Hello, we're going to jump on the highway and so it's time to start the engines, but I'm not going to talk about any medicine. I'm going to take you on the trip and as you know the trips begin at point A and gets to point B and sometime the road is straight and sometimes the road wiggles and jiggles. And I am going to ask you to travel along that road with me to see in fact how we get to medicines.

I'm going to give you an overview of pharmaceutical development. How medications in fact are created, not the specific medications called antihistamines, but basically how are medications brought to market. So this will be the road that we will travel. How does the system work? What are the methods and what are the systems and the processes? Out of curiosity, how may of you have ever participated in clinical research? And of those of you who have not, how many of you are considering doing it?

I want to include all the people here, so that leaves some people who have neither participated or are thinking of participating. But, hopefully this review will meaningful to you as well. We're going to be looking at again what is clinical research? Clinical research has some objectives. It has objectives to discover knowledge that can be generalized. To increase understanding of human biology and obviously for those of us in medicine to develop measures to improve health. Those are the objectives.

But we don't just do it, we have to have a set of rules and regulations. And we have to have certainly some ethical considerations. And I'd like to spend a few minutes on this because at the heart we're physicians and we care for people. And if we do things in clinical research which we have to do with people, we have to do them in an ethical way.

This paper that was released in JAMA last year talks about at least 7 measures and 7 considerations that we have to have. The first is social or scientific value, if we're going to do clinical research it has to have value. We have limited resources in terms of money and in terms of time and in terms of people. So we have to do something that is valuable. We have to do it with a social context and it can't be done for just one person, it 's supposed to have generalized knowledge. Remember one of the objectives of why we are doing clinical research, not only does it have to have information on more than one person it has to be shared with the medical community. So if you and I do stuff that's valuable, we should publish it and let it be known what it mattered.

We have to do it in a scientific way, so again our goal is to improve health. To do it either diagnostically or therapeutically, we have to do ethically social or scientific valuable projects. Secondly, we have to do projects which are scientifically valid. It has to have appropriate study design, we have to include the right number of patients. We have to have enough power to make meaningful conclusions. We have to be able to analyze the data and collect it appropriately because it has to have scientific validity to be ethical. Thirdly it has to have fair subject selection. The world has had some awful experiences. We all know about the Nazi's experimenting on people with the concentration camps, doing experiments on people who were clearly vulnerable. There have been vulnerable studies done on people in prison, or people who are challenged mentally. There is certainly the Tuskegee experience on syphilis. There have been lots of really poorly done, immoral kinds of acts on a clinical research basis.
So we have to have fair subject selection, conclusion criteria, exclusion criteria, which really are not culturally, racially, religiously, age dependent. Appropriate fair subject selection. Fourthly, we have to have a favorable risk benefit ratio to make it ethically.

The first rule of medicine is prima non nocera, first of all do no harm, we shouldn't do things that are at risk for the patient. There is a second principal called the beneficence principal, we should do things that are not harmful but in fact are good for people. So we look at studies, what are the risks and what are the benefits? Both socially and individually, what are the risks and what are the benefits? Fifthly, we have to have independent review, patients have vested interests, patients may be doing the study for economic purposes or to make somebody happy. Certainly those of us in clinical research also have conflict of interest. Economic conflict of interest, if we do more patients, we get more money. We have maybe career conflicts of interest, the better I do the more I'll be promoted in my medical school. So we have to do things in fact that have an independent review so we have some social amount of accountability so these conflicts of interest are not taken into account.

Informed consent, the patient has to be free to do these studies. This is not something you can gather some people to do, these are volunteers. Clinical research is voluntary. Patients can do it or not do it and they can stop when they want. Informed consent allows that and respect for potential and enrolled projects. So that before the project, during the project, and at the end of the project the patient is respected. We care for them in fact secrecy is a big part of the fact after the study is over so we have to have respect. Without these ethical clinical considerations, clinical research cannot be done appropriately. Let's turn now from the background of clinical research to how is pharmacologic research done. The industry conducts drug development research, and it does it in concert with the FDA and they have to have specific requirements and involvements. And it's not cheap, looking at some of the numbers, it averages about 6 billion dollars a year now worldwide. Over half of that is spent in the United States. The average cost of developing one drug, uno drug, half a billion dollars. And why do we have to hurry and get it done, why do they press us to get enrollment and have the documentation done and answer the queries? Because every day of delay costs over a million dollars, so it's a very expensive process for the industry. It's also a high risk undertaking in the number of years. It used to be 10 years then 12 years and now it's up to 15 years in some cases from drug discovery to market. And it's not like you pick on a project and you just move forward to 12 years. They come up with at least 5 thousand compounds which ultimately will result in one that makes it to market. And the one that goes into the clinical phase will only be one of 5 that actually makes it to market. So it's a very narrow window in terms of those which are discovered and those which ultimately are available market. But this is not a random system, the drug discovery system, the drug clinical trials, the way that medicines become available has a very rigorous system and if we follow the road signs, if we follow the guideposts, it can be done.

It's a logical stepwise process that's been developed over the last 50 years. For evaluation of safety and efficacy of an NCE, we're going to see a lot of acronyms and this is one of them A new chemical entity in support of regulatory or marketing application for registration as a therapeutic product. Ultimately you should leave this as knowing it was a road that we traveled but with a clear beginning and it had a stepwise process. This is the staging and these are the phases of the pre clinical, the IND, the NDA and the post marketing. We are going to go through each one of these steps so you have a clear picture so the time you leave, how in fact did this process begin and how did it end? And that we now have medications we can write for.

We begin at the beginning where NCE's new chemical entities are discovered. And new chemical entities go into a pre clinical research process. Pre clinical from direct discovery of the synthesis of the new chemical entity, the patent begins. So it takes from the time of discovery, you now file your patent and you have 20 years to get what you're going to get if you're a pharmaceutical company. What happens during the pre clinical time, it's primarily safety, toxicology both in vitro in tissues, in cells and also in vivo, in animals. They look specifically for carcinogenicity in both short term studies in high doses and in long term studies. And in the long-term studies they go into the clinical phase as well. There is also a lot of pharmacology done again using animal models, anywhere from rodent models through dogs through monkey's and this is looking at bio availability, potency, dose response, efficacy, drug interactions. And it takes a couple of years to get finished this drug phase called pre clinical. And only one of a thousand compounds will ultimately make it into the next phase. A tremendously narrow window and the patent life is already cooking. After the pre clinical work is done, they have all the toxicology and they have all the safety from the tissue and they have the pharmacology from animal models they submit it to the FDA for the next one of the acronyms called the IND. The investigational new drug application, and this then becomes a drug which is to be further studied and allows that drug to not only be in the local community but to be shipped to interstate and it's required to have the IND approval to go on with human trials. It's for all new drugs, it's for new dosage forms, so if you're going from tablet to liquid, if your going from new indication for asthma now moving to rhinitis or vise versa, you have to have an IND. And then we begin phase one, and phase one is the first dose in humans. Small numbers basically healthy people. Less than 100 not with disease, healthy volunteers. The primary objective is always safety the FDA lives on principle number one, safety. Principal number two, called safety and principal number three called safety. During that first initial look in human beings, they look at pharmacology, the pharmacogenetics, the pharmacodynamics, and they look at ADME, ADME stands for absorption, distribution, metabolism and excretion. How does the medicine get in and get out? Onset of activity, duration of activity in human beings. Typically these are open label, usually a single dose, or a single dose then given in multiple increments. Low dose, medium dose, high dose and also then a little later on short term multiple dose studies to see again what is the toxicity, what is the safety profile in these normal human beings. And out of those remember, one out of a thousand that cam through, 30% more do not pass through phase one without being excluded. And the patent life has gotten shorter now, it amounts to about 85%, I think it was.

The next phase is phase two, phase two now begins people with the targeted disease. Be it rhinits, be it asthma, be it diabetes, and again small numbers of patients who are generally healthy with the exception of having that targeted disease. Determination of safety and now because the patients have the disease to move to, does it work, does it do anything of value in altering the patients clinical condition. And they do it within a selected dose range which is based on the safety data. Usually there are dose ranging studies to get a sense of gee this dose doesn't do anything and this dose, and this dose which is the high dose doesn't do anything more than the medium dose. So they try to narrow what the ultimate dose will be and select an optimum dose. These are generally short term studies, double blind placebo controlled, sometimes they are dose comparison studies, low dose, medium dose and high dose. And another third of the studies will show if this medicine was not of value. So again we lost a third in phase one, we lost another third in phase two, and the patent life is no even shorter.

There are a number of participants in this clinical development process. Certainly the patients are one, but there are also a number of important agencies and organizations. The FDA, food and drug administration, that's key one, we'll come back to that in a second, pharmaceutical industry or the drug discovery people, there are clinical investigators like you and me, there are organizations that act as facilitators to these projects. Some are called CRO's, contract research organization's, or SMO's , site management organization's. And it is up to this whole network to ultimately design the study to implement it, to analyze the data to prepare the report. And ultimately to help us get some education about whether it was valued. Now one of the organizations, the FDA has been maligned and the FDA as you know is a government agency and I like this law, you've heard of Murphy's Law, for every action there is an equal an opposite government reaction. I think that's true in some place, I don't think it's true of the FDA, I've had the opportunity for several years to serve as a member of the Pulmonary Allergy Advisory Board, and my experience with the FDA is constituted by a bunch of very hard working, very sincere, very beleaguered group of people who are in large measure underpaid for what they get. They get beaten up by Congress, they get beaten up by consumers, they get beaten up by industry, but they are very sincere hard working folk. And I think we are very fortunate to have an organization that has the structure that is willing to maintain doing what they do to in a matter of fact find an make manufacturers show that their drug products passed the tests of safety and efficacy. They do it in different ways, they do it based on needs of the general community and the acute drugs like antibiotics, they typically do not need large populations of studies for long time lines. For chronic diseases such as we deal with, like rhinitis and sinusitis, and asthma and cholinergic urticaria, they will typically take and need more numbers of patients because they are going to be on them longer, and need longer studies to make sure there is no toxicity that's accumulative. So there is a real need to have an outside source that requires you meet the standard of public health and public safety. In addition to the FDA, we talked about the investigators contributing, the investigators are not people who drop by and say, "I'd like to do that". They have to be qualified, to be an investigator, to be responsible, you have to have education, you have to have training, you have to have experience, and you have to say not only do I have it, but I'm going to do it. It's not enough to say what you are, you gotta do it, you gotta be it. You have to come to a contractional basis with the FDA by signing this form 1572 which basically says, I am responsible for what happens. What happens in my office, what happens with my patients, what happens with my clinical coordinators. Ultimately the buck stops with me, I'm the responsible person and I will do it in a meaningful way and I'll do it according to good clinical practices. GCP's another one of those acronyms, but we'll come back to that.
The industry has criteria for the investigators, they require again that you be trained, that I be trained. That not only you trained and willing to do it, but that you are willing to spend the time that it takes. You have to have an interest in the research, and time to conduct the study. You can't do it on the wing.

While I have some space between 2:00 and 2:15, I don't think I have any patients scheduled, I think I'll do some clinical research now. It really requires designated time and space, you have to have access to sufficient numbers of patients, adequate support from people who are going to assist you in these projects, clinical coordinators as they are referred to, access to a properly constituted IRB which we will talk about in a second and accessibility to study monitors who are always reviewing and reviewing. This is a multi-tiered system for monitoring. If you haven't participated in clinical research, if you're interested in participating in more, it's not that difficult to get on the list. You contact you're sales rep, and you say to them, I really think I would like to be a clinical investigator. I have a real interest in it, I'm going to make the time, I'm going to make the space. I'm going to also make sure I have people to help me do that. An in addition, I am not only interested in doing projects referring to me. I happen to have an ideal for a project. You can have a study ideal and bring it to the sales rep and they will contact the research department of that particular research organization, and presumably the research organization will call you back. It is then facilitated by your sales rep.

After we finish this phase one and phase two, we also have phase three and most of us have been mostly involved in phase three studies. Of those phase three studies again are patients with the disease, and larger studies of up to 5,000 patients, per particular agent. And the objective is now to really define well, safety and efficacy. Closely monitored projects, and we need ultimately to decide what is the therapeutic ratio. What is the risk and what is the benefit? What are the adverse events that are associated with this particular compound. Also in addition to that targeted population which was pretty healthy, are not otherwise in the phase two studies because we are dealing with a much larger populations, we may now also have people who have comorbidities, they may have some hypertension, they may have some poor renal function, they may have some liver function studies that are abnormal. In phase three, we look at the elderly, we also look in pediatrics in phase three. So we're looking, expanding the opportunity for patients to get access to this clinical compound. The study designs are almost always placebo controlled, they are almost always double-blind, neither you, the patient or the investigator knows which is the active compound. There are often multiple endpoints, symptoms, plus some objective parameters. And they are almost always multi-centered, the larger studies. And even though we lost thirty percent in phase one and even though we lost thirty percent in phase two, we loose another five to ten percent of the compounds in phase three. Either for too much abnormalities in AE's, or not enough clinical efficacy.

Another contributor to this process along with the investigator and along with the FDA and along with the CRO's and along with industry are the patients. And patients are very precious, patients are to be cherished, these are volunteers who are making a contribution to help us secure knowledge which may benefit them directly. And some patients do participate clearly because of direct gain from them. But most know that it may not benefit them directly, so they know we need new means to secure knowledge and so they put themselves at risk. And for that reason we have to have great respect and we are not ever going to exploit them. We require that the patients be treated with respect, while they contribute to social good. Another member of the team and the ones who really oversee a lot of the GCP's are what are known as IRB's, institutional review boards or institutional experimentation committees. And they have the responsibility to making sure that we in fact can carry out the clinical research with these guidelines of good clinical practice. To make sure that the study is done ethically, these are human experimentation committee's essentially to make sure we're not treating poorly our patient subjects. And to make sure that the data collected is of high quality. Ultimately poor data in gives you no information out. We have to have quality data. Documentation includes almost everything. If it can be written down, it should be. And that's whether it is on the informed consent, on the protocol, on the FDA 1572, on your CV related to the laboratory studies, on your EKG's, related to when the drug comes in and the drug goes out. Related to the companion report forms the patients filled out. Or the adverse event forms and whether it was something you could attribute or not attribute to a particular agent. Everything has to be documented, this is part of the good clinical practice guideline.

We've now moved then from pre clinical through the IND submission, through phases 1 thru 3, again during phases 1,2 & 3 there is still some long-term animal testing as well as the clinical testing. And after all this is collected, then the NDA is submitted. The NDA is submitted to the FDA. And the NDA is the new drug application and this takes another year to be evaluated. There are lots of paper's and these include the chemistry and the manufacturing information on how it's going to be created in a particular laboratory or in a particular system. And also a summary of all the pre clinical data. They look at all the case report forms, they look at all the adverse events, and they decide is this enough, because if they don't think it's enough they can ask during that NDA review process, to the company, the industry, the investigators. This way they can go back and do more create more information. Because ultimately they want to make sure as they review that there is enough information on a safety and efficacy standpoint for approval. So they review the priority of this particular compound and ask, is it really critical we have it. Is this a "me too" drug or is this going to be life saving medication. Is this going to make a major change in aids to clinical care.

This is responded to by members of the FDA review teams, lots of teams, and again they can ask for more updates as they are going along. They ultimately will bring this data to a panel. An outside panel, an advisory panel, such as the pulmonary advisory panel or the bureau of biotics have a lot of vaccines. And then they will give an action letter and the action letter may say no it's not approved or yes it's approved or it's approvable, but we need more information. And this is not something that has been going on since the beginning of time, if you look back only a hundred years, there was no regulation of drugs. You could sell snake oil for pretty much anything. In 1906 the only thing they couldn't do was remove something if it was mislabeled. So at that point you were innocent unless proven guilty. It was ok unless, they could prove it was abnormal. About the mid-1930's they said we gotta have a little bit more accountability here, so they in 1938 passed a law that said, no you are guilty until proven innocent, at least on the safety side. It had to be safe before it was approved. And before 1938,anything which was commercially available like ephedrine for example, was considered safe and effective and so it continues without prescription and without regulation. In 1962, less than 40 years ago, it was only then they said you are---guilty unless proven innocent by an efficacy standard. So it's really only the last 40 years time we've all been around that we have medications either the antibiotics or vaccines, or antihistamines or anti-asthma medications which have required both the standards of regulation and efficacy for approval.

So we got through the NDA, during the NDA there may have been some additional studies going on requested specifically by the agency or generated specifically by the company. These are called phase four studies and phase four studies often have along term safety component to them, they also look for drug interaction issues, special disease states or populations again like pediatrics, which may not have been done in phase three. They will do drug comparisons, is my mouse trap better than your mouse trap? And they will look at some of the pharmacoeconmics, they have to do with making managed care happy. My good friend Richard Mabry taught me a new line about managed care. Managed care is, I didn't bring it with me rich, it's a great line hold it, this is a Richard Mabryism, "You've managed somehow, we don't care ". But they do care about money and so pharmacoeconomics is important and sometimes those phase four studies require pharmacoeconomics. There is also after the NDA has approved it and called it post surveillance information. They may get it and require additional data. We know for example that many of the intranasal steroids have been around for a long time, but they require now growth studies on the intra nasal steroids and on the inhaled studies. Those would be what we call post marketing surveillance studies. They also always require continued follow up of safety, initially more often, but ultimately forever with regard to serious and any unexpected side effects they need to know. So it's an ongoing process of surveillance. There is also something called phase five research, now phase five research has been called different things, not a formal title and different companies call it anything from medical school grants to they may have their own system of asking people to do these specific studies. But may of them are investigator initiated studies, you come up with an ideal and say I can learn a little bit more from your pharmacology or I can do a clinical study with some objective parameters that will in fact underscore or define further how affective your agent is. There may be some educational pieces that we can do with your agent, that will add benefit perhaps to the population and to you. It's not for registration or labeling change, it is additional data and we call them phase five studies.

And lastly there are two additional NDA types, which you are probably familiar with intuitively but, these have formal names called the supplemental NDA, supplemental new drug application. To change and approve a drug for example, if you're going to change it from an oral to an intranasal or from an intranasal to an inhaled, or you're changing the dose form, or from a tablet to a capsule or from a capsule to a liquid, or changing the prescription from a BID to once a day Or developing a new indication from the same medication. Not only is it good for rhinitis but, it's also good for non-allergic rhinitis. For adding something different to the packaging insert, which was required to be written in very specific terms by the FDA, now had to take out the food affect that might be there. So that was supplemental NDA. Abbreviated NDA's we're going to see even more often and that's when changing quote, " registered drugs to generic drugs". And this requires complete chemistry to make sure that it's pretty much the same stuff. They have to document how they are going to manufacture it, to show in fact some toxicology and some clinical testing, but not to the same degree. And so we now have NDA's.

And ultimately then, what I've tried to present to you is the fact that there is a very well organized system for drug development. To get to drug development you have to do pre clinical phase one, phase two, phase three, the FDA review, and it takes 10, 12, 15 years. There is an increased cost as time has gone on. It's gone from what was 50 million dollars to what is about 500 million dollars. There is a drop out rate, why 1 in 5,000 initially and when it gets to the human beings about 1 in 5. We lost some in phase 1, phase 2, phase 3, and even during the NDA. And after all of this we lose a lot of patent time. The patent life began at the beginning of the new chemical entity and it's really not available for the commercial use until 10 or 15 years of a 20-year patent life. And so in summary, drug development is a long and costly process that takes 12 to 15 years costs over a half of billion dollars. Drug development is associated with high risk, 1 in 5,000 synthesized reaches market, 1 in 5 tested human beings reaches market, 3 out of 10 that reaches market only a third actually recover the development cost. But ultimately this is what we are looking for, successful medications that favorably affect patient well-being. The objectives of clinical research, discover knowledge that can be generalized to increase understanding of human biology, develop measures to improve health. This is one of the most recent studies I've saw reported. Clinical researchers have discovered that chocolate produces some of the same reactions in the brain as marijuana. The researchers have discovered other similarities between the two but can not remember what they are. There is a number of us that are working on that, stay tuned we'll give you the report next year.

Thank you very much

Q&A

Q: Eli, how would you see if we changed the length of the patent protection affecting the cost of the pharmaceuticals?

A: Well who is the we that's going to change?, I would think that would have to be legislated and I don't know what's going to happen with that. That really reflects back on and let me just digress for a second, the issue of driving antihistamines from an Rx product to an OTC product. If we take patents and change the whole system of patents, I think it would be catastrophic. You know if you change it for antihistamines and people have a patent life on an antihistamine and somehow they've lost they're patent life it's been driven over the counter, same thing could be done with non-medicines, and so the whole capitalistic system of you invent it, you could make some money on it, you worked to do that, you were creative enough, I think would be disruptive. I don't know how you would change the length of patent time, it seems to me to be legislative unless you have a better ideal, I can't quite see who asked the question. Do you have a better idea? I was talking the other way, Eli. A 25 year patent life, they have a better amortization of recovering their costs. John Winder, it is, yes, John, I can't tell you how that would happen except legislatively. Do you have a better ideal or not. No I don't.

Q: Hi, Dr. Meltzer, quick question, you spoke about the post marketing surveillance aspect in respect to the safety issues, during the drug development process, I thought I would touch upon one other aspect which is the spontaneous reporting that goes on during the post marketing surveillance component and I really wanted to touch upon you're experience having worked for the FDA and specifically we know that the clinical trial data really has a large impact on how the FDA does business, but I was just curious, there is a large volume of sort of spontaneous reports, literature reports, regulatory authority reports that occur, after the post marketing phase, I just wanted to know having worked for the FDA, how much impact does this large volume reports have and how do you feel about sort of the way that they are handled?

A: I think it's critical. How many of you are familiar with MedWatch? MedWatch is one of the ways that we all can out of our office, submit an abnormal experience. I think the whole business with terfenadine was developed with post marketing surveillance. It had been available to millions of people, and only when individuals wrote in, I'm having some people with arrhythmia, I had a fatality, those kinds of things were put together and ultimately I ended up having clear understanding about abnormalities in the reaction potential and repolarization problem. So yes, post surveillance when you're doing clinical trials, you're talking about a small subset of the world. Thousand, five thousand people, when you take a look at something a little unusual, you don't see that until it's out and available. So critically it's our responsibility to send in those reports, if you have something and they will collect them. And I again believe that safety is they're heart and soul that they will look at them and follow up on them.

Q: One quick follow up on that? I believe that the way the European countries are handling that are through the PSUR's periodic safety reports that you sort of touched upon. In the US, I believe that we send our spontaneous reports right to the FDA and there is always a curiosity I think for many of us in the pharmaceutical world in terms of what exactly happens to those reports once they hit the FDA and how are they a priority? I don't know if you can answer that question?

A: I cannot.

Q: Actually I might be able to help answer that question there is an independent contractor.