Friday, October 31, 2014
Wednesday, October 22, 2014
EXCLUSIVE: The great tragedy for the pharmaceutical industry is that it keeps denying that it lobbies against transparency in clinical trials, says Ben Goldacre.
Ben Goldacre is a British physician, academic and author of the best-selling books Bad Science and Bad Pharma. He spoke to EurActiv's editor and publisher Frédéric Simon at the sidelines of the conference Transparency and public health - how accessible is scientific data?
What do you think of the EU’s clinical trials regulation for example in terms of transparency?
Well, I think the regulation is positive in many respects and it feels unkind to talk about its shortcomings when it was so hard won. Even that is progress. But the fact remains, it does not deliver all the methods and results of clinical trials, of all the uses, of all the treatments which are currently being prescribed by doctors.
You’re referring about the historical data issue?
It’s historical data, but it also does nothing to improve access to methods and results of clinical trials on uses outside of the marketing authorisation of a drug. Even though we know that drugs are very commonly and very sensibly prescribed outside of their marketing authorisation; out there in the real world, of doctors’ practices for patients across the whole of Europe, and the world. So it has several important shortcomings.
Lastly, I think there are very serious concerns around how all of these new changes are going to be implemented by EMA (the European Medicines Agency), because we know that they are going to be redacting clinical study reports on various different grounds such as commercial confidentiality and patient confidentiality.
Now that is reasonable in principle and the devil will be in the detail. Unfortunately, the only prior example we have to go on is what happened with AbbVie. In this case, even protocol changes had been censored from the clinical study reports on their drug Humira. It’s very widely used.
I cannot see how that can be commercially confidential information; a change in a protocol. But I can see that a change of a protocol is very important for any doctor or researcher trying to interpret the results of a clinical trial, because who knows what has happened with these protocol changes? Protocol changes can sometimes be done because somebody doesn’t like the way a trial is going. Perhaps they switch the way they are measuring an end point. Who knows what’s in there?
As a basic principle, protocol changes is something which doctors and researchers need to be able to see on any trial in order to understand what was done. In order to understand whether it was a fair test of the treatment or not. So from the very first example we have had about how EMA had dealt with actions, there are good grounds for concern.
I think there are also grounds for concern in the secret meetings that we know now the industry has had with the EMA. We have to accept that lobbyists… It’s an ugly truth. They will have meetings with elected politicians. But for a statutory body like EMA, I think it’s very concerning to hear that they have had meetings which are un-minted and inaccessible. We can’t know what was discussed.
The meetings that took place about the pro-active transparency policy?
This is correct. The ones that have been complained about by Jim Murray (EU health blogger and former director general of the European Consumers’ Organisation) in his latest complaint to the EU Ombudsman.
There’s a mention in the new clinical trials regulation which says that clinical trial information can be withdrawn from reports if they can be considered as commercially sensitive. We did hear today though at the conference that the concept of commercially-sensitive information is pretty vague. How much of a concern is this to you?
I think it would be naïve to imagine that if the Parliament was to give a clear definition of what commercially confidential information then that would suddenly resolve all the disputes. I think it would open up a whole new raft of legal arguments, but I think it would at least be a step forward.
So I think it’s problematic that there’s not a clear definition of that. I have to be clear: there are many commercial aspects of a drug have absolute no interest for doctors, researchers or patients. It’s boring, banal and nobody cares.
However, sometimes people try to say that if a competitor has applied for information about clinical trials that must by definition be the kind of commercial activity that we should automatically regard as unacceptable.
I think that that’s mistaken, because sometimes the people who are in best place to spot shortcomings in your trial design, or perhaps even risk signals in your data, are your competitors. They are best placed because they have the same academic skills set that you have so they are able to spot methodological shortcomings or risk signals in data. They are also highly motivated to spot those adverse signals.
But that’s not going to happen…
That’s not commercially confidential information. That’s absolutely fine. Some people say that they are very angry that drug companies have applied for other drug companies’ clinical study reports. I say “well, fine”. Very often drug companies spot or give a platform to concerns about side effects of their competitors’ drugs. That is perfectly acceptable within their rich ecosystem of public discussion.
They would probably have an interest in not doing that publically?
I think if a motivated and capable group of people are interested in spotting risk signals of side effects in another company’s information then that sounds like a very sensible use of everybody’s time. The whole point of science is about replication and reviewing it. It’s about showing your're working.
Unfortunately, we live in a world in which people are able to obfuscate the shortcomings of their trial design. They are able to obfuscate signals of harm from their drug. They do that for commercial reasons.
If you are asking me to suddenly feel upset that now there’s going to be a group of people who for commercial reasons are going to be enabled to help spot those risk signals which others have sought to hide, I would say that sounds fine to me. It’s a very different category of competitive commercial use of data to the things we can all agree on are unacceptable, like, for example, downloading one company’s clinical study report and then going to a developing country and getting a marketing authorisation for the same molecule. That is obviously unacceptable. And it’s very straightforward to put legal framework in place to stop that happening.
Similarly, I don’t think that we need to share any information in the discussion between a company and a regulator necessarily where they are saying “We’re thinking about applying for a marketing authorisation on x or y”, but if there’s clinical trials data that is germane to that commercial decision, then that trial data is also germane to treatment decisions being made by doctors and patients. So that should be made available.
A company’s commercial interest, I have absolutely no interest in. A company’s manufacturing methods, I have no interest in. But methods and results of clinical trials must always be in the public domain.
A number of concerns were being raised today at the conference about the ongoing EU-US free-trade negotiations. Do you think it’s going to shape heavily the way that clinical trials transparency is being done in the future ,or are we sort of safe now that there is a regulation in place?
No, no, quite the contrary. I think the big risk here is that bear traps will be laid in the woods so that there will be catchall phraseology used in TTIP. I can certainly envisage a situation where these bear traps will be laid with apparently neutral wording that will seem sensible and then that will be used as the foundation of subsequent derailment of positive developments within the clinical trials regulation.
So, yes, I think it’s a real threat and I think it’s an interesting example. I think there’s inequality of arms. Every word in a document like that has been thought over and in many cases by a large number of motivated, highly-educated individuals who can see significance in every word. Losers like me are not as capable at either being heard or analysing risks of the wordings of those documents.
What do you make of the argument of personal data privacy?
I wouldn’t like to say anything about any individuals, but it is increasingly clear to me that this is being used as a deliberate rhetorical tactic to derail a serious discussion around how to share individual patient data, and it is remarkable not just here but everywhere to see organisations, which report to patients, that as soon as trials transparency is mentioned, there’s no serious discussion of the mechanics of how we can positively work towards delivering it. There’s no serious detailed discussion of the huge benefits, especially for people with orphan diseases. It leads immediately to this idea that patients can be re-identified. That is of course a risk, but it’s a risk we have been managing in the world of epidemiology for generations now.
Nobody is suggesting that medical records should be posted openly on the Internet. Everybody is very clear that you need to have an application process. You have to demonstrate that you are a serious researcher with a serious question. You have to ensure that patient privacy is protected. When you see people repeatedly raising this, apparently not having heard the reassurance that came earlier in the conversation, to me that looks like it's strategic, rhetorical derailment rather than a serious attempt to engage in a discussion.
It’s very worrying to see that coming from patient groups, especially when we have already seen the leaked memo from pharma and EFPIA in which they talked under the heading advocacy strategy of how they would in their words “mobilise patient groups” to raise concerns about privacy.
I think there are a lot of people with good intentions in industry and some people with not so good intentions of course. But one thing I find very disappointing is when people imagine that they can get away with being disingenuous in public. I find it tiresome that people would say “We haven’t lobbied against transparency” when it’s clearly true. It just doesn’t seem to me that it gets us anywhere.
It’s hard to have respect for people who do that. I’m not even sure it achieves what they hope. It just looks incredibly bad. It’s the great tragedy of this whole area. The pharmaceutical industry makes products that save lives on a biblical scale. There’s this huge prize of public gratitude that is waiting to be claimed by them and they managed to shoot it all away with this incredibly seedy behavior by paying patient groups, by cover secret behavior and suing regulators to hide information.
I don’t think the benefits of that behavior are as great as the downsides. The downsides are a long game and they are collective for the whole industry. For an individual company it may seem attractive in the very short term to behave as badly as you can get away with by the letter of the law, but I think in the bigger picture, they have destroyed the reputation of the industry in which should be one of our most prized. They should be up there with teachers. It’s just extraordinary that they have managed to do that. It’s extraordinary that they have managed to do it before your very eye.
Turning to the EMA and its role as a regulator, are they not in an awkward position asking for documents to be handed over to them, but also running the risk of being sued? What is your feeling about the agency’s role generally and its job as a regulator?
I think it’s very interesting how everybody is stepping up and becoming critical of EMA. I think that makes things very uncomfortable for them. I think big and well-paid organised lobbying organisations can do a better, slicker job of talking in a very collegial fashion about their colleagues in the regulatory profession and be lovely to and about them while encouraging them to do what they want.
I’ll just say that it’s not good enough what they are doing. To an extent I think we should remember that EMA in particular over the past few years, after Guido Rasi has taken over, has made enormous leaps forward and very clearly against the hailstorm of anti-transparency lobbying from industry which they have ridiculously denied.
As a regulator, you are paid to be in that mediating position of dealing with people with conflicting demands. All I would say is that frameworks and principles have to put have to put public health first. Especially when it’s absolutely clear that transparency doesn’t conflict with commercial success. Nothing that I ask for undermines a company’s ability to make money.
Friday, October 10, 2014
Sunday, October 05, 2014
Thursday, September 25, 2014
But many of those doctors now work for hospitals that don't give them final say over what is on the menu of medicines they can pick. So when the GlaxoSmithKline GSK.LN +0.73% PLC saleswoman began plugging two new lung-disease drugs to a big San Diego hospital system this spring, it was to an administrator who doesn't see patients but helps write the menu, also called a "formulary," of approved medications.
Ms. French urged the administrator in the system, Sharp HealthCare, to consider the two drugs' effectiveness. It was the kind of pitch she once used to persuade doctors to write prescriptions.
The administrator, Electa Stern, said she would run the effectiveness data by doctors who are helping decide what to put on a systemwide formulary. "And then we will be taking a look at cost." There are about 2,600 doctors in the Sharp system.
Ms. French's sales calls are part of a shift that is rewriting the drug-marketing playbook. As hospital systems get bigger, they are putting distance between their doctors and drug sellers, making it harder for pharmaceutical companies to get quick acceptance of newly approved medicines and putting pressure on profits.
Today, 42% of doctors practice as salaried employees of hospital systems, up from 24% in 2004, according to Cegedim Relationship Management, a marketing consultant.
As a result, the pharmaceutical industry is shifting its sales efforts from doctors to the institutions they work for. In 2005, drug companies employed about 102,000 U.S. sales representatives, who mostly pitch to doctors. By mid-2014, according to ZS Associates, a consulting firm, their numbers were down to about 63,000.
Stepping in are so-called key-account managers like Ms. French who build relationships with administrators. The 20 biggest drug companies employ roughly 600 key-account managers, three times the number five years ago, according to ZS.
The trend is in early stages. Sales reps still account for the bulk of drug sales. But companies are increasingly deploying key-account managers in regions where hospitals have moved more quickly to buy practices.
Eli Lilly LLY +0.36% & Co., for example, last year scrapped its old sales-rep approach in six metropolitan areas including Boston and Salt Lake City in favor of key-account teams. For the industry, says Lilly commercial executive David Ricks, "one of the key questions is how do we get health-system adoption."
Getting a drug on the formulary at a big hospital system can mean potentially millions of dollars in sales from thousands of doctors' prescriptions. For Glaxo, getting its two new lung drugs on formularies is crucial to replacing revenue from its top-selling drug, a blockbuster called Advair that brought in $4.3 billion U.S. sales in 2013.
Advair, for asthma and a smoking-related disease, is expected to face generics in 2016 when its U.S. patent expires. Glaxo wants its new drugs, Breo and Anoro, to compete in the huge market for inhalers, which are often used for those diseases. Inhalers brought $13 billion in U.S. sales last year, according to IMS Health, IMS +0.45% a market-data company.
Drug companies used to send armies of sales reps to woo individual doctors after introducing new drugs like these. The reps—some, former cheerleaders with no experience in medicine—would sometimes take doctors to sports events or cater lunches for their offices, and they usually left samples.
Doctors were often more interested in a drug's clinical-trial results than cost. Reps could generate hundreds of millions of dollars over the few months after a drug's introduction.
But doctors are losing influence. Hospital systems are growing more powerful as they bulk up by buying doctors' practices, nursing homes, urgent-care centers and other hospitals. Insurers and the federal health-care overhaul are squeezing hospital and doctor payments and shifting reimbursement from how much care is given to how effective it is.
To manage costs, hospital systems are taking control of what drugs their physicians can prescribe. Many limit doctors' contact with salespeople. The gatekeepers are committees and administrators like Ms. Stern.
Today's key-account managers can spend many months trying to persuade administrators to put a drug on the formulary. And big systems have more negotiating power over price than small practices.
"Doctors mostly care about how the drug worked," says Pratap Khedkar, who heads the global pharmaceuticals practice at ZS. At health systems, "the sales emphasis has shifted to not just how the medicine works but how it also lowers the total cost of managing disease."
Committees at the University of Pittsburgh Medical Center system decide what drugs to recommend based on evidence of effectiveness, toxicity and cost. A committee recently standardized treatment of certain colorectal cancer patients around use of the drug Vectibix, which UPMC says costs about $38,000 for a 16-week course, removing a drug from its list that was found to be similar but cost about 15% more. It says doctors working in its 21 hospitals follow the cancer-drug-prescribing protocols about 80% of the time.
UPMC says it bars doctors from catered lunches and sponsored travel, and it requires sales reps to have an invitation from a physician to visit. UPMC official Barbara Barnes says drug companies should see her, not doctors, as their "central point of contact."
For drug companies, health systems' expanding control not only can slow new-drug acceptance but may also hurt profits by limiting a drug's peak sales and by driving down prices as systems use their increasing control over what doctors prescribe to press for discounts, says Richard Evans, an analyst at Sector & Sovereign Research LLC who used to head business policy at Roche Holding AG's U.S. pharmaceuticals business.
For patients, the trend can be a mixed blessing. They are more likely to get drugs that evidence shows will keep them healthy and out of the hospital, health experts say. But patients may face more restrictions on their choice of drugs.
Doctors, too, find the trend mixed. On one hand, "I don't know if you can run a practice by yourself anymore," says Paul Settle, a family physician in Danville, Va. He joined the Centra health system in Virginia in 2011 after 30 years practicing privately, because he lacked wherewithal to negotiate with insurers.
Centra says it bars its doctors from meeting drug-sales reps during office hours and is crafting formularies that will direct what they prescribe. "The good side is you spend more time on patient care and not spending your time on drug reps," says Dr. Settle. But it is harder to learn about new drugs, he says, and he has given up some autonomy. Centra declines to discuss Dr. Settle's views.
Glaxo has been reworking its sales strategy for about five years. Like others, its reps once approached doctors' offices as their main battleground. "We called it a war," says Deirdre Connelly, a sales rep at Lilly in the 1980s who now runs Glaxo's North American pharmaceuticals business.
Drug makers paid big fines for improperly promoting some drugs to doctors. In 2012, Glaxo agreed to plead guilty to misdemeanor charges of illegally marketing some drugs and to pay a $3 billion fine to resolve allegations of improper marketing involving drugs including Advair. Glaxo says it has changed its procedures since then.
Around 2009, Ms. Connelly says, Glaxo's research showed doctors were increasingly giving up independence to work for systems that wanted them seeing patients, not reps. "It was hurting sales," says Ms. Connelly, who joined Glaxo that year to fix the problem. "If you cannot get in to the doctor, that affects us."
She began testing key-account teams, taking them nationwide in 2011. The teams' key-account managers called on hospital-system administrators while traditional reps called on doctors in the networks where they could. Today, Glaxo deploys 41 of these "integrated customer teams" around the U.S.
The teams represented about 30% of Glaxo's $11 billion U.S. sales in 2013. Glaxo expects that to reach 50% within 10 years. In many areas, Glaxo's traditional reps still hold sway. Glaxo's key-account teams are concentrated in areas like Cleveland, Dallas and San Francisco, where health systems have expanded quickly.
One such market is San Diego. The Sharp health system, with nearly $3 billion in projected 2014 revenue, runs seven hospitals, three nursing homes, five urgent-care centers, two medical groups and a health plan in the area. The system, which is midstream in its shift toward standardizing patient-care procedures, has in recent years been creating systemwide formularies.
Ms. French, 52, joined Glaxo's San Diego account team last year after eight years as a Glaxo sales rep. Her first assignment after retraining was Glaxo's two new drugs, now approved for chronic obstructive pulmonary disease, or COPD, whose leading cause is smoking.
Getting on Sharp's formulary would be big. Last year, Sharp's hospitals treated nearly 2,700 COPD patients. Glaxo's Advair is on the systems' formularies for COPD; its two new drugs aren't. The disease is among the latest for which the system is creating a systemwide formulary.
In her sales-rep days, Ms. French carried a bag of samples and marketing materials to pass to a doctor. Often, she fetched Starbucks SBUX +1.85% coffee for the staff. She would typically leave after asking the doctor to please write some prescriptions right away—and they often would. Glaxo gave her bonuses if her doctors wrote enough prescriptions.
To her Sharp sales call, she toted a leather briefcase and planned no freebies. Sharp says its policy doesn't allow wining, dining and swag-taking. Her bonuses are based not on prescriptions but on factors such as profit and evaluations by system officials.
Ms. French's crucial visit was with Ms. Stern, a Sharp pharmacy supervisor who helps lead a committee creating the formulary. Sharp had taken months to consider one of the new drugs—a costly delay for Glaxo—and hadn't given any word on the other.
Ms. Stern gave some good news: Sharp was considering both. Ms. French, hiding her excitement at that hint of progress, brought up clinical-trial data on the drugs' effectiveness, which she said Ms. Stern might find helpful when making her recommendation to the formulary committee.
It was the kind of information Ms. French as a sales rep would have given a doctor to gin up enthusiasm and trigger prescription-writing.
But Ms. Stern wanted to talk about more than trial results. The hospital, she said, was cutting use of pricey inhalers—like the ones Glaxo's two new drugs use—in favor of cheaper and easier-to-use masks called nebulizers. Glaxo's two drugs cost close to $300 a month. Typical nebulizers costs between a fifth and a tenth that, Sharp says.
One factor behind Sharp's cost concerns: Starting this year, Medicare will cut reimbursements if COPD treatment doesn't stop enough patients from returning to the hospital. Expensive drugs can land patients back in the hospital more quickly if they can't afford to refill their prescriptions.
"You need to look broader than just the episode in the hospital: How are we going to manage the patient not just in the hospital" but after the patient leaves, says Sharp Chief Executive Mike Murphy.
Ms. Stern also wanted to know what discounts Glaxo might provide, given Sharp's size. Ms. French offered to return to explain how Glaxo's pricing schedule might benefit the system.
Back in meetings that afternoon, Ms. French faced more grilling about Glaxo's prices. "One of the biggest barriers, particularly for the older patients, with using these new medicines, is their cost," said Cecile Davis, a nurse helping remake Sharp's COPD procedures.
Ms. French said many insurers were covering the cost of Breo and described a Glaxo program that helps patients with out-of-pocket costs. Ms. Davis said the support didn't cover enough. "If it's not on the $4 Wal-Mart WMT +1.96% plan, they can't afford it."
Four months later, Sharp hasn't decided whether to approve the two Glaxo drugs. "You just have to stay on top of things," Ms. French says, "and when they get to the next layer, be there and make sure they have what they need."
Write to Jonathan D. Rockoff at firstname.lastname@example.org
The Justice Department said on Wednesday that the European drug maker Shire had agreed to pay $56.5 million to settle accusations of making false claims in the marketing of its attention deficit disorder drug Adderall XR and other medicines. The settlement involved charges that Shire, from January 2004 to December 2007, promoted its extended release Adderall with claims of superiority over rival medicines that were not supported by clinical data. The company was also accused of promoting the drug for unapproved uses and of making other false claims not supported by data, like that Adderall XR would prevent poor academic performance, loss of employment, criminal behavior, traffic accidents and sexually transmitted disease. The company said it had not admitted any wrongdoing in connection with the settlement.
Tuesday, September 16, 2014
By Brian Grow, P.J. Huffstutter and Michael Erman
Filed Sept. 15, 2014, 1 p.m. GMT
Pervasive use fuels concerns about impact on human health, emergence of resistant superbugs
Major U.S. poultry firms are administering antibiotics to their flocks far more pervasively than regulators realize, posing a potential risk to human health.
Internal records examined by Reuters reveal that some of the nation’s largest poultry producers routinely feed chickens an array of antibiotics – not just when sickness strikes, but as a standard practice over most of the birds’ lives.
In every instance of antibiotic use identified by Reuters, the doses were at the low levels that scientists say are especially conducive to the growth of so-called superbugs, bacteria that gain resistance to conventional medicines used to treat people. Some of the antibiotics belong to categories considered medically important to humans.
The internal documents contain details on how five major companies - Tyson Foods, Pilgrim’s Pride, Perdue Farms, George’s and Koch Foods - medicate some of their flocks.
The documented evidence of routine use of antibiotics for long durations was “astonishing,” said Donald Kennedy, a former U.S. Food and Drug Administration commissioner.
Kennedy, president emeritus of Stanford University, said such widespread use of the drugs for extended periods can create a “systematic source of antibiotic resistance” in bacteria, the risks of which are not fully understood. “This could be an even larger piece of the antibiotic-resistance problem than I had thought,” Kennedy said.
Graphic: how antibiotics can nurture ‘superbugs’
FDA has tested few veterinary drugs for resistance risk
Inside the troubles at Foster Farms
Reuters reviewed more than 320 documents generated by six major poultry companies during the past two years. Called “feed tickets,” the documents are issued to chicken growers by the mills that make feed to poultry companies’ specifications. They list the names and grams per ton of each “active drug ingredient” in a batch of feed. They disclose the FDA-approved purpose of each medication. And they specify which stage in a chicken’s roughly six-week life the feed is meant for.
The feed tickets examined represent a fraction of the tens of thousands issued annually to poultry farms run by or for major producers. The confidential information they contain nonetheless extends well beyond what the U.S. government knows. Veterinary use of antibiotics is legal and has been rising for decades. But U.S. regulators don’t monitor how the drugs are administered on the farm – in what doses, for what purposes, or for how long. Made public here for the first time, the feed documents thus provide unique insight into how some major players use antibiotics.
The tickets indicate that two of the poultry producers - George’s and Koch Foods - have administered drugs belonging to the same classes of antibiotics used to treat infections in humans. The practice is legal. But many medical scientists deem it particularly dangerous, because it runs the risk of promoting superbugs that can defeat the life-saving human antibiotics.
In interviews, another major producer, Foster Poultry Farms, acknowledged that it too has used drugs that are in the same classes as antibiotics considered medically important to humans by the FDA.
About 10 percent of the feed tickets reviewed by Reuters list antibiotics belonging to medically important drug classes. But in recent presentations, scientists with the U.S. Centers for Disease Control and Prevention said the use of any type of antibiotic, not just medically important ones, contributes to resistance. They said that whenever an antibiotic is administered, it kills weaker bacteria and enables the strongest to survive and multiply.
Frequent, sub-therapeutic use of antibiotics in low doses intensifies that effect, scientists and public health experts say. The risk: Any resulting superbugs might also develop cross-resistance to medically important antibiotics.
According to the feed tickets reviewed, low doses of antibiotics were part of the standard diet for some flocks at five companies: Tyson, Pilgrim’s, Perdue, George’s and Koch.
“These are not targeted uses aimed at specific bugs for defined duration. They’re multiple, repeat shotgun blasts that will certainly kill off weaker bugs and promote the stronger, more resistant ones," said Keeve Nachman, director of the food production and public health program at Johns Hopkins University’s Bloomberg School of Public Health.
“HIGHLY IMPORTANT” DRUGS
This month, Perdue Farms announced that it had stopped applying the antibiotic gentamicin to eggs in chicken hatcheries. Gentamicin is a member of an antibiotic class considered “highly important” in human medicine by the FDA. The company said it wants “to move away from conventional antibiotic use” because of “growing consumer concern and our own questions about the practice.”
The move won’t change what Perdue feeds its chickens, however. Some of its feed has contained low levels of one antibiotic, feed tickets show. Perdue said it only uses antibiotics that aren’t considered medically important by the FDA, and at some farms, it uses no antibiotics at all.
MEDICATED FEED: Nine-day-old chicks drink water at a Foster Farms ranch in Stanislaus County, California. Chicks are typically given various pharmaceuticals, including vaccines and low-level doses of antibiotics, in their water or food to ward off disease. REUTERS/Max Whittaker
The manner in which drugs are being given to poultry shows that “this could be an even larger piece of the antibiotic-resistance problem than I had thought.”
Donald Kennedy, former FDA commissioner
“We recognized that the public was concerned about the potential impact of the use of these drugs on their ability to effectively treat humans,” Bruce Stewart-Brown, Perdue’s senior vice president of food safety and quality, said when the hatchery policy was announced.
The poultry industry’s lobby takes issue with the concerns of government and academic scientists, saying there is little evidence that bacteria which do become resistant also infect people.
"Several scientific, peer reviewed risk assessments demonstrate that resistance emerging in animals and transferring to humans does not happen in measurable amounts, if at all," said Tom Super, spokesman for the National Chicken Council. He said using antibiotics to prevent diseases in flocks “is good, prudent veterinary medicine…. Prevention of the disease prevents unnecessary suffering and prevents the overuse of potentially medically important antibiotics in treatment of sick birds.”
Poultry producers began using antibiotics in the 1940s, not long after scientists discovered that penicillin, streptomycin and chlortetracycline helped control outbreaks of disease in chickens. The drugs offered an added benefit: They kept the birds’ digestive tracts healthy, and chickens were able to gain more weight without eating more food.
Over the years, the industry’s use of antibiotics grew. Early on, independent scientists warned that bacteria would inevitably develop resistance to those antibiotics, especially when the drugs were administered in low doses. In 1976, a landmark study by microbiologist Stuart Levy showed that potentially deadly bacteria in poultry were developing resistance to tetracyclines and other antibiotics. The resistant bacteria, E. Coli, were then moving from poultry to people.
That is when the FDA first tried to rein in drug use in food animals. The agricultural and pharmaceutical industries resisted, viewing low-level antibiotic use as a way to produce meat more quickly and cheaply.
Today, 80 percent of all antibiotics used in America are given not to people, but to livestock.
About 390 medications containing antibiotics have been approved to treat illness, stave off disease and promote growth in farm animals. But the FDA has reviewed just 7 percent of those drugs for their likelihood of creating antibiotic-resistant superbugs, a Reuters data analysis found.
The widespread use of antibiotics worries public health authorities. In a report this year, the World Health Organization called antibiotic resistance “a problem so serious it threatens the achievements of modern medicine.” The annual cost to battle antibiotic-resistant infections is estimated at $21 billion to $34 billion in the United States alone, the WHO said.
Each year, about 430,000 people in the United States become ill from food-borne bacteria that resist conventional antibiotics, according to a July report by the CDC. Overall, the CDC estimates that 2 million people are sickened in the United States annually with infections resistant to antibiotics. At least 23,000 people die.
“That’s the number we are certain of. The actual number is higher,” said Steve Solomon, director of the CDC’s Office of Antimicrobial Resistance.
This year, federal investigators tracking a salmonella outbreak traced virulent strains of the pathogen to chickens raised by Foster Farms, the largest poultry producer on the West Coast.
Investigators identified seven strains of Salmonella Heidelberg that had sickened at least 634 people across the United States and Puerto Rico this year and last. More than 200 of those people were hospitalized, according to the CDC. In July, Foster Farms issued a recall of some chicken products.
When epidemiologists examined 68 of the Salmonella Heidelberg cases linked to Foster Farms, they found that two-thirds of the bacteria were resistant to at least one antibiotic, according to the CDC. Half of these superbugs were impervious to drugs in at least three different classes of antibiotics.
In an effort to stop the spread of resistant bacteria, the FDA has issued voluntary guidelines to regulate antibiotic use by producers of poultry and other livestock. The agency says it also inspects the mills where animal feed is made. It considers those inspections to be a “more effective” use of its resources than examining how farmers administer feed.
“These are not targeted uses aimed at specific bugs for defined duration. They’re multiple, repeat shotgun blasts that will certainly kill off weaker bugs and promote the stronger, more resistant ones.”
Keeve Nachman, Johns Hopkins University
Not until 2016 does the FDA plan to gather data about antibiotic use on farms, said Craig Lewis, a veterinary medical officer with the agency. Today, “none of us have an idea first-hand of what’s going on” at the farm level, Lewis said this summer, at a public meeting on antibiotic resistance.
Super, the National Chicken Council spokesman, said the information on feed tickets “is available to FDA, the regulators, whenever they want to go see it.”
Still, companies are reluctant to discuss how they medicate their flocks.
One, Pilgrim’s Pride, said it would take legal action against Reuters unless the news agency gave the company access to Pilgrim’s feed tickets that reporters had reviewed. Reuters declined to do so.
The tickets show that Pilgrim’s added low doses of the antibiotics bacitracin and monensin, individually or in combination, to every ration fed to a flock grown early this year. Neither drug is classified as medically important by the FDA, although bacitracin commonly is used to prevent human skin infections.
The Colorado-based company wouldn’t address questions about its use of antibiotics. Its general counsel, Nicholas White, called the contents of its tickets “confidential business information.”
U.S. Sen. Kirsten Gillibrand, D-New York, said the feed tickets substantiate what she long suspected: "that the overuse of antibiotics on many chicken farms is rampant.”
Gillibrand has been pushing for regulators to more aggressively monitor low-level doses of antibiotics. Now, Gillibrand said, she hopes “the FDA will use the feed-ticket data obtained by Reuters as a wake-up call to re-evaluate their approach to the regulation of antibiotic use in food production.”
So does Rep. Rosa DeLauro, D-Connecticut, a member of a House subcommittee overseeing food safety. Told of the information in the feed tickets, DeLauro called on the FDA to “implement tighter restrictions on antibiotic usage.”
All the poultry giants state publicly that they use antibiotics for the limited purpose of keeping chickens healthy.
But the feed tickets, which list the medications included in chicken feed, highlight a second effect of many of the drugs: bulking up the birds.
Some of the tickets reviewed for this article state that the antibiotics promote feed efficiency or weight gain in chickens. The FDA requires companies to list growth promotion on feed tickets whenever feed includes antibiotics that have been approved for that purpose.
NOURISHMENT: Some Perdue flocks receive feed with an antibiotic, others don’t; here, Perdue feed containing a non-medically important antibiotic called narasin at C&A Farms in Fairmont, North Carolina. REUTERS/Randall Hill
Reuters found eight different antibiotics listed on the tickets it reviewed. The tickets come from a scattering of farms across the United States – in Mississippi, Alabama, South Carolina, Virginia and Washington State, among other locations.
George’s Inc, a poultry company based in Springdale, Arkansas, issued feed tickets last year to a chicken grower in Virginia. The tickets show that the antibiotics tylosin and virginiamycin were administered solely for “increased rate of weight gain.”
Tylosin belongs to a class of antibiotics the FDA considers “critically important” in human medicine, the most crucial of three ranks of sensitive drugs. Virginiamycin is part of a class in the FDA’s middle rank, “highly important.”
Other George’s Inc feed tickets, given to two growers in Virginia this year, show the antibiotics bacitracin and narasin and a non-antibiotic drug called nicarbazin were included in every poultry ration in different combinations until shortly before slaughter. Bacitracin can promote growth.
George’s said in a statement: “Occasionally (when necessary to control certain pathogens) appropriate FDA approved medications are utilized to prevent, control or treat specific diseases.” It declined to answer detailed questions.
Use of antibiotics to stave off disease in flocks “is good, prudent veterinary medicine…. Prevention of the disease … prevents the overuse of potentially medically important antibiotics in treatment of sick birds.”
Tom Super, National Chicken Council
At Tyson Foods, two feed tickets sent by the company to two Mississippi farms show that bacitracin and the non-antibiotic nicarbazin were among the drugs mixed into the feed. The tickets state the drug combination is “for use in the prevention of coccidiosis in broiler flocks, growth promotion and feed efficiency.” Coccidiosis is a common intestinal ailment.
Tyson, also based in Springdale, Arkansas, said it does not use bacitracin to promote growth, only to prevent disease. The FDA requires companies to list growth promotion on tickets if medications have that effect, Tyson said. The company said that its feed mixture changes throughout the year. In some seasons, it said, the feed doesn’t include bacitracin and nicarbazin.
At Koch Foods Inc, a Chicago-based supplier to fast-food chain KFC Corp, feed tickets contradict a statement on the Koch website about antibiotic use.
Until Aug. 27, the website said Koch Foods uses antibiotics for the narrow purpose of protecting the health of its chickens. “We do not administer antibiotics at growth promotion doses,” the statement read in part. “No antibiotics of human significance are used to treat our birds.”
Koch feed tickets dated from Nov. 30, 2011, through July 20, 2014, indicate otherwise. They list low-dose amounts of five different types of antibiotics in feed given to flocks at one Alabama farm. One was virginiamycin, in a class considered “highly important” to fighting infections in humans.
In 34 of the 55 Koch Foods feed tickets that Reuters examined, antibiotics at low-dose levels were listed “for increased rate of weight gain,” a related growth-promotion use called “improved feed efficiency,” or both. Each of those feed tickets also said the antibiotics were for the prevention of coccidiosis, another bacterial infection, or both.
Koch Foods changed the website after being asked by Reuters about its use of virginiamycin. “I regret the wording mistake on that particular letter” on the website, said Mark Kaminsky, Koch’s chief financial officer. The company said it is required by the FDA to list certain drugs as growth promoters if they have that effect; Koch says it does not use them for that purpose.
Koch said it has no plans to discontinue the use of virginiamycin, which it says may be used to prevent a common intestinal infection in chicken.
KFC U.S. said in a statement: “KFC’s supply partners must adhere to our strict standards and specifications, which in some cases are more stringent than the FDA’s regulations.” A spokeswoman didn’t address detailed questions about antibiotic use by Koch Foods and KFC’s other chicken suppliers.
The experience of one grower raises questions about whether preventive use of antibiotics has a meaningful effect on the health of chicken.
Craig Watts, who grows chicken for Perdue, says he sees little difference in outcomes for the birds he raises on feed containing an antibiotic and those he grows for the company’s antibiotic-free line.
Perdue mixes the antibiotic narasin into feed given to chickens in the company’s antibiotic-fed line. Its antibiotic-free line contains antimicrobial drugs that kill micro-organisms, but none that the FDA defines as an antibiotic, according to Perdue feed tickets shown by Watts. None of the drugs listed by Perdue on the feed tickets is considered medically important for humans.
Watts owns C&A Farms, about 20 miles north of Dillon, South Carolina. Since 2012, he has raised five antibiotic-free flocks for Perdue and seven flocks that received low doses of the antibiotic narasin, according to his records.
SAFETY CHECK: Craig Watts, a contract farmer for Perdue Farms, checks a euthanized chicken for disease. He says he finds little difference in outcome between chickens that are fed antibiotics and those that aren’t. REUTERS/Randall Hill
The mortality rates of the two flock types were nearly identical. About 900 birds died, per house, on the four-house farm. Flocks that received antibiotics and those that didn’t both hit Perdue's target weight of about 4.25 pounds per bird.
Perdue sees “similar” performance among birds fed antibiotics and those that do not receive the drugs, said Stewart-Brown, the Perdue official overseeing food safety. “We feel our current two approaches are both very responsive to public health concerns about antibiotic use in poultry.”
Perdue still uses antibiotics in some cases, because antibiotic-free flocks are “more expensive to run and more difficult to manage effectively,” Stewart-Brown said. The production complex served by Watts’ farm recently transitioned to all antibiotic-free flocks.
TRACKING AN OUTBREAK
One poultry giant whose antibiotic use has come into question is Foster Farms, based in Livingston, California. Its experience shows the difficulty of pinpointing when and how a bacteria turns into a superbug, say federal investigators.
Beginning last year, a salmonella outbreak spread across Oregon, Washington, California and 27 other states and territories. Federal investigators later linked the outbreak to chickens raised by Foster Farms and processed at a trio of its slaughterhouses in central California, according to USDA and CDC officials.
The scope of the outbreak reflected Foster Farms’ vast scale. Its operations in California’s Central Valley date to 1939, when Max and Verda Foster borrowed $1,000 against a life insurance policy and invested in an 80-acre farm.
Today, Foster owns large tracts of California farmland, chicken hatcheries in Colorado and train cars that haul grain from the Midwest. An estimated one of 10 chickens eaten in the United States is hatched, raised and slaughtered by Foster Farms, according to industry officials. The company dominates the chicken market west of the Rocky Mountains.
As the CDC studied what investigators informally called the “Foster Farms Outbreak,” researchers soon made a troubling discovery. Some of the Salmonella Heidelberg strains linked to Foster products proved resistant to a variety of antibiotics, the CDC concluded. Some of those drugs belonged to the same classes as penicillin and chlortetracycline, or CTC.
“The overuse of antibiotics on many chicken farms is rampant.”
U.S. Sen. Kirsten Gillibrand, D-New York
Some questions remain. Government investigators didn’t determine how the Salmonella Heidelberg traced to Foster Farms became resistant to antibiotics, and didn’t trace the resistant bacteria to specific farms. They didn’t examine Foster feed tickets from the outbreak period to see which antibiotics the company was using and how the drugs were being administered.
Reuters asked to see Foster Farms’ feed tickets from that period; the company didn’t respond to that request.
Foster Farms said it commissioned research that yielded findings very different from the CDC’s. The company declined to share the study. It summarized the research by saying scientists found no antibiotic resistance in two dozen salmonella samples collected from Foster Farms in 2012.
A CDC spokeswoman said the agency is aware that Foster Farms sponsored a study and has asked to review it, but hasn’t received a copy.
Foster Farms told Reuters it has administered CTC and penicillin at times, but selectively, not as part of standard feed. Foster said it had used CTC “as needed” to fight bacterial infections. It declined to say where or when it administered CTC. The company said it still uses penicillin to treat sick birds, but only “in critical situations when flocks are exposed to fatal diseases.” Foster doesn’t use antibiotics as growth promoters, it said.
CDC official Robert Tauxe helped investigate the outbreak. “Use of chlortetracycline could have contributed to the resistance patterns we saw” in the Salmonella Heidelberg, said Tauxe. “Penicillin, too.”
On July 11, the CDC said the Salmonella Heidelberg outbreak had ended. The USDA said it is monitoring the company’s new salmonella-prevention efforts. Agency officials and Foster’s chief veterinarian, Bob O’Connor, said the measures are working.
The company has reduced salmonella-infection rates on chicken meat from its California facilities to less than 3 percent, O’Connor said, far below the national average of 25 percent.
Despite the gains, O’Connor said the challenge of eradicating salmonella in the chicken industry remains. “For the people who wanted a silver-bullet-type story, there isn't one,” O’Connor said. “With salmonella, we're not going to be able to say, ‘It's over.’”
David Acheson, a former senior medical officer for the USDA and the FDA, now serves on a food safety advisory board for Foster Farms. He said the board never examined Foster’s use of antibiotics and whether its practices could have spawned superbugs.
“Does anyone know that it happened? No. Is it possible? Could it have happened? Yes,” Acheson said. “We know that antibiotic use, irrelevant of what you are treating, whether it be human or animal, can increase the likelihood of resistance. It’s biology at work.”
Reporting by P.J. Huffstutter in Chicago and Livingston, California, Brian Grow in Atlanta and Fairmont, North Carolina and Michael Erman in New York. Additional reporting Eric Johnson. Edited by David Greising and Blake Morrison.
FDA has reviewed just 7 percent of animal antibiotics for superbug risk
By Michael Erman
NEW YORK – Scientists fear the widespread use of antibiotics on the farm may be a factor in the rise of “superbugs” – bacteria that grow resistant to drugs, infect humans and defy conventional medicines.
Amid these concerns, the U.S. Food and Drug Administration has come under pressure to curb antibiotic use in farm animals. In 2003, the agency announced plans to evaluate every new animal drug based on the drug’s potential to create superbugs.
But the FDA hasn’t reviewed the vast majority of animal drugs now on the market, because most were approved before 2003.
Reuters found that the agency has evaluated such risks for only about 10 percent of the approximately 270 drugs containing types of antibiotics the FDA considers medically important for treating humans and are also used in chickens, pigs and cattle.
Overall, the FDA has evaluated the superbug risks for only about 7 percent of the approximately 390 drugs containing antibiotics that the agency has certified for veterinary use in chicken, pigs and cattle.
Since the 1940s, the animal husbandry industry typically has included low levels of antibiotics in feed, in part to promote the growth of animals raised for meat.
The FDA initiative to limit the risks posed by animal antibiotics took on new life last December. The agency issued a voluntary guideline calling on animal-drug makers to limit the approved uses of their drugs.
Aware that poultry, pork and beef producers were attracted to many antibiotics because of their ability to promote faster growth, the agency urged the drug makers to discontinue growth promotion as an approved use on labels of medically important antibiotics.
In a related initiative, the FDA by April 2015 intends to implement a “veterinary feed directive.” The new regulation will require veterinarians to oversee the use of antibiotics available over-the-counter that are mixed into feed.
Today, all major makers of animal drugs that contain antibiotics, including Zoetis Inc and Eli Lilly & Co’s Elanco Animal Health unit, voluntarily have agreed to start removing growth promotion claims on product labels, according to the FDA. Labels must be modified by December 2016.
As a result, 31 drugs have been withdrawn from the market by their makers, and manufacturers have changed the labels on two other drugs, according to the FDA.
Even so, the labeling changes leave a loophole. No matter what labels say, meat producers can continue to use existing antibiotics at low levels, so long as producers assert the drugs are used for treatment, control and prevention of disease.
Additional reporting by Brian Grow in Atlanta and P.J. Huffstutter in Chicago
Problems at Foster Farms plants emerged amid salmonella outbreak, documents show
By P.J. Huffstutter
NEW PROTOCOL: CEO Ron Foster. The company says it has new systems at farms and slaughterhouses to reduce salmonella rates in chickens. REUTERS/Max Whittaker
“The important point is that we have always worked quickly to fully address, correct any USDA concerns and improve our process.”
Foster Farms statement
LIVINGSTON, California – Sanitation problems at a slaughterhouse can promote the spread of antibiotic-resistant “superbugs,” by allowing dangerous bacteria to remain on meat that is shipped into the food supply. In the poultry industry, salmonella is a particular risk.
A review of government food-safety inspections from 2013 shows federal inspectors repeatedly cited Foster Poultry Farms for not complying with food-safety standards at three plants in central California linked to a salmonella outbreak that began that March. The 18-month salmonella outbreak ended in July of this year.
U.S. Department of Agriculture records show that inspectors found problems at two plants in Fresno and a third in Livingston, California. Investigators traced chicken handled at those plants to a Salmonella Heidelberg outbreak that made hundreds of people sick.
According to the USDA reports, raw chicken headed for chilling tanks was smeared with feces. At one plant, workers entered a packaging area wearing gloves that had not been properly cleaned.
Salmonella is common in chicken feces, feathers and other body parts, and it can cause diarrhea, fever, vomiting and other ailments in humans. Foster Farms and other poultry companies say they use antibiotics on live chickens to keep them healthy, and after the birds are slaughtered, they apply antimicrobial treatments to remove pathogens from raw meat.
“Foster Farms is fully committed to sanitary operations in all company facilities,” the company said in a statement.
Sanitation lapses can compromise food safety equipment, especially when problems occur at the final stages of processing, say epidemiologists and food safety consultants.
During the recent Salmonella Heidelberg outbreak, inspectors for the USDA’s Food Safety Inspection Service cited Foster Farms more than 480 times for not complying with food safety standards, according to agency records obtained by Reuters. The USDA records cover the period beginning February 1, 2013, a month before the outbreak began, and ending December 31.
On October 11, 2013, for instance, a USDA inspector at the Foster Farms plant in Livingston found fecal-filled intestines stored in tubs alongside raw chicken giblets. The giblets had been treated to reduce salmonella and other bacteria, and were nearly ready for shipment, according to the report.
A separate USDA inspector at the Fresno plant found feces on chicken heading into a chiller on June 28, 2013. One of 10 carcasses pulled from the chilling process was “contaminated with visible feces,” the inspector wrote.
Foster Farms said it quickly corrects problems found in such “routine in-process” inspections. “The important point is that we have always worked quickly to fully address, correct any USDA concerns and improve our process,” the company said.
This summer, Foster Farms said it has invested more than $75 million in new equipment and other efforts to reduce salmonella rates. Today, the company said, chicken processed at the Fresno and Livingston plants shows contamination in only 2.4 percent of tests, well below the industry’s 25 percent average.
Farmaceuticals: The drugs fed to farm animals and the risks posed to humans
By Brian Grow, P.J. Huffstutter and Michael Erman
Web programming: Charlie Szymanski
Data: Michael Erman
Graphics: Matthew Weber and Maryanne Murray
Photo editing: Jim Bourg
Design: Troy Dunkley
Editing: Blake Morrison and David Greising
Tuesday, September 09, 2014
BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g5524 (Published 09 September 2014)
Cite this as: BMJ 2014;349:g5524
Andrew Jack, deputy editor, analysis, Financial Times, London, UK
The government has extended the Cancer Drug Fund for a further two years and increased its budget. Andrew Jack explains how it works and why it is controversial
What is the Cancer Drug Fund?
The Cancer Drug Fund was created in 2010 by the coalition government to pay for new cancer drugs that the NHS would otherwise not have provided because the National Institute for Health and Care Excellence (NICE) considered they were not cost effective. A budget of £200m (€250m; $330m) a year was set for four years using money the government initially said had been saved by the NHS “through our pledge to stop the rise in employer National Insurance contributions from April 2011.”1
Oncologists can apply to the fund on a case by case basis, and they usually do this after a drug has been rejected by NICE. Committees of medical specialists decide whether to approve a drug for NHS use based on a 12 point scale for clinical effectiveness. Since it was created, the fund has approved about 43 drugs for 80 different indications,2 allowing an estimated 55 000 patients to receive treatment. Around 20 drugs (for 31 indications) have been refused.
Why was it set up?
NICE was rejecting a growing number of new cancer therapies because it considered them too expensive for their modest benefits (usually only a few months of extended life expectancy). It was attacked by patient groups and parts of the media, which highlighted cases of patients being refused treatment, criticised the agency’s methods, and pointed out the UK’s overall poor performance in successfully treating cancer compared with other countries.1 There was also argument over patients willing to pay out of their own pockets for drugs not recommended by NICE, and the obligations the NHS would have for their continued care.
Isn’t the fund a way of bypassing NICE?
Yes—critics say the creation of the fund was poor policy because it represents “onco-exceptionalism,” ignoring the cost effectiveness criteria by which most other drugs are assessed for reimbursement by the NHS and thus creating an inefficient allocation of scarce NHS resources not justified by evidence. NICE’s chief executive, Andrew Dillon, argues that it does not make sense that when NICE rejects a drug for routine use, “in most cases the Cancer Drug Fund then says yes to the treatments we have said no to.”3
The fund also takes away the incentive created by NICE for drug companies to reduce the prices of their new drugs for the NHS. Drug companies normally continue to apply to NICE for scrutiny of new cancer drugs and may offer discounts through “patient access programmes” if the initially proposed prices are judged too high. But if their products are rejected, they have recourse not available for other medicines: they can still seek approval from the Cancer Drug Fund at the price rejected by NICE
Why has the fund just been given additional resources and extended for two years?
As the fund has approved new, better drugs, none of the less effective products have been removed from its list and the number of patients on funded drugs has steadily risen. That has helped swell total demand, breaking the annual £200m budget originally agreed. In late August, it was expanded to £280m a year for an extra two years, 2014-16. On the current trajectory, it is set to spend up to £1.2bn in total.
Presumably that makes drug companies and patients very happy?
Not all of them. Roche, which produces many cancer drugs (including trastuzumab emtansine for breast cancer, which was rejected by NICE in August at £90 000 a treatment) has been a prime beneficiary. Others are less content. Under the terms of the most recent Pharmaceutical Price Regulation System agreed between the Department of Health and industry4 any increase this year in the total NHS medicines bill must be absorbed by companies. That means if the fund pays for more cancer drugs, the producers of drugs for other conditions must absorb the difference by reducing their prices.
Similarly, although cancer patients may be thrilled to have access to potentially life extending drugs, and politicians have stressed that the cancer fund’s annual budget does not displace other NHS spending, some clinicians have expressed concerns that the fund squeezed out money from other areas, especially at a time of intense cost cutting. Even some cancer specialists argue that better outcomes might have come from channelling additional funds into prevention, early diagnosis, radiotherapy, and surgery rather than expensive new treatments with limited effect. “It is inevitable if you choose to spend money on one thing you can’t spend it on something else,” says Dillon. “If you allocate more money to one condition, other conditions are getting less.”
Can NICE and the fund continue in their current form?
As part of its recent 40% funding increase, the Cancer Drug Fund has agreed to remove drugs from its list that are overpriced or produce little clinical benefit and try to align its assessment process more closely with that of NICE.5 The fund has also agreed to accelerate the process of gathering better data on the effects of supported cancer drugs in clinical practice. Currently the data collected are minimal. Better data would allow both a better assessment of the fund’s value and provide information to clinicians to help cancer patients more broadly. An evaluation of the fund’s performance suggested it had boosted use of drugs rejected by NICE but did not accelerate the uptake of treatments still under review by NICE that were subsequently approved.6 Uptake of some of these approved drugs was more rapid in neighbouring Wales (where the fund is not operating) than in England.
Andrew Dillon argues that the fund should be brought under the remit of NICE,3 but Stephen Whitehead, chief executive of the Association of British Pharmaceutical Industry, has argued that NICE’s process for assessing value needs urgent reform.5
Reform of the CDF is an early test for Simon Stevens as head of NHS England, who has chosen personally to lead the negotiation with patient groups, researchers, and NICE as part of new scrutiny to ensure clinically effective drugs are made available cost effectively—capping any further expansion of the NHS drugs bill. NICE continues to review its methods, and the latest statements suggest there is at the very least likely to be tighter collaboration.7 But scrapping the earmarked CDF now it has been created will prove politically sensitive.
Cite this as: BMJ 2014;349:g5524
Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare
Provenance and peer review: Commissioned; not externally peer reviewed.
↵HM Government. The coalition. Our programme for government. www.gov.uk/government/uploads/system/uploads/attachment_data/file/78977/coalition_programme_for_government.pdf.
↵NHS England. National cancer drugs fund list. Vers 2. 2014. www.england.nhs.uk/wp-content/uploads/2014/08/ncdf-list-july14.pdf.
↵Knapton S. Cancer Drugs Fund makes no sense, says head of drugs rationing body Nice. Telegraph 2014 Sep 2. www.telegraph.co.uk/health/healthnews/11071055/Cancer-Drugs-Fund-makes-no-sense-says-head-of-drugs-rationing-body-Nice.html
↵Department of Health. Pharmaceutical price regulation scheme 2014. www.gov.uk/government/publications/pharmaceutical-price-regulation-scheme-2014.
↵Hawkes N. Cancer Drugs Fund receives boost but will no longer fund “overpriced” drugs. BMJ 2013;349:g5382.
↵Chamberlain C, Collin SM, Stephens P, Donovan J, Bahl A, Hollingworth W. Does the cancer drugs fund lead to faster uptake of cost-effective drugs? A time-trend analysis comparing England and Wales. Br J Cancer2014 Feb 25. [Epub ahead of print.]
↵NHS England. NHS England sets out plan for a sustainable Cancer Drugs Fund. Press release, 28 August 2014. www.england.nhs.uk/2014/08/28/cdf-plan/.
Friday, September 05, 2014
Wednesday, September 03, 2014
Monday, September 01, 2014
BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g5382 (Published 01 September 2014)
Cite this as: BMJ 2014;349:g5382
The Cancer Drugs Fund has been given a 40% increase in funding and has agreed to remove from its list any drugs that are overpriced or produce little clinical benefit. The fund’s chairman also promised to try to align the fund’s assessments more closely with those of the National Institute for Health and Care Excellence (NICE).
NHS England, which is responsible for the drugs fund, has agreed to increase the amount the fund receives for the next two years from £200m (€252m; $332m) to £280m a year. The fund has treated 55 000 people since it began, using drugs that NICE did not recommend as cost effective because, in most cases, they offered patients only a few more months of life.
Originally launched by Andrew Lansley, the former health secretary, as a way to satisfy political pressures,1 the fund has succeeded in that objective but has always been regarded by NICE and its supporters as something of a fudge: it covers only cancer, not other end of life conditions.
The major beneficiary of the fund (apart from the patients treated) has been the leading manufacturer of cancer drugs, Roche. The fund was originally meant to act as a bridge between the NICE dominated era—with its hard luck stories of patients denied drugs that were available in other countries—and a new era of value based pricing, where every new drug would carry a price tag that reflected its value. But that never happened, and instead the Pharmaceutical Price Regulation Scheme was renegotiated to set a global ceiling on drug spending. Every costly new drug sold to the NHS now means less money for other medicines.
This has driven a wedge between Roche—which was suspended from the Association of the British Pharmaceutical Industry (ABPI) in 2008 for breaching the rules and has never rejoined—and the rest of the industry. In the ABPI’s view the fund is no longer a cost-free offering. Its chief executive, Stephen Whitehead, welcomed the cash injection but warned, “However, it is only a short term solution and ultimately the NICE value assessment process needs to be reformed urgently, so that more innovative cancer medicines can be made available to NHS patients.”
The fund’s existence has eased the downward pressure on cancer drug prices, which NICE believes are too high. Roche’s latest breast cancer drug—Kadcyla, for advanced breast cancer—costs £90 000 for a course of treatment with outcomes that, under NICE rules, would make it worth £10 000 to £25 000. NICE rejected the drug on cost effectiveness grounds, but it is available through the Cancer Drugs Fund.
In a letter to NHS England the fund’s chairman, Peter Clark of the Clatterbridge Cancer Centre in Merseyside, said that the fund paid for drugs that showed good benefit but also for “minority drugs of much less clinical value.” He added that the fund had offered an alternative funding source “on price terms which in some cases have represented poor value.” He also undertook to review drugs and withdraw reimbursement for any found to be ineffective or too expensive. But this would not affect patients already taking those drugs or others that were the only confirmed treatment, he wrote. “The result will be to ensure patients continue to access worthwhile cancer medicines whilst also creating financial headroom for new medicines within the significantly expanded funding allocation,” he added.
The fund’s assessments will still diverge widely from those of NICE, despite Clark’s promise to try to ensure “greater alignment” between the two bodies. He also promised a new “evaluation through commissioning” option that would reimburse new drugs in clinical practice but would also review outcomes to assess value for money.
While the fund has made many drugs available to patients who would not otherwise have got them, its overall effect is less clear-cut. A study published in the British Journal of Cancer earlier this year2 found that English patients were as much as seven times more likely to be prescribed drugs rejected by NICE than patients in Wales, which is not covered by the fund. But three new drugs that NICE approved (pazopanib, bendamustine, and abiraterone) were adopted more slowly in England than in Wales. The existence of the fund, the authors concluded, did not speed up access to cost effective drugs.
Cite this as: BMJ 2014;349:g5382
↵Wise J. Charities welcome £50m interim cancer drugs fund. BMJ2010;341:c5464.FREE Full Text
↵Chamberlain C, Collin SM, Stephens P, Donovan J, Bahl A, Hollingworth W, Does the cancer drugs fund lead to faster uptake of cost effective drugs? A time trend analysis comparing England and Wales. Brit J Cancer2014; published online 25 Feb. doi:10.1038/bjc.2014.86.
During the Middle Ages there were all kinds of crazy ideas, such as that a piece of of rhinoceros horn would increase potency. Then a method was discovered for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course, into science. And it developed very well, so that we are now in the scientific age. It is such a scientific age, in fact, that we have difficulty in understanding how witch doctors could ever have existed, when nothing that they proposed ever really worked--or very little of it did.
But even today I meet lots of people who sooner or later get me into a conversation about UFO's, or astrology, or some form of mysticism, expanded consciousness, new types of awareness, ESP, and so forth. And I've concluded that it's not a scientific world.
Most people believe so many wonderful things that I decided to investigate why they did. And what has been referred to as my curiosity for investigation has landed me in a difficulty where I found so much junk that I'm overwhelmed. First I started out by investigating various ideas of mysticism and mystic experiences. I went into isolation tanks and got many hours of hallucinations, so I know something about that. Then I went to Esalen, which is a hotbed of this kind of thought (it's a wonderful place; you should go visit there). Then I became overwhelmed. I didn't realize how MUCH there was.
At Esalen there are some large baths fed by hot springs situated on a ledge about thirty feet above the ocean. One of my most pleasurable experiences has been to sit in one of those baths and watch the waves crashing onto the rocky slope below, to gaze into the clear blue sky above, and to study a beautiful nude as she quietly appears and settles into the bath with me.
One time I sat down in a bath where there was a beautiful girl sitting with a guy who didn't seem to know her. Right away I began thinking, "Gee! How am I gonna get started talking to this beautiful nude woman?"
I'm trying to figure out what to say, when the guy says to her, "I'm, uh, studying massage. Could I practice on you?" "Sure," she says. They get out of the bath and she lies down on a massage table nearby. I think to myself, "What a nifty line! I can never think of anything like that!" He starts to rub her big toe. "I think I feel it," he says. "I feel a kind of dent--is that the pituitary?" I blurt out, "You're a helluva long way from the pituitary, man!" They looked at me, horrified--I had blown my cover--and said, "It's reflexology!" I quickly closed my eyes and appeared to be meditating.
That's just an example of the kind of things that overwhelm me. I also looked into extrasensory perception, and PSI phenomena, and the latest craze there was Uri Geller, a man who is supposed to be able to bend keys by rubbing them with his finger. So I went to his hotel room, on his invitation, to see a demonstration of both mindreading and bending keys. He didn't do any mindreading that succeeded; nobody can read my mind, I guess. And my boy held a key and Geller rubbed it, and nothing happened. Then he told us it works better under water, and so you can picture all of us standing in the bathroom with the water turned on and the key under it, and him rubbing the key with his finger. Nothing happened. So I was unable to investigate that phenomenon.
But then I began to think, what else is there that we believe? (And I thought then about the witch doctors, and how easy it would have been to check on them by noticing that nothing really worked.) So I found things that even more people believe, such as that we have some knowledge of how to educate. There are big schools of reading methods and mathematics methods, and so forth, but if you notice, you'll see the reading scores keep going down--or hardly going up--in spite of the fact that we continually use these same people to improve the methods. There's a witch doctor remedy that doesn't work. It ought to be looked into; how do they know that their method should work? Another example is how to treat criminals. We obviously have made no progress--lots of theory, but no progress--in decreasing the amount of crime by the method that we use to handle criminals.
Yet these things are said to be scientific. We study them. And I think ordinary people with commonsense ideas are intimidated by this pseudoscience. A teacher who has some good idea of how to teach her children to read is forced by the school system to do it some other way--or is even fooled by the school system into thinking that her method is not necessarily a good one. Or a parent of bad boys, after disciplining them in one way or another, feels guilty for the rest of her life because she didn't do "the right thing," according to the experts.
So we really ought to look into theories that don't work, and science that isn't science.
I think the educational and psychological studies I mentioned are examples of what I would like to call cargo cult science. In the South Seas there is a cargo cult of people. During the war they saw airplanes with lots of good materials, and they want the same thing to happen now. So they've arranged to make things like runways, to put fires along the sides of the runways, to make a wooden hut for a man to sit in, with two wooden pieces on his head to headphones and bars of bamboo sticking out like antennas--he's the controller--and they wait for the airplanes to land. They're doing everything right. The form is perfect. It looks exactly the way it looked before. But it doesn't work. No airplanes land. So I call these things cargo cult science, because they follow all the apparent precepts and forms of scientific investigation, but they're missing something essential, because the planes don't land.
Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Sea islanders how they have to arrange things so that they get some wealth in their system. It is not something simple like telling them how to improve the shapes of the earphones. But there is one feature I notice that is generally missing in cargo cult science. That is the idea that we all hope you have learned in studying science in school--we never say explicitly what this is, but just hope that you catch on by all the examples of scientific investigation. It is interesting, therefore, to bring it out now and speak of it explicitly. It's a kind of scientific integrity, a principle of scientific thought that corresponds to a kind of utter honesty--a kind of leaning over backwards. For example, if you're doing an experiment, you should report everything that you think might make it invalid--not only what you think is right about it: other causes that could possibly explain your results; and things you thought of that you've eliminated by some other experiment, and how they worked--to make sure the other fellow can tell they have been eliminated.
Details that could throw doubt on your interpretation must be given, if you know them. You must do the best you can--if you know anything at all wrong, or possibly wrong--to explain it. If you make a theory, for example, and advertise it, or put it out, then you must also put down all the facts that disagree with it, as well as those that agree with it. There is also a more subtle problem. When you have put a lot of ideas together to make an elaborate theory, you want to make sure, when explaining what it fits, that those things it fits are not just the things that gave you the idea for the theory; but that the finished theory makes something else come out right, in addition.
In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.
The easiest way to explain this idea is to contrast it, for example, with advertising. Last night I heard that Wesson oil doesn't soak through food. Well, that's true. It's not dishonest; but the thing I'm talking about is not just a matter of not being dishonest; it's a matter of scientific integrity, which is another level. The fact that should be added to that advertising statement is that no oils soak through food, if operated at a certain temperature. If operated at another temperature, they all will--including Wesson oil. So it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with.
We've learned from experience that the truth will come out. Other experimenters will repeat your experiment and find out whether you were wrong or right. Nature's phenomena will agree or they'll disagree with your theory. And, although you may gain some temporary fame and excitement, you will not gain a good reputation as a scientist if you haven't tried to be very careful in this kind of work. And it's this type of integrity, this kind of care not to fool yourself, that is missing to a large extent in much of the research in cargo cult science.
A great deal of their difficulty is, of course, the difficulty of the subject and the inapplicability of the scientific method to the subject. Nevertheless, it should be remarked that this is not the only difficulty. That's why the planes don't land--but they don't land.
We have learned a lot from experience about how to handle some of the ways we fool ourselves. One example: Millikan measured the charge on an electron by an experiment with falling oil drops, and got an answer which we now know not to be quite right. It's a little bit off because he had the incorrect value for the viscosity of air. It's interesting to look at the history of measurements of the charge of an electron, after Millikan. If you plot them as a function of time, you find that one is a little bit bigger than Millikan's, and the next one's a little bit bigger than that, and the next one's a little bit bigger than that, until finally they settle down to a number which is higher.
Why didn't they discover the new number was higher right away? It's a thing that scientists are ashamed of--this history--because it's apparent that people did things like this: When they got a number that was too high above Millikan's, they thought something must be wrong--and they would look for and find a reason why something might be wrong. When they got a number close to Millikan's value they didn't look so hard. And so they eliminated the numbers that were too far off, and did other things like that. We've learned those tricks nowadays, and now we don't have that kind of a disease.
But this long history of learning how to not fool ourselves--of having utter scientific integrity--is, I'm sorry to say, something that we haven't specifically included in any particular course that I know of. We just hope you've caught on by osmosis
The first principle is that you must not fool yourself--and you are the easiest person to fool. So you have to be very careful about that. After you've not fooled yourself, it's easy not to fool other scientists. You just have to be honest in a conventional way after that.
I would like to add something that's not essential to the science, but something I kind of believe, which is that you should not fool the layman when you're talking as a scientist. I am not trying to tell you what to do about cheating on your wife, or fooling your girlfriend, or something like that, when you're not trying to be a scientist, but just trying to be an ordinary human being. We'll leave those problems up to you and your rabbi. I'm talking about a specific, extra type of integrity that is not lying, but bending over backwards to show how you're maybe wrong, that you ought to have when acting as a scientist. And this is our responsibility as scientists, certainly to other scientists, and I think to laymen.
For example, I was a little surprised when I was talking to a friend who was going to go on the radio. He does work on cosmology and astronomy, and he wondered how he would explain what the applications of his work were. "Well," I said, "there aren't any." He said, "Yes, but then we won't get support for more research of this kind." I think that's kind of dishonest. If you're representing yourself as a scientist, then you should explain to the layman what you're doing-- and if they don't support you under those circumstances, then that's their decision.
One example of the principle is this: If you've made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish BOTH kinds of results.
I say that's also important in giving certain types of government advice. Supposing a senator asked you for advice about whether drilling a hole should be done in his state; and you decide it would be better in some other state. If you don't publish such a result, it seems to me you're not giving scientific advice. You're being used. If your answer happens to come out in the direction the government or the politicians like, they can use it as an argument in their favor; if it comes out the other way, they don't publish at all. That's not giving scientific advice.
Other kinds of errors are more characteristic of poor science. When I was at Cornell, I often talked to the people in the psychology department. One of the students told me she wanted to do an experiment that went something like this--it had been found by others that under certain circumstances, X, rats did something, A. She was curious as to whether, if she changed the circumstances to Y, they would still do A. So her proposal was to do the experiment under circumstances Y and see if they still did A.
I explained to her that it was necessary first to repeat in her laboratory the experiment of the other person--to do it under condition X to see if she could also get result A, and then change to Y and see if A changed. Then she would know the the real difference was the thing she thought she had under control.
She was very delighted with this new idea, and went to her professor. And his reply was, no, you cannot do that, because the experiment has already been done and you would be wasting time. This was in about 1947 or so, and it seems to have been the general policy then to not try to repeat psychological experiments, but only to change the conditions and see what happened.
Nowadays, there's a certain danger of the same thing happening, even in the famous field of physics. I was shocked to hear of an experiment being done at the big accelerator at the National Accelerator Laboratory, where a person used deuterium. In order to compare his heavy hydrogen results to what might happen with light hydrogen, he had to use data from someone else's experiment on light hydrogen, which was done on different apparatus. When asked why, he said it was because he couldn't get time on the program (because there's so little time and it's such expensive apparatus) to do the experiment with light hydrogen on this apparatus because there wouldn't be any new result. And so the men in charge of programs at NAL are so anxious for new results, in order to get more money to keep the thing going for public relations purposes, they are destroying--possibly--the value of the experiments themselves, which is the whole purpose of the thing. It is often hard for the experimenters there to complete their work as their scientific integrity demands.
All experiments in psychology are not of this type, however. For example, there have been many experiments running rats through all kinds of mazes, and so on--with little clear result. But in 1937 a man named Young did a very interesting one. He had a long corridor with doors all along one side where the rats came in, and doors along the other side where the food was. He wanted to see if he could train the rats to go in at the third door down from wherever he started them off. No. The rats went immediately to the door where the food had been the time before.
The question was, how did the rats know, because the corridor was so beautifully built and so uniform, that this was the same door as before? Obviously there was something about the door that was different from the other doors. So he painted the doors very carefully, arranging the textures on the faces of the doors exactly the same. Still the rats could tell. Then he thought maybe the rats were smelling the food, so he used chemicals to change the smell after each run. Still the rats could tell. Then he realized the rats might be able to tell by seeing the lights and the arrangement in the laboratory like any commonsense person. So he covered the corridor, and still the rats could tell.
He finally found that they could tell by the way the floor sounded when they ran over it. And he could only fix that by putting his corridor in sand. So he covered one after another of all possible clues and finally was able to fool the rats so that they had to learn to go in the third door. If he relaxed any of his conditions, the rats could tell.
Now, from a scientific standpoint, that is an A-number-one experiment. That is the experiment that makes rat-running experiments sensible, because it uncovers that clues that the rat is really using-- not what you think it's using. And that is the experiment that tells exactly what conditions you have to use in order to be careful and control everything in an experiment with rat-running.
I looked up the subsequent history of this research. The next experiment, and the one after that, never referred to Mr. Young. They never used any of his criteria of putting the corridor on sand, or being very careful. They just went right on running the rats in the same old way, and paid no attention to the great discoveries of Mr. Young, and his papers are not referred to, because he didn't discover anything about the rats. In fact, he discovered all the things you have to do to discover something about rats. But not paying attention to experiments like that is a characteristic example of cargo cult science.
Another example is the ESP experiments of Mr. Rhine, and other people. As various people have made criticisms--and they themselves have made criticisms of their own experiements--they improve the techniques so that the effects are smaller, and smaller, and smaller until they gradually disappear. All the para-psychologists are looking for some experiment that can be repeated--that you can do again and get the same effect--statistically, even. They run a million rats--no, it's people this time--they do a lot of things are get a certain statistical effect. Next time they try it they don't get it any more. And now you find a man saying that is is an irrelevant demand to expect a repeatable experiment. This is science?
This man also speaks about a new institution, in a talk in which he was resigning as Director of the Institute of Parapsychology. And, in telling people what to do next, he says that one of things they have to do is be sure the only train students who have shown their ability to get PSI results to an acceptable extent--not to waste their time on those ambitious and interested students who get only chance results. It is very dangerous to have such a policy in teaching--to teach students only how to get certain results, rather than how to do an experiment with scientific integrity.
So I have just one wish for you--the good luck to be somewhere where you are free to maintain the kind of integrity I have described, and where you do not feel forced by a need to maintain your position in the organization, or financial support, or so on, to lose your integrity. May you have that freedom.