Regulatory Education for Industry (REdI) Annual Conference 2023 - Slides and Recordings

Early this month, FDA conducted 'Regulatory Education for Industry (REdl) Annual Conference 2023'. This annual conference provided opportunity for health care industry professionals to Learn directly from the FDA’s regulatory experts in medical product centers: drugs, devices, and biologics. The course from annual conference is designed to provide participants with a strong, basic foundation in the FDA’s regulatory requirements, and also create awareness of current activities.

• The flyer about this conference: https://www.fda.gov/drugs/news-events-human-drugs/regulatory-education-industry-redi-annual-conference-2023-06052023
• The agenda for the conference: https://sbiaevents.com/files2023/REdI-2023-Agenda.pdf

All the FDA presentation can be watched on Youtube and the presentation slides are listed in the tables. 

There are two presentations by FDA statisticians: Dr Andrew Potter on "Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials" and Dr John Scott on "FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program".

Plenary + Drugs Day 1:

User Fee Impact on FDA Programs Jeff Shuren, Patrizia Cavazzoni, Peter Marks

Biosimilar Program Updates and What’s New Under BsUFA III Stacey Ricci and Kimberly Maxfield

FDA Formal Meetings: What’s New under PDUFA, BsUFA, and OMUFA Elizabeth Thompson

Electronic Submission Gateway (ESG): The Road to Modernization Jessica Bernhardt

ECTD v4.0 Implementation Update Jonathan Resnick

eCTD: More than a Document Heather Crandall

CDER-CBER Data Standards Program Ray Wang

Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials Andrew Potter

PDUFA VII Goals For Digital Health Technologies – A Technical Perspective Marry Ann Slack

Drugs Day 2: 

Leveraging Small Business and Industry Assistance (SBIA) Resources Renu Lal

Overview of FDA Split Real Time Application Review (STAR) Pilot Program LaShawn Schnupp

Use-Related Risk Analysis (URRA) and Human Factors (HF) Protocol Reviews: What to Submit for an Efficient Review Lolita Sterrett

The Modernization of Clinical Trials through Digital Health Technologies (DHTs), Decentralized Clinical Trials (DCTs), and Point of Care Trials Elizabeth Kunkoski

PDUFA VII Real-World Evidence Kimberly A. Smith

New PDUFA VII Commitments: Pre-approval & Post-approval Postmarketing Requirements (PMRs) Kathleen Weil

How CDER is Accelerating Rare Disease Cures and the PDUFA VII Rare Disease Endpoints Advancement Pilot Program Kerry Jo Lee

Chemistry, Manufacturing, and Controls Assessment for Expedited Programs Paresma Patel

Best Practices for Drug Product Recalls Doris Chin

Devices Day 1:

Medical Device Regulatory Framework: Where to Start? Kendra Holter

Biocompatibility Basics Jennifer Goode

Streamlining Conformity Assessment: Putting Standards to Work Scott A. Colburn

Detangling the 510(k) Process Andrew Sprau

CDRH Portal Overview and Feature Walkthrough Nelson Anderson

Reduced Medical Device User Fees: Small Business Determination (SBD) Program Jason Brookbank

Managing Medical Device Nonconforming Product with Quality Ruth Bediakoh

Handling Medical Device Compliant Files with Quality Tonya Wilbon

Devices Day 2/Biologics Day 1:

Addressing Regulatory Science Gaps in Artificial Intelligence (AI) / Machine Learning (ML) Alexej Gossmann

Radiation-Emitting Medical Device Update Laurel Burk

CDRH Medical Device Import Overview Yvette Montes

All about the Form FDA 483 and the ORA Electronic Reading Room William Chang

PDUFA VII Enhancements - Interaction with OTP Mara Miller

Overview of PREA, PSPs plus an Introduction to the Rare Pediatric Disease (RPD) Priority Review Voucher Program Adrienne Hornatko-Munoz

Nonclinical Development for Cellular and Gene Therapy Products from the Perspective of CBER/FDA Ernesto F. Moreira

Nonclinical Considerations for the Development of Cell and Gene Therapy Products for IND Submissions Gregory Conway

Clinical Readiness for IND Submissions Shelby Elenburg

Design Considerations for Clinical Trials in Rare Diseases

Rosa Sherafat

 

Biologics Day 2:

CMC Development and Readiness Pilot (CDRP) Program Ramjay S. Vatsan

CMC Considerations for Tissue Engineered Product Development Wen (Arron) J. Seeto

Identifying and Controlling Attributes Related to Potency for Cell and Gene Therapy Products Matthew Klinker

FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program John Scott

Postmarketing Safety and Pharmacovigilance for Vaccines Meghna Alimchandani

Expanded Access to Investigational Drugs for Treatment Use Lei Xu

CBER Inspections of Facilities for Biological Products Wei Wang

Story of BrainStorm's Stem Cell Treatment for ALS - Criticality of the Statistical Analyses

This past week, the biotech company BrainStorm announced the decision to submit a BLA to the FDA for NurOwn® (a stem cell treatment) for the treatment of ALS (Amyotrophic Lateral Sclerosis). The news stirred quite some discussions. The decision to submit the BLA is driven by the reanalysis or the corrected analysis of the previously announced negative results from their pivotal study. In their news announcement, they stated the following: 

New clinical analyses strengthen the conclusions from NurOwn's® Phase 3 clinical trial

A correction was made to the Muscle and Nerve publication from December 2021 describing the results of NurOwn's® Phase 3 clinical trial in ALS following new clinical analyses which strengthen the Company's original conclusions from the trial. The correction results in a statistically significant treatment difference (p=0.050) of more than 2 points for an important secondary endpoint, average change from baseline in ALSFRS-R, in the pre-specified efficacy subgroup of participants with a baseline score of at least 35. Analyses reported in the original publication utilized an efficacy model that unintentionally deviated from the trial's pre-specified statistical analysis plan by erroneously incorporating interaction terms between the subgroup and treatment. The newly published results, which includes supporting information to the publication, employ the efficacy model as pre-specified in the trial's statistical analysis plan, correcting the analyses. The correction also relates to the other subgroup analyses published for this endpoint, demonstrating that all subgroups with ALSFRS-R baseline scores of at least 26 to 35 showed a statistically significant benefit following treatment with NurOwn® (p≤0.050) on this secondary endpoint.

The reanalysis (or as they called it 'correction') was only on the pre-specified subgroup analyses for the secondary endpoint of ALSFRS-R total score (as highlighted in yellow below from the original publication). 

An erratum was issued to present the 'corrected' results for this endpoint: 

The original publication reported results for ALSFRS-R total score subgroup endpoint using a model that unintentionally deviated from the pre-specified statistical analysis plan by erroneously incorporating interaction terms between the subgroup and treatment. The error was made by the CRO who performed the statistical analyses. Applying the correct statistical model for that outcome resulted in the average difference between NurOwn- and placebo-treated patients going from 2.01 points to 2.09 points, but importantly this difference became statistically significant with a P-value of 0.05 (from a p-value of 0.20 in the original analysis). 

While the trial did not reach statistical significance on the primary or secondary endpoints, the company believes these corrected analyses support the conclusion that NurOwn has a positive treatment effect for patients with ALS. 

A year and a half ago, FDA put out a statement (unusual) to advise the BrainStorm not to file the BLA based on the announced results after unblinding of their phase 3 study. FDA specifically stated the following: 

With the recent completion of a randomized phase 3 controlled clinical trial comparing NurOwn to placebo, it has become clear that data do not support the proposed clinical benefit of this therapy. Data indicated that none of the primary or secondary endpoints were met in the group of patients who were randomized. For the main (primary) endpoint, 27.7% of people given the placebo were scored as responding compared to 32.6% of people given NurOwn. The 4.9% absolute difference in responders was not at all statistically significant, and the small difference between the two groups was most likely due to chance. In addition, there was a modest excess in deaths in those treated with NurOwn, the significance of which is unclear at this time. If BrainStorm plans further studies of NurOwn to determine if the product can provide clinical benefit to individuals with ALS, FDA will continue to provide advice to the company on their development program.

Now, A year after FDA slammed on the breaks, BrainStorm is hitting the gas with updated data, approval plans, we will see how the FDA will react to BrainStorm's plan and if FDA will accept the BLA filing by BrainStorm. 

No matter what the fate is for BrainStorm's BLA, one thing is clear: the statistical analyses are critical to the clinical trials and to the overall drug development. It is so important to avoid errors/mistakes in the statistical analyses. This important point has been discussed in previous posts such as "Statistician's nightmare - mistakes in statistical analyses of clinical trials" and "Futility Analysis and Conditional Power When Two Phase 3 Studies are Simultaneously Conducted" where the inappropriate method for futility analysis was implemented. 

It is surprising that the p-value and the statistical significance are still playing a critical role in regulatory decision-making after all of these discussions about retiring statistical significance and p-value. 

FDA's Priority Review Voucher for COVID-19 Vaccine

 To spur drug development in the under-developed area, FDA relies on various policies and programs to incentify the biotech and pharmaceutical companies. The most famous one is the orphan drug development. In the last 10 years or so, a program called 'priority review voucher' become popular. If the biotech and pharmaceutical companies develop a drug in certain underdeveloped areas, once the drug is approved (not emergency user authorization), FDA will issue the marketing authorization holder a priority review voucher. The priority review voucher can be redeemed for future NDA/BLA applications to shorten the review time by four months. The priority review voucher can be a commodity to be sold or transferred to another company for monetary gain. 

• FDA's Priority Review Voucher Programs

• RAPS: Regulatory Explainer: Everything You Need to Know About FDA’s Priority Review Vouchers
• Endpoints: Priority review voucher updates: Who's won PRVs, who's bought them, and how much they're selling for

FDA currently has three priority review voucher programs and each has its own guidance to industries:

• Tropical Disease Priority Review Voucher Program and its guidance
• Rare Pediatric Disease Priority Review Vouchers
• Material Threat Medical Countermeasure Priority Review Vouchers 

To qualify for a PRV for tropical disease, a sponsor’s application must be for a drug or biological product for the prevention or treatment of a “tropical disease,” where a list of tropical diseases are listed by FDA and additional tropical diseases may be added by FDA. For example, Ebola was not in the original list but was added in 2019.

To qualify for a PRV for rare pediatric disease, a sponsor's application must be for a drug or biological product for the prevention or treatment of a "rare pediatric disease," where the rare pediatric disease is defined as:

The 21st Century CuresAct (Cures Act) Section 565A of the FD&C Act was designed to encourage development of new drug and biological medical countermeasures (MCMs), by offering additional incentives for obtaining FDA approval of certain MCMs. While there are existing incentive programs to encourage the development and study of drugs and biologics that may also be applicable to MCMs, section 565A of the FD&C Act provides an incentive specifically for development of certain MCMs, which may be used alone or in some cases in combination with other incentive programs. Other FDA incentive programs include: orphan-drug designation and the associated benefits under the Orphan Drug Act for rare disease drugs; programs to encourage study of drugs used in pediatric populations; various programs to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening conditions; and programs for certain tropical disease products and antibacterial products. 

Last week (Jan 31, 2022), Moderna obtained the final approval (not emergency user authorization) for its Covid-19. After the approval, a brand drug name or proprietary name - SPIKEVAX - is approved. In the approval letter, FDA granted Moderna a material threat medical countermeasure priority review voucher (PRV).

Endpoints had an article "Exclusive: The curious case of the BioNTech priority review voucher" indicating that for Pfizer/BioNTech's Covid-19 vaccine (brand name Comirnaty) approval, the priority review voucher was not included at the time of the BLA approval. After the approval, BioNTech (as the market authorization holder) received a MCM priority review voucher even though the company did not announce it publicly. 

A priority review voucher can be worth hundreds of millions if transferred. however, the monetary awards from the MCM priority review voucher are trivial compared to the sales of the Covid-19 vaccines - PRV is just a nice-to-have incentive.  

Afghan Withdrawal and Accelerated Approval for Aduhelm

These two topics seem to be irrelevant at all, but have one thing in common: changing the subjects when the decision is questioned.

For the US withdrawal from Afghanistan, the decision to withdraw from two decades of war is the right decision and welcomed by the majority of the Americans. However, the execution of the withdrawal was a disaster. The execution of the withdrawal is not properly planned, botched, entirely a failure no matter how the Biden administration tries to spin and change the subject. When questioned by the reporters, the Biden administration keeps mentioning how correct the decision of withdrawal from Afghanistan is and avoids mentioning why the execution of the withdrawal goes so wrong.

• Afghanistan is much worse than the fall of Saigon. Biden needs to act like it
• Biden dodged duty when he left Bagram, and then he dodged the question about it
• Leaving Afghanistan Was the Right Call, But It May Haunt Biden—and the U.S.—Forever
• Even Biden allies question execution of Afghanistan withdrawal
• Jake Tapper: On Afghanistan, Biden “Keeps Trying To Change The Subject From This Inept Withdrawal”

Changing the subject is also the theme in the controversial approval of Aduhelm for the treatment of Alzheimer's disease through the 'accelerated approval' pathway. The full story of the Aduhelm approval is very well captured in a New York Times article "How an Unproven Alzheimer's Drug Got Approved" and ‎NEJM Interview: Dr. Gil Rabinovici on the FDA’s controversial approval of a new treatment for Alzheimer’s disease. on Apple Podcasts. 

'Accelerated approval' is a valid pathway for approving a drug based on the surrogate endpoint without waiting for the results from the lengthy confirmatory trial to demonstrate the clinical benefit.  "Accelerated approval" was one of the regulatory approval pathways listed in FDA's guidance for industry "Expedited Programs for SeriousConditions – Drugs and Biologics"

Facing the mounting criticisms, FDA officials published the papers to defend their decision - Approval of Aduhelm through the 'accelerated approval' pathway is the right decision. They changed the subject here. Rather than arguing if approval of Aduhelm is the right decision, they argued if 'accelerated approval' is an appropriate approval pathway. 

• An Appropriate Use of Accelerated Approval — Aducanumab for Alzheimer’s Disease
• Approval of Aducanumab for Alzheimer Disease—the FDA’s Perspective

The controversy is not about 'accelerated approval', it is about how the 'accelerated approval' is used in the approval of Aduhelm. 

Accelerated approval is appropriate if the following qualifying criteria are met: 

• Serious Condition
• Meaningful Advantage Over Available Therapy
• Demonstrates an Effect on an Endpoint That Is Reasonably Likely to Predict Clinical Benefit

In Aduhelm's situation, the third criterion was not met. The two confirmatory trials had already been completed and indicated the inclusive results in clinical benefit. There is no evidence to conclude the biomarker (beta-amyloid) will be 'reasonably likely to predict clinical benefit.' 

'Accelerated approval' is a valid pathway for drug approval for a serious condition, however, it can't be applied to a drug approval:

• as a remedy approach (when clinical benefit had been shown to be inclusive)
• retrospectively applied (when the lengthy confirmatory trials had already been completed)
• against the pre-specification rule (i.e., accelerated approval pathway had been discussed and agreed with the agency prior to the BLA/NDA submission)
• for pivotal studies that had been discontinued early due to futility 
• based on results largely from the post-hoc, sub-group analyses
• against the consensus objection from the FDA advisory committee members. 

No wonder there are so many controversies after FDA's decision to approve Aduhelm, The story is continuing,...

The New York Times (9/2, Belluck) reports two congressional committees “investigating the controversial federal approval of Biogen’s Alzheimer’s drug, Aduhelm [aducanumab], demanded extensive information and documents from the Food and Drug Administration in a letter released on Thursday, making it clear that the committees’ leaders are troubled by unusual actions the agency took in the course of evaluating and approving the drug.” The letter said the agency “granted accelerated approval for the drug despite concerns raised by experts – including the agency’s own staff’ and members of its independent advisory committee. ... We are also concerned by reports of unusual coordination between F.D.A. and Biogen throughout the drug’s approval process.” The Times adds, “While some Alzheimer’s experts did support the approval, given that there are so few therapies available for the devastating condition, many are concerned that the evidence does not convincingly show the drug can provide any benefit. There is also concern because the medication can cause brain swelling or brain bleeding.”

Afgan Withdrawal: the decision is right, execution is not!

Aduhelm Approval: accelerated approval is a valid pathway, the application of accelerated approval in Aduheml approval is not!

Are we moving away from data listings now that the standard data sets (such as CDISC-compliant SDTM and ADaM data sets) are mandated by FDA?

After a clinical trial is concluded, the statistical group (statisticians and statistical programmers) will generate the tables, listings, and figures (TLFs in short) for the clinical study report (CSR). If the clinical trial results are good, the CSR including the TLFs and the data sets where the TLFs are generated from will be submitted to the regulatory authorities (such as FDA) for marketing authorization application (such as new drug application (NDA) and biological license application (BLA). 

From the statistical standpoint, the clinical trial is a process to collect the data (demographic, efficacy, and safety). The data sets we collected will be converted and mapped to the standardized format according to the CDISC standards - SDTM for tabulation data sets and ADaM for analysis data sets. The standardized data sets are then used for generating the tables, listings, and figures (may also be called the post-text TLFs). The post-text TLFs will be the building block for constructing the CSRs. 

The data listings are required as part of the CSRs and post-text listings are included in the CSRs as appendices. As specified in ICH E3 "STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS", data listings will be organized according to the sections/numbers below: 

A data listing will be looking like the below with a listing of adverse events as an example (the mock-up shell). Notice that the listing for adverse events is numbered as Listing 16.2.7 corresponding to the section number indicated in ICH E3 (above).

With the FDA's mandate for submission of the standardized data sets, the CDISC standard tabulation data set is SDTM (study data tabulation model), the natural question is if the data listings are still needed. The data listings are just the simple display of the SDTM data set (or ADaM data set) with format/layout beautified. Some sponsors have moved to the direction of not generating the formal data listings and they think that the CDISC-compliant data sets will be sufficient to replace the data listings. 

According to an FDA Final Guidance Webinar Q&A at Pinnacle21 website, the response indicated that the data listings would be replaced by the standard data sets. 

28: With the advent of a new “misc folder” instead of listings do you think that FDA is getting away from generating listings for each study? It seems that the datasets (SEND, SDTM, and ADaM) would stand alone to support any listings.

Once the standards requirements are in effect, the idea would be that listings would be replaced by the SDTM tabulations data, so yes.

The Final FDA Guidance on Standardized Study Data was initially published December 17, 2014 and has subsequently been revised several times. The FDA Binding Guidance requires Sponsors whose studies start after December 17, 2016 must submit data in FDA-supported formats listed in the FDA Data Standards Catalog. The FDA Data Standards Catalog specifies the use of CDISC standards such as SDTM, ADaM, and Define-XML as well as Controlled Terminology.

FDA has organized or participated in multiple webinars to emphasize the criticality of submitting the data sets in standardized formation, however, there is no subsequent mention about the standardized data sets replacing the data listings. 

I did an informal survey and asked the statisticians and statistical programmers working in other pharmaceutical companies and CROs, almost all responses were that they continue to generate data listings and have no plan to stop generating data listings even though they have been fully compliant with the CDISC data standards for their clinical trials.

Even though the CDISC compliant data sets make the data listings redundant and unnecessary, stopping generating the data listings entirely is a risky approach at this point. The data listings should still be generated until we see FDA's guidance indicating otherwise or until the ICH E3 is revised to indicate that the data listings can be replaced by the standardized data sets. 

Some links to this topic: 

• FDA website: Study Data Standards Resources
• FDA website: Study Data for Submission to CDER and CBER
• FDA Webinar: The FDA Study Data Technical Conformance Guide v4.4 - Nov 22, 2019
• Study Data Technical Conformance Guide - FDACDER Small Business and Industry Assistance (CDER SBIA) Webinar - Study Data Standards in eCTD: What You Need to Know about the New Technical Rejection Criteria - October 12, 2016
• Duke Margolis Center for Health Policy in collaboration with FDA organized a public workshop: Advancing the Development and Implementation of Analysis Data Standard: Key Challenges and Opportunities:

120-Day Safety Update or 4-Month Safety Update - The Requirement for NDA/BLA

After the new drug application (NDA) or biological license application (BLA) is submitted by the sponsor and is accepted by FDA, FDA reviewers will take 10 months (regular review) or 6 months (expedited review) to review the submission package and issue a decision on or before the decision date (PDUFA date). FDA reviewers will evaluate marketing applications for efficacy and safety and consider benefit and risk and will expect to receive a complete application at the time of filing (exclusive of the 120-day safety update).

It is very possible that during the 6-10 month review time, the sponsor will have additional data to supplement the already submitted NDA/BLA package. The regulatory pathway for providing additional data to the FDA is through so-called ‘120-Day Safety Update’, also referred to as ‘4-Month Safety Update, 4MSU).

The ‘120-Day Safety Update’ or ‘4-Month Safety Update” is specified as a requirement in Code of Federal Regulations - 21CFR314.50.

 

The 120-Day Safety Update contains any new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft drug labeling.

The report must be received by the FDA within 120 days of drug approval submission (receipt by the FDA of the New Drug Application (NDA), comprising the CTD/Integrated Summary Report) to avoid triggering an extension of the review clock.

The 120-Day Safety Update Report is mandated for submission to the FDA 120 days after submission of the NDA/BLA, and is intended to provide a summary update of any new safety data gathered by the sponsor since the data cut-off for the NDA submission documents, which could have been as far back as 6 months prior to the NDA submission date. In effect, the 120-Day Safety Update report could represent almost 1 year’s worth of new safety data, which needs to be reviewed by the authorities to ensure there has been no change in the product’s recorded safety profile. This is particularly important for medications intended for long-term treatment.

The 120-Day Safety Update is focused on additional safety data. If additional data is collected for efficacy variables, the efficacy information can also be included - but in general, it is for the summary propose and there is no inferential statistics needed. 

The data to be included in the 120 Day Safety Update can include:

• The long-term follow-up data from the on-going clinical trials
• Open-label extension studies with patients rolled over from the pivotal studies (usually the double-blinded controlled studies)
• Additional data from later time points and from newly enrolled patients
• Newly initiated clinical trials

Depending on the type of data to be included in the 120 Day Safety Update, the submission package could be just a written report or a full submission package (including the report; post-text tables, listings, figures; the data sets; define documents; SDRG/ADRG, etc.).

There are a lot of examples of 120 Day Safety Update from market applications. Here are some examples:

Briefing Document for Advisory Committee Meeting on Novo Nordisk’s Insulin degludec/liraglutide (IDegLira) for Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus. The NDA submission was based on two pivotal trials. Two pivotal trials (Trial 3697 in patients inadequately controlled on OAD treatment and Trial 3912 in patients inadequately controlled on basal insulin treatment) were designed to assess the contribution of the individual components of the combination to its primary efficacy effect (i.e., overall glycemic control). Additional data from other ongoing studies and the studies initiated after the data cut for NDA submission were submitted to the NDA as ‘120 Day Safety Update’:

The NDA submitted to the FDA had a data cut-off of 31 March 2015. Additional blinded safety data from two phase 3 trials that were ongoing at the time of NDA submission (Trials 4119 and 4056) as well as from a trial that was subsequently initiated (Trial 4185) was submitted to the FDA in a 120 Day Safety Update with a cut-off date of 30 September 2015. A brief overview of the ongoing trials included in the 120-day safety update is provided in Table 1–1. The 120-day safety update included available blinded safety data from these trials on deaths, other serious adverse events, pregnancies (including updates for pregnancies reported as ongoing in the NDA) and adverse events leading to withdrawal. 

Sunovion Pharmaceuticals NDA of Latuda for treatment of major depressive episodes associated with bipolarI disorder in pediatric patients aged 10 and older. The NDA submission was mainly based on the pivotal study (Study D1050326). Subjects who completed Study D0150326 was recruited into an open-label study (D1050302). As a 120-day safety date, the date from the open label study was submitted to support the NDA.

Study D1050302 is a 104-week open-label trial designed to assess the long-term safety profile of lurasidone (dosed 20-80 mg per day) in pediatric patients recruited from the pediatric schizophrenia (Study D1050301), bipolar depression (Study D1050326), and autism trials. This study was scheduled for completion last December, 2017. The Applicant submitted preliminary data for 619 patients participating in this trial with a cutoff date of October, 2016. Additionally, the 120-day safety update submitted with this application focused on the available safety data from 305 patients recruited from Study D1050326 with a cutoff date of May, 2017. It should be noted that although the final report for Study D1050302 has not been submitted for review, the Applicant presented acceptable long-term data to make an approval determination for this sNDA, including lurasidone exposure of 153 patients for ≥ 52 weeks.

Clinical Review for BLA for Mepolizumab for Add-on maintenance treatment of severe asthma. The data from long-term open-label studies were not available at the time of BLA preparation but was submitted to FDA as a 120-Day Safety Update.

This safety review primarily relies on data from three placebo-controlled studies in a severe asthma population: MEA112997 (Study 97), MEA115588 (Study 88) and MEA115575 (Study 75) as these studies most closely approximate the patient population to receive mepolizumab in the clinical practice. Within this review, the pooled database for these studies is referred to as the Placebo-Controlled Severe Asthma Studies (PCSA). Longer term safety data are provided by two open-label studies, MEA115666 (Study 66), MEA115661 (Study 61). These studies were ongoing at the time of the BLA submission with updated data provided to the Division in a 120-day safety update. The data from this safety update used a cutoff date of October 27, 2014 and provides cumulative review of the data for the studies ongoing at the time of BLA submission25 .

Pediatric use and geriatric use of drug and biological products

In the United States, every marketed drug or biological product needs to have its product label or package insert. The product label contains the use in special populations including pediatric and geriatric population. Here is a paragraph from FDA guidance on "Labeling for Human Prescription Drug and Biological Products — Implementing the New Content and Format Requirements"

Use in Specific Populations (§ 201.57(a)(13))
Information under the Use in Specific Populations heading includes a concise summary
of any clinically important differences in response or recommendations for use of the
drug in specific populations (e.g., differences between adult and pediatric responses, need
for specific monitoring in patients with hepatic impairment, need for dosing adjustments
in patients with renal impairment). Typically, information under this heading includes
limitations or precautions for specific populations or established differences in response.

Absence of the clinical study data in pediatric and geriatric population could sometimes cause problems in product label or in the drug approval process. During the drug development process, it is prudent to consider the inclusion/exclusion of patient population in terms of the age limit. In the study protocol, the inclusion criteria pertinent to the age limits (upper and lower limits) should be carefully considered. In the statistical analysis, when data for pediatric and/or geriatric population is available, subgroup analysis should always be performed.

In regulatory environment, the classification of the pediatric and geriatric population are defined as:

Pediatric population: according to ICH guidance E11 "Clinical Investigation of Medicinal Products in the Pediatric Population", the pediatric population contains several sub-categories:

• preterm newborn infants
• term newborn infants (0 to 27 days)
• infants and toddlers (28 days to 23 months)
• children (2 to 11 years)
• adolescents (12 to 16-18 years (dependent on region))

Notice that in FDA's guidance "General Considerations for Pediatric Pharmacokinetic Studies
for Drugs and Biological Products", the age classification is a little bit different. I am assuming that the ICH guidance E11 should be the correct reference.
Geriatric population:
Geriatric population is defined as persons 65 years of age and older. There is no upper limit of age defined. The Food and Drug Administration has regulations governing the content and format of labelling for human prescription drug products, including biological products, to include information pertinent to the appropriate use of drugs in the elderly and to facilitate access to this information by establishing a “Geriatric use” subsection in the labelling.

Further readings:

• Regulatory requirements for the development of medicinal products for pediatric use by Dr. Tom Sam
• FDA good review process "Labeling for Human Prescription Drug and Biological Products — Determining Established Pharmacologic Class for Use in the Highlights of Prescribing Information"
• FDA's Pediatric Drug Development
• Pediatric Trials: a Worldview