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Sesen Bio Initiates Rolling Submission of BLA for Vicinium to FDA for the treatment of BCG-unresponsive non-muscle invasive bladder cancer

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Dec  09, 2019: Sesen Bio announced that on December 6, 2019, the Company initiated the submission of its Biologics License Application (BLA) for Vicinium for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) beneath Rolling Review to the U.S. Food and Drug Administration (FDA).

The initiation of the rolling BLA for Vicinium marks a tremendous achievement for Sesen Bio, to help save and renew the lives of patients with cancer.

The Company anticipates completing the BLA submission with the completion of the CMC module in 2020. If BLA filing accepted by FDA, the Company plans to request a Priority Review.

https://ir.sesenbio.com/news-releases/news-release-details/sesen-bio-initiates-rolling-submission-bla-vicinium-fda

First and only ingestible event marker (the ID-Cap® System)approved by U.S. FDA

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Dec 09, 2019: EtectRx® Inc. announced U.S. Food and Drug Administration (FDA) clearance of its breakthrough patented ingestible event marker, the ID-Cap® System (first and only ingestible event marker) in order to transmit digital messages from within the body to an external receiver not including the need for direct skin contact for the purpose of recording ingestion events.

Comprised of ID-Capsule, ID-Tag, ID-Cap Reader, and related software, the ID-Cap System provides real-time, dose-level ingestion event verification.

The ID-Cap Reader (worn on a lanyard) verifies the message as a valid ingestion event and forwards the data to a secure smartphone-based mobile application and to the healthcare provider in a very secure web-based portal.

This is a momentous event for etectRx and the larger digital health market.

EtectRx collaborates with  key stakeholders, including healthcare providers, health systems, pharmacies, pharmaceutical manufacturers, and clinical research organizations, in order to bring this innovative technology to digital medications of the future and other valuable applications in the medical, pharmaceutical, and consumer markets. https://etectrx.com/etectrx-announces-u-s-fda-clearance-of-novel-ingestible-event-marker/

Moberg Pharma meets primary endpoint for MOB-015 (topical terbinafine) in a phase 3 study for the treatment of Onychomycosis

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Dec 9, 2019: Moberg Pharma announces that MOB-015 (topical terbinafine) met the primary endpoint and also key secondary endpoints in the North American Phase 3 study including 365 patients with mild to moderate toenail onychomycosis (nail fungus).

At week 52, considerably more patients reached complete cure for MOB-015 than for vehicle (p=0.019), following 48 weeks of daily treatment.

The purpose of this randomized, multicenter, controlled clinical Phase 3 study was to evaluate the efficacy and safety of MOB-015 in patients with mild to moderate distal subungual onychomycosis (DSO) affecting 20-60 percent of the great toenail.

The study was conducted at 32 sites in the U.S. and Canada along with 365 patients, 246 patients receiving MOB-015 and 119 patients receiving vehicle.

Patients received treatment during 48 weeks and had the last follow-up assessment at week 52. in general MOB-015 was well tolerated.

cure rate in the study is extraordinarily high for a topical treatment, due to fungicidal activity of terbinafine in MOB-015. http://www.mobergpharma.com/press-releases/2019-12-09/moberg-pharma-meets-primary-endpoint-mob-015-phase-3-study-treatment

U.S. FDA approved Fast Track designation for Equillium’s itolizumab (EQUALISE Phase 1b study )for the treatment of lupus nephritis

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Dec. 09, 2019 : The U.S. Food and Drug Administration (FDA) approved Fast Track designation for Equillium’s itolizumab for the treatment of lupus nephritis. Equillium started the EQUALISE Phase 1b study of itolizumab in patients with lupus and lupus nephritis in September 2019.

The FDA’s Fast Track program is designed in order to facilitate the development of new treatments for serious or life-threatening conditions for which there is a considerable unmet medical need.

Frequent meetings or communications of Companies with investigational drugs that receive Fast Track designation benefit more with the FDA to discuss the drug’s development plan and may be eligible for accelerated approval and priority review.

Receiving Fast Track designation recognizes the capable therapeutic potential of itolizumab for the treatment for lupus nephritis for the most part given its ability just to modulate both the activity and trafficking of effector T cells. https://fda.einnews.com/pr_news/504425591/equillium-granted-u-s-fda-fast-track-designation-for-itolizumab-for-the-treatment-of-lupus-nephritis

Important data points in Protocol for CRFs Creation (CDM Prospective):

Reading of whole protocol is quite important and indispensable act but by keeping following points in mind, one can read protocol with more clarity and productivity.

  • Phase, Indication, Scope of study
  • Age, Sex, Demography and Race
  • Informed consent form
  • Inclusion Exclusion Criteria and Re-screening criteria.
  • Study design
  • Study arm
  • Study drug-Formulation, Dosing frequency
  • Dose reduction, Increase, interruption or Discontinuation criteria
  • Visit Schedule and Assessment (Please see the study arm related assessment if any)
  • Assessment to be performed in unscheduled visit or based on investigator judgement.
  • Labs and Image assessments
  • Drug dosing time points, Biomarker and PK data collection time (eg. Predose, post dose)
  • Adverse Event and SAE (serious adverse event) definition and reporting guidance and Severity criteria
  • Concomitant Medication and procedure reporting guidance
  • Medical History reporting guidance
  • Tumor Assessment criteria in oncology study (i.e RECIST)

Parts of a clinical trial protocol and Clinical Data Management (CDM) prospective to review

This blog talks about Protocol parts and key information needed for any Data Manager to design CRF. Protocols are quite specific to studies but share some common information and that is included in this blog to develop a general understanding about protocol. As per ICH, followings are the parts of any protocol.

  1. Protocol components:
  2. Study title
  3. Introduction/Background
  4. Objectives and End Points
  5. Study design and its rationale
  6. Population (Inclusion/exclusion criteria)
  7. Treatment
  8. Informed Consent Procedure
  9. Visit Schedule and Assessment
  10. Efficacy assessment
  11. Safety Assessment
  12. Discontinuation of the Study
  13. Data collection and its management
  14. Statistical methods
  15. Ethics
  16. Quality Control and Assurance
  17. Publication Policy
  18. Reference

1. Study title:  Protocol first page always has the title and Sponsor name. Example: “An Open label Phase III study to evaluate effectiveness of ATC-XX in treatment of Triple Negative Breast Cancer” The data Manager can easy interpret about Phase, Design and Target indication by just reading the study title.

2. Table of content: It is same as any book’s table of content. Protocol is a big document so it is easiest way to navigate in the protocol.

3. Introduction: It gives the overview of the disease, epidemiology and current treatments. It tells about investigational drug candidates and purpose of the study. Not important for designing CRF but quite useful while preparing study related presentations.

4. Objectives and End Points:  Primary objective and secondary objectives and their associated end points are described in this segment. All study specific assessments are done considering primary and secondary points. All studies do not have secondary objectives.    

5. Study design and its rationale: This segment provides the key information for the data manager. In case of blinded study, Clinical Data manager has to provide restriction based data base access. The site generally has Clinical research co-ordinator and Investigator access to add data into database.  If it is adoptive design, then one has to be ready for many post production data base changes. This part gives the insight about rationale for the study design. If any particular combination of drugs is used or risk/benefit associated with any combination then this segment provide the rationale behind that.

 For example, it is needed to blind prolactin for many antipsychotic interventional studies. It is well known that Antipsychotic drugs increase the level of prolactin and by knowing its level one can learn about subject’s randomized status. This segment gives information about number of participants, cohorts and randomization method. It describes the study arms and One CRF is dedicated for study arms in eDC. Many CRF pages can be dependent on particular study arm. Just note down the study arms and read all the protocol with respect to each arm because many data point including inclusion/exclusion criteria may differ in each study arm. It is one of the most important segments of a protocol from a data manager point of view.

6. Population (Inclusion/exclusion criteria):  It is key information which determines which subjects meet the all set criteria to participate in a study. Inclusion criteria/exclusion criteria may be as simple as age/sex/Demography/Race and it may be as complicated as looking for a particular mutation in a tumor. Any subject, which does not meet all inclusion criteria but continue in study, may be the case of protocol deviations. Rescreening criteria should be checked in this section carefully. Sometimes Protocol allows rescreening after a particular time window eg one month. Rescreened subject may have a different subject number. Inclusion criteria/exclusion criteria numbers need to be captured in CRF.   It is confusing sometime for <= or >= signs commonly used for laboratory values.  Some protocol allows performing retest if initial laboratory results do not meet the inclusion criteria. Data Manager has to note these minute details.

7. Treatment: Description of all investigational drugs with their dosage form, route of administration, dosages, duration and frequency of administration and supply type (bulk, vials etc) can be seen here. Prohibited medication, concomitant therapy, infusion reaction therapy and prophylaxis regimens are described in this section. Prior and Concomitant therapy CRF, Dose administration record CRF are the two CRFs which gets 90 percents information from here. This part can be further divided into these parts. A) Subject numbering, treatment assignment and randomization (if study has this). B) Guidelines for dose reductions/modification, determination of Maximum tolerated dose (If it is Phase I study). C) Determination of dose limiting toxicities. D) Handling of study treatment and additional treatment E) Instruction on how to administer the drugs. F) Additional guidance if any applicable.

8. Informed Consent Procedure: It suggests about things which are needed to convey to subjects such as study related risk, any pregnancy related restrictions, common side effect which are known about investigational drugs. IRB/IEC approved informed consent form need to be signed by Subject prior participating in a study. Informed consent CRF is commonest CRF among all study related CRFs.

9. Visit Schedule and Assessment: This segment provide a description about visits, cycle in each visit, time window between each visits and assessment to be carried out at each visit and cycle. Data Manager must read the table given in protocol in this section. Vital sign, physical examination, laboratory assessment, imagine assessment, ECG, PK evaluation; RECIST evaluation (oncology studies), study drug administration time, post treatment evaluation, baseline assessments and study specific assessments are the common points. 70 percents CRF pages can be prepared by just this table.

10. Efficacy assessment: The procedure or check which can clearly tells whether investigational drug works or not.  iRECIST and RECIST assessments are the common for oncology assessments and CRF for this is included in the database design. Measuring glucose level and Hba1c is done for diabetic studies quite commonly. It depends generally on primary and secondary end points in study.

11. Safety Assessment: It describes the definition of adverse events, serious adverse event and reporting requirements.  Duration, start date, end date, Outcome of adverse event, relationship to study drug, CTCAE Grades, are the common information required to report an adverse event. Protocol can provide study specific guidance for reporting the adverse event. CTCAE version is mentioned in the protocol.  Protocol says about timing for SAE reporting, In general, 24 hours it should be reported to sponsor after learning of its occurrence. Data Manager read this section carefully as there is one dedicated CRF for this crucial information.  Generally, AE is noted once subject signs the informed consent form and may be recorded even till follow up visit as per study requirement.

12. Discontinuation of the Study:  Protocol defines the circumstances under which study drug can be withdrawn. Generally they are; Subject or guardian decision, adverse event including death or major protocol deviation and early termination of study by sponsor. Data manger has to understand under which circumstance study treatment is discontinued and under which circumstance subject is discontinued from the study. Even after discontinuation of study treatment, subject can be in study. Protocol may suggest assessment before or after discontinuation of study treatment.

13. Data collection and its management:  It explains the process of data recording, format (electronic or paper), site monitoring, and review and query management.  It also mentions the names of dictionary for coding of concomitant medications, Medical history and adverse event. Recording keeping is done by sponsor designated portal which is matching regulatory stanadard.

14. Statistical methods: Protocol describes the statistical method to analyse the date. It talks about analysis of primary end point, secondary end point, handling of missing values, assessment of subject dosing, identification of recommended dose (Phase I), and PK data. It can include additional information based on study.

15. Ethics: Protocol mentions the statement about its commitment to follow ICH GCP and local guideline of particular country and other related information such role of IRB and Investigator. It is not important for CRF designing (Data Manager prospective)

16. Quality Control and Assurance: It contains the information about sponsor’s internal process of audit, standard operating procedure, all activities to meet GCP compliance. This segment does not have any particular information to be added directly into CRF. 

17. Publication Policy : It says where the protocol will be registered (eg clinicaltrial.gov), website of mode of publication of study results. Every sponsor may have different policy for publication.

18. Reference: List of all reference used in protocol to gather information.

Only treatment approved in the US for relapsed or refractory hairy cell leukemia Approved by FDA at ASH 2019

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Dec. 08, 2019: Innate Pharma shared new, long-term data from the pivotal Phase III trial of Lumoxiti (moxetumomab pasudotox-tdfk) at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, USA. 

The final analysis showed that 36 percent (29/80) of the relapsed or refractory hairy cell leukemia patients achieved strong response (CR) with Lumoxiti at Day 181 of patient’s respective evaluation as compared to the primary analysis in which 30 percent durable CR rate was reported.

Also, there was a 61 percent probability of the patients who achieved a CR would maintain it after five years.

The single-arm, multi-center, open-label Phase III ‘1053’ clinical trial assessed the efficiency, safety, immunogenicity and pharmacokinetics of Lumoxiti monotherapy in 80 patients with relapsed or refractory hairy cell leukemia who had already received at least two prior therapies, including one purine nucleoside analog. https://fda.einnews.com/pr_news/504317616/innate-pharma-highlights-fda-approved-lumoxiti-at-ash-2019

Amgen’s AVSOLA™ received FDA approval for AVSOLA™ (infliximab-axxq), For The Same Indications As Remicade® (infliximab)for the treatment of Rheumatoid Arthritis, Crohn’s Disease, Ulcerative Colitis, Psoriatic Arthritis

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Dec. 6, 2019: U.S. FDA has approved Amgen’s  AVSOLA™ (infliximab-axxq) for all approved indications of the reference product, Remicade® (infliximab): for the treatment of moderate-to-severe rheumatoid arthritis (RA), chronic severe plaque psoriasis (PsO), psoriatic arthritis (PsA),ankylosing spondylitis (AS),ulcerative colitis (UC) in the adult and pediatric population, AVSOLA (monoclonal antibody), an anti-tumor necrosis factor alpha (anti-TNF) was proven to be highly similar to Remicade with no clinically meaningful differences based on a totality of evidence which incorporated comparative analytical, nonclinical and clinical data.

The randomized, double-blind comparative clinical trial study evaluated the efficacy and safety of AVSOLA as compared to Remicade in patients with moderate-to-severe RA.

There were 558 patients enrolled and randomized (1:1) to receive either AVSOLA or Remicade at a dose of 3 mg/kg administered as an infusion on day 1, at weeks 2 and 6, and every 8 weeks thereafter. The primary endpoint was the response difference (RD) of 20% improvement in American College of Rheumatology core set measurements (ACR20) at week 22. Key secondary endpoints included DAS28-CRP change from baseline, RD of ACR20, ACR50 and ACR70 at weeks 2, 6, 14, 22, 30, 34, 38, 46 and 50. The study also incorporated the evaluation of a single transition in 119 subjects from Remicade to AVSOLA at week 22, which demonstrated similar safety and immunogenicity in patients who were previously on Remicade. 

Amgen has a total of 10 biosimilars in its portfolio,Ou of which four approved in the U.S. and 3 are approved in the European Union (EU). https://www.amgen.com/media/news-releases/2019/12/fda-approves-amgens-avsola-infliximabaxxq-for-the-same-indications-as-remicade-infliximab/

ViiV Healthcare submits New Drug Application to the US FDA for fostemsavir, an investigational, first-in-class attachment inhibitor for the treatment of HIV in adults

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Dec 05, 2019: ViiV Healthcare have completed submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in search of approval of fostemsavir, an investigational, first-in-class attachment inhibitor for the treatment of HIV-1 infection.

Fostemsavir is being developed for use in combination with other antiretroviral agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who are not able to form a oppressive regimen due to resistance, intolerance or safety considerations.

For the people living with HIV Fostemsavir may provide an imperative treatment option for the group.

This submission is supported by the data from the pivotal phase III BRIGHTE study in significantly treatment-experienced people living with multidrug-resistant HIV.

The results (96-week) from the BRIGHTE study were most recently presented in July at the 10th International AIDS Society Conference on HIV Science (IAS 2019) in Mexico City. https://viivhealthcare.com/en-us/us-news/us-articles/2019/viiv-healthcare-submits-new-drug-application-to-the-fda-for-fost/

FDA authorizes marketing of diagnostic test cobas vivoDx that uses novel technology to detect Methicillin-resistant Staphylococcus aureus (MRSA) bacteria

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Dec 05, 2019: Roche Molecular Systems Inc. received U.S. Food and Drug Administration approval for marketing of a new diagnostic test (Cobas vivoDx) based on bacterial viability and novel technology to detect Methicillin-resistant Staphylococcus aureus (MRSA) bacterial colonization to prevent and control MRSA in high-risk settings.

If a patient develops an infectionwith MRSA can lead to serious illness and even death. According to the Centers for Disease Control and Prevention (CDC), Not more than 5% of U.S. hospital patients carry the MRSA bacteria and many of those that carry the bacteria do not develop infections.

The cobas vivoDx MRSA test uses a new bacteriophage technology which is based on bioluminescence in order to detect MRSA from nasal swab samples in as little as 5 hours compared to 24-48 hours for conventional culture.

The FDA reviewed data from the performance studies in which the cobas vivoDx MRSA test precisely identified MRSA in roughly 90% of samples where MRSA was present and correctly identified no MRSA in 98.6% of the samples that didn’t have MRSA present. https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-diagnostic-test-uses-novel-technology-detect-mrsa-bacteria

First investigational drug therapy for liver disease non alcoholic steatohepatitis (NASH) awaiting FDA approval

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Dec. 05, 2019: A large Phase III clinical trial designed in collaboration with Virginia Commonwealth University is the first to demonstrate the safety and effectiveness of an oral medication to patients with nonalcoholic steatohepatitis (NASH), a chronic liver disease and a leading cause for liver transplantation in the U.S.(currently lack an approved drug therapy, but this may soon change).

As per the Results from the interim analysis of the REGENERATE study, sponsored by the Intercept Pharmaceuticals, will publish in the medical journal The Lancet this week.

Approximately 7 million and 30 million U.S. adults suffer from this desease, a severe form of fatty liver disease (unrelated to alcohol abuse) but closely related to obesity and Type 2 diabetes.

Patients suffering from NASH, fat deposited in the liver damages causes inflammation. NASH can progress in order to  include scarring, called fibrosis, which prevents the liver from functioning properly which can lead to liver cancer, liver failure or death. https://www.eurekalert.org/pub_releases/2019-12/vcu-fid120519.php

Data fron XOSPATA® in FLT3 Mutation-Positive Relapsed/Refractory Acute Myeloid Leukemia at the 2019 American Society of Hematology Annual Meeting

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Dec. 3, 2019: Astellas Pharma Inc. announced the presentation of new data in acute myeloid leukaemia (AML) at the 61st American Society of Hematology (ASH) Annual Meeting(Dec. 7-10) in Orlando, Fla.

Seven abstracts sponsored from  Astellas focus on patients with relapsed (a disease that has returned) or refractory (resistant to treatment) AML through an FLT3 mutation (FLT3mut+).

New findings from abstracts include the Phase 3 ADMIRAL trial – an oral presentation on emerging mutations in patients who  has develop resistance after an initial response to XOSPATA (gilteritinib) and also two poster presentations focused on patient-reported outcomes, as well as data on cost-effectiveness  testing and treatment patterns and venetoclax combination therapy. https://www.astellas.com/en/news/15466