How does a drug or vaccine get approved: a description of clinical trials

There seems to be a lot of misunderstanding of the long and complex process that a drug or vaccine has to go through in order to be approved here in the US. Its much more involved than the company just presenting data or applying to the FDA for approval. Drugs and vaccines go through years long testing that while not perfect (see Vioxx) certainly are pretty strict.



These regulations have been in place as we know it currently since 1978 when Good Laboratory Practices, Good Clinical Practices, and Good Manufacturing Practices were established to insure that the testing practices were closely monitored and standardized to some extent.



Initially there is an R+D period called "Discovery" where the basic composition of the product is established. This can be as much as 3-4 years.



Next there is the initial or pre-clinical testing. This is where animal studies are done to establish two things:

A) The properties and reactions of the product, especially what the therapeutic value is.

B)Toxicological studies are done with the animals to see what side effects are possible, and what the safe dosages may be (note: with vaccines toxicity studies are also done with various adjuvant and vaccine combinations to see which works best..therefore anyone who claims that they can't find adjuvant safety study data is looking in the wrong place. Its such standard work that you don't find it in scientific journals but in clinical trial data available from the FDA under the freedom of information act)

This stage can be anywhere form 1-4 years.



Then comes Phase I studies. This is usually the shortest stage of the study. It has a small amount of healthy volunteers to determine the most effective dose, and with drugs it also looks at how the drug is metabolized and excreted. It also looks for acute or harmful side effects. If nothing harmful is seen, this particular phase can be as short as 6 months.



Next is Phase II. Now the clinical trial starts to get into the heavy duty part of the study. The target population for the drug or vaccine is used. The number of test subjects is much larger and the length of the study is much longer than Phase I. It also establishes dose ranges and provides both safety and efficacy studies.



Next is Phase III. This is an even longer term study to get info for dosages and labelling purposes. An even larger group of targeted individuals is used. Critical large scale efficacy and safety studies are completed. The data is compared (if applicable) with standard therapies or perhaps a placebo (note: with vaccines that usually means giving the "placebo" group the adjuvant only to establish that the vaccine is actually creating antibodies to the pathogen it protects against because if it is only giving a generic antibody response, the vaccine is next to useless against the pathogen-this is called vaccine specificity).

Combined Phases II and III can often last between 4-7 years.

After Phase III is completed the data is submitted to the FDA for regulation review. The FDA then looks through and evaluates the data. This process can take anywhere from 6 months to 2 years. The FDA scientific advisor committees then decide whether to recommend the product or not based on the scientific data. If they don't recommend the product 90% of the time the FDA will not market the product. If they do recommend it 90% of the time the FDA will allow the product to be marketed.

Here is where politics come into play in the process. Sometimes political pressure is applied to approve a drug that perhaps should not have been approved (Avandia) and SOMETIMES believe it or not a drug is rejected for political reasons because the FDA is trying to do some PR work to protect its image. For example, recently a new drug of a similar class to Vioxx was rejected by the FDA but many on the advisory committees felt that it was a pretty safe and effective drug and that the FDA was being overly cautious in an effort to not look like they were simply being a rubber stamp for the pharmaceutical industry.

Finally, there is Phase IV- what is commonly known as the post marketing phase. If a drug/vaccine is approved and marketed, it is considered to be in Phase IV clinical stage-INDEFINITELY. In order to insure safety and because clinical trials are somewhat limited in the total amount of people and data they can collect, widespread distribution and use is likely to find what if any flaws there might have been in the trials. Also if there are similar type products on the market this is also when the efficacy of the new compound is compared with the other products. It also looks to see if new labels or warnings for a new drug or vaccine are needed as well as looking to see if its beneficial economically compared to other products.

Gardasil is in this Phase. But this is NOT an experimental phase as some claim (ie, the people now getting their vaccines are NOT guinea pigs). It is merely a recognition that its possible for even perfectly run clinical trial to miss something and this allows the FDA to keep track of new products and either relabel or change recommendation of use, or even yank the the product off the market.

Is this system perfect? No. Certainly there are ways to fudge data but the regulations are pretty tight when enforced. And the FDA has the right (and often does this) to conduct surprise inspections at any time with little or no notice. These days, however the FDA has had its staff and funding cut significantly so they don't have the resources needed to ensure full compliance.
However, most manufacturers have no desire to face multimillion dollar lawsuits so many will voluntarily conform. Also, even just getting a warning letter from the FDA can so damage a companies reputation that it can permanently hurt it (yes, I know of companies who have gone out of business because of this). Also all GLP/GMP companies must by law have a independent QA department whose so job is to make sure that a company is totally compliant with FDA regulations and that also helps keep most companies honest.

Blog Agaisnt Theocracy: How the infusion of religion into education and the public hurts us scientifically

In this day an age with the line between Church and State being made dangerously thin, one of the biggest areas of danger with this is the injection of religion into the last place it belongs..science classes.
There is a push to include Creationism and Intelligent Design as competing "theories" with Evolution. One of the thing that religious fundamentalists don't seem to understand is the difference between a theory and a hypothesis. An hypothesis is an idea that is going to be tested by the scientific method to see if it is valid. A theory while it can apply to unproven data or ideas from time to time (often in an incorrect way) is an idea that has been tested by the scientific method and shown to have scientific validity. That doesn't mean its "the truth" and therefore unassailable, it means that the basic ideas in the theory have shown scientific validity, but theories also can be challenged with new data on the mechanisms of that.
Evolution is an accepted theory, it is not an unproven (and really unprovable) hypothesis like Intelligent Design or the BELIEF of creationism. Neither of these topics have a place in a science or data based/critical thinking arena.
The fundamentalists make the case that science is a "belief" that challenges religion. It is NOT a belief and is a totally separate realm from religious beliefs. Again it seems that many have forgotten the difference between opinion, belief and verifiable facts.
But it isn't just the classroom where religious beliefs hurt our science. Look at the valuable research into such topics as Stem Cells. We have the potential as the wealthiest country in the world to help fight and cure some truly awful diseases like Parkinson's as well as some horrible conditions like spinal paralysis. But because of the religious "beliefs" that a bunch of frozen cells in a petri dish are the equivalent of a human baby (read the scientific definition of life sometime to see how incorrect this "belief" really is), we are terribly hamstrung in this field. Breakthroughs are coming, but its the Europeans and other western countries who don't quite have the resources that we do.
If we can separate out the religious beliefs from the field of science there is so much we as a country can accomplish.

For the Fourth...Freedom to think for ourselves

With the approaching holiday, its time to think about the history of this country and to celebrate what the Founding Fathers accomplished. Well I have some issues with them. I think they left out something when they wrote the Declaration of Independence. They wrote that all citizens have the "Unalienable Right...to Life, Liberty, and the Pursuit of Happiness". Well somewhere in that talk of Liberty they forgot to add something about the right to listen and learn and pursue the truth without hinderance or in other words the freedom to think for ourselves and not what the government WANTS us to think.
More and more it seems like our government likes to play the terrorist card. Much like al-Quaeda its in Bush and Co's best interest to frighten us into unquestioning obdeience. Because if people stop and think about what liberties are now being denied us in the name of being "free from terror" than Bush and friends won't get ANY of the things they want. Some it seems still think for themselves but less and less these days.
And what's worse the backlash from the way Bush and Company behave is making many so paranoid that fear that the government COULD be involved in something is blinding many to the reality of things and again causing an inability to reason things through. For instance a wonderful new vaccine that was recently approved as a way to prevent cervical cancer, a novel new technology, and a scientific breakthrough -never before had it been possible to use a simple vaccine as a preventive measure against cancer. But because of fear and paranoia (and some bad pr and marketing strategies on the vaccine makers ) it became an "untested substance foisted on young girls as a way for Bushie type corporations to make money". This is far far from the truth.
So my wish for the Fourth of July is this: Freedom from fear-mongering and the freedom to think clearly and rationally again without hindrance.

Vaccine FAQ's

Vaccine FAQ’s some basic information ( a series of posts)
So some of you know me some of you don’t so let me say a few words of intro first. There is a lot of misunderstanding of basic vaccinology on DU. I understand, it’s a somewhat complex field. I have numerous years of experience working as a technician in biotechnology lab- bench work is my passion. My work experience is now considered the equivalent of having a Master’s in biotechnology. I have extensive experience in diagnostics, as well as QA/QC type regulatory experience that makes me VERY familiar with the process the FDA uses to approve vaccines and other biologics. However, I recently discovered that my real passion is for vaccine development, it’s a fascinating field for a science orientated person like me. I also had the honor of working at NIH directly underneath one of the world’s foremost experts on malaria vaccines. His passion and dedication to the field infected me with the same enthusiasm. This self same scientist even once infected himself with the malaria parasite in order to produce the needed infected red blood cells for testing. Suffice to say, it was not a pleasant experience for him. That’s the level of dedication I often found in the scientists working both at NIH and at several private biotech companies I worked for. And while many of them made very good money, none of them were really driven by money or greed. It was the passion for science and the desire to help improve mankind that drives the vast majority. The purpose of this post will be to inform all of established scientific facts about this misunderstood field. I am not trying to influence anybody’s personal opinions, merely to inform. All this information is easily found in basic biology, and/or immunology text books. For those who wish to fact check or just learn more, instead of just trying to click on a link to a short article on the internet I would instead go to the library and read one of these types of textbooks. There are many on the subject. Now on to the basic biology of vaccines:
1) There are two basic types of vaccines: virus (attenuated, live etc) that are made directly with the antigen (i.e. virus) and recombinants which are made with small bits of the virus…bits that through extensive testing are determined to be the most likely to provoke the most useful antibody response. Recombinants are considered to be the wave of the future because since its only small bits and not actual virus they are less likely to have side effects.
2) A vaccine is neither a chemical or drug but something entirely different. It is designed to train the immune system into making antigen specific antibodies . Once the vaccine enters the bloodstream it is attacked by the immune system. A good vaccine provokes enough of a response that the immune system will remember it on encountering it again, but not enough that they person actually get sick. Sometimes that happens and people have side effects similar to the actual disease. Sometimes it takes more than one exposure so that the immune system remembers it. Those vaccines require boosters. Vaccines DO NOT linger in the body the way a chemical does. Once the immune system is done “attacking” the vaccine, the now defunct complex of antibody-vaccine(waste product) is removed from the body by the spleen, the same way the body removes the killed virus/bacteria/pathogen of any infection we pick up.
3) Adjuvants. This is actually a technology that has been quite widely accepted and used for years. Some of them have very frightening complex chemical names. In truth, they are small molecules that are attached to the vaccines to “boost” the effect of the vaccine. A good adjuvant can make the need for boosters much less. Some adjuvants work better than others with certain vaccines. A lot of pre-clinical trial work in vaccine R+D is determining what adjuvant works best with a particular vaccine. Since it is attached (or conjugated is the technical term) directly to the vaccine, like the vaccine it is bound tightly in the antibody-vaccine complex which is eventually taken out of the system within a short period of time by the spleen.
4) Side effects- all vaccines have side effects. The thing with vaccines is that they work really really well. However since they stimulate the immune system, autoimmune problems can sometimes result from a vaccine. And sometimes people have undiscovered allergies to some of the compounds and that can cause difficulties as well. As mentioned above sometimes somebody just can’t handle some of the very potent vaccines (the live virus ones usually) and they get sick. Mostly its minor, flu like symptoms aches etc, minor fevers. Sometimes for unknown reasons the reactions are far more severe. No one can predict how individuals are going to react to a vaccine. However the serious reactions are very very small in terms of percentages of overall population. Cold comfort perhaps to the few individuals that have suffered a bad reaction but true none the less. The golden rule on vaccines are this: only healthy individuals are vaccinated. Anything less than healthy is asking for trouble. In fact, it is my OPINION that many of the serious side effects that individuals suffer are due to previously undetected underlying health issues. But that’s only speculation on my part.
Now some of the popular “myths” about vaccines:
1) Vaccines cause autism due to mercury in them. There are two points here a) the scientific community in general does not believe there is any link between vaccines and autism (for various reasons I won’t go into here). This is a scientific consensus. Are there some in the community who believe there is a link? Sure. But the vast majority are skeptical. The mercury in the vaccines was part of the preservative called thimerosol. Preservatives are necessary to keep the vaccines potent enough for storage for a certain amount of time. Thimerosol has been removed from almost all vaccines with the exception of flu vaccines. However thimerosol free flu vaccines are available as well.
My old boss was one who wouldn’t even have thimerosol in the lab for use in non-vaccine related buffers. It is therefore now a non-issue
2) adjuvants are unsafe neurotoxins. Untrue as mentioned before they are an established technology. Before any vaccine+adjuvant gets approved for clinical trials they undergo YEARS of animal testing (usually in both mice, rats, rabbits and monkeys). And its not a few animals but hundreds for each candidate vaccine. Both safety (toxicity) and efficacy (potency) studies are conducted in these animal studies.
3) Vaccines are rushed onto the market before safety testing is finished. For the most part, wrong. Besides the years of animal studies done prior to clinical studies, the clinical trials themselves (usually conducted under very strict regs called Good Laboratory Practices and/or Good Manufacturing Practices) are long (usually in the 10 year area) where again both safety and efficiency are checked. Clinical trials are long enough to establish safety. Sometimes though when the data indicates a problem with the vaccine the study will be ended and the candidate vaccine withdrawn. This happens on a fairly regular basis but usually is not reported in the MSM. Some non-FDA approved vaccines have been rushed onto the market for use by the government from time to time. The anthrax vaccine of the mid to late 90’s is an example of this. Non-FDA approved vaccines are used in private industry for people doing experimental work. But all the vaccines used in the general population and distributed by pharmaceutical companies/biotech firms MUST be FDA approved and therefore must go through the GLP compliant clinical trials, after having extensive pre clinical testing.
4) Vaccines are huge money makers for Pharmaceuticals. Incorrect. Vaccine development and particularly production have such high costs of development and don’t have a large profit margin that many biotech’s and pharma’s do not feel the rewards are worth the risks of investing in a long drawn out research project. The UN is constantly begging Pharmas to invest more in the manufacturing of vaccines as there are constant shortages for them in the third world . Polio might be extinct in this country but it is a HUGE problem in Africa and there is not nearly enough vaccine to go around. In fact most vaccines are made by companies in Europe because laws and regs there with the funding is set up so that making the vaccines is not as expensive. The reason why there has been flu vaccine shortages in the past few years is because only 2 companies make it, and one had production issues that made them not be able to make any.
That’s the basics. Are there problems in the industry. Absolutely. I and other sensible techs/scientists often know what companies are more profit minded than science minded and avoid them like the plague (Pfizer has a real bad reputation in the professional community for example). Are there dishonest scientists? Sure and I have encountered them and fought them to the detriment of my career. Most scientists are more motivated by ego and reputation than greed though. The ability to publish and professional reputations are the big motivations for scientists . Some will massage or manipulate data to protect their intellectual reputations. Very few are motivated by simple greed although there are a few. But the vast majority of scientists and techs are dedicated and hard working and motivated to improving this world. That’s why the vast majority are registered democrats….

Note to science geeks: I am aware that I have very much simplified some very complex science in an effort to communicate and inform

My health issues:Colonoscopy and endoscopy of stomach

So last Friday I had both of these procedures done to see if they can pin down exactly what is wrong with me. By far the worst part was the night before. I had to drink 6 glasses of ginger ale spiked with a phospho soda to clean me out. Ugh. Not only was the drink nasty (and the first 3 glasses did not stay down) but the "cleansing" was not exactly pleasant. For those of you who have heard of the spa treatment called "calonics" thats exactly what that is. A voluntary cleansing. Ugh. Although it did clean me out and I had a couple of days free from the stomach/intestinal problems that had been plaguing me. They seem to be back so it was only a temporary relief it seems. Not something worth doing again if you ask me. Anyway the procedure itself wasn't that bad. I remember watching my doctor gown up in the procedure room and next thing I know I am stirring in bed wondering why I wasn't in my own bed...I didn't even notice them add the sedative to my iv. Anyway, the only noticeable things from the procedure was a bit of gastritus in the stomach. They did a biopsy on that and are testing for H.pylori, the bacteria associated with ulcers. Its possible that I have this bacteria and its irritating the stomach walls which could account for the lack of appetite and the loss of weight AND possibly the vomiting. Its possible then that I caught what might have been the beginning of an ulcer. The doctor is also checking to see if I have IBS (irritable bowel syndrome) something I have suspected for years. The last thing they are checking for is possible Celiac's disease. This would be incredibly ironic if true. Celiac's disease means you can't digest any kind of gluten like wheat rice rye or corn. Yes, the infamous wheat gluten! There is definitely a tinfoil hat part of me that is looking at this being really bad just in the last month or so and wondering! It could be very ironic that I thought I needed to protect my kitties from wheat gluten and it may turn out to be more of a "threat" to me. Ah well. It will be two weeks before I get my results. I would bitch more but I do realize that since they are probably doing a bacterial culture that does take some time. More and more something a friend said to me recently seems to be the case. He said "it seems like since they don't really have a clue what's truly causing everything, the doctors are just going to settle for treating the symptoms". That does seem to be the case. I go to my hematologist on Wednesday and hopefully he will finally green light me going back on my meds for my ET. I think that will really help some....

My health issues

So I keep trying to post info on DU, without soliciting advice, but there is at least one poster on that site that keeps messing me up and getting my threads locked so I will post my stories here.
First of all for the last couple of years I have had a couple of chronic conditions that have been pretty well controlled. One is sleep apnea. Through medications and a CPAP that is under control. The other condition is a rare blood disorder called Essential Thrombocythemia (ET for short). Its part of a group of disorders called Myeloproliferative Disorders (MPD's). Basically its a group of disorders in which the bone marrow makes too much of a particular type of blood cell. In my case, its platelets, which are the cells involved in clotting. Not only does my bone marrow make too many, but they are often made wrong (too big, incorrect structure ect) which can lead to both bleeding and clotting issues. A normal count on platelets runs between 100-400. On meds I am about 450ish. I start feeling unwell at about 700ish. To put things in real perspective on my illness my last count was an all time high of about 974! When it gets this high I get fatigue and headaches and tingling in hands and feet.
A couple weeks ago I started feeling ill. At first I thought it just was a stomach bug but it got worse. Crippling fatigue to the point now that all I can do is work on my computer in bed, just getting up and walking around is exhausting. Trying to run errands is difficult. And my job in the lab..impossible. I have been on indefinite (unpaid) leave for almost 3 weeks. Maybe I could work, but I don't want to push it and I have noticed that I seem to be good for about 2 hours before I wear out and then I pay for it later. Anyway, also I noticed it becoming harder for me to eat and then when I would eat a regular meal, I would vomit it up several hours later. For weeks I had noticed diminished appetite but had attributed that to stress. Now it is much worse and I noticed pain in my left side as well. My first thought is, my ET which I have been off meds for since last July is flaring up, simply going back on my meds (hydroxyurea) will solve it. Called my hem. Had a quick bloodwork exam. The bloodwork at that point was a little elevated (platelets at 630) but aside from the soreness in side there was nothing visibly wrong. My hem sent me for a CT scan to look at my spleen since enlarged spleen could have accounted for the symptoms. Nope. Negative. I went to my GP who had me do some bloodwork. Well my complete bloodwork showed everything is going crazy! Thats where I got the 974 platelet count along with high wbc's, high hemoglobin, high hematocrit, borderline high blood sugar, high blood pressure! My gp has simply given me meds to treat certain symptoms and referred me back to my hematologist and to a GI specialist. After confirming my blood counts with another test (and sitting there literally with his head in his hands in confusion) he also is waiting for my GI results. Finally after talking to my GI specialist he says he needs to look at both my stomach and large intestine. So on Friday I go to get not only a colonoscopy but and endoscopy of my stomach as well. In fact after 8am tomorrow morning (Thursday April 26th) I must start fasting in prep.You do not want to know what I need to do Thursday night to clean myself out in preparation...yuck! And I thought drinking banana smoothie flavored barium was bad...I will update my blog as things go on.

Scientific Bullying

So I recently posted about my experience at NIH. One of the problems there was that governmental employees felt safe and felt like they could get away with anything and therefore felt free to be lazy and dishonest because they "knew" there was no consequences for bad behavior. In order to get anything accomplished my supervisor at NIH had to use aggressive techniques, so aggressive that he was labelled "a bully". I knew he was exceedingly intolerant of bullshit. As a friend of mine who incidentally had followed him up here from Australia said that as long as "you were intelligent, honest, worked hard, and did your job competently you would not have a problem with Allan". In fact because he got tired of banging heads with idiots he brought me in to circumvent them. Which would have maybe worked if some of them hadn't had the ear of higher ups. I think it hurt that while most of the nasties were life long NIH employees, despite being tenured, Allan had only been there for 6 years. That probably didn't help. There were also rumors that he and others in the dept and NIH lost a "harassment" lawsuit about improperly hounding someone into quitting (sound familiar?). I have a feeling it was another less than honest researcher and Allan was doing what he had to get rid of them.
Up until then I always thought that a bully was a bully and it was cut and dry. Its not. I also have heard stories of true bullies who are nasty and vengeful even after people leave their positions. From what I can tell, especially in academia, bullying is very common, and at least in my case a necessary evil. I would be very interested to hear from anyone who has been on either end of a bullying situation.