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FDA approves Roche’s Phesgo for HER2-positive breast cancer

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FDA approves Roche’s Phesgo for HER2-positive breast cancer

“FDA approves Roche’s Phesgo (fixed-dose combination of Perjeta and Herceptin for subcutaneous injection) for HER2-positive breast cancer

June 29, 2020: Roche announced that the US Food and Drug Administration (FDA) has approved Phesgo™, a fixed-dose combination of Perjeta® (pertuzumab) and Herceptin® (trastuzumab) with hyaluronidase, administered by subcutaneous (SC; under the skin) injection in combination with intravenous (IV) chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer.

This is the first time that Roche has combined two monoclonal antibodies that can be administered by a single SC injection.

“The FDA approval of Phesgo reflects our commitment to improving outcomes for the many people living with HER2-positive breast cancer,” said Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development.

Related News: FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer

USFDA accepts Roche’s Biologics License Application for fixed-dose subcutaneous combination of Perjeta and Herceptin for the treatment of HER2-positive breast cancer

Phase II DESTINY-Gastric01 trial of Enhertu (trastuzumab deruxtecan) versus chemotherapy met primary endpoint

“Phesgo offers a treatment administration that supports the needs and preferences of individual patients, and helps to meet the increasing demand across the healthcare system for faster and more flexible treatment options.”

Phesgo is available in one single-dose vial. Administration can take approximately eight minutes for the initial loading dose and approximately five minutes for each subsequent maintenance dose.

 This is compared to approximately 150 minutes for a sequential infusion of a loading dose of Perjeta and Herceptin using the standard IV formulations, and between 60-150 minutes for subsequent maintenance infusions of the two medicines. 

Phesgo can be administered by a healthcare professional in a treatment centre or at a patient’s home.

The approval is based on results from the pivotal phase III FeDeriCa study, which met its primary endpoint with Phesgo showing non-inferior levels of Perjeta in the blood during a given dosing interval (Ctrough), when compared to IV administration of Perjeta.

The safety profile of Phesgo with chemotherapy was comparable to IV administration of Perjeta plus Herceptin and chemotherapy, and no new safety signals were identified, including no meaningful difference in cardiac toxicity.

The most common adverse events in both arms were alopecia, nausea, diarrhoea and anaemia. 

The phase II PHranceSCa study showed that 85% (136/160) of people receiving treatment for HER2-positive breast cancer preferred treatment under the skin to IV administration due to less time in the clinic and more comfortable treatment administration. 

FeDeriCa study
FeDeriCa is an international, multi-centre, two-arm, randomised, open-label, pivotal phase III study evaluating the pharmacokinetics, efficacy and safety of subcutaneous injection of Phesgo in combination with chemotherapy, compared with standard intravenous (IV) infusions of Perjeta and Herceptin in combination with chemotherapy, in 500 people with HER2-positive early breast cancer treated in the neoadjuvant (before surgery) and adjuvant (after surgery) settings.

The primary endpoint of the study is minimum levels of Perjeta in the blood during a given dosing interval (Ctrough), when compared to IV administration of Perjeta.

Secondary endpoints include safety; minimum levels of Herceptin in the blood during a given dosing interval (Ctrough); and total pathological complete response, meaning there is no tumour tissue detectable in the tissue removed at the time of surgery.

Data from the FeDeriCa study were presented at the San Antonio Breast Cancer Symposium in December 2019.

The FeDeriCa study met its primary endpoint of non-inferior levels of Perjeta in the blood. The geometric mean ratio (GMR; a type of average used when assessing pharmacokinetics) for the primary endpoint was 1.22 (90% CI: 1.14 to 1.31), with the lower limit of the 90% CI of the GMR=1.14≥0.80 (the pre-specified non-inferiority margin).

A secondary endpoint of non-inferior levels of Herceptin was also met, with blood concentrations for people receiving the fixed-dose combination non-inferior to those receiving IV Herceptin (GMR=1.33 [90% CI: 1.24 to 1.43]; lower limit of 90% CI of GMR=1.24≥0.80).

A non-inferiority endpoint was chosen for the study to ensure that people were receiving sufficient dosing with Perjeta and Herceptin as compared to the established IV doses at the same treatment intervals.

PHranceSCa study
PHranceSCa is a phase II, randomised, multi-centre, multinational, open-label, cross-over study evaluating patient preference for and satisfaction with subcutaneous administration of Phesgo in 160 people with HER2-positive early breast cancer.

All patients completed neoadjuvant (before surgery) treatment with Perjeta, Herceptin and chemotherapy and had surgery before randomisation.

The primary endpoint of the study is the percentage of participants who indicate that they prefer treatment with Phesgo compared to the standard intravenous (IV) formulations of Perjeta and Herceptin.

Secondary endpoints include participant-reported satisfaction and health-related quality of life outcomes; healthcare professionals’ perceptions of time and resource use and convenience compared with IV formulations; as well as the safety and efficacy of each study regimen.

Interim results from the PHranceSCa study were presented at the European Society for Medical Oncology Breast Cancer Virtual Meeting in May 2020. Primary results will be presented at a medical conference later in 2020.

Phesgo
Phesgo is a new fixed-dose subcutaneous (SC) formulation that combines Perjeta and Herceptin with Halozyme Therapeutics’ Enhanze® drug delivery technology. 

This is the first time that Roche has combined two monoclonal antibodies that can be administered by a single SC injection.

Halozyme’s Enhanze drug delivery technology may enable and optimise SC drug delivery for appropriate co-administered therapeutics.

The technology is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that temporarily degrades hyaluronan – a glycosaminoglycan or chain of natural sugars in the body – to aid in the dispersion and absorption of other injected therapeutic drugs.

Pertuzumab in Phesgo is the same monoclonal antibody as in intravenous (IV) Perjeta, and trastuzumab in Phesgo is the same monoclonal antibody as in IV Herceptin.

The mechanisms of action of Perjeta and Herceptin are believed to complement each other as both bind to the HER2 receptor, but in different locations.

The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of the HER signalling pathways. [8, 9]

The standard IV formulation of Perjeta in combination with IV Herceptin and chemotherapy (the Perjeta-based regimen) is approved in over 100 countries for the treatment of both early and metastatic HER2-positive breast cancer.

In the neoadjuvant (before surgery) early breast cancer (eBC) setting, the Perjeta-based regimen has been shown to almost double the rate of pathological complete response compared to Herceptin and chemotherapy. 

 Additionally, the combination has been shown to significantly reduce the risk of recurrence of invasive disease or death in the adjuvant (after surgery) eBC setting. 

In the metastatic setting, the combination has shown an unprecedented survival benefit in previously untreated (first-line) patients with HER2-positive metastatic breast cancer. “

https://www.roche.com/media/releases/med-cor-2020-06-29c.htm

Novartis announces MET inhibitor Tabrecta™ approved in Japan for advanced NSCLC with METex14

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Novartis announces MET inhibitor Tabrecta™ approved in Japan for advanced NSCLC with METex14
Jun 29, 2020: “Novartis Pharma announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) approved Tabrecta™ (capmatinib, formerly INC280), an oral MET inhibitor for MET exon 14 skipping (METex14) mutation-positive advanced and/or recurrent unresectable non-small cell lung cancer (NSCLC).

Tabrecta is approved for first-line and previously treated patients, regardless of prior treatment type.

“With the remarkable overall response rates seen both in treatment-naive and previously treated patients, we are thrilled that MHLW has added Tabrecta as a new treatment option for patients with advanced NSCLC with METex14,” said Brian Gladsden, President of Novartis Oncology Japan.

“Today’s approval reinforces the potential benefit this new MET inhibitor can bring to thousands of patients diagnosed in Japan each year and is a positive step in our journey to transform the lives of patients with lung cancer.”

The approval of Tabrecta is based on results from the pivotal GEOMETRY mono-1 Phase II multi-center, non-randomized, open-label, multi-cohort study.

In the METex14 population (n=97), the confirmed overall response rate was 68% (95% CI, 48-84) and 41% (95% CI, 29-53) among treatment-naive (n=28) and previously treated patients (n=69), respectively, based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1.

In patients taking Tabrecta, the study also demonstrated a median duration of response of 12.6 months (95% CI, 5.5–25.3) in treatment-naive patients (19 responders) and 9.7 months (95% CI, 5.5-13.0) in previously treated patients (28 responders).

The most common treatment-related adverse events (AEs) (incidence ≥20%) are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.

The companion diagnostic to Tabrecta, FoundationOne®CDx Cancer Genomic Profile, was approved by MHLW on May 25th of this year, to aid in detecting mutations that lead to MET exon 14 skipping in tumor tissue.

Tabrecta (capmatinib)
Tabrecta (capmatinib) is a kinase inhibitor that targets MET. Tabrecta was licensed to Novartis by Incyte Corporation in 2009.

Under the Agreement, Incyte granted Novartis worldwide exclusive development and commercialization rights to capmatinib and certain back-up compounds in all indications.

In May 2020, Tabrecta was approved by the US FDA for adult patients with metastatic NSCLC whose tumors have a mutation that leads to METex14 as detected by an FDA-approved test.

This indication was approved under accelerated approval based on overall response rate and duration of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).”
https://www.novartis.com/news/media-releases/novartis-announces-met-inhibitor-tabrecta-approved-japan-advanced-non-small-cell-lung-cancer-metex14

GSK receives first regulatory approval for Duvroq in Japan

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GSK receives first regulatory approval for Duvroq in Japan

“The approval marks a significant step in GSK’s global efforts to help patients with anaemia due to chronic kidney disease (CKD).

June 29, 2020: GlaxoSmithKline announced the approval of a Japanese New Drug Application (JNDA) by the Ministry of Health, Labour and Welfare for Duvroq (daprodustat) tablets, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the treatment of patients with anaemia due to chronic kidney disease (CKD).

Dr. Hal Barron, Chief Scientific Officer and President R&D, GSK, said: “The approval of Duvroq brings a new, convenient oral treatment option to nearly 3.5 million patients in Japan who have anaemia associated with renal disease.

We are pleased with this first approval and look forward to sharing data from our ongoing phase III programme as we seek to help many more patients suffering with this disease around the world.”

Anaemia is common in patients with CKD because the kidneys no longer produce adequate amounts of erythropoietin, a hormone involved in prompting the production of red blood cells.

HIF-PHIs are a new class of drug that trigger the body’s adaptations to hypoxia (i.e. oxygen deprivation) and encourages the bone marrow to make more red blood cells and so reduce anaemia, thereby benefitting patients.

The JNDA was primarily based on positive data from the phase III programme conducted in Japan.

The studies evaluated Duvroq for the treatment of anaemia in patients across the spectrum of CKD from stages 3-5.

This included patients on dialysis, including both hemo- and peritoneal dialysis, and those not on dialysis, regardless of prior anaemia treatment with erythropoiesis-stimulating agents (ESAs).

In contrast to current standard of care in patients with CKD which requires injections, Duvroq offers convenience with oral administration and flexibility with once-daily dosing for dialysis and non-dialysis patients.

Daprodustat is currently not approved as a treatment for anaemia due to CKD or any other indication anywhere else in the world other than in Japan.

The ongoing phase III global programme, which includes two cardiovascular outcome studies ASCEND-D and ASCEND-ND, will support additional regulatory submissions across the world.

Duvroq is one of the medicines in GSK’s growing portfolio of innovative specialty care products. In Japan, Duvroq will be exclusively distributed by Kyowa Kirin Co., Ltd. (KKC), following the strategic commercialisation deal announced in 2018. KKC has strong established expertise and experience in the treatment of anaemia due to CKD to ensure availability of this innovative medicine to patients.

Commercial promotional launch activities will be led by KKC. GSK will support scientific engagement through medical science liaisons.  

About the Japan clinical development programme

The three phase III studies in Japan included:

  • A 52-week study of 271 haemodialysis patients using ESAs prior to the study. It compared daprodustat versus darbepoetin alpha.
  • A 52-week study of 299 patients with stage 3-5 CKD not on dialysis, with or without prior use of ESA.
  • It compared daprodustat versus epoetin beta pegol. Additionally, it included a cohort of 56 patients on peritoneal dialysis who were all treated with daprodustat.
  • A 24-week open label study of haemodialysis in 28 patients who were not receiving ESAs at entry to the study and were all treated with daprodustat.

About the global clinical development programme

GSK also has an ongoing global phase III registration programme, including:

  • ASCEND-D (Anaemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis) enrolled approximately 3,000 dialysis dependent patients with anaemia associated with CKD switching from an ESA. Recruitment has completed.
  • ASCEND-ND (Anaemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Non-Dialysis) will enrol approximately 4,500 non-dialysis dependent patients with anaemia associated with CKD and will include patients either switching from or naive to an ESA. Recruitment remains ongoing.

For both studies, the co-primary endpoints are time to first occurrence of major adverse cardiovascular events (MACE) and mean change in haemoglobin between the baseline and efficacy period (mean over weeks 28-52).

The studies will assess whether daprodustat is non-inferior to ESAs on these endpoints as the primary analysis. If non-inferiority of the primary analysis is met, superiority will be assessed for the MACE endpoint.

Daprodustat

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, belongs to a new class of oral medicine indicated for the treatment of anaemia due to chronic kidney disease in adult patients not on dialysis and on dialysis.

Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilises hypoxia-inducible factors, which can lead to transcription of erythropoietin and other genes involved in the production of red blood cells and iron metabolism, similar to the physiological effects that occur in the body at high altitude.

Daprodustat has been developed to provide an orally-convenient treatment option which avoids the administration challenges and cold storage requirements of injectable ESAs/recombinant human erythropoietin.

The Japanese Prescribing Information includes the following:

Serious thromboembolism such as cerebral infarction, myocardial infarction and pulmonary embolism may occur during the treatment with daprodustat, sometimes resulting in death.

Significant Adverse Reactions:

Thromboembolism (0.8%). Thromboembolism such as Cerebral infarction (0.3%), Pulmonary embolism (0.3%), Retinal vein occlusion (0.3%), Deep vein thrombosis (0.3%) or Vascular access thrombosis (such as Shunt occlusion) (Frequency unknown).”
https://www.gsk.com/en-gb/media/press-releases/gsk-receives-first-regulatory-approval-for-duvroq-daprodustat-in-japan-for-patients-with-anaemia-due-to-chronic-kidney-disease/

Coronavirus (COVID-19) Update: Daily Roundup June 29, 2020

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Coronavirus (COVID-19) Update: Daily Roundup June 29, 2020
June 29, 2020: “The U.S. Food and Drug Administration announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:
  • The FDA and the Federal Trade Commission (FTC) jointly issued a warning letter to Hong Kong-based SuperHealthGuard and Loyal Great International, Ltd., advising these companies to cease selling unapproved products online to customers in the United States with misleading claims that such products mitigate, prevent, treat, diagnose, or cure COVID-19 in people.

    The FDA’s action is in support of its efforts to protect public health.

    FTC’s action enforces provisions of the FTC Act, 15 U.S.C. 41, prohibiting unsupported drug advertising claims. There are no drugs approved by the FDA to prevent or cure COVID-19 in people.

    FDA advised the companies to review their respective websites to ensure that they are not misleadingly representing unproven products as safe and effective for a COVID-19-related use.

    Failure to immediately correct the unapproved new drug and misbranding violations could result in legal action, including, without limitation, seizure and injunction.

    FDA is advising consumers not to purchase or use certain products that have not been approved, cleared, or authorized by FDA and that are being misleadingly represented as safe and/or effective for the treatment or prevention of COVID-19.

    Misbranded or unapproved new drugs are subject to detention and refusal of admission, if they are offered for importation into the United States.

    The list of firms that have received warning letters is located here.
  • FDA issued Emergency Use Authorizations (EUAs) for the following SARS-CoV-2 molecular diagnostic tests:
    • Inform Diagnostics, Inc.: Inform Diagnostics SARS-CoV-2 RT-PCR Assay
    • Diagnostic Solutions Laboratory, LLC: DSL COVID-19 Assay
  • FDA added the following products to the list of authorized ventilators, ventilator tubing connectors, and ventilator accessories under the ventilator Emergency Use Authorization (EUA)
    • Stewart & Stevenson Healthcare Technologies, LLC: Apollo ABVM emergency resuscitator
    • SAGICO USA, LLC: V2O SAGICO SYSTEM Ventilator
  • Testing updates:
    • To date, the FDA has authorized 155 tests under EUAs; these include 130 molecular tests, 24 antibody tests, and 1 antigen test.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-june-29-2020

Primary Endpoint and Secondary Endpoint (outcome measures)

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Primary Endpoint and Secondary Endpoint (outcome measures)

By Deeksha Soni-
“Clinical studies such as randomized controlled trials are designed to answer specific questions, e.g. whether one drug is more effective than another at preventing a particular event taking place and this is measured in terms of predefined criteria. these criteria are knows as end points.

As per National Cancer Institute (NCI)

“In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial.
The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.”

they are also know as outcome measures

There are two main end points, as discussed below.

  • Primary Endpoint
    • The specific event that the study is designed to assess the effect of the drugs upon
    • The primary endpoint is important to study design because the sample size required in order to adequately power a study is dependent on the number of primary events that are expected to occur over a given time period.
    • The incidence of some events of interest (e.g. death) in a particular study population being studied may actually be quite low in the period over which the study can be conducted – thus, in order to reliably study the effectiveness of two different interventions in preventing the event of interest, many study subjects would need to be enrolled in the study however if there is a large study population then this may make the study very expensive to conduct and recruitment of sufficient numbers of subjects into the study may be difficult –

A primary endpoint is the main measurement a trial is trying to assess. It answers the most important question in the trial. 

They are also know as Primary outcome measures

For example:

  • In a weight-loss study: What is the average weight loss after six months?
  • In a trial for a new cancer drug: What is the average increase in survival time? Or, What is the time to death?
  • In a migraine medicine trial: What is the number of migraines experienced by the patient?
  • Composite primary endpoints
    • Composite primary endpoints are frequently used to overcome the difficulties associated with designing a study around a single event of interest (e.g. death).
    • An example of a composite primary endpoint in a cardiovascular study might be cardiovascular death and/or non-fatal myocardial infarction and/or any kind of stroke – thus the study would be designed with such a composite primary endpoint (e.g. any major cardiovascular event) and would require fewer subjects, as the total number of the events to be detected is in effect increased.
    • However, when calculating the results of studies that combine several event types into one composite endpoint, it can be difficult to define the true effect of the intervention on each of the event types.

Secondary Endpoints

  • These are additional events of interest, but which the study is not specifically powered to assess.
  • They are also knows as Secondary outcome measures
  • Because the design of the study was not based around the secondary endpoint (s), analyses of secondary endpoints need to be viewed with caution.
  • The caution in interpreting results is also true with respect to subgroup analyses, in which primary or secondary endpoints are considered in a smaller sub-group of the whole study population (e.g. only those subjects with a specific baseline characteristic) – this is because the power of the study is based on the entire study population.
  • Secondary endpoints and any sub-group analyses should be pre-specified in the study protocol and methods section of the study report.
  • If the secondary endpoints and sub-group analyses have not been pre-specified then there is a possibility that the data from the study has been analysed in many ways to find any kind of positive result in favour of the intervention (data dredging).

    If this is the case then the study results cannot be relied upon alone as providing reliable information – because if a set of data is analysed and re-analysed enough times, a positive result may occur purely by chance.
  • Secondary endpoints do not have the same statistical authority as the primary endpoint, and it is more likely that positive changes in secondary endpoints are due to chance.

    It has been stated that secondary endpoint results should only be used to help interpret the primary result of the trial or to provide information, or prompts, for future research.
  •  For example, a drug designed to prevent allergy-related deaths might also have a measure of whether the quality of life is improved.

    A Secondary endpoint is therefore always paired with a primary one.
  • Secondary endpoints are usually not taken into consideration from a power or randomization standpoint when designing a trial; they are usually analyzed post-hoc.

    As they are not taken into consideration when designing the trial, secondary endpoints may not be statistically sound and should be interpreted with caution.”

How to resolve reference ranges issue in RAVE eDC- CRA, CRC and DM prospective.

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How to resolve reference ranges issue in RAVE eDC- CRA, CRC and DM prospective.
Whether you are a Clinical Research Associate (CRA), Clinical Research Coordinator (CRC) or a Clinical Data Manager (CDM), you all face some common issues with reference ranges.

This blog is written by focusing on RAVE but many issues are common in RAVE and other eDC such as OCRDC.

Let’s discuss them one by one:

Most common issue is “missing ref ranges”

Clinical data manager (DM)  shares the missing ranges listing/report to CRAs and then CRAs share this with CRCs based on issue types.

Below are the common reasons for missing reference ranges in the database (RAVE)

If Lab name and associated ref ranges are available : In this case,  CRAs send this to CRC to select the concerned lab name. Once CRC selects the Concerned lab name, then associated ref ranges start populating and the issue is fixed.

If CRA identifies that the wrong lab name is selected, then he/she can inform CRC to select the correct ref range.

If CRA identifies that Lab name and associated ref ranges are not entered then he/she has to enter all the ref ranges. Once all the ranges are entered, CRC can select the lab so that ref ranges can be populated.

But there are some special reasons as well for missing ranges:

  • Age type
  • Age
  • Effective Date
  • Gender
  • Parameter code
  • LNR document issue
  • Qualitative parameter
  • Discrepancy in the unit/ref ranges

If CRA has selected the wrong “age type” in the lab module (back-end to enter the ranges) then ref ranges will not populate and  In this case, we have to correct  age types. It is different for Adult population and pediatric population. It means Correcting the age type will be the solution for “missing ranges”.

Age for which ref ranges are applicable should match with subject age.

Effective date of ref ranges should accommodate /cover the collection date of the lab performed.

Gender is selected wrongly. Subject is male and CRA selects female in lab module for that particular parameter

Parameter code is wrongly selected . Lab modules should have parameter code as per annotated CRF (case report form). for example cardiac troponin I code is TRONINI and the lab module has TROPONIN3 then ref ranges will not be populated. CRA has to inform CDM in this case so that programming issue can be fixed

LNR (local lab ref ranges) received by the CRA from the site may not have all the parameters which are present in the CRFs, in this case, CRA has to contact local lab administration, CRA/PI to provide the all the ref ranges.

Related: What is the difference between the Central lab and local lab in clinical research?

Few parameters may not have ref ranges:
Few parameters/ lab results are qualitative and may not have ref ranges.

DM should excluded those qualitative parameter before sending reports to CRA. Some examples are:  Hepatitis B/C and HIV antigen test etc where results are reported as positive or negative. Some parameters which are quantitative such as creatinine clearance may not have ref ranges. It should be double check with protocol or other guidance document for the same.

Discrepancy in the reported unit and ref ranges are corrected by CRA by selecting the correct unit or range and if desired unit is not available, a synonymous unit can be used (conversion factor should remain same).

Other interesting readings for all CRA, CRC and DM:

What is the Phase-IV Clinical Trial?

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What is the Phase-IV Clinical Trial?

Phase IV trial is also known as post-marketing trial, or informally as a confirmatory trial.

Phase IV trials include a drug’s health surveillance (pharmacovigilance) and continuing clinical assistance until it gains clearance to be marketed.

Health surveillance is intended to track any unusual or long-term adverse effects over a significantly wide number of patients and longer duration than was feasible during clinical trials in Phase I-III.

These reports collect detailed knowledge on side-effects and health, long-term costs and benefits and/or how well the drug performs when commonly used.

One aspect of this work is a non-interventional analysis (NIS) designed to evaluate the health, tolerability, and effectiveness in clinical practice of a treatment.

These studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for the interactions with other drugs, or on certain population groups such as pregnant women, who are doubtful to subject themselves to trials).

Phase IV may also include drug use studies (DUSS) that tell us how a drug is being marketed and actually prescribed within a population.

Finally, there is the registry or a prospective observational study of the patients with a common condition or risk that can result in an accurate assessment of clinical practice, patient, and comparative outcomes

https://www.eupati.eu/glossary/phase-iv-trials/

What is Phase-III Clinical Trial?

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What is Phase-III Clinical Trial?

“Phase III trials are conducted to confirm and expand on the safety and effectiveness results from Phase I and II trials, to compare the drug to the standard therapies for the disease or condition being studied, and to evaluate the overall risks and benefits of the drug.

Phase III studies are commonly randomized multicenter controlled trials on large patient populations (300–3,000 or more depending on the disease/medical condition studied) and are meant to be the definitive measure of how successful the medication is relative to the existing ‘gold standard’ treatment.

Phase III aim is to determine how the new medication performs for the same condition relative to existing drugs.

Before continuing with the experiment, researchers need to show that the drug is at least as safe and successful as the treatment options that exist.

Because of their size and relatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions.

Once a drug has proved acceptable after Phase III trials, the trial results are generally combined into a large document containing a comprehensive description of the methods and results of the human and animal studies, manufacturing procedures, formulation details, and shelf life.

This collection of information makes up the “regulatory submission” that is provided for review to the suitable regulatory authoritiesin different countries.

Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with the proper recommendations and guidelines through a New Drug Application (NDA) containing all the manufacturing, preclinical, and clinical data.

In case of any side effects being reported anywhere, the drugs need to be recalled without any delay from the market.”

What is Phase II Clinical Trial?

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What is Phase II Clinical Trial?

“If a new treatment is found to be reasonably safe in phase I clinical trials, it can then be tested in phase II clinical trial to find out if it works.

During this trial, the investigational medicinal product is tested for efficacy (and safety).

These trials are designed to evaluate the drug’s efficacy in people with the disease or condition being studied and to determine the common short-term adverse effects and risks associated with the drug.

Phase 2 trials aim to find out:
  • if the new treatment works well enough to be tested in a larger phase 3 trial
  • more about side effects and how to manage them
  • more about the best dose to use

Phase 2 trials are usually larger than phase 1 and are performed on larger groups (50–300).

They are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

Phase II studies are sometimes divided into Phase IIA and Phase IIB.

  • Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept’ studies)
  • Phase IIB studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definite dose-finding’ studies).

Some trials combine Phase I and Phase II, and test both efficacy and toxicity.”

Best books on clinical research-Must read for all

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Best books on clinical research-Must read for all

Please note that this blog contains the affiliate links from Amazon and this is not a sponsored post. Selection and reviews of best books on clinical research, are based on many readers opinions. Any Purchase will give us some money to survive this community.

The following books are useful for all professionals who are involved in clinical research especially data managers, clinical research associates and clinical research coordinator and other professionals.

“Fundamentals of Clinical Trials”, by Lawrence M. Friedman, Curt D. Furberg, David DeMets

This is one of the most recommended books for all fresher. This book talks about organizational structure, sample size calculation, study design, randomization procedure, interim data, monitoring plan, analysis, reporting of trial results etc. You will have an in-depth understanding once you finish this book. https://amzn.to/3eA1GeJ

The Comprehensive Guide to Clinical Research: A Practical Handbook for Gaining Insight into the Clinical Research Industry.

Appears to be a good introduction to the world of working in clinical research sites, CROs, and Sponsors. For those just beginning their careers or those looking to connect the dots in their work lives

Publishing and Presenting Clinical Research Third Editionby Warren S. Browner MD

The Third Edition of Writing and Reporting Clinical Work is an outstanding primer for researchers who wish to know how to plan, document and report their research results.

Written by an experienced clinical researcher and editor, it uses hundreds of examples, tables, and figures to illustrate how to publish successful abstracts, posters, oral presentations, and manuscripts.

Foundations of Clinical Research: Applications to Practice (3rd Edition) 

This book has been revised to reflect the most recent changes in the field of clinical research in rehabilitation and medicine, including the growing emphasis on evidence-based, practise (EBP), a new chapter on statistical analyses and meta-analysis

Recommended website to explore

For ICH guidelines: https://www.ich.org/page/ich-guidelines

For basic statistics https://www.statisticshowto.com/

GCP https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice

Please provide the comments if you want to suggest any other book or does not agree with our selection of books.

Soleno Therapeutics Announces Closing of $57.5 Million Public Offering of Common Stock

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Soleno Therapeutics Announces Closing of $57.5 Million Public Offering of Common Stock
June 26, 2020: “Soleno Therapeutics announced the closing of its previously announced underwritten public offering of 34,848,484 shares of its common stock, including 4,545,454 shares sold upon full exercise of the underwriters’ option to purchase additional shares, at a public offering price of $1.65 per share.

The net proceeds of the offering were approximately $53.7 million, after deducting the underwriting discount and other offering expenses.

Guggenheim Securities, LLC acted as the sole book-running manager for the offering. Oppenheimer & Co. Inc. acted as lead manager for the offering, and Laidlaw & Company (UK) Ltd. acted as co-manager for the offering.

The offering was made pursuant to the Company’s shelf registration statement on Form S-3 (File No. 333-232068) previously filed with and subsequently declared effective by the Securities and Exchange Commission (the “SEC”) on July 23, 2019, and a preliminary prospectus supplement filed with the SEC on June 23, 2020, and a final prospectus supplement filed with the SEC on June 25, 2020.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.”
http://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-closing-575-million-public

Janssen Announces Discontinuation of Phase 3 LOTUS Study Evaluating Ustekinumab

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Janssen Announces Discontinuation of Phase 3 LOTUS Study Evaluating Ustekinumab

Jun 26, 2020: “The Janssen Pharmaceutical Companies of Johnson & Johnson announced today its decision to discontinue the Phase 3 LOTUS study of STELARA® (ustekinumab) in Systemic Lupus Erythematosus (SLE) due to lack of efficacy in SLE.

The decision is based on data from a pre-planned interim efficacy analysis. Interim safety findings were consistent with the known safety profile of STELARA, and no new safety signals were identified.

Investigators, study participants and health authorities have been informed of the decision.

The company intends to thoroughly analyze the totality of the study data and publish findings.

Related News: New Phase IIIb Interim Data from the STARDUST Study Shows about Two-Thirds of Patients with Moderately to Severely Active Crohn’s Disease Achieved Clinical Remission After Two Doses of the STELARA® (ustekinumab)

“Lupus patients are waiting for better treatments, which makes this outcome disappointing,” said Alyssa Johnsen, M.D., Ph.D., Vice President, Rheumatology Disease Area Leader, Janssen Research & Development, LLC.

“Our hope is that by ultimately sharing these data with the scientific community we can help inform lupus research and therefore still have a positive impact on the lives of patients living with SLE. Janssen continues to be strongly committed to research and development of novel therapies for lupus.”

The decision to discontinue the LOTUS study does not impact any other ongoing studies with ustekinumab or current indications.

https://amzn.to/31l1YCx

It enrolled 516 patients, including representation from minority populations who are disproportionately impacted by lupus.

The Primary Endpoint is the proportion of participants with a composite measure of SRI-4 (Systemic Lupus Responder Index) response at Week 52.


A second Phase 3 study, LOTUS-C, to be conducted in China was planned but will not start given this decision.

STELARA® (ustekinumab)
STELARA® (ustekinumab), a human IL-12 and IL-23 antagonist, is approved in the United States for the treatment of

1) adults and children 12 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy;

2) adult patients (18 years or older) with active psoriatic arthritis, used alone or in combination with methotrexate (MTX);

3) adult patients (18 years and older) with moderately to severely active Crohn’s disease;

4) adult patients (18 years and older) with moderately to severely active ulcerative colitis.

The Janssen Pharmaceutical Companies of Johnson & Johnson maintain exclusive worldwide marketing rights to STELARA®.”
https://johnsonandjohnson.gcs-web.com/static-files/ab880ddb-ceb2-4f65-9ef5-dcc55ea8d421

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