Sneak Peak: India dilemma

Dogs or Monkeys - The Indian Pharma Industry’s dilemma « The Great Indian Mutiny

But according to a Financial Times Report, the Indian Pharmaceutical Industry is facing a peculiar problem - traditional reverence to animals like rats and monkeys in India is apparently hindering progress in the R & D sector. The US Food and Drug Administration and other regulators around the world require new drugs to be tested on animals like rats and dogs whereas toxicology tests(that might kill the animals) on such animals are banned in India. This is apart from the likely opposition from animal rights groups like Peta.

Help wanted: No immune experience required

From the news release:

"Around 50% of adult human T cells are memory cells, having been activated by infections and illnesses during the course of a person's life. However, animal models, such as those used to test TGN1412 before tests were carried out on humans, do not have many memory T cells because they are deliberately kept in a sterile environment where they are shielded from infections."

Hmmm. Presumably all the specific pathogen free (SPF) colonies are part of a plan to eliminate pesky diseases that vivisectors view as confounding variables. Oh. You mean immune systems don't exist in a vacuum? And that species differences and experience influence immune function? Well go figure. (shucks)

"The research, by scientists from Imperial College London, King's College London, and the Babraham Institute, is presented today at the Club de la Transplantation conference in Cernay la Ville, near Paris.

Dr Federica Marelli-Berg, lead author of the research from the Department of Immunology at Imperial College London, explained: "The drug TGN1412 appeared to be relatively safe when it was tested in animal models. However, when the drug was tested on human volunteers, some experienced very severe side-effects."

I'm sorry. Did she say that some volunteers had very severe side effects? How would anyone in her right mind not admit that all six men suffered extraordinary, indeed life-threatening, effects?

"TGN1412 was developed to treat chronic inflammatory conditions, including rheumatoid arthritis, leukaemia and multiple sclerosis, which are caused by the body's immune system attacking itself. It was thought that by targeting CD28, the drug could over-stimulate the rogue T cells, making them burn out and die."

Doh!

Not everyone is so quick to buy this spiel. One expert consulted by the science journal Nature had a very different view:

As part of a report into how to minimize the risks of future clinical trials, immunologist Stephen Inglis of the National Institute for Biological Standards and Control in London developed a new test, using human cells in a test tube, that could have spotted the risk of a cytokine storm (see 'New test could weed out dangerous drug trials').

Inglis also doubts that Marelli-Berg's theory represents the whole story. Monkey cells did not respond to his test in the same way, suggesting that there is something fundamentally different about the two species' cells, rather than simply a question of which cells are present.

What's more, he says it is unclear whether or not lab monkeys do indeed have less-developed immune systems. "They're not like mice," he says. "Colonies of monkeys live in groups, they're not in individual cages, they do get infections and they're not pristine. We would now recommend using human cells for preclinical trials. But whether that is the cause is a different thing."

Maybe monkeys used in preclinical trials conducted in European labs live in groups. Those here in the US certainly do not.
Other posts on TGN1412 can be found in the pharma category at right.

Original news item: Researchers propose reason for severe side-effects of Northwick Park clinical trial

Poor predictors of human outcomes

From an LTE in response to Monday's article on primate testing at SNBL:

My last complaint is with Meyers' claims of good science. Even if we ignore the USDA violations for the moment, something few would be willing to do if the details had been reported, the science is dubious. Readers deserve a realistic view of what the so-called "good science" really achieves.

The FDA itself has reported that over 90 percent of drugs tested in animals eventually prove to be unsafe or ineffective in human trials. This figure doesn't even include drugs that get approved and then later get recalled. Let's not forget that Vioxx was tested in monkeys and went on to be a disaster. Recent independent studies published in highly respected medical journals, JAMA and BMJ, reported that animal tests were poorly designed and executed, and utterly miserable at predicting outcomes for people.

Click here for full letter - Animal Testing: Poor predictors of human outcomes

Industry-funded "marketing material" passed off as scientific articles

PLoS Medicine has just published a study which found that essentially ALL reports from clinical trials in one European survey (40 over one year) were written by industry ghost-writers rather than clinicians (all if we use the most liberal definition of ghost-writer, nearly all if a strict definition is used.) Conflict of interest and financial disclosure policies should preclude such nonsense, or perhaps such reports should be marked as advertisement. (Or, for the sake of public health, tossed.)

This is deeply disconcerting:

This study is the first that has systematically examined the prevalence of ghost authorship using a cohort of protocols and corresponding publications. The authors conclude that "ghost authorship in industry-initiated randomised trials is very common, and we believe that this practice serves commercial purposes". They go on to urge that in order to reduce the prevalence of ghost authorship, existing guidelines such as those drawn up by the International Committee on Medical Journal Editors, World Association of Medical Editors and European Medical Writers Association, are followed. This action could increase the chance that publications accurately, fairly, and comprehensively reflect the data collected from trials

A related perspective by Liz Wager, an independent editorial consultant, who has been involved in drawing up guidelines for medical writers, discusses the implication of these findings further.

Full article available online, here, at PLoS Medicine: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040019

Dubious drugs and devices due to double dipping

If you work for the government, your duty is to the public and as such, you must avoid conflicts of interest that might interfere with that duty. The rules are strict. I know because I was a federal employee at one time.

It seems some feds are breaking the rules. A scientist from the NIH has entered a guilty plea to criminal charges made because he accepted hundreds of thousands of dollars from Pfizer. It seems more convictions might be on the way:

Another senior researcher, Thomas J. Walsh, head of the Pediatric Oncology Branch at the National Cancer Institute, may be of increased interest to federal prosecutors now that Sunderland's case has been concluded, a government source said. Walsh engaged in "serious misconduct" by accepting more than $100,000 in consulting fees from drug and biotech companies, according to an internal NIH document obtained by the Los Angeles Times. He accepted fees from 25 companies and has led government-sponsored research involving some of those companies' drugs, according to the document.

Vicki E. LeDuc, spokesperson for the U.S. Attorney's Office in Baltimore, told The Scientist she could neither confirm nor deny that prosecutors planned to pursue criminal action against the researcher. Walsh did not respond to a request for comment, but has previously denied wrongdoing. "We have not heard anything from prosecutors," his attorney, H. Bradford Glassman, told The Scientist on Friday.

NIH scientists are balking at the rules, but in a climate where ethical conduct is on the minds of many - perhaps from post-Hwang paranoia - their whining seems especially arrogant. Government scientists make a fair wage, have good benefits and secure jobs. If they don't like what they get in exchange for their work, they can always go to the private sector. (Hooray for free will) If my tax dollars pay their salaries, I expect them to do the best and most ethical science possible. They are duty bound to do so.

For more details, see The Scientist.

Some of my previous posts on scientific misconduct:

Ethics rules send NIH scientists packing

Former FDA chief charged with conflict

Journal editor quits over conflict of interest

(how about that alliteration in the title, eh?)

Animal tests did not predict failure of heart drug - Pfizer reeling

Stocks fell sharply earlier this month when Pfizer announced that trials of its drug candidates were being terminated because of deaths linked to the drug. The drug was supposed to be a new blockbuster, something Pfizer apprently needed because patents on older drugs are expiring.

From the news item:

Drug company Pfizer announced on 2 December that it was cancelling all clinical trials of torcetrapib, a drug designed to raise heart-protective high-density lipoproteins (HDLs). In a trial of 15000 patients, a safety board found that more people died or suffered cardiovascular problems after taking the drug plus a cholesterol-lowering statin than those in a control group who took the statin alone.

The news came as a kick in the teeth to many cardiologists because earlier tests in animals and people suggested it would lower rates of cardiovascular disease. "There have been no red flags to my knowledge," says John Chapman, a specialist in lipoproteins and atherosclerosis at the National Institute for Health and Medical Research (INSERM) in Paris who has also studied torcetrapib. "This cancellation came as a complete shock."

[emphasis not in original]

You'd think that with Vioxx, TGN1412 and other failures looming so large in the media and the courtroom that the shock factor of these sorts of failures would wear off.

See the full story over at Nature.

Recommendations clinical trial safety post-TGN1412

There are lots of ideas out there for improving the safety of drug tests - but the efficacy of pre-clinical systems is not often one of them. This Duff report may be an exception - at least the reporting on the report in an industry newsletter:

Duff reports on clinical trial safety:

"The report called for increased communication between the drug developer and the regulatory body before application for Phase I trials. Pre-clinical trial safety information should be submitted to a database to speed-up the process. This should allow the regulators to identify potential concerns and discuss these with appropriate independent specialist experts. "

This could be part of a system of registering pre-clinical trials, perhaps based on the model for clinical trials registration proposed by the Ottawa Group.

This item also happens to mention the pre-clinical trials in macaqaues:

No adverse effects were observed in monkeys even though they were given a dose 500 times greater than the human volunteers.

Viet Nam News

Viet Nam News

Revenge of the cloned monkeys

JAMA article cautions on reliability and utility of animal testing

The predictive value of animal studies has been questioned yet again by a new, independent study that found only one in ten successful animal trials might lead to an approved drug for humans.

Researchers from the University of Toronto reviewed 76 prestigious animal studies, each originally published in such journals as Science and cited by at least 500 other papers, to see if any had resulted in a human trial of the treatment in question. Despite all the animal studies being positive (that is, the treatment was effective) only 8 of the studies resulted in approved drugs for humans – that’s a mere 11%.

Despite the prestigious journals in which they originally appeared, more than half of the 76 highly-cited animal studies used methods and design that rated poor or low. Quality of the design, however, didn't appear to affect the main outcome: studies with "good" methods were no more likely to be replicated in human studies.

The authors of the new study warned that even the very limited success rate of 11% was likely to be an overestimate because they examined only highly-cited studies featured in very prominent journals. They went on to conclude that,

“...patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease”.

The reference for the study is: Hackman, D.G. and Redelmeier, D.A. 2006. Translation of research evidence from animals to humans. Journal of the American Medical Association 296, 1731-2.

From ECEAE newsletter "Testing Times" November issue

Elephant Man drug trial victims 'injected too quickly' | the Daily Mail

I bet this guy hated being experimented on, too.

Elephant Man drug trial victims 'injected too quickly' the Daily Mail

TGN1412 - What the hell happened?

NEJM has published an article which chronicles the events in the 30 days after dosing with the experimental drug, TGN1412, in six healthy volunteers. All went into multi-organ failure.

Pre-clinical studies in monkeys showed two mild side effects: irritation at the injection site and a mild swelling of the lymph nodes in some animals. These effects were mils, despite the fact that they received considerably higher concentrations of the drug.

Compare that to the long list of effects shown in Table 3 of the NEJM article! These include:

Capillary leak
Hemodynamic instability
Lactic acidemia
Early acute renal impairment
Acute pulmonary changes (six patients)
Met criteria for acute lung injury (two patients)
Met criteria for acute respiratory distress syndrome (one patient)
Lymphopenia
Monocytopenia
Thrombocytopenia
Disseminated intravascular coagulation
Normochromic, normocytic anemia
Delirium
Partial amnesia
Paresthesia or localized numbness
Difficulty concentrating (late)
Headaches (early and late)
Nausea or vomiting

Differences between humans and the animals used in preclinical studies are identified as factors that ultimately lead to this disaster - because the effects were not predicted by the results of the animal experiments.

Link to full article below.

NEJM -- Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412

Drug companies accused of manipulation

'The main aim of drug companies is to sell a drug -- they don't deny that -- and our main aim is to help people,' Clarke said. 'Those two things don't always go together. "

How do we get good and fair drug trials in a system that is driven by profit and shrouded in secrecy?

Why do we rely on a system where 92% of drugs that enter human clinical trials fail? These miserable rates of failure don't even begin to address the drugs that are abandoned at earlier stages of discovery and testing.

Aussie claims drug trials are trash

TGN1412: Disastrous drug trial victim has cancer

And I bet he was just starting to think it couldn't get any worse.

Disastrous drug trial victim has cancer

Drug trial rules 'should change'

BBC NEWS Health Drug trial rules 'should change'

"In the light of the TGN 1412 incident, there is a need to look at the future safety of clinical trials involving novel and potentially higher risk drugs "

Sure...but are we to think that the earliest human trials are the best and only place to institute change? Or that registering clinical trials once they are underway will solve our problems? Or that forcing financial disclosure statements of authors who publish trial results in medical journals will make us all safe? Our current system is broken in several places, and there is no band-aid large enough to fix it.

Safety requires change *upstream* as well. What happens before drugs get to clinical trials and is current practice effective?

Pharmaceutical firm reluctant to tout AIDS drugs as possible preventive

NO vaccine that has proven effective in non-human primates has subsequently proven effective in humans.

Pharmaceutical firm reluctant to tout AIDS drugs as possible preventive

TRIM5(alpha)
siglecs
human - nonhuman primate differences in genes for transcription factors and related gene regulation

Survey Reveals Seven Out of 10 Doctors Concerned About Safety of Prescription Medicines; Risk/Benefit Thinking Supports Generics

Maybe if we didn't rely on a model system that failed to predict safety and efficacy at least 92% of the time, we wouldn't be in this mess.

Survey Reveals Seven Out of 10 Doctors Concerned About Safety of Prescription Medicines; Risk/Benefit Thinking Supports Generics

Animal experiments do not prove that drugs are safe. Failed animal experiments don't guarantee that a drug would not be safe for people.

OT - WHO quashes requests for continued secrecy in drug trials�-�Early stages of testing should be made public, say public-health experts.

If we cataloged and analyzed data from pre-clinical animal experiments, we might better understand 1) the inefficency and poor predictive value of animal tests, and 2) the risks that participants in early stage trials face.

http://www.nature.com/news/2006/060515/full/060515-16.html