Interesting transcript. Both Elite Pharma AND Dr. Setnik are referenced and quoted.
http://www.fda.gov/downloads/Drugs/NewsEvents/UCM428296.pdf
Just info to chew on as we wait for July 14th!
****************************
One that could be seen at a pretty high level
17 is separate multiparticulates for antagonist and
18 agonist in a technology like Elite Pharmaceuticals
19 are developing, or the agonist and sequestered
20 antagonist in the same bead, like Embeda.
*****************************
DR. SETNIK:
Mine's fairly easy, too. Thank
17 you for the opportunity to speak today. My name is
18 Beatrice Setnik. I'm with INC Research. I'm a
19 former employee of King Pharmaceuticals and Pfizer.
20 The opinions are my own, and I'm not being paid to
21 speak today.
22 I wanted to thank the FDA for this
1 opportunity to speak. I commend the FDA for
2 standardizing, or attempting to standardize, the
3 in vitro approach, as I think this will enable
4 sponsors to be able to come up with a consensus on
5 how to test in vitro products.
6 My concerns do lie with the attempt to
7 correlate in vitro to in vivo testing. When we look
8 at bioequivalency on the terms of efficacy, we are
9 dealing in a more simplified fashion. You have an
10 in vivo study. You have two endpoints on which you
11 establish bioequivalency. In the in vitro setting,
12 you're discussing the potential of looking at
13 various solvents and different conditions, with the
14 possibility of having upwards of a hundred different
15 testing conditions.
16 Not only do you need to standardize the
17 definition of how you define bioequivalency or
18 equivalency from your test to your reference
19 compound on each individual condition, but then be
20 able to define bioequivalency across a multiple of
21 almost hundreds if not more of actual testing
22 parameters, which in itself is a challenge.
1 Given the infancy of this field, and this
2 challenge is enough, which will be to standardize
3 across different products, the definition of what
4 will be bioequivalent is in itself another
5 challenge.
6 Not only do you have these confounders, you
7 have the variability in manufacturing which will
8 cause differences. The sheer number of conditions
9 in which you're testing statistically will pose a
10 high likelihood that you will not have two products
11 that will look identical in a panel of batteries
12 that are as extensive as what one tests in an
13 in vitro panel.
14 Furthermore, you will need to contend with
15 the fact if there are 90 percent homology,
16 95 percent, how well that be interpreted? How
17 will that be defined as equivalent to a reference
18 product? And furthermore, as has been stated
19 earlier, there have been cases where in vitro data
20 can be different from in vivo. So one has to be
21 cautious in the interpretation of what a
22 bioequivalent standard in an in vivo paradigm would
1 translate to in terms of in vivo.
2 Certainly when we do establish bioequivalency
3 to efficacy, we do so by testing in in vivo
4 conditions. We don't look at dissolution to
5 establish clinical efficacy in terms of
6 bioequivalence. And the same nature of this
7 conundrum would apply to the abuse-deterrent
8 formulations in itself. So I caution the committee
9 and the FDA to be careful about labeling claims on
10 an in vivo nature simply based on in vitro
11 paradigms. I think the science is too young for
12 this.
13 The second, I also wanted to point out that
14 with in vitro testing, the time component and the
15 complexity are two very important factors. A third
16 component is the toxicity, and also looking at the
17 different solvents that may be used, and what
18 toxicity and safety implications may be from using
19 different types of manipulation techniques.
20 The third point I also wanted to make was
21 that generally, abuse is a dynamic process. And
22 although we look at the types of behaviors that are
1 engaged today, these behaviors will change over
2 time. Certainly as more ADFs come to market, the
3 behaviors of the abusers will change over time.
4 Hays pointed out in a study that abusers over a
5 course of 19 months went from oral to intravenous
6 use. Individuals change. The trends change.
7 We also need to, as we are developing these
8 products, not only think about what routes of
9 administration are relevant today but also what will
10 be relevant tomorrow in the future years, as we are
11 dramatically changing the landscape of the abuse by
12 introducing ADFs potentially into the marketplace.
13 My last point is really the uptake and the
14 success of these types of products really will be
15 dependent not only on uptake of this, but also
16 understanding the limitations and the important part
17 that they play as a tool with other management of
18 careful risk evaluation and management in the clinic
19 setting of patients.
20 Not only do patients, providers, and
21 manufacturers need to play a role, but managed care
22 will also need to embrace the concept and play a
1 part in terms of promoting the safe and effective
2 use of opioid medications in the population. Thank
3 you.
http://www.fda.gov/downloads/Drugs/NewsEvents/UCM428296.pdf
Just info to chew on as we wait for July 14th!
****************************
One that could be seen at a pretty high level
17 is separate multiparticulates for antagonist and
18 agonist in a technology like Elite Pharmaceuticals
19 are developing, or the agonist and sequestered
20 antagonist in the same bead, like Embeda.
*****************************
DR. SETNIK:
Mine's fairly easy, too. Thank
17 you for the opportunity to speak today. My name is
18 Beatrice Setnik. I'm with INC Research. I'm a
19 former employee of King Pharmaceuticals and Pfizer.
20 The opinions are my own, and I'm not being paid to
21 speak today.
22 I wanted to thank the FDA for this
1 opportunity to speak. I commend the FDA for
2 standardizing, or attempting to standardize, the
3 in vitro approach, as I think this will enable
4 sponsors to be able to come up with a consensus on
5 how to test in vitro products.
6 My concerns do lie with the attempt to
7 correlate in vitro to in vivo testing. When we look
8 at bioequivalency on the terms of efficacy, we are
9 dealing in a more simplified fashion. You have an
10 in vivo study. You have two endpoints on which you
11 establish bioequivalency. In the in vitro setting,
12 you're discussing the potential of looking at
13 various solvents and different conditions, with the
14 possibility of having upwards of a hundred different
15 testing conditions.
16 Not only do you need to standardize the
17 definition of how you define bioequivalency or
18 equivalency from your test to your reference
19 compound on each individual condition, but then be
20 able to define bioequivalency across a multiple of
21 almost hundreds if not more of actual testing
22 parameters, which in itself is a challenge.
1 Given the infancy of this field, and this
2 challenge is enough, which will be to standardize
3 across different products, the definition of what
4 will be bioequivalent is in itself another
5 challenge.
6 Not only do you have these confounders, you
7 have the variability in manufacturing which will
8 cause differences. The sheer number of conditions
9 in which you're testing statistically will pose a
10 high likelihood that you will not have two products
11 that will look identical in a panel of batteries
12 that are as extensive as what one tests in an
13 in vitro panel.
14 Furthermore, you will need to contend with
15 the fact if there are 90 percent homology,
16 95 percent, how well that be interpreted? How
17 will that be defined as equivalent to a reference
18 product? And furthermore, as has been stated
19 earlier, there have been cases where in vitro data
20 can be different from in vivo. So one has to be
21 cautious in the interpretation of what a
22 bioequivalent standard in an in vivo paradigm would
1 translate to in terms of in vivo.
2 Certainly when we do establish bioequivalency
3 to efficacy, we do so by testing in in vivo
4 conditions. We don't look at dissolution to
5 establish clinical efficacy in terms of
6 bioequivalence. And the same nature of this
7 conundrum would apply to the abuse-deterrent
8 formulations in itself. So I caution the committee
9 and the FDA to be careful about labeling claims on
10 an in vivo nature simply based on in vitro
11 paradigms. I think the science is too young for
12 this.
13 The second, I also wanted to point out that
14 with in vitro testing, the time component and the
15 complexity are two very important factors. A third
16 component is the toxicity, and also looking at the
17 different solvents that may be used, and what
18 toxicity and safety implications may be from using
19 different types of manipulation techniques.
20 The third point I also wanted to make was
21 that generally, abuse is a dynamic process. And
22 although we look at the types of behaviors that are
1 engaged today, these behaviors will change over
2 time. Certainly as more ADFs come to market, the
3 behaviors of the abusers will change over time.
4 Hays pointed out in a study that abusers over a
5 course of 19 months went from oral to intravenous
6 use. Individuals change. The trends change.
7 We also need to, as we are developing these
8 products, not only think about what routes of
9 administration are relevant today but also what will
10 be relevant tomorrow in the future years, as we are
11 dramatically changing the landscape of the abuse by
12 introducing ADFs potentially into the marketplace.
13 My last point is really the uptake and the
14 success of these types of products really will be
15 dependent not only on uptake of this, but also
16 understanding the limitations and the important part
17 that they play as a tool with other management of
18 careful risk evaluation and management in the clinic
19 setting of patients.
20 Not only do patients, providers, and
21 manufacturers need to play a role, but managed care
22 will also need to embrace the concept and play a
1 part in terms of promoting the safe and effective
2 use of opioid medications in the population. Thank
3 you.
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