Aggregate Reports: USFDA structured Approach to Benefit-Risk assessment for drug use in humans-What it is and how it came to be? A deep dive!
Dr. Aditi Sheth (????? ???) MBBS ???????????
??????? Manager Safety Solutions- Indegene | Bookworm | 900+ Certificates | PBRER | Aggregate reports | Artificial Intelligence | Trained Psychologist | Introvert | Dog parent | ISFJ |29K+| MBBS MBA MPH | ?????? ????
Continuous Benefit/Risk Assessment through drug life cycle remains the end-goal of both Aggregate Reports (PBRERs, PSURs and PADERs) as well as Pharmacovigilance RMPs! Naturally, considering the nature of these verticals, this activity remains highly complex, nuanced and subjective. Benefit-Risk assessment also means bread and butters for regulators at USFDA and EMA and other agencies. In this article, I've tried to tell the story of thought development and evolution of USFDA approach (aka BRF- Benefit Risk Framework) towards Benefit-Risk Assessment for human use of medicines.
There's a caveat here! One might think, there is so much work to do and why should I read an article about how current USFDA thinking and framework to establish BRF? How it will serve me, which is a valid question..fair..
But regulatory thinking frameworks are continuous and ongoing affairs..This article is about how it all started and what current structured BRF at FDA is. This knowledge will help to both aggregate reports/PBRER team members as well as RMP team members..Since regulators are the people who ultimately validate (or not!) our work..Justify our bread and butter as AR/RMP professionals. The story is also intriguing since regulators worldwide look at USFDA and EMA as ideals and more or less emulate (or even copy!) them! USFDA is very transparent in how they make decisions! This makes for an interesting story to understand their thought process and evolution thereof itself as well as to generally understand what goes into these major regulatory authority departments regardless of the actual BRF.
I've structured this article with focus about USFDA, after intro and definition of BRF etc..The article is structured as below:
·??????USFDA Approach for benefit-risk analysis: The story
·??????Timeline of USFDA approach
·??????Fundamentals of USFDA thinking in benefit risk assessment
·??????‘The Human factor’ in USFDA decision making
·??????Why such standardized uniform framework is ideal in B/R context?
·??????Development of a Benefit-Risk Framework (2009,2011,2013,2014 and beyond, but in more detail)
·??????USFDA Benefit risk assessment principles
·??????The raging debate amongst regulators: “qualitative” versus “quantitative” approaches to benefit- risk assessment
·??????How and when FDA uses qualitative vs quantitative approach for BRF
·??????Comparison between USFDA approach vs EMA approach for BR analysis in very brief
·??????The areas FDA gives considerations in B/R analysis
·??????The five components of structured BRF at the USFDA
·??????The structured USFDA approach to BR assessment, the table, what each component means for real
·??????Key considerations for pre-marketing BR assessment in USFDA
·??????Periodic evolution of BRF at the USFDA
·??????In the end, I've tried to discuss the other side, all the challenges USFDA regulators face in this activity as well as in general (must read part comes in the end!)
lets jump in the matter of this article now, from the very definition of the topic!
Definition of benefit risk assessment:
The comparative evaluation or weighing of benefits (positive effects) and risks (potential harm) of various medical options for treatment, prophylaxis, prevention or diagnosis.
The Benefit-risk is the product of the weight and the value.
Importance of Benefit/Risk analysis in Aggregate Reports:
Why discuss B/R balance of a molecule at all??
? PBRER it self is periodical analysis of benefit/risk balance of a molecule
? B/R analysis remains the cornerstone for marketing approval by regulators
? Maximizing B/R ratio is one of the major principles of RMPs
? B/R is subjective yet it remains one indicator to ensure individual patient and public health protection
One example of benefit risk assessment method:
Steps
?1.?Define problem
?2.?Value tree
?3.?Evidence synthesis
?4.?Assign value to each criterion
?5.?Assign weight to each criterion
USFDA Approach for benefit-risk analysis: The story
? To be approved for marketing, a drug must be safe and effective for its intended use.
? USFDA published a document detailing implementation of PDUFA plan in 2013
? This document serves as a cornerstone for structured benefit-risk analysis of a molecule and the whole USFDA decision making process.
Timeline of USFDA approach:
? In 2009 --> FDA initiated an effort to explore more systematic approaches to benefit-risk assessment and communication as part of the human drug review process and CBER took lead and the whole thing started.
? Initial Work (FY 2009-2011) -> FDA studied prior challenging BR decisions and documented regulatory rationale that was not yet documented
? USFDA came up with the tabular systemic approach to B/R assessment
? Pilot project--> in 2012, USFDA did a pilotà piloting the framework in the drug review process using applications under review in CDER
? FY 2013—> Further Development of the Framework à FDA gave commitments in PDUFA à Adaptation to Key Considerations in the Post-Market Setting?à Characterization of Uncertainties in Benefits and Risks
? FY 2014-2017—> Implementation --> Training of personnels --> Training and communications à Benefit-Risk Advisory Group --> Benefit-Risk Workshops in PDUFA V --> Evaluation of the Benefit-Risk Frameworkà Patient centered drug development
Fundamentals of?USFDA thinking in benefit risk assessment:
· To be approved for marketing, a drug must be safe and effective for its intended use.
· Although the meaning of “safe” is not explicitly defined in the statutes or regulations that govern approval, and recognizing that all drugs have some ability to cause adverse effects, the safety of a drug is assessed by determining whether its benefits outweigh its risks.
This benefit-risk assessment is the basis of FDA’s regulatory decisions in the per-market and post-market review process.
USFDA factors in benefit risk assessment:
2. The nature and severity of the condition the drug is intended to treat or prevent
3. The benefits and risks of other available therapies for the condition
4. Any risk management tools that might be necessary to ensure that the benefits of the drug outweigh its risks
? This assessment involves both quantitative analyses and a subjective qualitative weighing of the evidence.
? Regulatory decisions that FDA makes in both the pre-market and post-market drug review process are based on the components of Law, Science, Medicine, Policy, and Judgment.
? The intersection of these components constitutes the framework in which FDA makes regulatory decisions.
? This framework begins with FDA’s legal authority embodied in the Federal Food, Drug, and Cosmetic Act (the FD&C Act), the Public Health Service Act (PHS Act) and the regulations that the Agency issues to implement these Acts.
? Beyond the clinical study of drugs, the Agency must also consider how people will actually use newly approved drugs once they are marketed.
? FDA communicates this policy through guidance and other policy documents.
? Guidance represent the Agency’s current thinking on a topic and have general applicability, but are not legally binding.
Some notable industry guidance from FDA include:
2. Guidance on development of specific classes of products
3. How to assess both general and specific aspects of safety in the pre- and post-market setting
‘The Human factor’ in USFDA decision making (aka the 'juicy part' of this article):
? Beyond the clinical study of drugs, the Agency must also consider how people will actually use newly approved drugs once they are marketed.
? The clinical trial experience may not perfectly reflect how the drug will be used in the health care system.
? This is where social and behavioral science can inform regulatory decision-making.
? Human factor brings subjectivity and residual uncertainty in this regulatory benefit-risk assessment and cannot be done away with completely.
? This residual uncertainty creates the need for judgment in decision-making that is based on training and experience and allows regulators to determine whether a decision fits within the existing legal and policy framework, despite the uncertainty.
? Variations in clinical and scientific judgments among FDA experts can lead to differing individual opinions and conclusions regarding the benefit-risk assessment.
? Two assessors may agree on what risks and benefits of a drug are perhaps, but they might not agree to accept (or reject) the forthcoming risk for the benefit established for a drug!
? The decision on what to do would obviously depend on the nature and severity of the specific toxicity, how often available treatments fail, the severity of the condition being treated, and many other factors.??
? Reconciling such differences and understanding where tradeoffs are made can be a challenging task for a regulator.
Ideal framework for USFDA B/R assessment (the BRF):
1.The relevant facts
2.Uncertainties
3.Key areas of judgment
4.Clearly explains how these factors influence a regulatory decision
Why such standardized uniform framework is ideal in B/R context?
? Such a framework can greatly inform and clarify the regulatory discussion.
? Such a framework can provide transparency regarding the basis of conflicting recommendations made by different parties using the same information.
? When the final decision is made, a single framework provides a standardized, predictable, and accessible form that communicates the basis for FDA’s regulatory decision to the public, while also documenting the decision for reference as FDA considers similar benefit-risk assessments in the future.
Development of a Benefit-Risk Framework:
? In 2009, FDA initiated an effort to explore more systematic approaches to benefit-risk assessment for human drugs and CDER took a lead in this.
CDER leadership role in 2009-
? Desire to be clearer and more consistent in communicating the reasoning behind drug regulatory decisions,
? Which benefits and risks are considered
? How the evidence is interpreted
? What the implications of the evidence are for the benefit-risk assessment.
? A need to ensure that reviewers’ detailed assessments could be readily placed in the larger patient care and public health context
USFDA Benefit risk assessment principles:
2. A systematic approach to benefit-risk assessment should support the work of review staff throughout the lifecycle of a drug by capturing the full range of decisions from pre-market review through any regulatory actions that are necessary in the post-market setting.
3. It should facilitate identification of the critical issues regarding benefit and risk and faithfully capture the review team’s deliberation on those issues.
4. The approach should also focus discussion and communication on the weighing of those issues, ensuring that benefit and risk considerations are kept in mind throughout review.
5. Finally, a systematic approach should efficiently integrate into a review teams’ existing processes and work products.
The raging debate amongst regulators: “qualitative” versus “quantitative” approaches to benefit- risk assessment
? In the last few years, other disciplines such as decision science and health economics have been applied to drug regulatory decision-making.
? There has been much discussion among regulators, industry, and other stakeholders regarding “qualitative” versus “quantitative” approaches to benefit- risk assessment.
What is ‘quantitative benefit-risk assessment’?
? A quantitative benefit-risk assessment encompasses approaches that seek to quantify benefits and risks, as well as the weight that is placed on each of the components such that the entire benefit-risk assessment is quantitative
? It usually requires assigning numerical weights to benefit and risk considerations in a process involving numerous judgments that are at best debatable and at worst arbitrary
Drawbacks of quantitative B/R assessments:
2. Not transparent
3. Subjective judgments and assumptions
4. Appropriate where application of quantitative decision modeling seems most appropriate for decisions that are largely binary but regulatory B/R decisions are so much more complex and nuanced than that
5. There is significant concern that reliance on a relatively complex model would obscure rather than elucidate a regulator’s thinking.
USFDA qualitative descriptive approach for B/R analysis:
? To overcome arbitrariness and subjectivity of quantitative B/R assessment approach (useful in binary decisions but not in complex nuanced regulatory decisions of drug B/R assessment in humans), FDA came up with qualitative B/R method.
? FDA considers it most important to be clear about what was considered in the decision, to be as quantitative as possible in characterizing that information, and to fully describe how that information was weighed in arriving at a conclusion.
? Quantitative assessments certainly underpin the qualitative judgments of FDA’s regulatory decisions, but FDA has adopted a structured qualitative approach that is designed to support the identification and communication of the key considerations in FDA’s benefit-risk assessment and how that information led to the regulatory decision.
USFDA BRF structured qualitative approach: The Five Questions
? FDA BRF focuses on structured qualitative approach that provides a high-level snapshot and the concise bottom-line descriptions of the relevant issues to the regulatory decision in words.
FDA BRF asks five relevant questions for qualitative approach:
1."what is the problem?"
2."what other potential interventions exist?"
3."what is the benefit of the proposed intervention?"
4."what am I worried about?"
5."what can I do to mitigate/monitor those concerns?"
To sum up this raging debate Take home msg:
USFDA forms their BRF/Assessment based on quantitative methods, brings clarity about 'what and why' of their BR decision using quantitative way and uses qualitative approach to justify the decision and to explain 'the how' of these decisions (to support the identification and communication of the key considerations)
Inter- regulatory synergies in B/R assessments:
? FDA’s work in structured benefit-risk assessment coincided with efforts elsewhere in industry
? At the same time other regulators such as EMA came up with their own approach for these assessments
Synergies/ similarities between USFDA and EMA Benefit-Risk Assessment approaches:
FDA vs EMA approaches are quite similar in their most basic forms:
2. Identifying the important relevant information and data regarding benefit and risk
3. Assessing that relevant information with respect to its bearing on the decision
4. Drawing conclusions from the information based on expert judgment
5. Communicating the decision and its rationale
How B/R assessment approaches evolved at the FDA?
? First task of USFDA was to make ‘the implicit’ into ‘the explicit’ and document the present yet undocumented conventions
? Study past regulatory decisions and focused on prior cases that represented relatively challenging benefit-risk assessments
? Understand and describe the approach, the rationale that was already used by FDA but was not documented yet
? USFDA sought to develop a structure that faithfully represented the Agency’s thought process and how they weigh the information when FDA makes regulatory decisions
? FDA rationale being where a regulatory decision is complex and not straightforward, clearly communicating the reasoning behind the decision to all audiences is particularly important.
? FDA recognized that a framework must be able to handle challenging benefit-risk decisions at any point in a drug’s lifecycle.
? FDA consulted all stakeholders with roles in decision making and took inputs to understand the important benefit-risk considerations that weighed on the regulatory recommendation and decision
? FDA analysis of stakeholder inputs indicated that review considerations could be appropriately grouped in several areas.
So what came off this? --> The areas FDA gives considerations in B/R analysis
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? The necessary information about the demonstrated benefits and risks of the proposed drug identified through careful review of the submitted clinical data.
? Risk management considerations, including recommended labeling language, represented another key consideration if review staff felt these were needed to manage important safety concerns
? Consideration was also given to information about the disease to be treated or prevented and the benefits and risks of other available therapies for the disease
So what USFDA structure for B/R analysis looks like?
USFDA developed a basic structure of a benefit-risk framework that includes the following categorization of key decision factors:
1.Analysis of Condition
2.Current Treatment Options
3.Benefits
4.Risks
5.Risk Management
Analysis of Condition and Current Treatment Options:
? Analysis of Condition and Current Treatment Options provide a summary and assessment of the severity of the condition that the product is intended to treat and other therapies available.
? This is very similar to section 18.1 of EU PBRERs: Medically important alternatives section.
? This represents the context of the decision that can provide useful information for weighing the benefits and risks of the drug under review.
? Similar approach is taken by EMA and JP as well..In section 18.1, a backgrounder about the indication to be treated is given with all pharmacological as well as non-pharmacological treatment options available in the market based on best available current scientific information.
? Risk Management provides a summary and assessment of any efforts that could help to mitigate the identified safety concerns, or ensure that the drug is directed to those patients for whom the risk is considered acceptable.
Benefit and risk sections analysis in USFDA:
? Benefit and Risk provide a summary and assessment of the submitted evidence concerning the drug under review.
? Key considerations of benefit include the results of the clinical trials and the clinical meaning of primary and secondary endpoints, as well as appropriate analyses of sub-populations.
? Key considerations of risk include the adequacy of the safety database, the severity and reversibility of adverse events, and the potential for sub-optimal management in the post-market setting that may be of concern.
In assessing benefit and risk, consideration is also given to other factors that may be relevant for a particular drug review such as:
1.Non- clinical pharmacology and toxicology data
2.Clinical pharmacology (e.g., mechanism of action, pharmacodynamics, and pharmacokinetics);
3.Chemistry, manufacturing, and controls (CMC)
4.Clinical microbiology.
Two considerations for each of those factors:
Within each of these factors (Indication/condition to be treated and treatment options, Benefits and risks and risk mgmt.), there are two considerations that inform the regulatory decision:
2. Conclusions that must be made about each decision factor
These conclusions are the subjective interpretation of the evidence for each aspect of the benefit-risk assessment categorized into two categories as below:
2. Conclusions and Reasons captures the implications of the facts, uncertainties, and assumptions with respect to regulatory decision-making, drawing conclusions from the evidence and uncertainties and explaining the bases for those conclusions.
USFDA Benefit-risk structured approach explained:
? The first two decision factors, Analysis of Condition and Current Treatment Options, represent the framework’s therapeutic area considerations and are distinct from the other drug-specific considerations in the framework.
? The therapeutic area information represents the current state of knowledge regarding the condition and the available therapies and can be completed for any disease area.
? As the available therapies for a disease area change or as knowledge and understanding of the disease improves, this information can be updated.
? The additional factors of Benefit, Risk, and Risk Management represent the product-specific area of the framework.
? The information found here relates specifically to the drug under review.
? As our knowledge of a drug’s benefits and risks changes post-approval, this information can be updated in the framework, reflecting the dynamic nature of benefit-risk assessment during the drug lifecycle.
? The final row of the framework is the Benefit-Risk Summary Assessment, a succinct well-reasoned summary that clearly explains FDA’s rationale for the regulatory action including important clinical judgments that contributed to the decision.
Benefit-Risk Summary Assessment summary:
? It is the final row of the USFDA B/R approach table
? This summary clearly explains FDA’s rationale for the regulatory action including important clinical judgments that contributed to the decision
? Summary should integrate the analyses of benefit and risk and the applicable statutory and regulatory standards into a coherent explanation of the conclusions reached
? The assessment draws on the key supporting evidence and uncertainties, accounts for the understanding of the condition, and considers the available therapies that establish the context in which benefits and risks are weighed.
? It also includes the rationale to support the labeling and other risk management as well as post-marketing requirements/commitments if more information is necessary to further characterize the benefits or risks of the drug.
? Where there are differences of opinion within a review team with respect to scientific or clinical judgment, they are noted in the assessment along with an explanation of how the differences were resolved or taken into account in the final decision.
Key consideration for USFDA pre-Market Benefit-Risk assessment of NDAs
USFDA’s PDUFA V commitments (2013):
? Reference to revision of CDER’s Clinical Review Template
? The Office and Division Director Summary Memoranda Templates
? Equivalent Center for Biologic Evaluation and Research (CBER) documents to incorporate structured benefit-risk assessment in the human drug review process.
What after authorization? Adaptation to Key Considerations in the Post-Market Setting
? Once a drug is approved and marketed, we often gain additional information as the drug is used and studied in broader and more diverse populations
? Sometimes this new information pertains to the benefit of the drug, particularly if health outcomes trials (e.g., those that identify cardiovascular benefits in lipid-altering drugs) are conducted after the drug is approved as is often the case. In many cases, the new information relates to the drug’s safety
? Agency’s commitments in PDUFA V concerns enhancing and modernizing the FDA drug safety system
? Authority to require risk evaluation and mitigation strategies (REMS) to manage a known or potential serious risk associated with a prescription drug or biological product in the post-approval context
? The FDA Amendments Act of 2007 granted FDA the authority to require REMS, if FDA becomes aware of new safety information and determines that such a strategy is necessary to ensure that the benefits of a drug outweigh its risks
Characterization of Uncertainties in Benefits and Risks:
? Although drug regulatory decisions are informed by an extensive body of evidence on the safety and efficacy of a proposed product, in many cases, FDA must draw conclusions from imperfect data.
? This imperfection and uncertain data is the part of the B/R game
? Identifying and evaluating sources of uncertainty (e.g., absence of information, conflicting findings, marginal results) is an important part of reviewers' work
? FDA has to acknowledge the role of uncertainty in the benefit-risk framework
? Drawing conclusions in the face of uncertainty can be a complex and challenging task
? Being explicit about the impact of uncertainty on decision-making is an important part of communicating regulatory decisions
? FDA focuses on two key areas: The first is characterizing the uncertainty in how well the benefit-risk assessment based on pre-market clinical trial data translates to the post-market setting after the drug is approved and used in a much wider patient population.
? The second area pertains to our level of uncertainty about a result or finding, particularly a new finding that becomes available in the post-market setting where the basis for the finding comes from sources of varying levels of rigor.
? In contrast to the prospective and highly planned studies of effectiveness, safety findings emerge from a wide range of sources, including spontaneous adverse event reports, epidemiology studies, meta-analyses of controlled trials, or in some cases from randomized, controlled trials.
? Data gained from CT can?sometimes provide contradictory and inconsistent findings on safety as well as on risks!
Evaluation of the Benefit-Risk Framework:
? The PDUFA V Commitments also require that this draft five-year plan include a plan to evaluate the impact of the benefit-risk framework in the human drug review process
? Review staff acquire experience and provide feedback on the framework and its implementation in drug review
? FDA anticipates that this evaluation will consider the utility of the framework in communicating key benefit and risk considerations both internally and externally, facilitating decision-making including decisions about risk management, and training new review staff.
FDA focus areas for this evaluation include:
2. Whether the framework provides value to internal reviewer communications and discussions related to pre-market regulatory decisions
3. Whether the framework provides value in supporting consideration of emerging safety and efficacy information in post-market drug decision contexts
Now the challanges part!
Challenges in establishing B/R ratio for a molecule:
Lack of uniformity-
? B/R analysis is very subjective and varies person to person a great deal
? No uniform method to decide B/R ratio acceptable to all MAHs/industry and regulators
2- Innate variation in safety profile of a molecule through lifecycle-
? Each molecule or combination is different and consistently evolves in terms of drug, adverse event, therapeutic indication and alternative treatments.
? As a molecule matures, more data becomes available, risk benefit both aspects change as data across all population subgroups becomes available.
3- Perceptions-
? Public perceptions of a particular molecule as well as that of the credibility of ability/willingness of regulatory authority to safeguard patients from side effects of a molecule and risks keeps changing.
? Mass media and social media effects on these perceptions.
Challenges for FDA reviewers in benefit- risk assessments:
2. Subjectivity in interpretation of risk allowed in context of benefits gained
3. Variations in clinical and scientific judgments among FDA experts can lead to differing individual opinions and conclusions regarding the benefit-risk assessment
4. The human factors- patients use medicine in a much different manner compared to clinical trials than real world
5. Intense media glare and scrutiny- allegations of being in cahoots with ‘big pharma’
6. Applying the scientific method to understanding drug safety is often more challenging, because the signals of serious safety concerns are often quite small during pre- approval drug development.
7. So less data- premarketing phase and too much data in post-marketing period both lead to problem in overall B-R assessment in the larger context.
The complexity of Benefit Risk Assessment:
Balancing benefits with risks is complex, as it involves:
1.Uncertainty (difficult to estimate probability of desirable and undesirable effects, effect size, etc. due to limited and sometimes conflicting data)
2.Differences in perspectives (patient, societal, regulatory perspectives)
3.Heterogeneity of effects across patient populations
4.Ill-defined preferences and utilities of outcomes
5.The difficulty of trading off effects of differential importance
6.Lack of agreement on what valuation criteria to use
The 10 unique challanges USFDA Reviewers face in their work:
1-?????Heavy Workload
2-?????Work across multiple molecules all at once
3-?????Training requirement-
Before reviewing documents, reviewers must learn the regulatory language and regulations plus prior Agency decisions.
Such kind of training requires massive efforts, time and investment.
4-?????High turnover rate- As people who learn the FDA review process are very attractive to the pharmaceutical industry.
5-?????Complicated process of FDA drug review-
FDA reviewers must consider:
·????????The stage of drug development,
·????????The regulatory history for the molecule and of same drug class
·????????Prior commitments between the sponsor and FDA or between FDA and others.
So, naturally work of a FDA reviewer is not as straightforward as reviewing a report or data!
6-?????Ability to connect the dots:
During sponsor meetings, reviewers sometimes have to read between the lines of the questions to determine what exactly is being asked; reviewers know that every study is done for a purpose.
7-?????Large bureaucracy-
FDA review processes are done by large multi-disciplinery teams, extensive collaboration within various FDA teams and with sponsors and media can naturally be draining and requires special collaboration skills!!
8-Background and required domain knowledge-
A reviewer must have a deep understanding of the topic and scientific area under review, as well as knowledge of how to use available literature.
9-?????Taking the past along:
Drug development is extensive and exhaustive as a process.
Point is to build on the prior experience and real world knowledge gained.
Each step builds upon all previous steps in the process by that stage.
You need special skills to review and write feedback accordingly!
10-??Intense public scrutiny and media glare!
This one is a real doozy! People want to know! They want to get cured and they want the drug RIGHT NOW!
Phew, this was one long article but I hope you find the article and the subject it addresses as interesting and as relevant as I do!
There is a lot published on the subject and upon ending this article, I've added links to many such essential further readings, including link to a 222 slide PPT by USFDA itself on how they think. If you feel like it, check out these below :)
It's a complex, subjective, relevant and equally interesting topic! I intend to write more articles on Benefit-Risk assessment process/ approaches and practical aspects of this assessment in the future as well. Keep coming back for the same on my Linkedin profile!
I hope you enjoyed the article and found it relevant and informative..If you have doubt/clarifications/ point of view/ opinions on BRF, I'd love to know and we can discuss...Please reach out to me in comments or DMs for the same!
I wish you a very happy weekend! :)
You can read more on this subject of Benefit-Risk Asessment and USFDA here.
Recomended further readings:
Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions:
Benefit-Risk Assessment for New Drug and Biological Products Guidance for Industry
Benefit-Risk Considerations for Product Quality Assessments Guidance for Industry