Act Now to Stop Genetically Engineered Fish from Receiving Approval

By Dr. Mercola

On December 21, 2012 — while everyone was busying themselves with preparations for holiday festivities—the US Food and Drug Administration (FDA) took a giant step closer toward the final approval of the first genetically engineered (GE) fish food — a salmon designed to grow abnormally fast.1

It’s a move that many, including myself, have worried might happen, and it now appears the first GE fish could reach your dinner plate within the next year or two, unless a sufficiently strong opposition is mounted.

According to the FDA,2 the GE salmon is “as safe as food from conventional Atlantic salmon,” but many have brought up significant flaws and limitations of the environmental assessment (EA) on which this conclusion is drawn. The FDA’s draft EA3 is now open for public comment.

Genetically Engineered Fish

Story at-a-glance

  • The FDA is getting closer to issuing final approval of the first genetically engineered food animal—a salmon designed to grow up to five times faster than normal. The draft environmental assessment is now open for public comment for 60 days
  • FDA has allowed this GE fish to move forward based on tests of allergenicity of only six engineered fish, and those tests actually did show an increase in allergy-causing potential
  • The environmental risks are also tremendous. In a previous Purdue University computer model that tracked the effects of releasing just 60 “Frankenfish” into a population of 60,000, there was a complete extinction of the normal fish in just 40 fish generations
  • Alaska’s congressional delegation is united in its opposition against the approval of AquaBounty’s GE salmon, and Rep. Don Young has announced a plan to introduce legislation that will, at minimum, require GE salmon to be labeled

What are the Potential Dangers Associated with GE Salmon?

According to Andrew Kimbrell, executive director of the Center for Food Safety:4

“The GE salmon has no socially redeeming value. It’s bad for the consumer, bad for the salmon industry and bad for the environment. F.D.A.’s decision is premature and misguided.”

Two years ago, GMO expert Jeffrey Smith, founder of the Institute for Responsible Technology, called the potential approval of genetically engineered salmon “a move that will go down in history as one of the most asinine and dangerous ever made by our government.” According to Smith, evidence5 suggests the buffed-up salmon might have higher levels of a potentially cancer promoting hormone, IGF-1, more antibiotics, and more of potentially life-threatening allergen(s).

In a recent statement, Michael Hansen PhD, Senior Scientist with Consumers Union said:6

“The Environmental Assessment (EA) states that the FDA has found that the salmon is safe to eat. However, we are deeply concerned that the potential of these fish to cause allergic reactions has not been adequately researched. FDA has allowed this fish to move forward based on tests of allergenicity of only six engineered fish — tests that actually did show an increase in allergy-causing potential.” [Emphasis mine]

But that’s not all. The salmon — which contains a spliced-in growth hormone gene that makes it grow up to five times faster, reaching market size in about 18 months instead of three years — poses a significant threat to the environment and natural fish stocks as well. According to a Purdue University computer model that tracked the effects of releasing just 60 “Frankenfish” into a population of 60,000, there was a complete extinction of the normal fish in just 40 fish generations. It appears the larger size, which attracted mates more easily, combined with a slight reduction in survival rates, was a killer combination. Furthermore, according to Jeffrey Smith, Canadian scientists also engineered their own set of fast growing salmon and tested their behavior in tanks with other fish.

“When there was sufficient food, all was fine. When food stocks decreased, the Frankenfish freaked,” he says. “They became cannibals, attacking and killing other fish — whether GE or natural. Their unexpected behavior resulted in population crashes or complete extinctions in the fish tanks. The study also suggested that if released, these ravenous aggressive salmon would pursue and consume other types of fish.”

The FDA pooh-pooh’s such fears. As reported by the New York Times:7

“The agency [FDA] said the chance this would happen was ‘extremely remote.’ It said the salmon would be raised in inland tanks with multiple barriers to escape. Even if some fish did escape, the nearby bodies of water would be too hot or salty for their survival. And reproduction would be unlikely because the fish would be sterilized, though the sterilization technique is not foolproof.”

The issue of the sterility of the fish is a can of worms in and of itself. According to Hansen:

“…We are also concerned that FDA puts great weight, in their finding of ‘no significant impact,’ on the fact that the engineered salmon would be sterile females. However FDA indicates that only 95 percent of the salmon may be sterile, and the rest fertile. When you are talking about millions of fish, even one percent comes to thousands of fish. Moreover, perhaps even more important, the fish at the egg production facility in Prince Edward Island, Canada would obviously not be sterile — otherwise they could not produce eggs…”

And what about the promise that these GE salmon will be firmly landlocked, with no possibility of escape? This may sound good and well to some people, but it’s important to remember how the process typically ends up working — “give them an inch and they’ll take a mile,” as the saying goes. George Leonard, writing for the National Geographic recently addressed this with the following statement:8

“While this initial application to grow GE salmon is for land-based facilities, the prospect of even larger profits from growing GE salmon in the ocean will certainly create pressure for approval in these more environmentally risky systems in the future.

The U.S. is poorly equipped to deal with this future scenario. In June 2011, NOAA Administrator Dr. Jane Lubchenco released a National Aquaculture Policy to guide how marine aquaculture proceeds in our ocean waters. While the policy includes some strong environmental provisions, it does not categorically prohibit the growing of GE fish in the ocean. It should.

Given FDA’s action yesterday and NOAA’s failure to prohibit GE fish in its aquaculture policy, the time has come for Congress to intervene. Congress should work to pass Senator Mark Begich’s PEGASUS Act or similar legislation that requires FDA to take the environmental risks seriously before approving GE fish. If Congress doesn’t act soon, the nation’s ocean may suffer from FDA’s efforts to chart a course for GE salmon.”

Environmental Assessment ‘Woefully Inadequate,’ Scientist Says

The video above is two years old, but the arguments made in it remain unchanged. The video features Michael Hanson, a brilliant senior scientist with the Consumers Union (the publisher of Consumers Reports), and Val Giddings, a biotechnology consultant to various governments and companies. One major concern is that the containment systems designed to segregate these fish from wild fish could fail. I am convinced this is the MAJOR argument against the approval of these GE fish, not the allergencity of them. As explained by Hanson, the fact that the FDA is only looking at two facilities, both outside the United States, and that they’ve only performed an environmental assessment on ONE facility, specifically located on Prince Edward Island (PEI), is of major concern. There’s no assessment of the environmental impact if the fish are produced elsewhere.

In his 2010 comments to the FDA Veterinary Medicine Advisory Committee Meeting, he stated:9

“A fundamental problem with all the phenotypic characterization data, and indeed all the nutritional and food safety assessment data, is that they all come from GE Salmon raised in the PEI facility, not at the facility in Panama. FDA admits that the culture/husbandry conditions at the facility in Panama will likely differ significantly from the conditions at the PEI facility with unknown effect on the GE salmon’s phenotype but then concludes that it has no concerns with the different culture conditions: ‘the culture (e.g., water temperature, pH, alkalinity, etc.) were likely to be significantly different from the facility at PEI as a result of differences in, among others, water surface, facility design, and environmental factors due to geographic location. …the effect of the difference between the PEI and Panama facilities, especially temperature, on the resulting AquAdvantage phenotype is unknown.

Conclusion: The husbandry and rearing conditions at the PEI and Panama facilities do no present concerns with respect to animal health.’

We do not understand how FDA can conclude, in the absence of any data on the phenotype of GE salmon raised at the Panama facility, that there are no animal health concerns with GE salmon raised at the Panama facility. This lack of data is highly problematic as the GE salmon that consumers will be exposed to will be those grown at the Panama facility. FDA appears willing to conclude that there are no animal or human safety problems from AquAdvantage salmon raised in Panama based on no data at all…”

Furthermore, another major concern that environmental activists have is that if the fish accidentally get out into the wild, they’re more aggressive; they feed more, and can easily outcompete not only other salmon but any local fish. As mentioned earlier, Canadian researchers showed this to be the case — when food supply was scarce, the GE salmon turned cannibalistic, resulting in complete extinctions within the fish tanks…

The approval of these salmon is just the beginning, and for that very reason, we should insist on caution and the strictest, most detailed scientific inquiry possible, and this is simply NOT the case here… As Giddings says, if these fish are approved, “it will demonstrate that there’s a functional regulatory system that is able to look at the data and make a reasoned, science-based decision based on the data,” and this would naturally open the door to the introduction of other genetically engineered animal-based foods. According to Hanson, the scientific bar should be set very high when it comes to evaluating the health- and environmental impact of GE animals, but the FDA is “setting it about an inch off the floor.”

Breakdown of the Federal Government’s Science Integrity Process

Forbes magazine10 recently ran an article questioning whether the federal government’s science integrity process has completely broken down as the White House administration stands accused of openly meddling with the approval of the controversial Frankenfish.

Two years ago, the FDA promised to release the environmental assessment of AquaBounty’s modified salmon “within weeks.” But it didn’t… A draft assessment was eventually produced, dated April 19, 2012, but it ended up not being released. Why? According to Forbes, the draft was blocked on orders from the White House, and subsequently delayed seven months — presumably to protect President Obama’s reelection efforts.

“Genetically modified plants and animals are controversial among the president’s political base, which was thought critical to his reelection efforts during a low point in the president’s popularity,” Forbes writes.11

“…According to sources, the White House political block — a direct violation of numerous ethics regulations and possibly of federal laws — was instituted over the objections of scientists at the FDA, but with the awareness of HHS Secretary Sibelius, her senior adviser Andrea Palm and the Office of Science and Technology Policy and its director John Holdren, who is responsible for enforcing ‘science integrity’ across government agencies. The OSTP had overseen an inter-agency review process that was completed by early spring. According to sources, Holdren stood by as the White House openly meddled.

The revelations have come as an embarrassment to the administration, say sources. As president, Barack Obama had pledged to change ‘the posture of our federal government from being one of the most anti-science administrations in American history to one that embraces science and technology.’ To publicly guarantee that, the White House had issued a science integrity memorandum in 2009 pledging, ‘Political officials should not suppress or alter scientific or technological findings and conclusions,’ and putting Holdren in charge of enforcement.

FDA scientists and staffers say they were instructed not to discuss the decision to approve the salmon — a violation of the agency’s scientific integrity guidelines adopted last February that require the FDA to shield its staff from ‘political influence’ and to allow officials and scientists to ‘communicate their personal scientific or policy views to the public, even when those views differ from official Agency opinions.'”

Will Congress Protect You From this Potentially Hazardous Food?

Fortunately, some congressional members are not sitting idly by, waiting for the devastation to take place. Alaska’s congressional delegation is united in its opposition against the approval of AquaBounty’s GE salmon,12 Senator Mark Begich calls the notion that GE salmon is safe for human consumption and our oceans “a joke,” and Senator Lisa Murkowski has stated:

“I am concerned with the recent news that FDA is moving forward with the approval of genetically modified fish. This is especially troubling as the agency is ignoring the opposition by salmon and fishing groups, as well as more than 300 environmental, consumer and health organizations.”

Of course, another major area of concern is, if the salmon is approved, whether you will be able to know when you’re buying it, since GE foods are still not required to be labeled. Consumer advocates are concerned about how large the no-labeling problem will grow, since genetically engineered beef, pork and other fish are next in line behind salmon for FDA consideration. For example, Science Nordic13 has announced its intentions to create a salmon with higher omega-3 content than regular salmon. In response to these growing concerns, Rep. Don Young recently announced a plan to introduce legislation that will, at minimum, require GE salmon to be labelled.14

Action Items to Stop Approval of GE Salmon

Without labeling, there’s no way for you to tell how the food you eat was grown, and while this is bad enough as it relates to GE corn, soy, sugar, and other common food ingredients, it’s an issue that will become increasingly important with the introduction of animal foods where the entire animal itself has been genetically altered.

I believe the old adage that “you are what you eat” is rooted in basic truth, and I for one do not think there’s any possible way to achieve the same health benefits from a genetically altered food source as from “the real deal” produced by nature. These are remarkable times, but it’s become quite clear that we must vigorously protect and defend natural foods of all kinds. We cannot afford to stick our heads in the sand and hope for the best on this issue.

Serious Bradycardia Risk With Amiodarone Plus Hep-C Antivirals, FDA Cautions

The US Food and Drug Administration (FDA) is updating labeling information for the hepatitis C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after their manufacturer reported bradycardia, pacemaker intervention, and even death in patients who took the medications along with the antiarrhythmic agent amiodarone[1].

Gilead Sciences reported these serious treatment-related adverse events for nine patients. All were taking amiodarone, with three also taking ledipasvir/sofosbuvir, five also taking sofosbuvir and daclatasiver (Daklinza, Briston-Myers Squibb), and one also taking sofosbuvir and simeprevir (Olysio, Johnson & Johnson). Seven were also taking a beta-blocker.

All of the patients developed symptomatic bradycardia after taking the combinations, with six developing the condition 24 hours after use. In addition, one patient died from cardiac arrest after treatment and three others underwent pacemaker implantation.

There have been no cases of bradycardia reported for patients taking sofosbuvir plus ribavirin alone or with pegylated interferon.
The new FDA labels for both antivirals recommend that clinicians discuss the potential risks with patients who “have no other alternative, viable treatment options.” Plus, they should undergo cardiac monitoring for 48 hours after first administration and then daily heart-rate monitoring done in the outpatient or home setting for 2 weeks afterward.

The same monitoring rules should be followed for those who discontinue amiodarone, because of the medication’s long half-life.

Postmarketing Studies Lag After FDA Approvals.

Of the 20 new drugs approved for marketing by the US Food and Drug Administration (FDA) in 2008, 8 received expedited reviews after significantly fewer patients were studied, according to an article published online October 28 in JAMA Internal Medicine. In addition, 50 of 85 postmarketing study commitments, included as conditions for approvals, remained unfulfilled as of January 2013.

Thomas J. Moore, AB, from the Institute for Safe Medication Practices, Alexandria, Virginia, and Curt D. Furberg, MD, PhD, from the Wake Forest School of Medicine, Winston-Salem, North Carolina, conducted a descriptive study of 2008 FDA new molecular entity approvals using FDA documents, drug information databases, prescribing information, and other data sources.

They found that the drugs approved under the accelerated approval program received approval after a median of 5.1 years (range, 1.6 – 10.6 years) compared with 7.5 years (range, 4.7 – 19.4 years) for drugs approved under the standard review process (P = .05). Moreover, approvals for expedited-review drugs came after efficacy testing in a median of 104 patients (range, 23 – 599 patients) compared with a median of 580 patients (range, 75 – 1207 patients) for standard-review drugs (P = .003).

The 20 drugs approved in 2008 were split evenly between inpatient and outpatient use. Seven of the drugs were approved with orphan drug status for rare diseases, including 6 of those that received expedited review. (The FDA also approved 4 diagnostic tests in 2008, which the researchers did not include in their current analysis.)

All 20 drugs were still marketed as of January 2013. However, drug sponsors had completed just 26 of 85 (31%) postmarketing studies and submitted data for FDA review for another 8 (9%). In other words, drug sponsors had not yet met their commitments for 50 of the 83 postmarketing commitments that were required by the agency as part of the approval process.

Interestingly, commitments remained unfulfilled for both drugs that received accelerated approval (18/48 [38%]) and those that received standard approval (23/37 [48%]).

The researchers note that postmarketing commitments occur a median of 11 years after approval; their study only covered 4 years. Of 48 studies that were scheduled for completion by study time, 34 (71%) had been submitted.

At the time of approval, 5 of the 20 drugs carried a boxed warning of a significant safety risk, 8 carried a requirement of special risk management, and 8 carried a warning or contraindication for hypersensitivity. Since approval, 5 drugs received a new or expanded boxed warning, raising the total number to 7 drugs. One drug received new contraindications, and 4 drugs received additional warnings or precautions.

Shifting Situation

“The testing of new drugs has shifted from a situation in which most testing was conducted prior to initial approval to a situation in which many innovative drugs are more rapidly approved after a small trial in a narrower patient population, with extensive additional testing conducted after approval,” the researchers conclude. “Our findings suggest that the shift has made it more difficult to balance the benefits and risks of new drugs.”

The seriousness of the problem can hardly be overstated, according to Daniel Carpenter, PhD, from the Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts. “If the FDA’s requirements for new drugs, both premarket and postmarket, are weakened, trust in both the efficacy and safety of prescription drugs is likely to be weakened,” he writes in an accompanying commentary. “The stakes of the current policy debates could not be higher. There is scarcely a feature of the American health care system that does not depend on evidence-based trust in prescription drugs, ratified and enforced by the FDA.”

Toward Patient-Centered Drug Development in Oncology.

As an oncologist, when I sit with patients to discuss starting a new chemotherapy regimen, their first questions are often “How will it make me feel?” and “How did patients like me feel with this treatment?” Regrettably, this information is generally missing from U.S. drug labels and from published reports of clinical trials — the two information sources most commonly available to people trying to understand the clinical effects of cancer drugs.

In 2011, 15 hematology–oncology drugs were approved by the U.S. Food and Drug Administration (FDA). In only one case — that of ruxolitinib for the management of myelofibrosis — was symptom information included in the portion of the label that manufacturers can legally use for marketing purposes. In fact, ruxolitinib was the first cancer therapeutic in more than a decade for which symptom information was included in a U.S. drug label.

Cancer-drug labels stand in sharp contrast to labels for other types of drugs, about 25% of which list the drugs’ effects on patients’ symptoms or functioning.1 That disparity is surprising, given how common symptoms and functional impairment are in patients with cancer and how toxic oncology drugs can be.

The FDA has taken several recent steps toward encouraging inclusion of the patient perspective in drug development. It issued highly influential guidance on the use of patient-reported outcomes (PROs) in drug development,2 collaborated with the Critical Path Institute and industry to form the PRO Consortium with the aim of developing robust symptom-measurement tools, and obtained support from Congress in the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA) to expand its internal expertise on the methodology of measuring PROs. (Unfortunately, allocated PDUFA funds have been withheld, which substantially impairs the FDA’s ability to implement planned patient-centered programs.)

These FDA efforts are evident in the ruxolitinib label and in the label for abiraterone acetate, approved this year for metastatic prostate cancer, which describes beneficial delays in time to the development of pain and the need for opioid use. Yet in preapproval trials in patients with cancer, symptom or functional-status evaluations that meet the FDA’s standards remain rare.

Some experts have argued that the FDA has raised the methodologic bar too high, whereas others accuse the pharmaceutical industry of paying too little attention to patients’ experiences. The bottom line is that both regulators and industry continue to prioritize survival-based end points rather than patient-experience end points in cancer-drug development.

Yet as patients live longer with cancer, they must increasingly choose among agents with varying efficacy–toxicity balances. And as approved drugs continue to yield only tiny median survival benefits (often measured in weeks), patients understandably want to know how their peers felt during and after a treatment. Moreover, payers increasingly seek information about patients’ comparative experiences with different products, because patients with worse symptoms or functional status utilize more supportive services.3

On the industry side, information about the patient experience is sometimes gathered in preapproval “pivotal” clinical trials (trials intended to provide evidence of the safety and efficacy of a product to support regulatory approval) through questionnaires focused on health-related quality of life (HRQOL). Often, this information is gathered to satisfy European regulators as well as payers, who seek a demonstration of economic value. Unfortunately, these end points are generally exploratory, and protocol-specified hypotheses and analytic or statistical plans are lacking. Data are commonly missing, and the results are rarely (or highly selectively) included in primary publications of trial results4 and are generally not intended for inclusion in U.S. oncology-drug labels.

We can, and ought to, aim higher. The examples of ruxolitinib and abiraterone, as well as experiences outside oncology, demonstrate six key steps that can move drug development toward a more patient-centered approach — one in which developers and regulators systematically consider patient perspectives in the design, conduct, and reporting of research .

In the case of ruxolitinib, the sponsor was a small company whose leadership was committed to including the patient perspective in key trial end points. When early clinical experience and published data for the target population revealed a constellation of symptoms related to the disease that were viewed as important by patients (step 1), the company began discussions with the FDA (step 2) and collaborated with academic researchers and a consulting firm to develop a patient-reported outcome measure (step 3). This measure was tested and refined through use with patients representing the target population before it was employed in a pivotal trial (step 4). The questions were loaded into a handheld device that patients used to report their own responses daily, with near perfect levels of compliance — despite their debilitating symptoms. The company had ongoing communication with and feedback from the FDA throughout this process.

Ruxolitinib demonstrates the particular value that PROs provide for understanding clinical benefits when studies are not designed to detect overall survival advantages and instead rely on end points such as tumor response, progression-free survival, or noninferiority. Although overall, ruxolitinib represents a success story, measurement of fatigue and HRQOL decrements — which are prevalent and widely viewed as important to patients — were not included as key end points because the FDA had methodologic concerns about them; these omissions resulted in a label containing an incomplete picture of the patient experience (steps 2 and 6 might have prevented this).

In the case of abiraterone, the company took a risk in its pivotal trial by expending statistical power to measure the time to opioid use among men with minimal baseline symptoms, when little was known about this end point in prostate cancer (step 4). It would also have been useful to include information about symptoms other than pain that are of interest to men with this disease; according to qualitative research conducted before the pivotal trial and formal patient-engagement activities, these would include symptoms such as tiredness or sleep disturbance (steps 1 and 5). Although a broad HRQOL tool was administered with positive results, there was no protocol-specified analysis plan for it, and it did not meet the FDA’s current methodologic threshold (steps 2 and 6).

For these key steps to be taken routinely, a fundamental shift in cultural orientation among drug developers and regulatory reviewers is imperative. Specifically, the patient experience of treatment with a given drug must be regarded as essential information about the properties of the product, without which our understanding of its risk–benefit profile is incomplete. This requirement applies equally to studies with end points based on survival (such as abiraterone) and those focused on tumor response (such as ruxolitinib).

Methodologic challenges exist but should not continue to be cited as insurmountable. They have been shown to be addressable in many trials,1 and multiple documents offering guidance on methods are available.2,5 Examples include minimizing and analyzing missing data, identifying meaningful score changes for questionnaires, and analyzing PRO data in nonblinded trials. Additional research is warranted both to advance measurement science in these areas and to develop measures in the public domain that meet regulatory standards.

But the principal barrier remains a failure to prioritize the identification and confrontation of these challenges up front. Moreover, when PRO measurement is left until the postmarketing phase, it is often too late to adequately measure outcomes in a comparative trial, which leaves the true effect of a product on the patient experience uncertain. Ideally, moving forward, whenever representatives of a pharmaceutical company and a regulatory agency sit down to discuss a product-development program, they will ask the same question my patients ask of me: “How does this product make people feel?”

Source: NEJM