Hello. It is Week 2 in NURS615, and we are going to talk about Drug Development: Concept to Market.
Drug development is dependent on several factors like medical need, disease prevalence, likelihood of success. In fact, only 1 in every 1000 ideas for drugs are selected for progression to actually use in patient care.
The success rate of different kinds of drugs varies; 20% of cardiovascular drugs are successful in actually being developed; 5%–8% of oncology and CNS drugs are successful for several reasons. A lot of times they are pulled because after the first or second phase of clinical trials there are problems, so there are multiple reasons why they don’t always make it to market. The drugs must be obviously safe and efficacious, and they must be proven to be effective across racial and ethnic groups and several age points.
There are several chemical starting points. Drugs can be derived from plants, such as digoxin which originally came from the foxglove plant. Some of our drugs have their origins from animals such as some insulin. Now it is all synthetic, but originally we did get insulin from animal sources. There are some human components we can get drugs from, but by and large most components are often chemically synthesized in terms of how we get our drugs.
This slide just talks about how animal sources have been used in the past, which we mentioned.
Synthetically, as we talked about, most drugs used today are synthetic chemical compounds, and some of them can be wholly synthetic and then some can be partially synthetic.
Now we are going to switch gears to talk about the clinical trial. A preclinical trial is the first step in discovery of whether a potential drug this possible. They are designed to provide just basic safety data, bioavailability, pharmacokinetic and just efficacy data about the drug. We also can learn some reproduction toxicology data from the preclinical trials and also some carcinogenic testing from these trials as well.
If everything is okay with preclinical trials, then the drug will progress to Phase I, which is the first administration of the drug to human healthy volunteers. In preclinical trials, those are usually done on some type of animal. In Phase I we are progressing to human healthy volunteers. If it is a cardiovascular drug, maybe say hypertension, in Phase I the drug is not given to patients with hypertension. It is actually given to healthy volunteers to see how they will react with the drug.
The purpose of Phase I testing is to evaluate safety, tolerability, pharmacodynamics in a healthy human (because remember we haven’t evaluated any of that data in humans thus far) so we are looking at the effect of the drug on heart rate, blood pressure, EKG data and that sort of thing.
In Phase I testing, researchers and drug companies must complete an investigation New Drug Application, which summarizes all of the Phase I data. If there are any irregularities, the trial will be stopped. If they have poor half-life or poor bioavailability. Phase I studies do start with very low sub pharmacological doses and then are escalated, assuming that the safety data is all there.
The cost of Phase I testing is astronomical; $500,000 to $1.5 million, and this is just Phase I. You can see why many drugs are so expensive when they come out first launched, because there is a lot of money behind the research and development.
Now, Phase II we are doing the efficacy and safety testing on the actual target population. If we go back to our hypertension example, we are going to actually test the drugs in patients with hypertension. This is the kind of proof of concept. Does it do what we want it to do? We have proved that it is safe in humans. Now does it actually lower blood pressure? It is limited to a single maximal tolerated dose, so this is where we kind of push the dose and see if it works. We do test several dose levels, and this is where you get the information where the starting dose is recommended, and then if it doesn’t work you go to this dose. That is where that kind of information is obtained.
During Phase II you are allowed to progress to Phase III if you have the data to say the drug is efficacious relative to leading competitors. You’ve got the safety profile data there, probability of technical and regulatory success, so you can say, ‘Here are our numbers. We are very likely to be successful in the treatment of hypertension.’ You have the money to produce the drug like market share, price, and reimbursement, all of those things, so this is where you kind of have to prove that the drug will get enough of the market share. It’s worth even bothering to make this drug. If there are already say, 15, drugs out there in your same category, the FDA is going to say, ‘Why is it worth it? Is this drug even necessary?’ You have to be able to answer those types of questions as well.
In Phase III, you have to have a minimum of two trials with many thousands of patients, so several thousand patients who are going to confirm those clinical doses that you set in Phase II that confirm how often this drug needs to be taken, timing of administration, adverse effects, benefit-risk potential—all of that data needs to be there in Phase III.
You need to use mortality and morbidity end points. These Phase III trials can take a very long time because mortality and morbidity data is not something that you can obtain in a very short amount of time. All Phase III trials must ensure appropriate patient recruitment and timely completion of the study. They are looking at this very, very carefully. If you have dropout rates, they want to know why. If the rates are too high they are probably not going to approve your Phase III trials.
Then Phase IV is aftermarket. If they do approve you, Phase IV begins post marketing, and the FDA will continue to look at things and make sure that you are watching for any post marketing things that, it, because you can only see so much during a Phase III trial, and sometimes it can take a long time for adverse effects to show up with the medication, so very diligent surveillance is warranted here, so they are going to be watching very closely at the Phase IV surveillance to make sure that the drug companies are watching for any adverse reactions. Sometimes it can take years and years for things to show up.
Here is a diagram of the procedure from drug development and approval. It is a little difficult to see. It might be a little small, but you can go back and enlarge it and take a look. This shows in a little simplified form what we were talking about earlier.
Orphan drugs are drugs that are used to treat rare disease. The Orphan Drug Act allows fast tracking for these types of drugs and gives them market exclusivity for 7 years, so they are kind of fast-tracked. They have to have safety data and that sort of thing, but they don’t have to have as long, say, Phase III trials and that kind of thing, and they are allowed to be the only “drug on the block” you could say for that type of disease.
These are some really good resources if you would like to read further about drug safety and voluntary reporting. If you do prescribe a drug and see an adverse event, it is important to report that. It helps the FDA and it also helps the drug manufacturers. They are required to keep track of that, but if health care providers don’t report these incidents then they don’t necessarily know about them.