Post-Marketing Compliance &

Health Canada Progressive Licensing

Professor Peivand Pirouzi

2006

FDA/Health Canada Guidances

Reporting Adverse Events for Drugs, Devices, Biologics and Dietary Supplements

FDA's Medwatch program allows health care professionals and consumers to report to the FDA serious problems with the medical products they prescribe, dispense, or use. These reports, along with follow-up investigations, can help to identify important safety concerns. Take the example of the antibiotic Zyvox. Within the first six months of Zyvox's marketing, FDA began getting MedWatch reports of myelosupression from clinicians who suspected that the drug might be responsible. After investigating the problem, we worked with the manufacturer to change the Zyvox labeling to warn about the potential for myelosuppression. Sometimes MedWatch reports highlight errors in prescribing or administering medications. For example, FDA received reports of patient injuries due to name confusion between LANOXIN, a heart medication, and what used to be called LEVOXINE, a thyroid medication. As a result, FDA asked the manufacturer to change the name of Levoxine, and now it's known as LEVOXYL, which is less likely to be confused with LANOXIN. The MedWatch system can also help detect problems with medical products other than drugs. For example, FDA received two reports of pneumococcal eye infections in patients who'd received corneal transplants. An FDA inspection identified numerous manufacturing problems, which led the company to recall the implants.

Reporting Adverse Events for Drugs, Devices, Biologics and Dietary Supplements

Of course, MedWatch reports by themselves can not usually establish a causal relationship between an adverse event and a medical product - it may take a formal epidemiologic study to do that. Still, MedWatch reports are vital in making sure that medical products are safe, because they provide a rapid signal to FDA that problems may be occurring. It is important to keep the MedWatch system working, and we can not do that without your help. Here are the kinds of reports we need from you: • First of all, we are asking that you report any serious adverse event that might be associated with a drug, biologic, medical device, or dietary supplement. By "serious" we mean fatalities, hospitalizations, and medically significant events. We're especially interested in serious adverse events that aren't listed in the product labelling. • Secondly, report therapeutic failures - cases where the drug or device failed to work as it should. For example, let us know if a patient has to switch from one brand of a drug to another because the original one was ineffective. • Third, tell us about cases of use errors with medications or devices, including situations where the error may have been due to poor communication, or to ambiguities in product names, directions for use, or packaging. • And finally, we would like to know about product quality issues, such as suspected counterfeit products, defective components, potential contamination, device malfunctions and poor packaging.

MedWatch: Reporting Adverse Events

1. FDA's Medwatch program allows health care professionals and consumers to report to the FDA serious problems with the medical products they prescribe, dispense, or use. These reports, along with follow-up investigations, can help to identify important safety concerns.

2. It is important to keep the MedWatch system working, and we can not do that without your help. Here are the kinds of reports we need from you:

– Report any serious adverse event that might be associated with a drug, biologic, medical device, or dietary supplement. By "serious" we mean fatalities, hospitalizations, and medically significant events. FDA is especially interested in serious adverse events that aren't listed in the product labeling.

– Report therapeutic failures - cases where the drug or device failed to work as it should (e.g., if a patient has to switch from one brand of a drug to another because the original one was ineffective).

– Report cases of use errors with medications or devices, including situations where the error may have been due to poor communication, or to ambiguities in product names, directions for use, or packaging.

– Report product quality issues, such as suspected counterfeit products, defective components, potential contamination, device malfunctions and poor packaging.

Stronger Risk Management Program for Accutane (isotretinoin)

Isotretinoin is now a restricted distribution drug. This means that wholesalers won't be able to distribute the drug, pharmacists won't be able to dispense it, physicians won't be able to prescribe it, and patients won't be able to receive it unless they register. Doctors, patients, and pharmacies can obtain program information and register with iPLEDGE either online or by telephone at 1-866-495-0654. There is also a possible link between taking this drug and depression, suicidality, and psychosis. And for that reason, FDA has strengthened the labeling to help practitioners and patients identify and manage these risks. Any patient being treated with this drug should be carefully monitored for symptoms of depression, or suicidalility or psychosis. Patients should be told to stop the drug and contact their health professional if they experience any of these symptoms. Stopping the drug by itself, however, may not be sufficient. Psychiatric evaluation and intervention may be needed to prevent patients from harming themselves.

Stronger Risk Management Program for Accutane (isotretinoin)

Revised October 28, 2005: The implementation dates of the iPLEDGE program have been revised. The date by which wholesalers and pharmacies must be registered /activated in IPLEDGE has been changed from November 1, 2005 to December 30, 2005. By March 1, 2006, only prescribers registered and activated in iPLEDGE can prescribe isotretinoin and only patients registered and qualified in iPLEDGE can be dispensed isotretinoin. Patients can begin registering and qualifying on December 30, 2005. FDA has developed stronger requirements to prevent fetal exposure to the drug Accutane (isotretinoin) along with its generic equivalents, such as Amnesteem, Sotret and Claravis. Isotretinoin is used to treat severe, recalcitrant, nodular acne, but it can cause serious birth defects if taken by pregnant women. These requirements are now going into effect in a new program called iPLEDGE. Under this program, wholesalers, prescribers, pharmacies and patients, both men and women, must register. Also, women who are capable of becoming pregnant must have two negative pregnancy tests before isotretinoin can be dispensed to them. They also must have a negative pregnancy test each month while taking the drug.

FDA Studying Potential Safety Issues with Several Drugs

FDA has informed the health care community about ongoing safety reviews of several drugs. FDA is doing this as part of its commitment to inform health care professionals and the public about its ongoing drug safety reviews. Because this information is preliminary and there is scientific uncertainty, FDA is not taking regulatory action at this point, and is not advising health care professionals to stop using the drugs. FDA is continuing to evaluate the safety of these products, and will issue updates as more information becomes available.

• CellCept (mycophenolate mofetil) and Myfortic (mycophenolic acid) • Singulair (montelukast) • Spiriva Handihaler (tiotropium)

New Rule Enhances the Safety of Human Cells and Tissues

FDA recently finalized a new rule that's designed to increase the safety of human cells, tissues and cellular and tissue-based products that are used for transplantation. The regulations apply to a broad range of products, including bone, ligaments, skin, corneas, and hematopoietic stem cells. They also apply to human heart valve and human dura mater allografts. The rule requires that manufacturers of these products recover, process, store, label, package and distribute them in a way that prevents the spread of communicable diseases. In this rule, FDA uses the word "manufacture" as an umbrella term to capture the many different actions an establishment might take in preparing these products for use. Many types of establishments may be involved in various steps from recovery, donor screening and testing, to storage and distribution. If an establishment is involved in any of the steps covered by the new regulation, FDA calls it a manufacturer. Prior to the new rule, there were some regulations in place to help assure the safety of human tissue. But the new rule covers a broader range of products and has more comprehensive requirements. This will help assure health care providers that the tissue and cellular products they use are the safest available.

Reporting Adverse Events from Vaccines

Every year, tens of millions of vaccinations are given to children and adults in this country to prevent serious infectious diseases. FDA and CDC work together to monitor the safety of these vaccines using a registry known as Vaccine Adverse Event Reporting System, or VAERS. The VAERS registry contains reports of adverse events from patients, parents and health care providers, and it can help to identify important new vaccine safety concerns. Take the example of the rotavirus vaccine. During the first months after this vaccine was approved, epidemiologists at FDA and CDC noticed 15 VAERS reports of infants who had developed a particular type of intestinal obstruction after receiving the vaccine. The reports signaled a potential problem, which led to further investigations. As a result, the vaccination program was suspended, and then later, as investigations verified the serious risk, the manufacturer voluntarily removed the vaccine from the market.

Reporting Adverse Events from Vaccines

Of course, it takes multiple reports and thorough investigation to confirm a causal relationship between an adverse event and a vaccine. Still, VAERS reports are on the front line in making sure that vaccines are safe, by providing a rapid signal that problems may be occurring. Sometimes VAERS reports highlight errors in prescribing or administering vaccines. For example, the VAERS registry was found to contain reports of 22 pregnant women who had received live virus varicella vaccine by mistake after being exposed to chickenpox. These women should have received a different product, varicella zoster immune globulin, or "VZIG." In this case, FDA and CDC worked with the varicella vaccine manufacturer to publish details about the 22 cases. By publishing this information, we were able to alert health care professionals of this potential mix-up, and thus help prevent future cases. It's important to keep the VAERS system working, and we can't do that without your help. We're asking that you report any significant adverse event that occurs after a vaccination, even if you're not sure that the vaccine caused it. It's easy to report by internet, phone, fax, or mail.

PHARMACOVIGILANCE AND RISK MANAGEMENT THROUGHOUT THE PRODUCT LIFECYCLE

http://www.hc-sc.gc.ca/dhp-mps/homologation-licensing/develop/proglic_homprog_discus-eng.php

Progressive Licensing 2006

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/homologation-licensing/plfs_hpfd-eng.pdf

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/proglic_homprog_discus-eng.pdf

Progressive licensing

Presentation of Dr. Agnes Klein, Health Canada:

What is a Pharmacovigilance Plan?

A plan proposed by a sponsor – for the ongoing evaluation of safety

signals identified with the use of a product

– to monitor at-risk populations which have not been adequately studied

Plan may be developed at the time of product launch or after a signal is identified

What is a Pharmacovigilance Plan?

A sponsor’s plan for an ongoing evaluation of safety signals*.

May involve: – Expedited reporting of serious adverse events

– Submission of adverse event report summaries at more frequent, pre-specified

intervals

– Implementation of active surveillance activities to identify adverse events that may or may not be reported through passive surveillance

– Creation of registries or conducting patient/healthcare provider surveys

– Conduct of Pharmacoepidemiologic studies using cohort study design

* A safety signal is an apparent excess of adverse events associated with use of a product

Post market Requirements and Commitments

Post market requirement and commitment studies and clinical trials occur after a drug or biological product has been approved by FDA.

Guidance for Industry (PDF - 456KB) (Post market commitment-non-clinical). A separate Web site is available for post approval studies for medical devices.

Website for Post market Requirements and Commitments Database (FDA):

http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm?StartRow=2&StepSize=1&Paging=Yes

The need

Regulatory agencies are increasingly proactive in seeking out potential safety issues with marketed drugs

Political and social pressures have increased along with faster communication channels

Litigation due to the lack of Pharmacovigilance can be devastating for all concerned

Failure to practice pharmacovigilance can lead to the suspension or withdrawal of license