Feb 15

Draft Guidance of the Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products

By: Juliati Rahajeng, Ph.D., Clinical Strategy Scientist at Cato Research, and Dieanira Erudaitius, Ph.D., Scientist at Cato Research


A draft guidance with regards to the formal meetings between the FDA and sponsors or applicants of biosimilar or interchangeable products regulated under the Biosimilar User Fee Act (BsUFA) was published in June 2018. It describes the good meeting management practices (GMMPs) and the standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.


Types of Meetings

Various types of formal meetings occur between applicants or sponsors and the FDA to discuss development and review of a biosimilar or interchangeable product (as summarized in
Table 1). The type of requested meeting will depend on the stage of development of the biosimilar or interchangeable product and on the type advice being sought. Typically, a sponsor is granted one Biosimilar Initial Advisory (BIA) meeting and one Biosimilar Biological Product Development (BPD) Type 4 meeting for a single biosimilar or interchangeable product. However, a sponsor may request as many BPD Type 2 and Type 3 meetings as needed. These meetings can take place as face-to-face, teleconference or videoconference, and written response only (WRO) formats of communication. WRO meetings can only be requested for BIA and BPD Type 2 meetings.

Table 1           Formal Meeting Types between the FDA and Sponsor of BSuFA Products

Name of Meeting Objective Details of Meeting Type
Biosimilar Initial Advisory meeting To discuss whether licensure under Section 351(k) of the PHS Act may be feasible for a particular product ·         Meeting package should include:

(a) preliminary comparative analytical similarity data from a particular biosimilar or interchangeable product compared to the reference product

(b) an overview of the development program with the synopses of all completed, ongoing, and future studies

·         This meeting type is not for discussions involving significant review of summary data or full study reports

BPD Type 1 To discuss how to address a stalled development program or an important safety issue ·         Examples of topics to discuss include:

(a)    Input on how to address the hold issues should be seek from the FDA when a clinical hold is in place.

(b)   A new path forward needs to be discussed when the applicant has submitted the response to clinical hold issues and the response has been reviewed by the FDA but both the FDA and the sponsor agree that the development is stalled.

(c)    Input on how to address issues from the FDA upon receipt of an FDA nonagreement Special Protocol Assessment letter

(d)   Important safety issues

(e)    Dispute resolutions as described in 21 CFR 10.75 and 312.48

BPD Type 2 To discuss a specific issue so that FDA will provide advice with regards to an ongoing development program ·         Meeting package may include significant review of summary data, but does not include full review of study reports
BPD Type 3 To discuss an ongoing development program ·         This meeting type includes full review of study reports or in-depth data review

·         FDA advice with regards to the similarity between a particular biosimilar of interchangeable product and the reference product

·         FDA advice with regards to the need for additional studies including their design and analysis

BPD Type 4 To discuss content and format of a complete application or supplement submitted under Section 351(k) of the PHS Act ·         A pre-submission meeting for a biosimilar or interchangeable product application

BPD = Biological Product Development; BSuFA = Biosimilar User Fee Act; CFR = Code Federal Regulation; PHS = Public Health Service Act


Planning an Effective Meeting

To have an effective meeting with the FDA, adequate information should be included in the meeting request. Sponsors or meeting requesters are encouraged to consult the information that are publicly made available by the FDA with regards to biosimilar or interchangeable product development and other relevant FDA guidance when planning, developing, and providing information needed to support a meeting with the FDA. Deviations of a product development plan from the current practices or guidance should be recognized and explained. In the meeting package, sponsors or requesters should define the specific areas of input needed from the FDA, which include the objectives of the meeting, the meeting agenda, list of questions for the FDA, list of attendees representing the sponsors, and list of FDA attendees.


Where to Submit Materials

A sponsor has to submit a written meeting request to the FDA through paper submission or via the electronic gateway, as applicable. Meeting requests should be directed to the appropriate review division or office. If previously assigned, a meeting request should be submitted to the pre-investigational new drug file (pre-IND) file or application. A meeting request for the development of a biosimilar or interchangeable product with multiple indications that requires multiple division reviews, should be addressed to the division that has the regulatory oversight of the reference product. The Center for Drug Evaluation and Research (CDER) prefers for copies of the meeting packages to be submitted in electronic and paper format, whereas the Center for Biologics Evaluation and Research (CBER) prefers for copies of the meeting packages to be submitted only in electronic format.


What to Expect After Submitting a Meeting Request to the FDA

Upon receiving a meeting request, the FDA assesses each request and determines whether or not the request will be granted. The FDA will specify the meeting type and format of communication. The FDA will notify the sponsor or requester in writing the decision for the requested meeting within 14 days of BDP Type 1 meeting or 21 days for BIA and BDP Types 2, 3, and 4 meetings. Notification from the FDA usually includes the date, time, conferencing arrangements or location of the meeting, and the expected FDA attendees for the face-to-face and the teleconference or videoconference meetings.

For WRO meeting requests, BIA and BDP Types 1, 2, 3, and 4 meetings are scheduled within 75 days, 30 days, 90 days, 120 days, or 60 days, respectively, from receipt of WRO meeting package. For BIA and BDP Type 2 WRO meetings, the response time are within 75 days and 90 days, respectively, from receipt of WRO meeting request and package.


Reasons the FDA Denies or Cancels a Meeting Request

Requests for BPD Types 2, 3, and 4 meetings are usually granted except in the most unusual circumstances. However, the FDA will deny a meeting request for any of the following reasons:

  • The meeting request is not in an appropriate format
  • The meeting request is considered by the FDA as incomplete (i.e., the request is not accompanied with a meeting package containing adequate information for FDA review)
  • Failure to pay the required BPD fees for a biosimilar or interchangeable product within the required time frame, may result in the cancellation of a scheduled meeting.

BsUFA Fees

Under the BsUFA user fee provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act), BDP fees are applied to biosimilar or interchangeable products in the BDP program. There is no fee associated with a BIA meeting. BDP fees include the initial, annual, and reactivation fees. Sponsors are encouraged to review the draft guidance of Assessing User Fees under the Biosimilar User Fee Amendments of 2017 to obtain more information related to BsUFA fees.

How to Handle Preliminary Responses from the FDA

Communications between the FDA and sponsors that take place before the formal meeting may serve as the foundation for the discussion during the meeting. However, preliminary responses from the FDA should not be considered as final responses unless there is an agreement that further discussions are not required. In addition, new information and questions should not be generated based on the preliminary responses from the FDA. Preliminary responses are sent to the sponsors or requesters no later than 5 calendar days before the face-to-face, teleconference, or videoconference meeting date for BDP Types 2 and 3 meetings. For other meeting types, preliminary responses are sent no later than 2 calendar days before the face-to-face, teleconference, or videoconference meeting.

The Formal Meeting

Formal meetings are chaired by an FDA staff. The meetings usually start with introductions and an overview of the agenda. Formal presentations during the meetings are usually not required because adequate information should have been provided in the meeting package. However, if a presentation is necessary, it should be discussed ahead of time with the FDA project manager, who will determine whether a presentation will take place during the meeting. Additionally, presentation materials should be submitted ahead of the scheduled meeting.

Meeting summaries can be generated by an FDA or a sponsor attendee. However, the FDA’s meeting minutes are the official records of meetings and have to be preserved for meeting attendees and future reference. The FDA generally issue the official meeting minutes to the sponsors or meeting requesters within 30 calendar days after the meeting.

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Feb 11

New FDA Guidances for January 2019

By Zachary Swan, Ph.D., RAC (US), Regulatory Scientist at Cato Research

 FDA draft and final guidances released from CDER, CBER, and CDRH in January are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Rare Diseases: Common Issues in Drug Development Guidance for Industry Rev. 1 – Draft Guidance 31 Jan 2019
Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format Guidance for Industry – Draft Guidance 30 Jan 2019
Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products – Final Guidance 29 Jan 2019
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications – Final Guidance 29 Jan 2019
REMS Assessment: Planning and Reporting – Draft Guidance 24 Jan 2019
Immunogenicity Testing of Therapeutic Protein Products —Developing and Validating Assays for Anti-Drug Antibody Detection Guidance for Industry – Final Guidance 23 Jan 2019
Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway – Final Guidance 22 Jan 2019
ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs Guidance for Industry – Draft Guidance 16 Jan 2019
Upcoming Meetings (* = New)
February 12, 2019: Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* February 12, 2019: Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* February 26, 2019: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
* March 6 – 7, 2019: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
* March 8, 2019: Microbiology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* March 21, 2019: Neurological Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* March 27, 2019: Meeting of the Pulmonary-Allergy Drugs Advisory Committee Meeting Announcement
Last updated: 11 February 2019


Feb 08

Big Data, RWE, and AI Made Simple

By Hadas Jacoby Adani, Marketing Manager, Israel, Cato Research

Technology is slowly but surely penetrating the healthcare industry in general and the clinical trials sector in particular. New and advanced solutions offer a variety of possibilities aimed to both improving existing processes and creating new and more efficient ones. And on top of all stands the desire to make clinical trials more patient-centric.

In all of this, even though some of the technologies have yet to mature enough to meet the high quality standards necessary, it is important to know them and begin imagining the promise they hold for clinical trials.

Download Presentation – Click Here

Jan 29

New Year New FDA Strategic Framework on Real World Evidence Program

By Dieanira Erudaitius, Ph.D., Postdoctoral Research Fellow at Cato Research



Today there remains an ever-growing ability to generate, collect, and store vast amounts of health-related data. Availability of such data has opened the doors for the opportunity to leverage this information when developing drugs, for example in designing clinical trials. Having all this data at our fingertips is exciting as it has many potential uses but also leads to many questions: How can we best use this data for good? When is it appropriate to use this type of data? Are there standards for how to analyze the data? How can we guarantee the data is of the highest quality? How do we ensure the data is both reliable and relevant?


These types of discussion are by no means new topics in the regulatory world. There have been numerous ongoing discussions regarding how to leverage this vast amount of available information and the appropriate ways to integrate it into the regulatory-life cycle. Many strides have already taken place to assess the use of health-related data as evidence for safety of certain drugs. Now, progressing forward, we begin to step into the realm of how to use such data when establishing evidence for drug efficacy.


On 06 December 2018 the United States Food and Drug Administration (FDA) announced the release of a strategic framework to evaluate the potential use of real-world evidence (RWE) to support regulatory decisions on the development of drugs and biologics. The RWE program is issued in response to the 21st Century Cures Act. Specifically, the program is designed to incorporate a framework where RWE may be used to (1) support approval of a new indication and (2) support or satisfy postapproval study requirements for both drugs and biologics.[1] Medical devices, however, are not within the scope of this framework.


RWE can support a new indication only for drugs or biologics already approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act. Similarly, RWE used to support a new indication for biologic products will be applicable for biologics licensed under section 351 of the Public Health Service Act.




The FDA defines:


  • Real world data (RWD) as “data relating to patient health status and the delivery of health care routinely collected from a variety of sources.”[[1]]


  • Real world evidence (RWE) as “clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.”[1]


Reasons for Capturing RWD

RWD is collected for a number of different reasons. Some example uses are to develop analysis infrastructures to support study designs (i.e., randomized trials or observational studies), collecting data to generate RWE, and for improving efficiency of clinical trials.[[2]]


Current Use

The FDA already considers RWD and RWE in evaluation safety for drugs, devices, and biologics.


Current uses of RWD and RWE include:

  • The Sentinel System, which evaluates drug or biologic safety by monitoring electronic health and administrative data.[[3]] In some cases, the Sentinel System has accelerated and provided more effective postmarketing evaluations, saving time and money.[2, [4]]
  • The FDA-Catalyst program, part of the sentinel initiative, surveys and researches medical products on the market by obtaining patient reported information (PRO) via smart devices (e.g., FDA MyStudies mobile application project).[4, [5]]
  • The Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) use pharmacoepidemiologic research projects to conduct safety monitoring.[4]
  • CDER uses RWD from the Center for Disease Control and Prevention (CDC) and Prevention National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance Project to investigate drug abuse, misuse, etc.[4]
  • CBER also uses RWD for focused surveillance of existing databases (e.g., vaccine safety using the Post-Licensure Market Rapid Immunization Safety Monitoring (PRISM) or Blood components and blood derived products with Blood Surveillance Continuous Active Surveillance Network (BloodScan)).[4]
  • FDA issued The Best Practices for Conducting and Reporting Pharmacoepidemilogic Safety Studies Using Electronic Healthcare Data[6] which describes utilizing RWD from electronic healthcare systems.[4]


Sources for RWD

RWD can be obtained from a number of sources; such as, electronic health records (EHR), administrative and medical claims databases, product and disease registries, patient-generated data, and other sources (i.e., mobile devices).[4] Part of the scope of the RWE program will be to evaluate what types of RWD are acceptable and whether RWE is properly generated from RWD.


Benefits of Using RWD and RWE

Using RWE can aid in supporting a product’s effectiveness. Some of the benefits of using RWD and RWE are:

  • Faster approval for label modifications or revisions (e.g., adding or changing an indication; modifying dose, dose regimen, or route of administration; safety and efficacy information).
  • Faster data collection
  • Improvements for cost savings (e.g., preventing the need for extended clinical trials)
  • Collecting data more representative of actual use in the target population
  • Proving more information to patients and providers


Implementation of the Framework

The FDA’s goal is to develop a platform that integrates RWE into the drug development and regulatory life-cycle.[1, 2] Table 1 summarizes the plan for the multifaceted program which engages various stakeholders, issues new guidance documents for developers, and assess the type of RWD and RWE being generated to develop standards for appropriate use across disciplines.


Table 1. Implementation of the Strategic Framework.

Scope Purpose Comments
Guidance How to assess reliability and relevance of RWD from electronic healthcare data used to generate RWE on a product’s effectiveness


·         RWD sources include medical claims, EHRs, registries, and international electronic healthcare data

·         Reliability regarding data accrual and control

·         Will build upon Pharmacoepidemiologic Guidance[[6]]


Guidance Potential gaps in RWD sources and strategies to address them How to use other RWD sources (mobile technologies, electronic PROs, wearables and biosensors) to generate RWE that may be difficult to demonstrate solely using RWD sources (EHRs and medical claims)


Guidance Consideration for designing clinical trials that include pragmatic design elements and that generate evidence of effectiveness for regulatory decisions While evidence from traditional clinical trials are not considered RWE, hybrid (or pragmatic) trial designs and observational studies are potential sources capable of generating RWE
Guidance Use of RWD to generate external control arms A potential guidance for historical controls used as external control arms using data from past traditional clinical trials.[6, [7]]
Guidance How observational studies can be used to generate RWE to support product effectiveness Build off Pharmacoepidemiologic Guidance[7] to support changes in labeling that require evidence of effectiveness


Guidance Different study designs using RWD to generate RWE to determine effectiveness Will build off available guidance documents such as Use of Electronic Informed Consent[[8]], Electronic Source Data in Clinical Investigations[[9]], and Use of Electronic Health Records in Clinical Investigations[[10]]
Guidance Using different sources of RWD to generate RWE regarding safety and effectiveness This is a potential guidance to be issued after FDA evaluates whether the current available guidances collectively do not provide sufficient information to developers.[6]
Assessment FDA will conduct a variety of assessments to integrate usage of RWD and RWE in the drug development and regulatory process ·         Data standards

·         Implementation strategies

·         Identifying gaps

·         Recommending paths forward

Consultation Engagement of internal and external stakeholders to include senior leadership input into the evaluation of RWE and promote shared learning and consistency when applying the framework ·         Internal – RWE evidence subcommittee of leadership (CDER and CBER)

·         External – representatives from industry, academia, medical professional and consumer organizations, patient advocacy groups, disease research foundations, etc.

·         Consultation formats: public workshops, public-private partnerships, etc.

CBER = Center for Biologics Evaluation and Research; CDER = Center for Drug Evaluation and Research; EHR = Electronic health record; PRO = Patient reported outcome; RWE = Real world evidence; RWD = Real world data; Italicization indicates a potential guidance


Currently, there are a number of guidance documents pertaining to use of RWD and RWE which focus on the product’s safety rather than efficacy. These guidances will be leveraged to create new guidance documents that describe acceptable use of RWE to support efficacy claims.



The FDA intends to allow RWE to support approval of new indications and support or satisfy postapproval study requirements for both drugs and biologics. The new RWE program will be implemented through the utilization of a multifaceted framework. The framework outlines a number of guidance documents, their plans to engage experts across specialties and fields, and various assessments to produce acceptable standards for developers (e.g., so that the RWE submitted in the FDA package supplements the totality of evidence for efficacy). Together each of these components will provide appropriate integration of RWE for routine use in the drug development and regulatory process.


[[1]] “Real World Evidence”. The U.S. Food & Drug Administration. 12 December 2018.

[[2]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA’s new strategic framework to advance use of real-world evidence to support development of drugs and biologics”. The U.S. Food & Drug Administration. 06 December 2018.

[[3]] “Sentinel System Overview.” CDER FDA Presentation. 2017.

[[4]] “Framework for FDA’s Real-World Evidence Program”. The U.S. Food & Drug Administration. December 2018.

[[5]] “Collection of Patient-Provided information through a Mobile Device Application for Use in Comparative Effectiveness and Drug Safety Resarch.” FDA-Catalyst Project. 03 January 2017.

[[6]] “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.” Guidance for Industry and FDA Staff. May 2013.

[[7]] “E 10 Choice of Control Group and Related Issues in Clinical Trials”. FDA Guidance for Industry. May 2001

[[8]] “Use of Electronic Informed Consent Questions and Answers.” FDA Guidance for Institutional Review Boards, Investigators, and Sponsors. December 2016.

[[9]] “Electronic Source Data in Clinical Investigations.” FDA Guidance for Industry.  September 2013.

[[10]] “Use of Electronic Health Record Data in Clinical Investigations.” FDA Guidance for Industry. July 2018.

Jan 24

Cervical Health Awareness Month – Cervical Cancer: Prevention, Detection, Development

By Amy Lane, Scientist at Cato Research


As Cervical Health Awareness Month comes to a close, it is a good time to review the state of cervical cancer, what you can do personally, and what is happening in drug development.

Cervical cancer is most often caused by the human papillomavirus (HPV) and generally develops slowly with abnormal cells eventually becoming malignant in the tissue of the cervix. This transformation from healthy to abnormal to malignant cells takes time to develop1,2. In the United States, the National Cancer Institute (NCI) estimated there would be 13,240 new cervical cancer cases and 4,170 deaths3.

Prevention of cervical cancer is ideal, and from 2006-2015, new cases of cervical cancer had stabilized and death rates were declining at 0.7% annually3. Much of this is due to the availability of HPV vaccines. There are seven types out of the more than 100 kinds of HPV that are responsible for the majority of cervical cancers as well as two indicated in genital warts. In 2006, the FDA approved the HPV vaccine, Gardasil®, to prevent four of the nine types damaging to cervical health. The vaccine was available to females 9 – 26 years old and according to the CDC cut rates of infection by 64% in American teenagers and 34% in women in their early 20s6. In December, 2014, Gardasil-9®, a vaccine against 9 types of HPV was approved to provide further protection.

According to the NCI, the age group most commonly diagnosed with cervical cancer are women 35-44 (23.6%) years old3. In October of 2018, the FDA expanded the ages approved for the HPV vaccine to include ages 27 – 45 years. While it is too soon to determine the effect of extending vaccine protection to the most often diagnosed age group, it provides another route to continue the decline of cervical cancer incidence.

Unfortunately, the HPV vaccine is not 100% effective, therefore, early detection remains important. Regular testing by a pap test (or pap smear), can identify abnormal changes in cervical cells indicating follow-up testing. Follow-ups may include another pap smear, an HPV test or a cervical biopsy. Due to the slow development, pap smears are recommended every three years for women between the ages of 21 and 65 years with a healthy cervical history4. Women 30 years and older may select a pap smear every five years in combination with HPV testing5.  When identified early there are often positive outcomes, 5-year relative survival rates are 91.5% in women diagnosed with localized cervical cancer3.

Even with positive outcomes in localized cases, the 5-year survival rate is 66.2% leaving a need for continued improvement in late-stage and recurrent cancer treatments3. In addition to chemotherapy, early treatments included single-agent immunotherapy drugs intended to remove the barrier that cancer cells build to block immune response. Alone, these drugs have shown activity in 15% to 25% of patients, leaving ample space for improvement7.

Currently, combined therapies are being investigated, including two studies in advanced, recurrent cervical cancer. One pairs an immunotherapy drug (atezolizumab) with an antiangiogenic agent (bevacizumab). Preclinical data suggest the use of the antiangiogenic agent may improve immunotherapy efficacy8. The other combines two immunotherapy drugs (durvalumab and tremelimumab) with radiotherapy. Researchers are investigating the potential for radiation to improve the immune response9. Both studies have anticipated completion dates in the next one to two years.

Progress for improving cervical cancer outcomes has increased through prevention opportunities with vaccine availability and with continued diligence in regular appointments allowing early detection and treatment. Today efforts continue in drug development studies for late-stage and recurrent treatments to continue to discover more efficient and effective pathways to improve outcomes as we move forward with those still fighting.




  1. Cervical Cancer Treatment (PDQ®)-Patient Version. National Cancer Institute Website. Available at: https://www.cancer.gov/types/cervical/patient/cervical-treatment-pdq#link/_117. Accessed 17 January 2019.
  2. Improving Your Odds for Cervical Health. U.S> food & Drug Administration website. Available at: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm383757.htm. Accessed 21 January 2019.
  3. Cancer Stat Facts: Cervical Cancer. National Cancer Institute, Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/cervix.html. Accessed 15 January 2019.
  4. Cervical Cancer Screening Guidelines for Average-Risk women. Available at: https://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf. Accessed 21 January 2019.
  5. Pap Smear. Mayo Clinic website. Available at: https://www.mayoclinic.org/tests-procedures/pap-smear/about/pac-20394841. Accessed 21 January 2019.
  6. Markowitz LE, Liu G, Hariri S, Steinau M, Dunne EF, Unger ER. Prevalence of HPV After Introduction of the Vaccination Program in the United States. American academy of Pediatrics. 2016. Available at: http://pediatrics.aappublications.org/content/137/3/e20151968. Accessed 21 January 2019.
  7. New Clinical Trials Test Immunotherapy for Cervical Cancer. Insight from Dana Farber Cancer Institute. Available at: https://blog.dana-farber.org/insight/2018/03/new-clinical-trials-test-immunotherapy-cervical-cancer/. Accessed 22 January 2019.
  8. Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer. ClinicalTrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03104699#contacts. Accessed 22 January 2019.
  9. Durvalumab, Tremelimumab + Radiotherapy in Gynecologic Cancer. ClinicalTrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/NCT03277482. Accessed 22 January 2019.


Jan 17

Stay on the Safe Side- Reference Safety Information – Europe

Vivienne Ben-David, B.Sc. (Pharmacy) PGDip.

Project Manager & Associate Director, Pharmacovigilance ROW Cato Research


Aside from New Year’s resolutions and a clean sweep, what else should you refresh in 2019?

I politely suggest your understanding of Reference Safety Information (RSI) in the EU.

In Nov 2017, the Clinical Trials Facilitation Group published the Reference Safety Information Q&A document, and followed in March 2018 with a cover note. The latter explains that the recommendations in the Q&A document will be implemented more strictly from the beginning of January 2019.

The RSI future is now. Or is it old news? Well, it’s a bit of both, seemingly.

In 2011, the EU guidance (CT-3) on adverse events and reactions clearly stated that the expectedness of an adverse reaction is determined by the sponsor in the reference safety information (‘RSI’).

More recently, Competent Authorities across Europe have since provided sponsors with detail on what Reference Safety Information is and isn’t. For example, the Investigator’s Brochure is not the RSI; there should be a distinct section in the IB entitled ‘Reference Safety Information’.

The RSI should list serious adverse reactions (SARs) which are considered expected with the investigational product. It should not include SARs observed with any similar products in the same drug group. And note: SARs that have occurred once are generally consider unexpected. You have to provide a robust justification for including those one-timers in the RSI.

Seriously?  Absolutely, include only SARs in your RSI; non-serious reactions can be included in a different section.

It’s not hard to understand, but ignore it and you might feel the only heat in wintery Europe.

If you want your clinical trial application to go smoothly or approval of your next IB update – brush up on the details by reading the Q&A, clarify your understanding with your pharmacovigilance colleagues and keep your clinical trial subjects, and your product, on the safe side.


Jan 04

New FDA Guidances for December 2018

By Michelle Villasmil, Ph.D., RAC (US), Regulatory Scientist II at Cato Research

FDA draft and final guidances released from CDER, CBER, and CDRH in December are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Labeling of Red Blood Cell Units with Historical Antigen Typing Results – Final Guidance 20 Dec 2018
Developing and Submitting Proposed Draft Guidance Relating to Patient Experience Data – Draft Guidance 20 Dec 2018
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics – Final Guidance 19 Dec 2018
Breakthrough Devices Program – Final Guidance 18 Dec 2018
Clarification of Radiation Control Regulations For Manufacturers of Diagnostic X-Ray Equipment – Draft Guidance 17 Dec 2018
User Fees and Refunds for Premarket Approval Applications and Device Biologics License Applications – Final Guidance 12 Dec 2018
Data Integrity and Compliance With Current Good Manufacturing Practice – Final Guidance 12 Dec 2018
Biomarker Qualification: Evidentiary Framework – Draft Guidance 11 Dec 2018
Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009 – Draft Guidance 11 Dec 2018
The “Deemed to be a License” Provision of the BPCI Act: Questions and Answers – Draft Guidance 11 Dec 2018
New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2) – Draft Guidance 11 Dec 2018
Questions and Answers on Biosimilar Development and the BPCI Act – Final Guidance 11 Dec 2018
Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act – Draft Guidance 10 Dec 2018
Bacterial Risk Control Strategies for Blood Collections Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion – Draft Guidance 04 Dec 2018
Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA – Final Guidance 03 Dec 2018
Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment – Final Guidance 03 Dec 2018
Upcoming Meetings (* = New)  
  January 11, 2019: Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
  January 16, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement
  January 17, 2019: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
* February 6-7, 2019: Tobacco Products Scientific Advisory Committee Meeting Announcement
* February 12, 2019: Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
Last updated: 31 December 2018

Dec 27

What’s New Health Canada?

By Amelie Rodrigue-Way, Ph.D., RAC (CAN), Associate Director, Regulatory Strategy


What’s New in:

Therapeutic Products Directorate:



Biologics and Genetic Therapies Directorate:


Medical Devices: https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-devices/what-new.html

Natural and Non-prescription Health Products Directorate: https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-prescription/what-new.html


Updates from Health Canada (Drugs and Biologics)


Type of Update and Link Date Posted
Notice: Validation rules for regulatory transactions provided to Health Canada in the “non-eCTD electronic-only” format 30 November 2018
Notice – Validation rules for regulatory transactions submitted to Health Canada in the electronic Common Technical Document (eCTD) format 30 November 2018
Updated: Notice – Revision to the Post-Notice of Compliance (NOC) Changes – Notices of Change: Level III Form 30 November 2018
Health Canada Notice regarding products that contain human placenta 29 November 2018




Santé Canada: Quoi de neuf?

Par Amélie Rodrigue-Way, Ph.D., RAC (CAN), Directrice associée, Stratégie réglementaire


Quoi de neuf :

Direction des produits thérapeutiques



Direction des produits biologiques et thérapies génétiques:



Instruments médicaux: https://www.canada.ca/fr/sante-canada/services/medicaments-produits-sante/instruments-medicaux/quoi-neuf.html


Direction des produits de santé naturels et sans ordonnance:



Mises à jour de Santé Canada (Médicaments et Produits biologiques)


Genre de mise à jour et lien Date
Avis : Règles de validation des transactions réglementaires envoyées à Santé Canada en format « électronique autre que le format eCTD » 30 novembre 2018
Avis – Règles de validation des transactions réglementaires soumises par Santé Canada en format electronic Common Technical Document (eCTD) 30 novembre 2018
Avis – Révision du Formulaire de déclaration de changements de niveau III de Santé Canada : Changements survenus après l’avis de conformité (AC) 30 novembre 2018
Avis de Santé Canada concernant les produits contenant du placenta humain 29 novembre 2018


Dec 11

New FDA Guidances for November 2018

By Joanne McNelis, Ph.D., RAC (US), Clinical Strategy Scientist II at Cato Research

FDA draft and final guidances released from CDER, CBER, and CDRH in October are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use – Draft Guidance 30 Nov 2018
Blood Glucose Monitoring Test Systems for Prescription Point-of-Care Use – Draft Guidance 30 Nov 2018
Recommendations for Dual 510(k) and CLIA Waiver by Application Studies – Draft Guidance 29 Nov 2018
Nonmetastatic, Castration-Resistant Prostate Cancer: Considerations for Metastasis-Free Survival Endpoint in Clinical Trials – Draft Guidance 13 Nov 2018
Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biological Products Guidance for Industry – Draft Guidance 06 Nov 2018
Hypertension: Developing Fixed-Dose Combination Drugs for Treatment Guidance for Industry – Final Guidance 06 Nov 2018
Unique Device Identification: Policy Regarding Compliance Dates for Class I and Unclassified Devices and Certain Devices Requiring Direct Marking – Immediately in Effect Guidance for Industry and Food and Drug Administration Staff – Final Guidance 05 Nov 2018
Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment – Draft Guidance 01 Nov 2018
Upcoming Meetings (* = New)
December 17-18, 2018: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
* January 11, 2019: Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
* January 16, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement
* January 17, 2019: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
Last updated: 07 November 2018

Dec 04

Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

By Denis Okumu, Ph.D., Postdoctoral Fellow at Cato Research Ltd

Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

Section 801 of the Food and Drug Administration Amendment Act of 2007 (FDAAA) amended section 402(j) of the Public Health Service (PHS) Act[1] to require that responsible parties and/or submitters of certain applications and submissions to FDA regarding drug products, biological products, and device products (hereafter, “submitters”) submit registration and/or results information to the ClinicalTrials.gov data bank and/or certain certifications to FDA for certain “applicable clinical trials.”  Form FDA 3674[2] offers guidance on certifications to accompany such applications/submissions.  42 CFR Part 11 stipulates that a clinical trial must be registered within 21 calendar days of enrollment of the first subject, and results must be submitted no later than 1 year after the primary completion date of the applicable clinical trial.  Section 303(f)(3)[3] of the Federal Food, Drug, and Cosmetic Act (FD&C Act) authorizes FDA to assess civil money penalties against submitters who violate applicable prohibitions found in section 301(j) of the FD&C Act relating to requirements cited above under section 402(j).  Accordingly, FDA’s Draft Guidance  (September 2018) describes the current thinking of FDA’s Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH) (hereafter, “Center” or collectively, “the Centers”), regarding civil money penalties against submitters who fail to submit required clinical trial registration and/or results information to the ClinicalTrials.gov data bank, submit false or misleading information to the data bank, fail to submit to FDA the certification required, or knowingly submit a false certification.  The draft document comes against a backdrop of recent findings that show increasing numbers of clinical trials on the European Register, as well as US industry trials and NIH-sponsored research did not report results as required.[4],[5]

The Centers intend to identify violations relating to posting on ClinicalTrials.gov data bank through evidence collected during inspections conducted as part of FDA’s Bioresearch Monitoring Program (BIMO) as well as from complaints the agency may receive.  FDA’s Bioresearch Monitoring Compliance Program Guidance Manual 7348.810 for Sponsors, Contract Research Organizations and Monitors[6] outlines how the Centers will gather information to assess compliance with the above requirements:

  • determine whether the study is an applicable clinical trial
  • determine the submitter, the address, and contact information for the submitter
  • determine whether the study was registered on ClinicalTrials.gov and identify the National Clinical Trial Number
  • determine whether the study was registered not later than 21 days of enrollment of the first subject
  • determine the study’s completion date
  • determine whether the submitter has completed and submitted Form FDA 3674
  • determine whether, on the informed consent form, it states that a description of the clinical trial will be available on ClinicalTrials.gov

When a Center believes an infraction has occurred, it will send the submitter a Preliminary Notice of Noncompliance (Pre-Notice) Letter that describes the potential violation and asks the submitter to review the online data bank and make any necessary revisions within 30 days of receiving the letter.  The Center makes it clear in this letter that a further review and assessment of the online data bank will be done after 30 days, and that failure to comply with the requirements may result in the issuance of a Notice of Noncompliance under section 402(j)(5)(C)(ii) of the PHS Act.[7]  The Notice of Noncompliance gives the submitter an additional 30 days to remedy noncompliance.  If noncompliance is not remedied after 30 days, the Center will seek civil money penalties, injunction, and/or criminal prosecution.

Civil money penalty actions start when the responsible Center files a Complaint with FDA’s Division of Dockets Management and serves the Complaint on the submitter.  The Complaint will detail allegations of liability, violations, reasons why the submitter is responsible for the violations, and the amount of money penalties and assessments sought.  The Complaint also includes instructions to the submitter on how to file an Answer to request a hearing within 30 days of service, and warns that failure to do this will lead to imposition of the sought amount of penalties and assessments as provided in law.  Upon being served, the submitter may pay the penalty sought in the Complaint, or file an Answer to contest some or all of the Center’s allegations.  While waiting for a hearing, a submitter and its representatives may engage in settlement discussions with the Center regarding the civil money penalty.  If the case is decided by a presiding officer, any dissatisfied party can appeal to the Department of Health and Human Services (HHS) Departmental Appeals Board (DAB), pursuant to 21 CFR 17.47.  As outlined in section 303(f)(6) of the FD&C Act,[8] the respondent may appeal an adverse DAB decision to the U.S. Court of Appeals for the District of Columbia or any other circuit in which the respondent resides or transacts business.

If a violation is not corrected within 30 days following notification of such violation, section 303(f)(3)(A) of the FD&C Act[9] stipulates statutory maximum penalties of not more than $10,000 for all violations adjudicated in a single proceeding, and not more than $10,000 for each day that the violation continues uncorrected as described in section 303(f)(3)(B) of the FD&C Act.[10]  Per section 303(f)(5)(B) of the FD&C Act,[11] the amount of civil money penalty under the relevant statutory limits is dependent on the nature, circumstances, extent and gravity of the violation(s), and the violator’s ability to pay, effect on ability to stay in business, any history of prior such violations, the degree of culpability and any other considerations as justice may require.


[1] 42 U.S.C. 282(j)

[2] Form FDA 3674 – Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions

[3] 21 U.S.C. 333(f)(3)

[4] Goldacre et al., 2018. Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource

[5] Anderson et al., 2015. Compliance with Results Reporting at ClinicalTrials.gov

[6] FDA Compliance Program Guidance Manual 7348.810 Sponsors, Contract Research Organizations and Monitors

[7] 42 U.S.C. 282(j)(5)(C)(ii)

[8] 21 U.S.C. 333(f)(6)

[9] 21 U.S.C. 333(f)(3)(A)

[10] 21 U.S.C. 333(f)(3)(B)

[11] 21 U.S.C. 333(f)(5)(B)

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