Animal/Human Testing for advances in drugs/medicine

Some matter:
The largest pharmaceutical companies are Pfizer (USA), Novartis (Switzerland), Merck & Co (USA), Bayer (Germany)
A 1993 report by the Congressional Office of Technology Assessment estimated the cost of developing a new drug to be $359 million.Newer figures place the cost at more than $500 million.
Unlike other industries, the drug business is very risky. For instance, only one out of every ten thousand discovered compounds actually becomes an approved drug for sale. Much expense is incurred in the early phases of development of compounds that will not become approved drugs.[6] In addition, it takes about 7 to 10 years and only 3 out of every 20 approved drugs bring in sufficient revenue to cover their developmental costs, and only 1 out of every 3 approved drugs generates enough money to cover the development costs of previous failures. This means that for a drug company to survive, it needs to discover a blockbuster (billion-dollar drug) every few years.

The cost of developing a successful new drug (New chemical entity or NCE), has been estimated at about 1.3 billion USD. (not including marketing expenses). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades.

Process of drug development:
Pre-clinical (chemical analysis, animal testing)

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds which emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease; however, little will be known about the safety, toxicity, pharmacokinetics and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-in-man" [FIM] or First Human Dose [FHD]).
In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a medicinal chemist, it can be manufactured on the kilogram and then on the ton scale. It will be further examined for its suitability to be made into capsules, tablets, aeresol, intramuscular injectable, subcuteneous injectable, or intravenous formulations. Together these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).

Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.

The information gathered from this pre-clinical testing, as well as information on CMC, and is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug application or IND. If the IND is approved, development moves to the clinical phase.

Clinical phase (humans)

Clinical trials involves three steps:
Phase I trials, usually in healthy volunteers, determine safety and dosing.
Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients.
Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients.

The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).

If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.

Pharmaceutical fraud
involves activities that result in false claims to insurers or programs such as Medicare in the United States or equivalent state programs for financial gain to a pharmaceutical company. There are several different schemes[1] used to defraud the health care system which are particular to the pharmaceutical industry.

$3 billion GSK settlement: On 2 July 2012, GlaxoSmithKline pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company.[10] The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data,[11] bribing doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were Paxil, Wellbutrin, Advair, Lamictal, and Zofran for off-label, non-covered uses. Those and the drugs Imitrex, Lotronex, Flovent, and Valtrex were involved in the kickback scheme.[12][13][14] The government investigation of GSK was launched largely on the basis of information provided by four whistleblowers who filed two qui tam (whistleblower) lawsuits against the company under the False Claims Act. GSK settled the whistleblowers’ lawsuits for a total of $1.017 billion out of the $3 billion settlement, the largest civil False Claims Act settlement to date.[15]

Pfizer $2.3 billion settlement: Pfizer settled multiple civil and criminal allegations for $2.3 billion in the largest case of pharmaceutical and health care fraud in US history. The drugs involved were Bextra (an anti-inflammatory drug), Geodon (an anti-psychotic drug), Lipitor (a cholesterol drug), Norvasc (anti-hypertensive drug), Viagra (erectile dysfunction), Zithromax (antibiotic), Zyrtec (antihistamine), Zyvox (an antibiotic), Lyrica (an anti-epileptic drug), Relpax (anti-migraine drug), Celebrex (anti-inflammatory drug), and Depo-provera (birth control).

Merck $650 million settlement: Merck settled a nominal pricing fraud case in which the company was accused of taking kickbacks and violating Medicaid best price regulations for various drugs."Huge Percentage of Financial Fraud Against U.S. Government Comes From Healthcare Industry". Deep Harm. 2009-09-02.</ref>"Top 20 Cases". Taxpayers Against Fraud. 2011-06-01.</ref>
United States et al., ex rel. Jim Conrad and Constance Conrad v. Forest Pharmaceuticals, Inc, et al. involved a drug manufacturer selling a drug, Levothroid, that had never been approved by the FDA. These allegations settled for $42.5 million due to multiple whistleblowers stepping forward to provide detailed information on the alleged fraud. The collective reward to the relators in this case was over $14.6 million

ANIMAL TESTING

Animal research has played a vital role in virtually every major medical advance of the last century -- for both human and animal health. Many diseases that once killed millions of people every year are either treatable or have been eradicated altogether.
- From antibiotics to blood transfusions, from dialysis to organ-transplantation, from vaccinations to chemotherapy, bypass surgery and joint replacement,
- practically every present-day protocol for the prevention, treatment, cure and control of disease, pain and suffering is based on knowledge attained through research with animals.
- Immunizations against polio, diphtheria, mumps, rubella and hepatitis save countless lives, and the survival rates from many major diseases are at an all-time high, thanks to the discovery of new drugs, medical devices and surgical procedures.

Where is animal research done? Who does them? (From Wikipedia)

The research is conducted inside universities, medical schools, pharmaceutical companies, farms, defense establishments, and commercial facilities that provide animal-testing services. Sources for laboratory animals vary. They are primarily and mostly purpose-bred.

It is rare that animals are procured from sources other than specialized dealers as this poses the threat of introducing disease into a colony and confounding any data collected. Some are caught in the wild and obtained in auctions.

Estimates of the total number of animals used annually in research around the world range from between 50 to 100 million. In the UK, 2.72 million animals were involved in scientific procedures initiated in 2003, with about a third of these carried out by the pharmaceutical industry, and one third used in basic biological research. The US has more than 1000 chimpanzees.

Animals are used for many purposes other than research. To put this into context, approximately one billion animals are used for the production of food in the UK per year, while 20 billion animals are consumed in the US. It is estimated that 60 billion animals (including all the little sea creatures, pigs, cows, birds, chickens etc.) die for human consumption every year around the world. (more at http://animalrights.about.com/od/animalrights101/tp/How-Many-Animals-Are-Killed.htm)

However, it’s not like we eat rats or primates. Both of which are the most used animals in animal research.

What animals are used?
In the UK in 2003, the majority of procedures, which is 87%, used mice and rats. Other mammals accounted for around 3% of the total, including 11,000 pigs, 5000 dogs and 3000 primates (for example, monkeys and marmosets). Birds account for 4%. Fish account for 6%. Reptiles only account for .3%.

WHY RATS?

Mice and rats are used because they are more similar to humans compared to fish or dogs and the fact that they can’t feel what humans feel. Rodents are also the animal model of choice for modern medical researchers because they have a naturally short life span -- two to three years -- that allows scientists to observe in "fast forward" what happens during the progress or pathogenesis of a disease.

You can see how a compound would react in a young animal, then in the same geriatric animal, and then in the next-generation animal, all in a time frame that is reasonable. Then if a product or a compound is determined to be safe in a rodent, another species is used. For example, if it's a neurological compound, oftentimes the cat is the preferred model because the neurological system of the cat more closely mimics that of a human. If it's a cardiovascular study, it might be a dog (although dogs are not used as frequently as they might have been a decade ago, since scientists have determined that pigs also serve as excellent models for some cardiovascular work).
(Read more: http://www.time.com/time/health/article/0,8599,1815241,00.html#ixzz2GX8paWP1)

Primates such as the macaque monkey (which is the most used one) have similar brain structures to humans. That is why they are preferred. Tests on them should have similar effects to testing humans. However, there are concerns that they also have high cognitive abilities, sociability, are sentient and so can feel pain just like humans. So some believe it's just almost as cruel as torturing humans. At least more cruel than torturing rats. And they are typically held captive for up to 30 years until they die.

How reliable is animal testing?

Thalidomide may be the best-known medication that harmed humans even after extensive animal testing. Like all drugs, it was tested on animals prior to being released. However, not until babies whose mothers had taken the drug had no limbs, did it undergo extensive animal tests for teratogenesis, which is prenatal toxicity characterized by structural or functional defects in the developing embryo or fetus. (more at http://www.independent.co.uk/arts-entertainment/how-reliable-is-animal-testing-podium-1079311.html)

The researchers working with Thalidomide had done experiments on rats, but had not produced the characteristic limb abnormalities seen in humans. After clinicians warned that they suspected Thalidomide of causing this devastating birth defect in children, researchers raced back to the lab to see if their clinical brethren were correct. Despite testing Thalidomide on scores of species, breeds, and strains of animals, phocomelia was infrequently seen. Testing on more than 50 types of animals did not consistently produce the side-effects that crippled thousands of children.

There is no way to know whether the rabbit, the beagle or the chimp will respond as does man, until one knows how man responds. The dead and crippled are unlikely to be comforted by the fact that they react as New Zealand white rabbits do but differently from guinea-pigs. An animal that responds like humans to one medication will not necessarily respond the same way to another medicine. How well the animal test predicts outcomes in humans depends on the animal species picked. However, you don't know which one to pick until after you know what the medication does to humans.

There is no single animal that makes a perfect test subject as of yet. (based on my google searching at least)
It's an evolving scientific study/research...... with strides being made i.e. rodents being made to be more human.

HUMAN TESTING

Before being marketed, human trials are undertaken to verify that the animal tests have accurately predicted the effects and side- effects of the new drugs on humans. Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA (US food and drug administration). The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.
(more at http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm)

It's the clinical trials that take so long--usually several years. Human clinical trials take place in many forms. In this case, studies are usually first taken on healthy volunteers to determine what the drug’s most frequent side effects are.

Some believe that patients with potentially fatal diseases such as cancer or Aids who are likely to die from their disease, have nothing to lose and potentially much to gain from trying new, untested drugs. Co-ordinators of human trials can also ask for volunteers, to take the medication and then undergo blood tests and report side-effects. The humans volunteering for clinical trials are assured that the risk they are taking is minimal. After all, the drugs have already passed animal trials. If they haven’t been tested yet and it’s urgent like hypothetically there is a global pandemic rapidly killing millions then they have nothing to lose as well by going straight to human testing. Or even if there’s no pandemic. That’s debatable.

Besides Drug/Pharmaceutical entities, militaries used human testing as well. The Nazi experiments are notorious. i.e. testing the effects of poisonous substances on humans. Testing effectiveness of different ammunitions on human anatomy. Finding the best ways to do surgery on live people and many other crazy stuff.

Militaries such as the US conducted voluntary human testing. The CIA had programs such as MKUltra. In a memo describing one subprogram of it, Richard Helms said: “We intend to investigate the development of a chemical material which causes a reversible, nontoxic aberrant mental state, the specific nature of which can be reasonably well predicted for each individual. This material could potentially aid in discrediting individuals, eliciting information, and implanting suggestions and other forms of mental control.” In addition to testing the effects of mustard gas decades ago to see the effectiveness of equipment. And then there are soldiers volunteering and dying painfully after taking untested drugs during world war 2 among many other examples...

Some believe that volunteering to be a test subject to fight a war on disease is just as noble as fighting any other war. In this war, however, you are essentially tortured and you’re not supposed to get tortured in war.

In 1952, professional tennis player Harold Blauer died when injected with a fatal dose of a mescaline derivative at the New York State Psychiatric Institute of Columbia University, by Dr. James Cattell. The United States Department of Defense, which sponsored the injection, worked in collusion with the Department of Justice, and the New York State Attorney General to conceal evidence of its involvement for 23 years.
(might be a useful name to use)

From Kip's debate in CSB IVs

"bitter pill" pun lol

1. Patients = people with stuff like pancreatic cancer (survival = less than 1%) or high stage of brain cancer. Drugs aren't just random stuff. They've been through preclinical research (chemical analysis, tests on animals and possibly third world humans).
2.It's sad that in the status quo this policy isn't allowed simply because these people are deemed incapable of making rational choices.
3. People have control over what harm can possibly be done to them. We already allow soldiers to fight wars abroad and possibly get tortured by terrorists. In fact, this is more noble since you are fighting a war within our own borders against something that kills us. It's about saving lives, not just stuff like oil and killing others. It isn't against the idea of do no harm. Surgery does harm in order to get well. Everything has risk, even the sophisticated stem cells for diabetes.
4. When they are terminally ill, they are thinking about two things: prolonging life i.e. how can i have a few more years with my family and doing whatever they can left for humanity. Dying people can self-actualize/leave a legacy through this. They have nothing to lose and everyone has a lot to gain.
5. Pharma industry = hard since 1. it takes ages to approve drugs cz of the robust testing stages. 2. it's very easy to lose a lot of money because even if just one guy sues they can lose hundreds of millions to billions of dollars. 3. rival companies make similar drugs just for sake of being able to profit too. This policy changes that since they have test subjects now. Companies won't take forever to release drugs because they want to make sure they don't get sued.
6. It will then be less exploitative since there will be more oversight in this model. 1. pharma companies don't have to go to the third world to test their drugs to be able to speed up their profit-making. 2. Assuming these patients are desperate, they won't need to go to the third world to try get tested in a riskier setting. They don't need to take these drugs without oversight (since the policy makes it legal and supported) After all, people can be willing to do anything from spiritual dancing to praying to the Gods, that sort of thing. So they'll be willing to do the stuff above too.
7. Urgency. Time is very important. More people die from disease as time is wasted. More people are exploited by pharma companies as time is wasted because of a lack of oversight.