United states of america food & drug administration

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DECEMBER 12, 2008

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KIMBERLY RAINS, MD, Presenter, FDA Senior Regulatory Programs Manager
ANDREA FURIA, Host, FDA Health Programs Coordinator


10:49 a.m.

DR. RAINS: -- in the Electronic Orange Book, and I've included the URL at the end of this slide, at the end of presentation, excuse me.

There are a number of myths about generic drugs. One of these myths are generic drugs are not safe. Another is generic drugs are not as potent as the innovator product.

It is also thought that generic drugs take longer to act in the body than the innovator product. It's also thought that generic drugs are made in sub-standard manufacturing facilities.

Here, working at the Office of Generic Drugs, I can assure you that all these myths are false. The FDA has worked diligently to dispel a lot of these myths that are currently in the general population.

In 2003, there was a large public service announcement that was posted through the FDA to get people to know more about generic drugs and their safety.

This is just an example of one of the promotions that were put out to describe the safety of generic drugs and the regulation that it goes through.

Not only has the FDA worked on a public level to show the safety of generic drugs and promote them, they've also worked on the legislation level.

In 1984, the Drug Price Competition and Patent Term Restoration Act was made where it allowed abbreviated new drug applications, or ANDAs, possible by creating a compromise between generic drug companies and innovator drug companies.

The generic drug companies were gained greater access to the market for prescription drugs, and the innovator, or brand name companies, were gained and restored some of their patent life of their products that were lost during the FDA approval process.

So why is it important to have the generic drugs on the market here in the US? Generic competition is good. Some of the reasons why are:

Generic drugs help to meet the patient demands. A number of drugs out there have a large demand and need multiple manufacturers to make them to keep up with the US population's demand of these drugs.

Another reason is to keep insurance premiums down. If insurance companies can purchase drugs for a smaller amount of money, they can charge less in their premiums.

Also on the financial side, generic drugs save consumers over $10,000,000,000 yearly. And also what is unknown is that generic drugs represent approximately 65 percent of the total prescriptions dispensed in the US today.

So this shows the importance of generic drugs in our market.

So as I mentioned in the legislative slide, innovator products can get some type of patent protection, which helps the generic drugs.

Just as a basis, a patent protects the investment of the drug company that developed the innovator or the brand-name product, and gives the drug company the full right to sell the drug while the patent is in effect.

So what the Act of 1984 helped was it extended the life of the patent, so these innovator products could be on the market fully, longer. But once their patent life was over, generic drugs were allowed to enter the market.

So patent protection shows that when the patent of the brand-name drug nears expiration, drug companies can then submit applications for generic drug product and apply to sell this generic drug product on the market.

So here in the Office of Generic Drugs, generic drugs undergo review similar to that of the new drug applications in our counterpart, the Office of New Drugs.

And here I've just done a comparison of the review process for generic drug product.

On the left you'll see the requirements for a new drug application, or an NDA, which an innovator product is required to submit. It must undergo chemistry, manufacturing, quality control testing, labeling, testing, which also includes animal studies, clinical studies, and studies on bioavailability.

And the generic drug review, or the abbreviated new drug application, ANDA, has many of the same requirements with chemistry, manufacturing, quality controls, labeling, and testing. But it has merged three groups together, so animal studies, clinical studies, and bioavailability have all been grouped together into bioperformance.

And this is just a road map of how the generic process begins. The application comes through the door, it's assigned a number.

And we take things as they come in, no priority, except for there are some HIV-related drugs that do get priority in the generic drug process.

And once a drug enters, it goes through the regulatory support branch, which can determine if the application is acceptable for filing or not.

If this application is acceptable by filing, it is then dispensed out to generic drug reviewers. So reviewers like myself in the Department of Bioequivalence, also reviewers in chemistry, microbiology, labeling. And also we have an inspection of manufacturing and clinical sites, so reviews are also sent out to them.

If once at this review process there's any deficiencies, the firm has the opportunity to come back and answer these deficiencies and continue in the review process.

If answers to these deficiencies are not acceptable, the application gets thrown out. But if the deficiencies are answered properly, the application continues on to the approval process.

And if all patent -- if the patent is expired on the innovator product and there is no other blocking petition, the application may be approved.

So what I'll concentrate on now is the bioequivalence review process or my job day to day.

Just a little basics. How do drugs work?

So here I have a diagram, a cartoon, per se, of a tablet. A person taking a tablet, it first gets taken into the gastrointestinal tract. The GI tract is initially acidic. And upon traveling through the tract, it changes pH to basic.

This helps in the dissolution or dissolving of the drug product. Depending on how the drug product is formulated, this may happen quickly or slowly. And this is all a part of drug design.

Once the drug has traveled through the GI tract, it then enters the intestines. Once in intestines, it can begin to undergo metabolism, which is the breakdown of the drug. So the drug may be broken down further into other active metabolites or inactive metabolites. Upon at this time, it's entered into the systemic circulation.

This cartoon only applies to drugs that are systemically acting. There are local drugs that do not follow this pathway.

So once the blood is in the systemic system or in the bloodstream, the drug can be eliminated in a number of ways. One is through the intestines. It could also be broken down even further by metabolism in the liver. And it can be excreted as well through the kidney.

In the Code of Federal Regulations they have a definition of bioequivalent. The definition is the absence of a significant difference in the rate and extent to which an active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action, when administered in the same molar dose under similar conditions and in appropriately designed studies.

I know it's a mouthful and it's really a complicated definition, so I would like to break it down piece by piece to tell you exactly what they mean.

We'll start by the rate at which the active ingredient or active moiety becomes active.

The rate of activity can be measured indirectly by Cmax, which is concentration maximum that a drug reaches once in the systemic bloodstream. This Cmax, although a good indirect measure, also has a high variability depending on interpatient variability, just from person to person, also absorption variability.

So to eliminate or downgrade this variability, we need an adequate sampling time points to get an exact measurement, as well as adequately powered or have enough subjects in a study to draw appropriate Cmax.

And I know this slide may be a little busy and present a lot of information, but what I wanted to show is that the same drug with different absorption rates can have different Cmax profiles.

So as you can see, the blue, which has a very long absorption half-life, has a high Cmax, where the green, which is the same drug, has a much lower Cmax.

MS. FURIA: Excuse me. I'm sorry to interrupt but can someone please press *6? We're hearing something in the background. Thank you.

DR. RAINS: Next, I would like to concentrate on the extent of the active drug. This extent can be measured directly through area under the curve, commonly known as AUC.

AUCt, which is measured over a distinct time point, is a measure of the total exposure of the drug to the body up until the last sampling time. This also stresses the point that sampling time is accurate over the duration of the drug in the body.

There is also a theoretical measure called AUC-infinity, and this measure of total exposure of drug from the body, administered till the drug is eliminated.

And here's an example of an AUC graph, and you see the area under the curve. So we have the plasma concentration versus time. And you see that it reaches a Cmax approximately at five hours, and the ten hour time point could be an approximate AUCt. And on pass the 20 hour time point would be a theoretical AUC-infinity.

So one of the confusing parts about this definition is the absence of a significant difference. It doesn't say an identical. So where does this leave us reviewers in understanding what an -- how do we define an absence of significant difference?

And what we use is a 90 percent confidence interval to determine this. This tells us that we're 90 percent confident that the AUC, Cmax, and AUC-infinity, will fall between 80 and 125.

As you see here, there are blue and green examples. If we look at the first blue example where we see the bell curve present within the 80 to 125 percentages, we see that is acceptable.

Further definition will show that this would mean that the test product for ratio to the reference product would always fall between 80 and 125 percent.

The next blue has a lower variability, but also falls in between the 80 and 125 percentage.

As we can see in the green, these fall outside of our 80 to 125 percentage for the confidence intervals. These drugs would not be acceptable. These would not pass our limited significance of difference. So these would not be identical.

And this is just an example of some output data that we've received from firms. So firms conduct studies and take blood plasma concentrations of the drug product to determine what the AUCt, AUC-infinity, and Cmax values are.

They test these patients for test products as well as the innovator reference product, and they determine the ratio of test over reference to calculate the confidence intervals.

As you can see, the AUCt, AUC-infinity and Cmax all fall between 80 and 125. Therefore, this drug product would meet our definition of bioequivalent.

There are a number of methods of establishing bioequivalence of a solid oral dosage form. One is the in vivo study, as I've been discussing here.

We've been discussing the pharmacokinetic model in which you can take blood concentrations. And with a drug that acts systemically, it would mimic the site of activity. And here we can take measurements of Cmax, AUCt, AUC-infinity.

Another in vivo method of establishing bioequivalence is a pharmacodynamic study. This is often used when the drug plasma concentration, or the level of drug in the blood, is not an accurate measure of the activity of the drug.

And this is often used in drugs that do not act systemically, which are locally acting.

If in vivo testing isn't possible, there are a number of in vitro testing that can also be done. In vitro testing is done outside of the body. And here, two methods that we use extensively here are dissolution or the dissolving of the drug.

And this is for drugs that have no known bio problems. Therefore, not testing it in the body does not pose an issue. And this is also done for waiver requests of non-bio strengths.

So in most bioequivalent studies, we ask firms to do studies on the highest strength for safety reasons, and then we ask them for waivers using this in vitro dissolution testing for their lower strengths.

Another method of testing for bioequivalence in vitro is BCS, which is the Biopharmaceutical Classification System.

BCS Class I drugs are highly permeable and highly soluble drugs. These drugs are known not to pose a lot of problems systemically because they're not affected by absorption or first-pass metabolism. And in these cases, we do accept in vitro testing.

So I've mentioned that pharmacokinetic studies are conducted determining a Cmax, AUCt and AUC-infinity. Now, I want to go into how these studies are designed and what firms submit to the FDA for approval.

So first is the study and design. Study and design is used to allow us to assess absorption, and differentiate between the test formulation, which is the generic drug product, and the innovator product, which is the reference product.

The most popular study design that we get in the Office of Generic Drugs is a two-way single dose crossover design.

In this study, there are two treatments: a single dose of the test product, and a single dose of the reference-listed drug or innovator product. And this occurs over two periods.

So, for example, we have subject one who is getting test product A in the first period and RLD product B in the second period. And we can compare these sequences to determine our pharmacokinetic data. And the sequences would be AB and BA.

In most cases, all these subjects are randomly assigned to these sequences to remove bias.

This is just an example of how a study would be carried out. As I mentioned, Sequence I would be subject one, Sequence II could be perhaps subject two.

And as you can see in Period I, subject one is given drug A and subject two is given drug B. There's a washout period to remove any drug from the system after taking it. And then the study's starting again where Period II, subject one is given drug B and subject two is given drug A.

From these studies, we can make comparisons to determine if there's differences in formulation.

Although this is the most popular design, there are also other study designs that are utilized.

One is the parallel design where a subject is given one test, one drug A and another subject is given one drug B. This design is usually done when a drug has an extremely large half-life, where doing a two-period study would not be possible.

There's also another study called a replicate design study. And in this study, a subject is given four treatments: twice with the test product and twice with the reference product.

This allows us to look at intra-subject variability. This is important in drugs that are highly variable. It's good for us to know the intra-subject variability before comparing it to other subjects.

Now that I've gone over the study design, what types of studies do the drug companies conduct?

The three most common studies are a fasting study, where subjects have usually fasted for ten hours prior to administration of drug, a non-fasting or a fed study, where subjects are fed a high-fat diet 30 minutes before administration of a drug, and the third most popular is a sprinkled-fast or sprinkled-fed study, and this is for capsules that can be broken up where the capsule is sprinkled in usually applesauce and then given on a fasting or a fed state.

There are three components of an in vivo bioequivalent study: clinical, bioanalytical, and statistical. Reviewers are responsible for reviewing all three of these subject matters.

In the clinical study, the following considerations are taken into account:

The type of subject. In most cases we request that drug testing be done on normal healthy subjects to preclude any other possible medical issues that may come into play. There are some exceptions, especially in cancer drugs that are cytotoxic, that we require testing to be done on patients.

Another example is products that may cause birth defects. We ask that females of child-bearing age be excluded.

And we also like to request racially-diverse subjects for our studies.

And the clinical studies also determine the strength of the test product chosen. As I mentioned before, we usually accept studies on the highest strength for safety to make sure there are no safety concerns. For drugs with known safety concerns, for the safety of the subject we may request a lower dose.

The clinical study is also the time in which we analyze the sampling time to make sure it covers the length of the time that the drug is in the system.

We examine the protocols that are submitted and make sure they have no deviations that may cause the study to fail.

We also monitor adverse events, and if any subject has had a serious adverse event or dying, to see what the relationship this has to the drug.

And also in the fed study, as I mentioned before, we use a high-fat, high-calorie breakfast as an extreme to see what effect absorption has on the drug.

The next part I'll talk about is the statistical considerations. When doing statistics on these analyses, we want to make sure that we have no subjects included that may affect or alter the outcome.

Some of the things that we looked at are emesis, or if a subject has vomited, therefore effectively altering their plasma concentration of the drug.

We want to see if any of the subjects have a non-zero concentration greater than its Cmax, meaning that there was not adequate time sampling where the Cmax was missed, and the first non-zero point was actually the Cmax.

We want to see if there's any pre-dose concentration. So this may mean that there was some drug present in the body before the study was conducted, or after a washout period the drug had not fully left the system.

And also in our statistical considerations, we want to see if the metabolite may be active and may also be causing some of the active effects of the drug. So we may choose to measure the parent as well as the metabolite, or fully measure the metabolite, which we would determine at this time.

The statistical considerations are very important in developing the 90 percent confidence and role acceptance, which I mentioned before, between 80 and 125.

If you have a possible outlier or possible subject that may be fueling your data, this may lead it to be outside or negatively within our confidence intervals.

So now I'll move on to the in vitro testing.

As I mentioned, we use dissolution testing for granting of waivers and also BCS Class I drugs. The definition of dissolution is a process of going into solution, commonly known as dissolving.

And this is important in the bioavailability information, making sure that the formulation batch is consistent, and also developing an in vitro process of testing of the drug.

As I mentioned, we use dissolution testing in a number of studies, in vitro characterization, granting biowaivers for lower strengths, and also in the BCS Class I drugs.

So some basics just to know about dissolution. It involves apparatus. The two standard apparatus are apparatus 1, which is a basket, and apparatus 2, which is a paddle. And it's done in various medias to mimic the in vivo system or the body from various pHs, from pH 1.2 to pH 7.4, various volumes, speeds, and times.

So we can use dissolution testing for a number of comparison roles. We can compare the test versus the test and reference versus the reference to see how they release, and if their release is similar.

We can look at different release in products, if something is supposed to be a delayed release or an extended release product, to make sure it meets what the label says.

And also we can look at dose dumping. And this in effect is saying that a dose may dump based on its formulation at a certain pH or in the presence of alcohol. And this is very important for some drugs that may become toxic if given in a high dose very frequently.

And we can also calculate a similarity factor. And this is test-test, but we're looking at different strengths of the drug. So we compare these different strengths to see if they release similarly, no matter what strength of the drug it is.

And with the similarity factor, if it's greater than 50, a drug is considered similar.

We also use dissolution testing to set quality controls, and we set dissolution specifications. And we set these specifications for immediate release products, delayed release products, as well as extended release products.

The FDA has a website in which it lists all the dissolution methods we recommend for certain drug products, and it's available to the public. And I've just included a screen shot here.

And here we see for abacavir, which is in its tablet form, used as a USP apparatus of the paddle at a speed of 75 RPMs, and the dissolution medium is 0.1 molar HCL, which would be approximately a pH of 1.2, and recommended sampling times.

And these sampling times indicate the maximum would be 30 minutes in which 80 percent of the drug should be dissolved.

As I mentioned, we do in vitro testing for biowaivers. So many would ask why don't we ask for additional in vivo studies where we measure the bioequivalence to pharmacokinetic models for these lower strengths.

Reasons why we offer biowaivers are to cut down the costs. Bioequivalent studies are quite expensive. The clinical-run trials are very taxing. And if at the highest strength it's meeting our bioequivalence standards, we trust the in vitro model would give us a good predictor of the lower strengths.

And for some drugs, they have several strengths, five to ten different strengths. So that would be very cumbersome on a company to complete bioequivalent studies for so many strengths of a product. And waivers are granted for non-biostrengths as well.

Next, I'll go into the formulation. As bioequivalence reviewers, we also look at formulation of the drug products in comparison with the innovator products as well.

And this is just an example of a fictitious drug, and here we're just looking at the formulation.

And for biowaiver, we do require that the highest strength and the lower strength be proportionally similar. So here you can see that the 300 milligrams is proportionally similar to 150 milligram strength.

And we also look at the -- not only do we look at the active ingredients, we look at all of the inactive ingredients.

The FDA also has a website where it lists inactive ingredients and the maximum daily dose that can be taken of those inactive ingredients. And we make sure all of the generic drugs fall within these realms.

And this is just an example of the dissolution profile, for example, for the granting of a biowaiver.

So first, we've seen that the formulations are proportionally similar, and now we're looking at the similarity of the dissolution profiles. So you can see the 300 and the 150 milligram dosages have similar dissolution profiles. We also calculated the f2 similarity factor, which is over 50. Therefore, this would qualify as similar and we could grant the 150 milligram strength a biowaiver.

Thank you for your attention for this talk. I greatly appreciate the opportunity.

And I just wanted to leave you with some additional information where you can get a lot more information on the Office of Generic Drugs, as well as a lot of information on generic drugs themselves, at the Orange Book, which is the second URL there.

I would like to acknowledge my director, Dr. Barbara Davit, my deputy director, Moheb Makary, my team leader, Kuldeep Dhariwal, and also help from fellow team members, Partha Chandaroy and Ethan Stier, who helped with the presentation.

I welcome any questions at this time.

(Whereupon, the above-entitled matter was concluded at 11:29 a.m.)




(202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433

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