a better job of predicting early on which chemical compounds will be safe in humans.

As an important step in this direction, NIH-funded researchers at the Morgridge Institute for Research and University of Wisconsin-Madison have produced neural tissue chips with many features of a developing human brain. Each cultured 3D “organoid”—which sits comfortably in the bottom of a pea-sized well on a standard laboratory plate—comes complete with its very own neurons, support cells, blood vessels, and immune cells! As described in Proceedings of the National Academy of Sciences [2], this new tool is poised to predict earlier, faster, and less expensively which new or untested compounds—be they drug candidates or even ingredients in cosmetics and pesticides—might harm the brain, particularly at the earliest stages of development.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Cost of Compassionate Use is Simply Too High

by Craig Klugman, Ph.D.

Johnson & Johnson’s Janssen Pharmaceutical Company announced that it has contracted with New York University’s Division of Medical Ethics to assemble an external Compassionate-Use Advisory Committee (CompAC) to examine requests for investigational new drugs (INDs) outside of clinical trials. Arthur Caplan will lead this group, which will be composed of bioethicists, physicians, and patient advocates. The goal of this group is to provide recommendations on which patients should be given compassionate use access to experimental drugs.

This step is a reaction to increasing publicity on compassionate use as well as 17 states having passed “Right to Try” laws that allow residents of those states to directly contact drug companies to request experimental drugs.

Compassionate use is also known as expanded access, a program created by the FDA in 1987 that allows people with life-threatening disease to request access to investigational new drugs outside of clinical trials. These are drugs that have not been approved by the FDA, have not been proven safe, and have not been proven effective.

To be considered for compassionate use, the FDA requires that the patient has a serious disease/condition or has an immediately life-threatening condition and:

  • “There is no comparable of satisfactory alternative therapy
  • “The patient cannot obtain the drug under another IND or [research] protocol
  • “The potential patient benefit justifies the potential risks
  • “Providing the investigational drug will not interfere with the initiation, conduct, or completion of clinical investigations”

Then the company has to agree to provide the drug under a physician that will closely monitor the patient.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

“Right to Try” Laws, Compassionate Use, and Adverse Events: A Second Cautionary Tale

by Alison, Bateman-House, Ph.D., MPH

In 2014, Colorado became the first state to debate and then pass a so-called “Right to Try” law. In early 2015, there are now five states that have such laws: Colorado, Michigan, Louisiana, Arizona, and Missouri. The Utah and Virginia state legislatures have passed their own right to try laws, both of which await signature by their respective governors, and over twenty other states are actively debating right to try legislation.

These right to try state laws are based on a model bill that was circulated by the Goldwater Institute, a libertarian think tank based in Arizona. According to the Goldwater Institute, the U.S. Food and Drug Agency’s regulations for new drugs take a toll on terminally ill Americans, a number of whom die before they can get access to potentially lifesaving experimental treatments. Thus, the model law cuts the FDA out of decisions about whether patients may be granted access to experimental treatments. Under right to try laws, a patient may ask the company developing a drug or device to make that experimental medical product available to her. The company does not have to provide it, and if the company does decide to provide the patient with the experimental drug or device, they may charge her for it (and her insurance company has no obligation to pay for it). But, if the patient and the company come to a mutually agreeable decision, there is no need to seek FDA approval of their plan. This is a controversial change in that such decisions were previously understood to be regulated by the FDA under its federal legal mandate.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Deregulation and Free Markets for Stem Cell Products

Paolo Bianco and colleague Douglas Sipp wrote a very
provocative and interesting piece recently published in the journal
Nature (http://www.nature.com/news/regulation-sell-help-not-hope-1.15409)discussing
a movement to permit stem cell medicines, among others, to be sold in the
market without the requirement to show much safety and efficacy data permitting
the market to determine safety and effectiveness of compounds. Here, patients
would basically pay to obtain products and also be research subjects. Certain
powerful groups are calling for the deregulation of clinical medicine as a
business model to bring innovative products to the marketplace. But before I
begin explaining what Bianco and Sipp discuss, we need to cover the current
system of regulatory oversight of medical products.

The Clinical
Translation Process

The current standard for market approval of drugs,
devices, biologics and other products is known as clinical translation. The
clinical translation process involves moving research from preclinical phases
to clinical phases. Preclinical research aims to provide evidence of
proof-of-principle and product safety through in vitro (e.g., cell-based assays) and in vivo (e.g., cell transplantation in disease animal model)
experiments. The idea here is that work using animals will help to ensure that
outcomes in humans will be clinically relevant and safe. However animal models
are not always the best indicators of effectiveness of interventions in humans
despite how genetically similar they are to humans. Demonstration of safety and
efficacy in preclinical research is required to persuade regulatory authorities
like the US Food and Drug Administration (FDA) to permit approval for
researchers to enter phase 1 clinical trials.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Rescue Me: The Challenge Of Compassionate Use In The Social Media Era

The Development of Brincidofovir And Its Possible Use To Treat Josh Hardy

Last March 4, seven-year old Josh Hardy lay critically ill in the intensive care unit at St Jude Children’s Hospital in Memphis, Tennessee with a life-threatening adenovirus infection. His weakened immune system was unable to control the infection, a complication of a bone marrow stem cell transplant he needed as a result of treatments for several different cancers since he was 9 months old.

His physicians tried to treat the adenovirus with an anti-viral agent, Vistide (IV cidofovir), but had to stop due to dialysis-dependent renal failure. They were aware of another anti-viral in Phase 3 clinical development, brincidofovir, an oral compound chemically related to Vistide. In earlier clinical testing brincidofovir had shown the potential for enhanced antiviral potency and a more favorable safety profile.

Chimerix (where one of us, Moch, was CEO), a 55 person North Carolina-based biopharmaceutical company, had previously made brincidofovir available to more than 430 critically ill patients in an expanded access program for the treatment of serious or life-threatening DNA viral infections, including adenovirus as well as herpes viruses (such as cytomegalovirus) and polyomaviruses.  This program started in 2009 as a series of individual physician-sponsored emergency INDs — investigational new drug exemptions issued in physician-certified compassionate use situations.

The program evolved via word of mouth to the extent that brincidofovir was made available under emergency INDs for more than 215 patients. During 2011, Chimerix received funding from Health and Human Service’s Biomedical Advanced Research and Development Authority (BARDA) to provide brincidofovir to an additional 215 critically ill patients for the purpose of gaining insights into the potential use of brincidofovir as a medical countermeasure against smallpox.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Ebola Pandemonium: Urging Cautious Approaches in Desperate Contexts

Lisa Schwartz describes the necessary conditions for the ethical provision of experimental Ebola drugs and vaccines.

_____________________________________________________________
The sudden outpouring of investigational drugs and vaccines in response to the Ebola crisis in West Africa is laudable. However, desperate emergencies do not mean we can forego caution. The World Health Organization (WHO) declared the outbreak of Ebola Virus Disease a Public Health Emergency on August 8, 2014 and struck an ethics committee that, on August 12, advised it is permissible to distribute experimental drugs and vaccines in response to the outbreak – even drugs and vaccines as yet untested in humans.

I believe the WHO was right to do this; speed is what is needed right now.  However, the WHO was also rightly cautious in advising that these experimental interventions (for treatment or for prevention) should be used with care and under the vigilant scrutiny of, at the very least, observational research. Someone needs to be taking account of the results of these vast experiments, otherwise the risks taken by Ebola affected communities will be for naught.

Canada has offered an experimental vaccine, called VSV-EBOV, and Canadian based research laboratories have played a major role in the development of other early, untested medications – including the much talked about ZMapp. This is something that politicians say we ought to be very proud of, and so we should. But we must also be aware that there will likely be many such offers pouring in from experimental labs all over the world, mainly for the best reasons, but always with a mixture of hope and dread.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

The Ethics of Ebola and Scarce and Experimental Drugs

by: J.S. Blumenthal-Barby

Yesterday I was contacted by the L.A. Times to answer a simple question: Should we give people access to the experimental Ebola drug, ZMapp?

The Drug and Clinical Trial Phases
So, I did a little digging to try to find out some more details about the drug. From what I could find in published news reports, the drug was developed by Mapp Biopharmaceutical Inc., with support from the NIH and the Defense Threat Reduction Agency. It has been tested on 8 monkeys. 4 of them were given the treatment 24 hours after being infected and all 4 survived. The other 4 were given the treatment 48 hours of being infected and 4 of those survived.  One monkey was not treated and died. Ebola has a morality rate of 50-90%. From what I could gather, the drug had not been tested on any human yet. In research ethics lingo, it had not even gone through Phase 1 trials (to test safety and toxicity), let alone Phase 2 (to test efficacy) or Phase 3 (further, RCT, testing of safety and efficacy) trials.

Access and Compassionate Use
Under what justification could we give people access to an experimental drug that has not even been tested for safety in humans? The ready justification is a “compassionate use” exception.  From the FDA website: “Expanded access, sometimes called “compassionate use,” is the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options. 

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Individual Patient Expanded Access: Developing Principles For A Structural And Regulatory Framework

Individual patient expanded access, sometimes termed “compassionate use,” refers to situations where access to a drug still in the development process is granted to patients on a case-by-case basis outside of a clinical trial, prior to completion of mandated clinical trials and approval by the Food and Drug Administration (FDA). This typically involves filing a single patient or emergency investigational new drug (IND) request with the Food and Drug Administration and voluntary release of the drug by the manufacturer.

Generally, the following criteria must be met: there is reasonable expectation of meaningful benefit despite the absence of definitive clinical trial data, the patient has a serious or life-threatening condition, there are no comparable or satisfactory treatment alternatives, and there are no suitable clinical trials for the drug available to the patient. This form of expanded access, which is the focus of this paper, is different from the situation in which a drug is discharged to a large group of needy patients in the interval between successful phase 3 trials and presumed FDA approval, a strategy often termed a “treatment” IND or protocol, which was initially used in the 1980s for releasing zidovudine to patients with acquired immune deficiency syndrome.

A Call to Action: The Importance of Expanded Access Programs

The Engelberg Center for Health Care Reform at the Brookings Institution recently invited senior leaders from several pharmaceutical companies, two bioethicists, a senior FDA representative, and a patient advocate to share experiences and discuss organizational strategies related to expanded access (see acknowledgements). A driving factor for this meeting was a recent flurry of highly public cases of desperate patients seeking access to experimental drugs, which lead to social media campaigns and media coverage.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.