New FDA Guidances for May 2017

By Sheila Plant, Ph.D., R.A.C., Assistant Director, Regulatory Strategy, US at Cato Research
One revised draft FDA guidance, released from CBER, and two MAPPs, released from CDER, in May 2017, are posted.  In addition, upcoming advisory committee meetings to be held in June and July are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Corrected Draft Guidance May 2017
Special Interest Manual of Policies & Procedures (CDER) Date Posted
CDER FTE Tracking and Table of Organization Review Process 30 May 2017
Good Review Practice: Clinical and Consultative Review of Drugs to Reduce the Risk of Cancer 16 May 2017
Upcoming Meetings (* = New)
* June 20, 2017: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting
* June 21-22, 2017: Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee Meeting
* July 28, 2017: Vaccines and Related Biological Products Advisory Committee Meeting
Last updated: 1 May 2017
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New FDA Guidances for March and April 2017

By Joanne McNelis, Ph.D., Clinical Strategy Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH, and Manual of Policies and Procedures (MAPPs) of interest, released from CDER in March and April are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Extending Expiration Dates of Doxycycline Tablets and Capsules in Strategic Stockpiles – Draft Guidance 24 Apr 2017
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications – Final Guidance 07 Apr 2017
Delayed Graft Function in Kidney Transplant: Developing Drugs for Prevention: Guidance for Industry – Draft Guidance 22 Mar 2017
Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims (Expiration date, updated) – Final Guidance 14 Mar 2017
Special Interest Manual of Policies & Procedures (CDER) Date Posted
Consulting the Controlled Substance Staff on Drug Abuse Potential and Labeling, Drug Scheduling, Dependence Liability and Drug Abuse Risks to the Public Health 06 Mar 2017
Upcoming Meetings (* = New)
* May 17, 2017: Gastroenterology and Urology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* May 17, 2017: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
* May 24, 2017: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
* May 25, 2017: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
2017 Advisory Committee Tentative Meetings
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What’s New Health Canada? March – April 2017

By Sandra Salem, Ph.D., Regulatory Scientist, Amelie Rodrigue-Way, Ph.D., RAC (CAN), Associate Director, Regulatory Strategy, and Christine Straccini, B.Sc., Regulatory Associate; Cato Research Canada

 

What’s New in:

Therapeutic Products Directorate:

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/update-miseajour/index-eng.php

 

Biologics and Genetic Therapies Directorate:

http://www.hc-sc.gc.ca/dhp-mps/brgtherap/update-miseajour/index-eng.php

 

Medical Devices: http://www.hc-sc.gc.ca/dhp-mps/md-im/update-miseajour/index-eng.php

 

Natural and Non-prescription Health Products Directorate: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/new-neuf-eng.php

 

 

Health Canada New Guidance Documents (Drugs and Biologics):

March-April 2017

Health Canada Guidance Type Date Posted
Guidance Document – Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act Draft Guidance 09 Mar 2017
Notice: Guidance Document – Fees for the Right to Sell Drugs Guidance Document 14 Mar 2017
Notice: Guidance Document: Cancellation of a Drug Identification Number (DIN) and Notification of the Discontinuation of Sales Guidance Document 14 Mar 2017

 

Updates from Health Canada (Drugs and Biologics):

March-April 2017

Type of Update and Link Date Posted
Notice – Upcoming Changes to the Annual Drug Notification Form 14 Mar 2017
Health Canada New Drug Authorizations: 2016 Highlights 15 Mar 2017
Notice: Availability of Summary Basis of Decision Documents and Regulatory Decision Summaries on the Drug and Health Products Register 29 Mar 2017
Health Canada and United States Food and Drug Administration Joint Public Consultation on International Council on Harmonisation Guidelines for Registration of Pharmaceuticals for Human Use 31 Mar 2017
Notice – Intellectual Property Hold for Notifiable Change Submissions 07 Apr 2017
Submissions Under Review 10 Apr 2017
Product Monograph Brand Safety Updates 10 Apr 2017

 

Santé Canada: Quoi de neuf?

 

 

Par Sandra Salem, Ph.D., Scientifique Réglementaire, Amélie Rodrigue-Way, Ph.D., RAC (CAN), Directrice associée, Stratégie réglementaire, et Christine Straccini, B.Sc., Associée réglementaire ; Cato Recherche Canada

 

Quoi de neuf :

Direction des produits thérapeutiques

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/update-miseajour/index-fra.php

 

Direction des produits biologiques et thérapies génétiques:

http://www.hc-sc.gc.ca/dhp-mps/brgtherap/update-miseajour/index-fra.php

 

Instruments médicaux: http://www.hc-sc.gc.ca/dhp-mps/md-im/update-miseajour/index-fra.php

 

Direction des produits de santé naturels et sans ordonnance:

http://www.hc-sc.gc.ca/dhp-mps/prodnatur/new-neuf-fra.php

 

 

Nouvelles lignes directrices de Santé Canada (Médicaments et Produits biologiques):

Mars-Avril 2017

Ligne directrice de Santé Canada Genre Date
Lignes directrices – Communication de renseignements commerciaux confidentiels aux termes de l’alinéa 21.1(3)(c) de la Loi sur les aliments et drogues Ébauche de la ligne directrice 09 Mar 2017
Avis : Ligne Directrice – Frais à payer pour le droit de vendre une drogue Ligne Directrice 14 Mar 2017
Avis : Ligne directrice : Annulation d’une identification numérique de drogue (DIN) et avis de cessation de la vente d’une drogue Ligne Directrice 14 Mar 2017

 

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

Mars-Avril 2017

Genre de mise à jour et lien Date
Avis – Changements à venir au formulaire de notification annuelle de drogue 14 Mar 2017
Autorisations de nouveaux médicaments par Santé Canada : Faits saillants de 2016 15 Mar 2017
Disponibilité des sommaires des motifs de décision et des sommaires des décisions réglementaires sur le Registre des médicaments et des produits de santé 29 Mar 2017
Consultation publique conjointe entre Santé Canada et de la Food and Drug Administration des États Unis sur les lignes directrices de l’International Council on Harmonisation pour l’enregistrement des médicaments à usage humain 31 Mar 2017
Avis – Les présentations de préavis de modification qui ont été mise en suspens pour des motifs rélatifs à la propriété intellectuelle 07 Apr 2017
Présentations en cours d’examen 10 Apr 2017
Mises à jour concernant l`innocuité des monographies de produits pour les médicaments innovateurs 10 Apr 2017

 

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CANCER IMMUNOTHERAPY: A NEW HOPE

By Reshma Jagasia, Ph.D, Scientist at Cato Research

The current standard of care for cancer treatment is surgery, chemotherapy, and radiation therapy – a standard that has persisted for decades. These treatments are invasive and not specific, killing healthy cells and tissues along with tumors. In the past decade, more targeted therapies have emerged, including the monoclonal antibodies (mAbs) rituximab (Rituxan® or MabThera®) and trastuzumab (Herceptin®), and the chemotherapy drug imatinib (Gleevec®). These treatments target cancer cells by taking advantage of the inherent molecular differences between cancer and healthy cells. Now a new class of treatment is emerging, one that purports to harnesses the patient’s own immune system to combat the patient’s disease. Called immunotherapy, this class of treatment is being described by researchers as the “fifth pillar” of cancer treatment. There are currently five types of FDA-approved immunotherapy for the treatment of cancer: (1) monoclonal antibodies, (2) immune checkpoint inhibitors, (3) cancer vaccines, (4) oncolytic viruses, and (5) other, non-specific immunotherapies. This article reviews these commercially available immunotherapies for cancer.

Monoclonal Antibodies

Monoclonal antibodies (mAbs) have been used to treat cancer and a number of other diseases. A therapeutic mAb functions by binding to a specific (targeted) antigen to elicit an immune response in the body against that target. In some cases, a toxin or radioisotope can be attached to the mAb, essentially turning the mAb into a drug-delivery system to an individual cancer cell. The key to this therapeutic strategy lies in identifying an antigen that is specific to the cancer cell over healthy cells. For some cancers, the identification of such an antigen has been difficult, hindering mAb drug development for these cancers.

There are currently over two dozen FDA-approved mAbs for the treatment of various types of cancer (see Table 1). Still more mAbs are in clinical trials. As suitable antigens for cancer treatment are identified, new mAbs are being developed for cancer treatment. New developments also include modifying mAbs to reduce potential adverse events, and combining the binding regions of two different mAbs (known as a bispecific antibody) to enhance cell targeting.

Table 1: Current* FDA-Approved Monoclonal Antibodies for Cancer Treatment

Monoclonal Antibody

Brand Name

Target

FDA Approval Date

Indication

alemtuzumab

Campath®

CD52

2001

Chronic lymphocytic leukemia

atezolizumab

Tecentriq®

PD-L1

2016

Bladder cancer
Non-small cell lung cancer

bevacizumab

Avastin®

VEGF

2004

Colorectal cancer

2006

Non-small cell lung cancer

2009

Glioblastoma
Renal cell cancer

2014

Cervical cancer
Ovarian epithelial, fallopian tube, or primary peritoneal cancer

blinatumomab

Blincyto®

CD19 and CD3
(bispecific)

2014

Acute lymphoblastic leukemia

brentuximab vedotin

Adcetris®

CD30

2011

Anaplastic large cell lymphoma
Hodgkin lymphoma

cetuximab

Erbitux®

EGFR

2004

Colorectal cancer

2006

Head and neck cancer

daratumumab

Darzalex®

CD38

2015

Multiple myeloma

denosumab

Prolia®
Xgeva®

RANKL

2013

Giant cell tumor of the bone

dinutuximab

Unituxin®

GD2

2015

Neuroblastoma

elotuzumab

Empliciti®

CS1

2015

Multiple myeloma

gemtuzumab ozogamicin
(discontinued in 2010)

Mylotarg®

CD33

2000

Acute myeloid leukemia

ibritumomab tiuxetan

Zevalin®

CD20

2002

Non-Hodgkin lymphoma

ipilimumab

Yervoy®

CTLA-4

2011

Melanoma

necitumumab

Portrazza®

EGFR

2015

Non-small-cell lung cancer

nivolumab

Opdivo®

PD-1

2014

Melanoma

2015

Non-small-cell lung cancer
Kidney cancer

2016

Classical Hodgkin lymphoma
Head and neck cancer

obinutuzumab

Gazyva®

CD20

2013

Chronic lymphocytic leukemia

2016

Follicular lymphoma

ofatumumab

Arzerra®

CD20

2009

Chronic lymphocytic leukemia

olaratumab

Lartruvo®

PDGFR alpha

2016

Soft tissue sarcoma

panitumumab

Vectibix®

EGFR

2006

Colorectal cancer

pembrolizumab

Keytruda®

PD-1 receptor

2014

Melanoma,

2015

Non-small-cell lung cancer

2016

Head and neck cancer

pertuzumab

Perjeta®

HER-2

2013

Breast cancer

ramucirumab

Cyramza®

VEGFR-2

2014

Adenocarcinoma of the stomach or gastroesophageal junction
Non-small cell lung cancer

2015

Colorectal cancer

rituximab

Rituxan®,
Mabthera®

CD20

2006

Non-Hodgkin lymphoma

2010

Chronic lymphocytic leukemia

siltuximab

Sylvant®

 

2014

Multicentric Castleman disease

tositumomab
(discontinued in 2014)

Bexxar®

CD20

2003

Non-Hodgkin lymphoma

trastuzumab

Herceptin®

HER-2

2006

Breast cancer

2010

Adenocarcinoma of the stomach or gastroesophageal junction

*As of the authorship of this article. Information was acquired from the American Cancer Society website, www.cancer.org.

 

Immune Checkpoint Therapies

The immune system functions by recognizing foreign or sick cells from healthy ones using “checkpoints”, stimulatory or inhibitory mechanisms that prevent autoimmunity. Some cancers are able to adopt checkpoint mechanisms, thereby evading detection by the immune system. By inhibiting such checkpoint mechanisms, a cancer cell could become unmasked and potentially be killed.

Two checkpoint receptors have emerged as accessible targets for cancer treatment: PD1 and CTLA-4, two cell-surface proteins expressed by T cells. When PD1 on a T cell binds its native ligand, PD-L1, on a healthy cell, the T cell is prevented from attacking. Some cancer cells display large quantities PD-L1, mimicking healthy cells. Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®) are both FDA-approved monoclonal antibodies that target PD1 for the treatment of several types of cancer, including melanoma, non-small cell lung cancer, kidney cancer, head and neck cancers, and Hodgkin lymphoma. Atezolizumab (Tecentriq®), also a mAb, targets PD-L1 for bladder and metastatic non-small cell lung cancer (NSCLC). Ipilimumab (Yervoy®), is an FDA-approved mAb that targets CTLA-4, a checkpoint receptor that functions similarly to PD1.

A concern for checkpoint inhibitors is that they can target normal cell functions, affecting healthy cells as well as tumors. Many new checkpoint inhibitor drugs are currently being studied. Also being considered is the use of combination treatment, such as nivolumab, which targets PD-1, and ipilimumab, which targets CTLA-4, to improve efficacy. Use of this combination has been shown to work well in melanoma patients but comes with an increased risk of serious side effects.

Cancer Vaccines

Traditional vaccines against viruses are intended to prime the body’s immune system to mount a response should a viral infection occur. Some cancers appear to be linked to viral infections. Various strains of the human papilloma virus (HPV) have been linked to cervical, anal, and throat cancers. People with chronic hepatitis B virus (HBV) are at a higher risk for liver cancer. Traditional vaccines targeting these viruses potentially could reduce the risk of an infected but otherwise healthy person developing one of these associated cancers.

Cancer vaccines, on the other hand, are intended to treat patients already diagnosed with cancer. These vaccines attempt to boost the patient’s own immune system to attack cancer cells in the body.

Tumor cell vaccines: These vaccines are made from cancer cells that have been removed from the patient during surgery or biopsy. These cells are altered (and killed) in the lab to improve immunogenicity, then injected back into the patient with the intent to elicit a strong immune response. Most tumor cell vaccines are autologous, but allogeneic vaccines are much easier to make. It is not yet clear if one type works better than the other.

Antigen vaccines: These vaccines boost the immune system by using only one (or a few) antigens rather than whole tumor cells. These antigens are often proteins or peptide-segments of proteins. Often, these antigens are specific to certain types of cancer mutations and may not be effective for all patients with similar cancer.

Dendritic cell vaccines: Dendritic cells are antigen-presenting cells that can be recognized by T cells. The resulting activated T cells then initiate an immune response against any cells in the body that present these antigens. The manufacturing process of dendritic cell vaccines is complex and expensive, involving the removal of white blood cells (primarily dendritic cells) from the patient, modification of the dendritic cell to present the patient’s cancer antigen on its surface, and reinfusion of these cells into the patient to enhance the immune response. Because the starting material for the manufacturing of this “live drug” is the patient’s own white blood cells, each batch of drug is precisely intended only for that patient. It is hoped that the vaccine might continue to work long after being administered, as well as become incorporated into the immune system’s memory.

Sipuleucel-T (Provenge®) is a dendritic cell vaccine and the only cancer vaccine currently approved to treat cancer in the United States. This therapy is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer. While this therapy has not been shown to cure the patient, it has been shown to extend patients’ lives on average of several months.

Dendritic cell vaccines have shown the most success among vaccines in treating cancer, and have accordingly garnered much excitement in the research community. The concept of adoptive cell therapy (ACT) – the removal, modification, and reinfusion of a patient’s own T cells – is being researched heavily with many new therapies entering early-phase clinical trials.

Vector-based vaccines: These vaccines use vectors to deliver a vaccine drug to the tumor site, potentially improving treatment efficacy. Vectors can be viruses, bacteria, yeast cells, or other structures. While these vaccines differ from other vaccine categories only by their delivery system (e.g., there are vector-based antigen vaccines), they do offer some benefits over their counterparts. Vectors allow for the delivery of multiple antigens at a time, increasing the likelihood of an immune response by the body. In fact, the vector itself is a potential immunogen. Vector-based vaccines may also be less expensive to manufacture compared with some other vaccines.

Oncolytic Viruses

Talimogene laherparepvec (Imlygic®) is an injectable oncolytic virus approved by the FDA in 2015 for the treatment of melanoma lesions that cannot be surgically removed in the skin and lymph nodes. This novel product uses a herpes virus to infect cells at the injection site. While the virus can infect both healthy and cancerous cells, it has been engineered to not replication inside healthy cells. When inside a cancer cell, the replicating virus synthesizes and secretes GM-CSF, a protein that boosts the immune response. The proliferation of the virus and the increased concentration of GM-CSF afford a heightened immune response targeted at the sight of virus delivery, i.e., the tumor. This treatment has been shown to shrink treated tumors but not to affect tumors in other parts of the body.

Non-Specific Immunotherapies

Instead of targeting cancer cells specifically, non-specific immunotherapies stimulate the immune system globally with the intent to improve the response to a patient’s cancer cells. These therapies can be administered alone as cancer treatments or used as adjuvants with other treatments. Cytokines are the most common non-specific immunotherapeutic. One cytokine, interleukin-2 (IL-2), is approved to treat advanced kidney cancer and metastatic melanoma. Other interleukins, such as IL-7, IL-12, and IL-21, are currently being studied for cancer therapy. Another cytokine, interferon-alpha (IFN-α), is known to enhance the overall immune response but may also directly inhibit cancer cell proliferation and angiogenesis. IFN-α has been used to treat a variety of cancers, including hairy cell leukemia, chronic myelogenous leukemia (CML), follicular non-Hodgkin lymphoma, cutaneous (skin) T-cell lymphoma, kidney cancer, melanoma, and kaposi sarcoma.

Other non-specific immunomodulating drugs include thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®). These drugs are used to treat multiple myeloma and some other cancers. Imiquimod (Zyclara®) is a topical cream that stimulates a local immune response against skin cancer, especially early-stage cancers located in sensitive areas on the body. Bacille Calmette-Guérin (BCG) is an attenuated version of a Mycobacterium bovis, a bacterium closely related to Mycobacterium tuberculosis, the agent responsible for tuberculosis. BCG does not cause serious disease in humans but can activate the immune system. BCG was one of the earliest immunotherapies used against cancer and is still being used today to treat early stage bladder cancer.

Immunotherapies are quickly gaining momentum to become an important option for cancer treatment. Immunotherapy development has proven to be more difficult than originally anticipated by researchers due to the complex nature of the immune system and the adaptability of cancer to evade immune attack. However, over the past three decades, new knowledge about cancer and immunity has abounded, and researchers are hopeful that, alongside chemotherapy, radiation therapy, and surgery, immunotherapy will play a key role in the future of cancer treatment and prevention.

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New FDA Guidances for February 2017

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

FDA draft and final guidances, released from CDER, CBER, and CDRH in February 2017 are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Q11 Development and Manufacture of Drug Substances—Questions and Answers (regarding the selection and justification of starting materials – Draft Guidance 17 Feb 2017
Requirements for Transactions with First Responders under Section 582 of the Federal Food, Drug, and Cosmetic Act— Compliance Policy – Final Guidance 16 Feb 2017
Guidance Agenda: Guidances CDER is Planning… – Draft Guidance 15 Feb 2017
Dear Health Care Provider Letters: Improving Communication of Important Safety Information – Final Guidance 08 Feb 2017
Upcoming Meetings (* = New)
Pediatric Advisory Committee Meeting; 06 March 2017; Silver Spring, MD
Pediatric Advisory Committee Meeting; 07 March 2017; Silver Spring, MD
Vaccines and Related Biological Products Committee Meeting; 09 March 2017; Rockville, MD
Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee; 13-14 March 2017; Silver Spring, MD
Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting; 15 March 2017; Washington, DC
Joint Meeting of the Ophthalmic Devices Panel of the Medical Devices Advisory Committee and the Risk Communication Advisory Committee; 17 March 2017; Gaithersburg, MD
* Blood Products Advisory Committee Meeting; 4-5 April 2017; Silver Spring, MD
2017 Advisory Committee Tentative Meetings
* new entry
Last updated: 01 March 2017
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