1. - Japan Bioanalysis Forum

Japan Bioanalysis Forum
1. 規制当局とのオープンディスカッション
Open discussion with regulatory authorities
Chairs:
Noriko Katori, Kenji Yahata
Panelists: Daisuke Iwata, Toru Yamaguchi,
Yoshinobu Yamai, Brian Booth (web)
The views expressed are those of the author and do not reflect official views of each regulatory
authority. No official endorsement is intended or should be inferred.
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Japan Bioanalysis Forum
Part 1 -Q&A session •
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Re-analysis, ISR
Stability
Tiered approach
Biopharmaceuticals, LBA
Validation
Future perspectives
Others
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Re-analysis, ISR
ISR for hardly absorbed drugs
パッチ剤、吸入剤など体内にほとんど吸収されない薬剤の臨床試
験において多くの定量結果が低濃度QC以下になることが予測さ
れる場合、ISRの実施意義は低いと考えられます。このような場合、
治験参加者への負担を考慮し、ISRを実施しないとの考え方も可
能と考えていますが、このような考えは受け入れ可能でしょうか？
In clinical studies for drugs hardly absorbed into the body such as
inhalation or patch formulations, quantification results in almost
samples are estimated to be lower than the low QC concentration.
In these situation, we don't think that ISR is scientifically
reasonable. Is this thinking acceptable for you?
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Re-analysis, ISR
Answer from EMA:
This is a strange question. If concentrations are almost all below
the low QC than your calibration range curve is too wide and your
QC concentration levels are not covering the study samples
concentration range. If this would be applied in a bioequivalence
study (if possible considering the difficulties as expressed in the
question), this would raise concerns.
In case of bioavailability study, the lack of ISR may be acceptable.
Note: ISR could still be considered with widened acceptance
criteria in order to take into consideration the higher analytical
variability at very low levels of concentration, between the LLOQ
and the LQC.
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Re-analysis, ISR
Answer from FDA:
No. ISR is an external test of the assay validation
- Assay is designed to assess systemic exposure of a drug.
• Monitoring safety: systemic exposure to monitor
adverse reactions
• If the samples are below LLOQ, you may need to
adjust the assay.
• If early PK studies demonstrate lack of systemic
absorption, why would you continue to assay?
-no need for ISR
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Re-analysis, ISR
Number of ISR samples
米国で7％のサンプル数でISRを評価した試験を日本及びEUでの
申請資料として使用することを許容可能かどうかお聞かせ下さい。
If the study is performed in the US by evaluating 7% ISR, is it
acceptable for drug application in Europe or Japan?
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Re-analysis, ISR
Answer from EMA:
As the guidance indicates "...as a guide, 10% of the samples
should be reanalysed in case the number of samples is less than
1000 samples and 5% of the number of samples exceeding 1000
samples." this would be acceptable. Furthermore, this figure of
7 % was published in a draft guidance and may be modified in
the final guidance. In any case there is no incompatibility
between the two recommendations. In order to avoid discussions
and loss or time, laboratories may chose to use the formula
giving the highest number of ISR samples (EMA formula if the
study has less than 2500 samples, FDA formula above).
Answer from FDA:
This agreeable to FDA.
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Japan Bioanalysis Forum
Re-analysis, ISR
Number of ISR samples
現在、ISRに必要なサンプル数はMHLW及びEMAでは総サンプル
数の10％、FDAのドラフトガイダンスでは7％とされています。これら
の数値の根拠について解説していただけますでしょうか？
Could you explain how did you decide the number of ISR samples
described in your guidance or guideline?
FDA draft guidance: 7% of actual samples
EMA: 10% of actual samples
MHLW: 10% of actual samples
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Re-analysis, ISR
Answer from EMA:
Based upon discussion outcomes Crystal City and White papers.
Answer from FDA:
Example 1: 7% ISR
1000 samples x 0.07 = 70 ISR samples
Example 2: 10%/5%
1500 samples= (1000 x 0.1)+ (500 x 0.05) = 125 ISR Samples
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Japan Bioanalysis Forum
Re-analysis, ISR
Number of ISR samples
Scientific recommendationとしてはGBCのA7 harmonization teamより、サンプル
数の5％及び最低必要なサンプル数は6が提案されています。これらは
Analytical runにおけるQCサンプルの数に基づいて提案されており、実際に試験
を実施する側としましても実試料測定における問題の有無を検出可能な数であ
ると考えます。ISRのサンプル数についてGBCのrecommendationを受け入れ、3
極でハーモナイズする可能性についてご意見をお聞かせ下さい。
The number of ISR samples are recommended to be 5% of actual samples and at least 6
samples from GBC A7 harmonization team. The proposal is based on number of QC
samples in an analytical run, and enable to detect if any problem exists in the intended
analysis.
Do you think about the possibilities to accept the GBC recommendation to your agency
and to harmonize among FDA, EMA and MHLW?
参考 ): Repeat Analysis and Incurred Sample Reanalysis: Recommendation for Best Practices and
Harmonization from the Global Bioanalysis Consortium Harmonization Team, Eric Fluhler et al, The AAPS
Journal, vol16, No.6, 2014
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Re-analysis, ISR
Answer from EMA:
No. At this moment this is not a topic for discussion. However 5 %
would result in too low a number of ISR repeats in studies with a
limited number of samples.
Answer from FDA:
No, the GBC recommendation will not be adopted by FDA.
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Japan Bioanalysis Forum
Re-analysis, ISR
Re-analysis in BE study
BMVガイドラインにおいて、BE試験では薬物動態的理由のみによる（定量値の入れ替えを
想定した）再分析を認めていません。 例えば、薬物動態的な不自然さにより、分析の異常
が懸念される場合，その値の再現性を確認するための再測定は許容されるでしょうか？
また，その結果，初回測定値に分析的なエラーがあったと判断された場合には、初回測定
値を棄却し、再測定値を採用することは許容されるでしょうか？
再測定の基準及び結果の採否については事前に計画書あるいはSOPで規定しておくこと
は前提です。
分析的なエラーの例：
投与前試料に分析対象物質が認められた場合
ISの添加量ミス
サンプルの入れ間違い など
In bioequivalence studies, reanalysis of study samples because of a pharmacokinetic reason is not acceptable. In
case of a quantification result having an abnormal pharmacokinetic profile and concerning to be analytical error
described below, is reanalysis acceptable to confirm the reproducibility of the result according to predefined
reanalysis procedures?
After the confirmation, we recognize that the original result was produced by an analytical error. In these situation,
we think that the original result should be rejected and reanalysis result is adopted. What do you think about that?
Example of analytical error:
analyte observed in pre-dose sample,
abnormal IS response,
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Re-analysis, ISR
Answer from EMA:
If the analytical error is documented, this would be acceptable.
In case the error is only detected due to abnormal results not.
For the given examples, it is accepted to reanalyse predose
samples in case of a positive value. Reanalysis for an abnormal IS
response may be also an acceptable reason.
The problem with a reanalysis for PK reasons is that no clear
guidances and cut-of values can be given (i.e. when is the
concentration abnormal or not). Furthermore, abnormal values
may be a trigger for inspection.
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Japan Bioanalysis Forum
Re-analysis, ISR
Answer from FDA:
If the cause is an unambiguous analytical failure, it may be
reasonable to reanalyze.
- For example, a power failure during a run; documented
sampling error, analyte in pre-dose sample etc.
However, some issues deemed as bioanalytical error may be
subjective, and a reanalysis in these cases are not acceptable
For example, an abnormal IS response is problematic—there is
no standard definition for an abnormal response, and the user
makes a judgment about the IS.
This would probably not be acceptable.
Finally, the analytical problem would need to be documented.
Both the original and re-analyzed value(s) should be included in
the submission.
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Japan Bioanalysis Forum
Stability
Matrix-based stability
安定性試験における試料の調製方法について、予め評価予定の
n数の保存容器に小分けして保存し、それぞれの保存容器から
n=1で採取して測定する方法と、小分けせずに、評価予定のn数を
一つの保存容器から繰り返し採取して測定する方法のいずれも
同様の結果がでると考えられ、いずれの方法も受け入れ可能と
考えますが、この点についてご意見をお聞かせください。
Regarding the matrix-based stability experiments, there are two approachs.
1) Prepare the multiple aliquots for storage(n=3 or more), and then analyze
each aliquots (n=1)
2) Prepare one bulk sample for storage, and then analyze replicate(n=3 or
more) from one bulk sample.
We think that we can obtain the similar results from both approaches,
therefore, we can accept both approaches. What do you think about it?
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Japan Bioanalysis Forum
Stability
Answer from EMA:
It was expected that for stability, samples/aliquots would be
stored as multiple aliquots. However it appeared that this may be
not the case always. This issue has not (yet) been discussed, but
the feeling is that stability experiments should mimic the storage
conditions of the study samples. And this is not the case when
stability samples are stored in bulk. Further discussion is
encouraged between regulators and industry in order to better
understand the reluctance and the drawbacks seen by industry in
the use of separate aliquots.
Answer from FDA:
We have seen studies conducted with both approaches
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Japan Bioanalysis Forum
Stability
Necessity beyond highest calibration range
1. マトリックス中の安定性評価において、分析対象物質の安定性に濃度依存が
なければ、検量線上限を超える濃度での安定性評価は不要との理解で良いで
しょうか？
2. これまでの審査経験で下記①②以外で高濃度での安定性が懸念されるケー
スがあったら教えていただきたい。
①尿中親水性物質を測定する場合において濃度依存的な吸着や沈殿が懸念さ
れる場合
②高分子の濃度測定において、高濃度で凝集などによる影響が懸念される場合
1.
2.
We don't think that a stability evaluation is required at a concentration exceeded the
upper limit of calibration range when the analyte stability is not depended on its
concentration within the calibration range. What do you think about this?
Could you let me know if you have any experiences that the matrix stability is
concerned at higher concentration except for the cases described below;
(1) Concentration dependent adsorption or precipitation of hydrophilic analytes in
urine
(2) Agrregation at higher concentration of large molecule analysis
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Stability
Answer from EMA:
1. This is not a requirement in the guideline. If there are no
indications that stability is concentration dependent, the lack
of such experiments is acceptable.
2. No experience so far.
Answer from FDA:
1. This practice is not required or specified in the guidance.
However, you must use sound scientific reasoning in your
studies. If you suspect that this phenomenon could be
problematic for your drug, you should take appropriate
measures to address it.
2. None come to mind.
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Stability
Whole blood stability
一般的に血漿または血清中における安定性との間に大きな乖離
はないと報告されていますが、N-oxide,またはヒドロキサム酸を部
分構造に有する場合など、分析対象物質の構造的特徴によって
は全血中の安定性が顕著に低いことが報告されています。このよ
うな不安定性が分析対象物質の構造的特徴から懸念されない場
合には、血漿あるいは血清中の測定法において、採血から凍結保
存までの安定性確認の手段として、全血の代わりに血漿あるいは
血清で安定性を担保することは許容可能でしょうか？
In general, there are no major differences in analyte stability between in
plasma or serum and in blood except for analytes having N-oxide or hydroxamic
acid. When the instability would not be concerned based on the analyte
structure, we think that the stability data in plasma/serum can be used instead
of blood stability data. What do you think about this approach?
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Japan Bioanalysis Forum
Stability
Answer from EMA:
The EMA guideline does not require a systematic evaluation of
the stability in whole blood, but indicated that:
- sufficient attention should be paid to the stability of the analyte
in the sampled matrix;
- a demonstration of this stability may be needed on a case-bycase basis, depending on the structure of the analyte.
Differences in enzymatic activities may preclude the extrapolation
of stability data from plasma or serum to whole blood.
Answer from FDA:
You should assess the stability of your drug in the same matrix
that samples will be collected and analyzed from study subjects.
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Japan Bioanalysis Forum
Tiered approach
Non clinical PK study（non GLP）
以下の試験においては、Tiered approachの分類１）における’Qualified method’
あるいは'Research method'の条件を満たす分析法で測定したデータであれば
申請資料として利用できると考えていますがご意見をお聞かせ下さい。
①血漿中濃度（未変化体/代謝物）:Qualified method
②尿中濃度：Qualified method
③組織中濃度: Qualified method
④タンパク結合試験: Research method
Regarding non-clinical studies as listed below, we think that bioanalytical data obtained by using
'qualified method' or 'research method', categolized by JBF discussion group as shown in the table
(see, another sheet 'tiered approach category'), can be used for drug application. What do you think
about that?
1. Plasma concentration of unchanged drugs or metabolites analysed by the qualified method.
2. Urinary concentration of unchanged drug or metabolites analysed by the qualified method.
3. tissue concentration of unchanged drug or metabolites analysed by the qualified method.
4. Concentrations on Protein-binding study analysed by the research method.
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Japan Bioanalysis Forum
Tiered approach
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Tiered approach
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Tiered approach
Answer from FDA:
You should consult with the Pharmacology & Toxicology groups
in the therapeutic review divisions concerning these proposals.
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Tiered approach
Biomarker
探索的バイオマーカー測定法のバリデーション
Phase1試験においてTiered approachの分類の'Research method'
で取得したデータを次相試験の投与量設定根拠とした場合、受
け入れ可能でしょうか。
Can the exploratory biomarker data obtained in Phase I trial
using "Research method" be used as the rationale for the dose
selection of Phase II study?
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Tiered approach
Answer from EMA:
Pivotal information submitted in marketing authorization
applications should have been obtained using methods which are
demonstrated to be fit for their intended purpose. If the "research
method" is demonstrated to be fit for purpose the data could be
accepted. Due to the exploratory nature of biomarker data in a
Phase I trial it might be acceptable to only perform a full
demonstration after the end of the trial, while the development
of the product progresses.
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Tiered approach
Answer from FDA:
This practice happens often, especially in oncology.
Typically, once the phase 2 dose is selected, a clinical endpoint is
selected for the Phase 2 study.
The risk is that an ineffective dose is selected.
Fully validated methods are needed when data are used to
support decisions about safety and efficacy (approval), and/or
patient dosing.
Caution should be taken in early studies when that data may
later become pivotal in future decisions about safety and efficacy
of the product.
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Biopharmaceuticals, LBA
Interference of concomitant on bioanalysis
高分子 vs 低分子
Crystal City VのConference Reportでは、低分子医薬品とバイオ
医薬品は構造的に類似していないため、相互の測定法への影
響について、通常評価する必要は無いとされています。この点
についてご意見をお聞かせ下さい。
The conference report of CCV says "Since small molecule
concomitant medications are not structurally similar to large
molecule therapeutics, these typically do not need to be tested for
interference in the assays."
What do you think about it?
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Biopharmaceuticals, LBA
Answer from EMA:
Agreed.
Answer from FDA:
You are responsible for demonstrating the selectivity/specificity
of your assay. Usually, this situation is true.
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Biopharmaceuticals, LBA
Interference of concomitant on bioanalysis
高分子 vs 高分子
ヒト抗体医薬品の測定法は内因性のヒトIgG存在下でバリデート
されているため、他のヒト抗体医薬品を併用しても影響を受けな
いと考えられます。ヒト抗体医薬同士が併用される場合、測定法
への影響について評価する必要はないと考えていますが、問題
ないでしょうか。
Since PK assays for human/humanized antibody are validated in
the presence of excess amount of endogenous immunoglobulin,
the assay response would not be interfered by comcomitant
antibody druds. Do you think the evaluation of interference of
concomitant antibody drug is needed in this case?
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Biopharmaceuticals, LBA
Answer from EMA:
Probably OK as long as the concomitant Ab has no common
epitope / target / ligand / whatever with the analyte, which could
interfere in the analysis.
Answer from FDA:
You are responsible for demonstrating the selectivity/specificity
of your assay. If you are adding a known Ab drug to your Ab drug,
why wouldn’t you test for interference?
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Biopharmaceuticals, LBA
Critical reagents
重要試薬の品質に関して、各測定バッチのQC試料の分析結果を
モニタリングすることで、その品質に問題が無かったことを確認で
きると考えておりますが、このような安定性評価の方法は受け入
れ可能でしょうか。
The stability and quality of critical reagents can be generally
verified by monitoring the results of QCs in the daily analysis.
Are any additional assessments necessary to ensure the stability of
critical reagents?
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Biopharmaceuticals, LBA
Answer from EMA:
This may be a solution, however, analysts should be aware of
decreasing analyte concentrations in calibration standards and
QC samples. Response evaluation may help, but is dependent on
the response of the detector over time.
Answer from FDA:
I think this is the typical approach, but I agree with the EMA
response; it is unclear if people use other orthogonal methods to
assess stability/quality.
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Biopharmaceuticals, LBA
ADA
ADA測定では、バリデーション時に患者の真の陽性サンプルを
入手することは困難です。
動物由来の陽性対照をヒトマトリックスに添加して安定性試験を
実施する必要はあるでしょうか。
For ADA assay, it is difficult to obtain true positive samples prior to
clinical trials. There seems no scientific meanings to conduct
stability study by the addition of positive control to human matrix
to ensure the stability of real human sample. What do you think
about the necessity of this type of stability study in pre-study
validation?
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Biopharmaceuticals, LBA
Answer from FDA:
The current approach may be imperfect, but if the positive
control is selected well, it provides some understanding of what
can be expected from the assay.
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Biopharmaceuticals, LBA
ADA
EMAのBMVガイドラインでは、溶血や高脂血の影響を評価する
ことが求められております。ADA測定では、これらが分析に影響
するという特別な懸念がある場合にのみ実施すれば良いでしょ
うか。
Is it necessary to evaluate the influence of hemolysis and/or
lipemia in ADA assay if there is no special concern?
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Biopharmaceuticals, LBA
Answer from EMA:
What exactly is meant by "there is no special concern" ? It is
difficult to know if there is no influence until the test has been
performed. In a real-life study hemolysed and lipemic samples
are likely to be analysed. However, if a generic method is used
which has been demonstrated previously to be insensitive to
hemolysis and lipemia, a specific demonstration ay not need to
be brought for each adaptation of the method.
Answer from FDA:
You are expected to make an evaluation of the need to assess
hemolysis or lipemia on the analyte, as well as other factors as
appropriate.
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Validation
Cross Validation
クロスバリデーションの実施が不可能な場合、測定施設の違いの
影響がでる可能性を考慮しながら、異なる測定法から得られた試
験間の比較や母集団解析を進めるしかないと考えます。それ以
外に、申請者側で対応できる事項があるかどうか、考えをお聞か
せください。
In case that cross-validation can not be conducted between
laboratories, we have no choice but to compare PK results among
multiple studies or perform population PK analysis, considering
the possibility of impact on these evaluation due to the difference
of assay laboratories.
Do you have any ideas what should sponsors do anything else
about this issue?
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Validation
Answer from EMA:
If cross-validation cannot be conducted, comparing between
study PK results and performing popPK analysis with different
labs as covariate would be a suitable approach.
Answer from FDA:
Comparison of PK or population PK may not be sufficient to
compare methods, if the studies were small and there are
relatively few samples.
• insufficient power to detect differences.
• The importance depends on the purpose of the study.
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Validation
Partial Validation
測定者変更について、FDA draft guidanceではPartial validation
(PV)が必要とありますが、EMA、MHLWのガイダンスでは、必要
性を言及されていません。
測定開始前に、変更後の測定者に対するトレーニングは実施さ
れていることを考慮すると、PVは不要と考えていますが、この点
について、考えをお聞かせください。
Regarding partial validation, the method transfer between analysts has been
mentioned in FDA draft guidance, but not in EMA and PMDA guidance.
Considering an appropriate training is provided for new analysts prior to
bioanalysis of study samples, it is not mandotory to perform this partial
validation about the method transfer between analysts.
What do you think about it?
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Validation
Answer from EMA:
A partial validation may need to be considered on a case-by-case
basis, if the bioanalytical method uses specific, non-standard
procedures, and depending on the training of the analysts at the
laboratory.
Answer from FDA:
Agreed.
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Validation
Validation of racemic compounds
①測定系への影響
S体を対象とした測定法を立ち上げたとき、R体がS体の測定に及ぼす影響（分離状態）
をバリデーション試験の中での確認が必須かどうか。（測定法開発時には確認済みで
あることが前提）
②安定性への影響
S体の測定法を確立したとき、S体のみを添加した試料の安定性試験で十分かどうか。
R体又はラセミ体添加の試料に対する検討は不要か。
1) Impact on assay performance
If we develop the assay method for S-form, do we need to assess the impact on assay
performance by R-form during validation study? (In the preliminaly investigation before
validation, this impact has been already assessed)
2) Impact on stability
If we develop the assay method for S-form, Is it sufficient to assess the stability samples
spiked only S-form?
Do we also need to assess the sability samples spiked R-form and/or racemic body?
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Validation
Answer from EMA:
1. If there is no conversion from the R-form into the S-form or visa versa
during assay performance or during storage, an assay for only the S-form
may be acceptable. The selectivity of the method should be
demonstrated with regards to the R-form.
2. Regarding stability, as the other form may be considered as an
concomitant administered drug, specific for bioequivalence studies,
attention should be paid to stability of the analytes in the matrix
containing both R- and S-form. It should be clearly demonstrated that
there is no interconversion between the R and the S forms in vitro.
Answer from FDA:
1. Yes—you have determine if there is any S and R interconversion during
the assay.
2. Yes—you have to determine if there is any metabolic or bioconversion of
R to S (or vice versa) that will affect stability.
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Future perspectives
Guideline/Guidance
生体試料中の薬物及びその代謝物を測定するガイドラインは各極において整
備されてきましたが、以下の分野におけるガイドライン/ガイダンスの今後の必
要性について、考えをお聞かせください。
Guidelines on bioanalytical method validation about drugs and its metabolotes
has been recently established in FDA, EMA and PMDA. In the future, do you
have any ideas about the need of guidances/guidelines for following topics?
1) Anti-drug antibody (ADA)
2) Biomarker
3) MS imaging
4) Assay of maclo-molecule using mass-spectrometry (including Hybrid LBA/LCMS)
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Future perspectives
Answer from EMA:
This depends on the number of applications submitted
and the difficulties occurring with these applications.
Answer from FDA:
Certainly for topics 2-4, as applications increase further
Clarity around the specifics of each topic will be needed.
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Future perspectives
Submission
イメージングマスで取得した薬物の分布データ等を、今後、申請
資料として受け入れ可能でしょうか。
Is the drug distribution data obtained using imaging-MS
acceptable for the drug approval?
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Future perspectives
Answer from FDA:
We have not seen this application yet. We would have to discuss
the suitability with an applicant, but the FDA encourages the
development of new scientific techniques and works with drug
sponsors on the appropriate use of these applications.
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Others
TK study
対照群における薬物濃度測定の実施について最近の毒性試験では汚染対策
が徹底され、対照群では定量可能な値はほとんど得られなくなっていると考え
ます。今後も対照群を測定する必要性があるとお考えでしょうか？以下の選択
肢から最も近いものをお選び下さい。
①媒体群のサンプルは測定不要と考える
②Tmax付近のみ測定が必要である
③媒体群においても実薬群と同じ時点での測定が必要
Recently, quantifiable concentrations have not been observed in control animals in TK
studies.
Do you think drug concentration measurements are required still for animals given vehicle
in TK studies? Please select an answer which is the closest to your opinion.
1. Not require for measurement of samples given vehicle.
2. Require for measurement of samples around Tmax even though animals are given
vehicle.
3. Require for measurement of all samples given vehicle as same as those administered
drugs
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Others
Answer from FDA:
Option 3
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Part 2
How should we insure the
reliability in drug application?
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Part 2
• Change before and after issue the BMV
guideline
• Study record
• Self check
• Blind
• Validation report
• Generic drug
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Change before and after issue of BMV guideline
ガイドラインの発出の前後で、バリデーション試験及び実検体測
定の報告書、生データの確認する項目について、何か変わった
点がありましたら、具体例をお聞かせください。
Before and after issue of BMV guideline, are there any change of
data review and/or assessments for validation reports and sample
analysis reports?
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Change before and after issue of BMV guideline
Answer from EMA:
The most specific one is the request for ISR.
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Study record
パーシャルバリデーションを実施する事例として、分析機器の変
更がありますが、同一又は類似の機器への変更については、
適切に機器がメンテナンスされている又はシステム適合性試験
が実施されていることを考慮すると、パーシャルバリデーション
を実施せずに、変更の記録を生データに残すことで十分と考え
ますが、この点について考えをお聞かせください。
Change analytical instruments is one of case of partial validation.
Based on what the analytical instruments are maintained
appropriately and system suitability is performed, the change to
same or similar type of the original instruments is reasonable to
record as raw data without partial validation.
What do you think about it?
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Study record
Answer from FDA:
Agreed.
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Japan Bioanalysis Forum
Self check
CTD作成時のQCにおいて、根拠資料との整合性を100％確認す
る場合と、海外のようにある一定数を抽出して確認する場合があ
ります。医薬品開発の効率を考えると一定数を抽出する方向に
すべきと考えますが、これについてご意見をお聞かせ下さい。
また、仮に書面調査等において未QCの部分に間違いが発見され
た場合には、原因を追及し、再発防止策を徹底するという対応を
とることになりますが、これについてもご意見をお聞かせ下さい。
Regarding QC process for CTD preparation, there are two approaches.
1) Perform 100% QC between CTD and original reports
2) Perform QC for extractions (percentage of extractions is pre-defined by SOP)
Considering the efficiency of drug development, the second approach (QC for
extractions) should be accepted.
What do you think about it?
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Self check
Answer from FDA:
The meaning of #2 is a little unclear, but would
recommend option 1.
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Blind
バイオマーカーの測定結果によって実薬が投与されたことが推
察可能な場合がありますが、このような場合にバイオマーカー
の測定に関してPK測定と同様、盲検性維持のために必要な管
理下に置く必要があるでしょうか。
The double-blind nature of clinical trial may be compromised by
the results of biomarker assay. Should we blind investigators and
relevant sponsor staffs to the results of biomarker assay to
maintain the blind in such cases?
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Blind
二重盲検比較試験でPK測定を実施する際に、PK測定の外部委
託をモニターと同じ部署の職員が行う場合に、測定結果の妥当
性確認の観点から当該業務を行う職員を非盲検とすべき事情が
あります。これら職員がモニターと同じ部屋を作業場所として使
用する場合、盲検性維持のための手順書の整備、書類・電子
データの保存場所の管理の他に配慮すべき点があるでしょうか。
A sponsor staff who is responsible for PK assay transfer to a CRO
sometimes needs to review the PK data under unblinded condition
to ensure the validity of the assay results. When he/she uses the
same office as clinical trial monitors, the preparation of SOPs for
review process and appropriate management of data storage are
important to maintain the blind. Do you have any ideas what
should sponsors do anything else about this issue?
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Validation report
臨床試験において、試料の採取方法及びバリデーション項目
（長期安定性を除く）が実験的に完了すれば、実試料測定の計
画書を最終化し、実試料測定を実施することは科学的に妥当と
考えますが、この考えについてご意見をお願いします。
Once a validation study is experimentally completed and sampling
procedures are decided, a bioanalytical study for a clinical study
can be started without a validation report is provided. What do
you think about it?
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Generic
後発品の開発における生物学的同等性は、予備試験又は本試
験のBE試験で評価されます。予備試験でISRの評価基準を満たし
たとき、この測定法によるBE試験の測定は適切に行われていると
判断して、本試験でのISR実施は行わないという考え方について、
ご意見をお聞かせください。
In BE studies of generic pharmaceuticals, preliminary and main
experiments are performed.
If ISR results of preliminary experiments are satisfied the criteria,
can ISR of main experiments be skipped?
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Generic
後発医薬品のBEガイドラインにおいて，原則として有効成分の未変化体を測
定成分とするが，合理的な理由がある場合に主活性代謝物を測定成分とする
こともできると記載されています。
合理的な理由の具体的な例として、未変化体より活性が高い代謝物がある場
合や、未変化体が速やかに消失しガイドラインで規定されている時点の採取
が難しい場合などは代謝物で評価するという理解で良いでしょうか？
また、他に代謝物で評価すべき考え方の基準などありましたらご教授頂けま
すで しょうか？
In the BE guideline for generic drugs, unchanged drug should be an analyte,
but main active metabolite could be an analyte if scientifically reasonable.
Can metabolite be an analyte in following cases?
1) The activity of metabolite is higher than the unchanged drug.
2) An elimination of unchanged drug is very fast, so it is hard to collect
quantifiable sampling points for the unchanged drug.
Are there other thinking that metabolite to be an analyte?
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Generic
後発医薬品の承認申請において、CTDを採用する今後のスケ
ジュールについてご教授頂けますでしょうか？
Could you let us know the plan for adopting CTD to gneric drug
submission?
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Japan Bioanalysis Forum
• Back up
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Japan Bioanalysis Forum
Survey about matrix stability in Japan
Q1. Companies participated to
the survey
Q2. Which regulation do you
according to?
Multiple answers are available
Article 43*
CRO (Japan),
6
GLP
Generic drug
manufacturer
(Japan), 7
New drug
manufacturer
(Japan), 17
Others
New drug
manufacturer
(Foreign
owned), 4
0
10
20
30
Number of voters
40
*The reliability standard for application
materials in Japan.
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Q3. How do you store and analyze matrix
stability samples?
A
Timing
to to
evaluate
stability
Sample
prep.
Number
of tubes
to store
Take
aliquots
/ tube
Analyze/
aliquots
A
4
1
1
n
1
B
4
1
4
n
1
C
4
1
4xn
1
1
1
B
17
C
21
Others
4
0
10
20
30
Number of voters
Multiple answers are available
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Comments about Q3
Comments for B:
• To reduce blank plasma volume
• One tube storage is enough to evaluate the stability
Comments for C:
• To store as well as actual samples
• To evaluate the stability during the storage
• To consider the variance among tubes or storage
conditions, but no difference has been observed
among storage tubes
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Comments about Q3
Others
• Depends on the development stage or CRO
• According to FDA guidance (2001)
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Other comments
• Why this notice was released? Want to know
the purpose, background or episode.
• Please share if any difference was observed
among different tubes
• How is the possibility that variances exist
during sample storage?
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