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Category: Clinical Safety and Pharmacovigilance

Responsible Person for EudraVigilance

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Introduction

EudraVigilance is a centralised European database of suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the European Economic Area (EEA).

EudraVigilance is the system for managing and analysing information on suspected adverse reactions to medicines which have been authorised or being studied in clinical trials in the European Economic Area (EEA). The European Medicines Agency (EMA) operates the system on behalf of the European Union (EU) medicines regulatory network.

EudraVigilance supports safe and effective use of medicines by facilitating:

  • Electronic exchange of ICSRs (Individual Case Safety Reports) between EMA, NCAs, MAHs and CT Sponsors in the EEA
  • Early detection and evaluation of possible safety signals
  • Better product information for medicines authorised in the EEA.

This electronic reporting is mandatory for marketing authorisation holders and sponsors of clinical trials. Marketing authorisation holders and sponsors of clinical trials must report and evaluate suspected adverse drug reactions during the development and following the marketing authorisation of medicinal products in the European Economic Area (EEA). Marketing authorisation holders must also electronically submit information on medicinal products authorised in the European Union (EU).

Why do we need a Responsible Person for EudraVigilance (RPEV)?

The Qualified Person for Pharmacovigilance (QPPV, for MAHs), or the Responsible Person (RP, for Sponsors/ Non-Commercial Sponsors) is responsible for managing an organization and its users in the EudraVigilance Production system.

For an individual to provide RP services to a sponsor/non-commercial sponsor, any one user in the individual’s organization should successfully complete the EudraVigilance ICSR knowledge evaluation and XEVMPD knowledge evaluation. To ensure the quality of data submitted to the EMA, the EMA offers training courses on ICSR and Product submissions using EVWeb, after which users may undergo knowledge evaluations.

Registration of Responsible Person in EudraVigilance

Registration of a Responsible Person could entail one of the following two scenarios:

Scenario 1: Change of RP (when there is still an RP in the organization), or

Scenario 2: New RP registration (when the first user of a new organization is registering as RP)

A set of documents must be submitted to the EMA to register the Responsible Person in either of the above scenarios.

Documents Required Scenario 1

(Change of RP)

 Scenario 2

(New RP)
Cover letter from the headquarters lever of the organization on a headed paper. The Cover letter should be signed by the new RP of by a person in a position above that at the headquarters leverl= (i.e., director of the organization or similar), or by the legal representative or Commercial and Non-Commercial Sponsors. The cover letter should state the name and position of the previous RP and the name, position and contact details of the new RP. The cover letter should state the name, position and contact details of the new RP.
Email Confirmation from the OMS Data Stewards acknowledging the successful creation of the new organization. Not required, as the organization is already registered with OMS by the

older RP.

 Required
Copy of the ID card or driver’s license or passport, with the full name and signature visible. Any other information contained on the ID document may be blacked out. Required Required

 

Documents Required Scenario 1

(Change of RP)

 Scenario 2

(New RP)
User declaration form for RP, including the type and same of the organization, user’s details, and dated and signed by the user Required Required
EudraVigilance ICSR and XEVMPD submission training. A declaration from the QPPV/RP that the organization has a suitably trained person or submission of ICSRs and XEVPRMs. This declaration can be included in the cover letter or in the body of the email submitted via the EV Registration Service Desk. Submitting copies of ICSR and XEVMPD Certificates is not necessary when changing the QPPV/RP. A copy of the notification of successful completion of the EudraVigilance ICSR

and XEVMPD knowledge evaluation for at least one user to access the production environment, as applicable
Form A- for Sponsor based

in the EEA. Signed by the Sponsor’s legal representative person appointing the new responsible person for clinical trials, including the

name and the contact

details of this person.

The legal representative

person and responsible

person address should be

for the respective

organizations the work for.

 Required Required
Form B- for Sponsor’s based outside the EEA only. Signed by someone from the Sponsor appointing the Sponsor’s legal

representative person in the EEA, including the name and the contact details of this person.

 Required Required

The legal representative person address should be for the organization the legal representative works for.
A EudraCT number for a study the sponsor is conducting. Required Required

Conclusion

We hope that this blog was helpful in understanding the role of a Responsible Person and the process of registration of a RP with the EMA. Please reach out to us if you require RP services in the EEA or wish to understand more about the registration process for the RP.

Serious Adverse Event Reconciliation in Clinical Studies

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What is Serious Adverse Event (SAE) Reconciliation and why is it required?

The aim of Good Clinical Practice (GCP) and Good Pharmacovigilance Process (GVP) is to keep patients at the centre of drug development efforts and ensure their safety and wellbeing, while at the same time researching more effective, safer cures for diseases. At the juncture of GCP and GVP is the process of SAE Reconciliation, which ensures that the clinical database and pharmacovigilance database are in sync with each other. Completeness and accuracy of data in these two databases is a significant driver in determining outcomes in a clinical trial, affecting clinical reports and safety reports, data management reports, etc. This blog post emphasizes the importance of this critical process in order to achieve better outcomes for clinical trial sponsors and patients alike.

Key Stakeholders in the SAE Reconciliation process

SAE Reconciliation is a group effort by teams that manage the clinical database (i.e., sites, data management), and the safety database (i.e., pharmacovigilance). Support is often required from Clinical Operations in co-ordinating with sites & site personnel in resolving issues that arise, Regulatory in co-ordinating submissions where required, and contract research organizations that may have been contracted by Sponsors in the study.

Manual vs. Automated SAE Reconciliation

SAE Reconciliation may be a manual or automated process, depending on the size of the study population and the volume of adverse event data in a study. Sponsor personnel, along with their Data Management and Pharmacovigilance teams, agree to a list of fields that would be reconciled during the course of a study, and the frequency at which such reconciliation is to be done. Detailed documents, e.g., Data Management Plans may be prepared to document the process, responsibilities & timelines. Regular meetings may be required for parties to clarify any discrepancies that may arise during the SAE reconciliation process.

Frequent challenges faced during SAE reconciliation and their remedial measures

Some frequent challenges include MedDRA version differences, irresolvable discrepancies, disagreement between involved parties, lack of responses from sites, etc. With effective management of the process, and automation tools, where the volumes justify their use, the process efficiency can be maximized, thus bringing about higher accuracy of data across both the databases.

SERIOUS ADVERSE EVENT RECONCILIATION IN CLINICAL STUDIES

Aim: To ensure the completeness and accuracy of the clinical trial data which is the key driver in determining outcomes in a clinical trial, affecting clinical reports and safety reports, data management report.

Here is the updated and organized table as per your request:

GVP SAE Reconciliation and GCP Manual Reconciliation

Reconciliation Type Details
Manual Reconciliation – Lower AE volume

– Smaller Studies
Automated Reconciliation – High volume of data to be reconciled

– Larger Studies

Frequent Challenges

  • MedDRA Version Differences
  • Irresolvable Discrepancies
  • Disagreement Between Involved Parties
  • Lack of Response from Sites

Stakeholders Involved in the Process

  1. Regulatory
  2. Data Management
  3. Clinical Operation
  4. Pharmacovigilance

Liver Injury With Cancer Chemotherapy

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Liver Injury with Cancer Chemotherapy -Importance of the Product Label in Risk Satisfaction

Cytotoxic chemotherapy is frequently associated with serum Aminotransferase elevations that are self-limited and that may subside with continued therapy. However, rare occurrences of jaundice and liver failure have been reported in association with many of these drugs. Hepatotoxicity identified during clinical development (instead of post-marketing data) is often the basis for the liver toxicity information in the labels for oncology drugs.

Generally, the evidence of potential liver injury is consistent with hepatotoxicity information in the EU Summary of Product Characteristics (SmPC) and U.S. Product Information (PI). However, there is a lack of harmonization regarding location, format, and details of information on hepatotoxicity. Although guidance on liver monitoring is generally mentioned; time to onset of Drug-induced liver injury (DILI), dose modification tables, biochemical profile, or re-challenge information are not always provided.

It is recommended to standardize the information obtained during drug development relating to liver toxicity (time of onset, pattern of injury) and to harmonize the location (sections within the label), format, and level of detail (e.g., monitoring schedule, dose modification table) in the product label.

For combination drugs, the information on liver toxicity of individual drugs (i.e., mechanism, time of onset, pattern of injury) should be used for assessing overlapping liver toxicities.

In oncology clinical trials, the NCI-CTCAE grading system is generally used for grading the severity of liver test abnormalities for suspected DILI cases, and risk management actions are recommended in the product labels based on these severity grades. Standard serum liver testing should be performed in all oncology patients prior to, during and after chemotherapy, immunotherapy or new treatments that cause liver injury.

Pre-treatment analysis for hepatic metastases with CT or MRI imaging is recommended in all oncology patients who are at increased risk for hepatic spread of tumour, prior to administration of potentially hepatotoxic chemotherapy or immunotherapy. It is important to understand the pattern of hepatotoxicity with standard chemotherapeutic drugs and the newer class of immunotherapies.

I) Standard Chemotherapeutic Drugs

Some level of hepatotoxicity as well as toxicity to other organs is generally associated with almost all anticancer drugs. With standard chemotherapeutic drugs, the hepatotoxicity is generally direct and dose-dependent; however, with many drugs, serious liver injury may also be due to idiosyncratic mechanisms. Further, hepatotoxicity may manifest in a variety of abnormal histological forms and clinicopathological phenotypes (few examples are mentioned in the Figure below).

Type Mechanism(s) of Hepatotoxicity (Known or Suspected) Examples of Associated Drugs Liver Injury Phenotype
Direct Alkylation of DNA leads to damage to small blood vessels in liver

Inhibition of methionine synthesis leading to endoplasmic reticulum (ER) stress & activation of stellate cells by excess of homocysteine

 Busulfan (when given for prolonged periods), Methotrexate Nodular regenerative hyperplasia (NRH), Steatohepatitis, Fibrosis, Cirrhosis
Indirect Estrogenic effects on fat metabolism in the liver

Secondary to effects on gastrointestinal motility, gut microbiome, and bile acid levels

 Tamoxifen, Octreotide Fatty liver, Steatohepatitis, Acute liver injury
Idiosyncratic Unclear Temozolomide, Cyclophosphamide, Melphalan, Chlorambucil, Azathioprine, Tamoxifen Acute liver injury (mostly cholestatic)

II) Immunotherapy

Immunotherapy includes drugs that are intended to activate or increase immunological activity against the patient’s neoplasm.

  • Immune checkpoint inhibitors (ICIs)

The patient survival in several metastatic solid organ tumours has significantly improved by immunotherapy, but these generally results in immune-related adverse events (IRAEs) including hepatotoxicity in both clinical trials and post-marketing set-up.

The use of hepatotoxic immunotherapy drugs and/or biological agents with certain other cancer drugs may result in more severe hepatotoxicity than treatment with each single drug.

The hepatic abnormalities with ICIs may range from asymptomatic increases in aminotransferases to acute hepatitis resulting in fulminant hepatic failure. These usually occur 6 to 14 weeks after initiation of treatment, although liver injury can occur after longer treatment duration and even after drug discontinuation.

  • Protein kinase inhibitors

The protein kinases whose activities are altered in cancer cells are specifically targeted by these anticancer drugs. The clinically evident liver injury with many protein kinase inhibitors is usually self-limited but may be fatal with some drugs and may be hepatocellular or cholestatic.

Features of autoimmunity have been observed in some cases of protein kinase-induced DILI, suggesting that the liver injury may be caused by an immunological autoreactive reaction. Imatinib and nilotinib have been linked to the reactivation of hepatitis B that may be due to the potentiation of hepatitis B virus replication or due to the drug’s immunosuppressive effects.

Many of the protein kinase inhibitors have been on the market only for just a few years and there is currently limited understanding as to why protein kinase inhibitors are hepatotoxic. Although there are various mechanisms that may explain the hepatotoxicity with many of these drugs, there is not enough scientific evidence in this area to make solid conclusions.

  • An overview of some of the newer cancer drugs and their currently known hepatotoxic potential is provided in the figure below:

Drug Class Mechanism of Action Examples Currently Observed Liver Injury Potential
Immune Checkpoint Inhibitors (ICIs) Blocks cell surface activities of CTLA-4, PD-1, or PD-L1 to stimulate anti-tumor immune responses CTLA-4 inhibitor: Ipilimumab, PD-1 inhibitors: Pembrolizumab, Nivolumab, PD-L1 inhibitors: Atezolizumab, Durvalumab Immune-mediated liver injury including hepatitis (a) with some distinct histological patterns (b)
Antibody Drug Conjugates (ADCs) Cytotoxic drugs covalently linked to monoclonal antibodies directed to antigens differentially overexpressed in tumour cells Gemtuzumab ozogamicin, Trastuzumab deruxtecan, Trastuzumab emtansine Most but not all ADCs are associated with liver toxicity, including fatal liver failure. The pattern of liver injury may differ depending on the toxophore.
Alpha-Specific VEGF Inhibitor and PD1/PDL-1 Combination VEGF inhibitors may potentiate the effect of PD1/PDL-1 Pembrolizumab plus axitinib, Avelumab plus axitinib These combination treatments with axitinib increase the rates of higher CTCAE grades of hepatotoxicity.

It can be difficult to characterize the risk of DILI because of low occurrence of event, limited information available, and uncertainties in pathogenesis.

In a real-world scenario, post-marketing risk management is vital to manage the risk of DILI. This is accomplished by periodic reviews and updates to the safety profile of a drug along with risk minimization measures. The product label is the basic information for healthcare professionals to refer for product safety and efficacy and which contains both preclinical and clinical information in a structured format. The product label discusses product risks in the patient population who may potentially be treated with the drug.

Risk stratification is a method for determining and predicting the possibility of a specific outcome among patients who may be exposed to certain anticancer drugs. The product label forms the basis of risk stratification by which the risks of the drug are communicated with the patients who may be treated with the drug. A risk management plan may be effective to manage the risk of DILI if the risk factors are characterized, if there are well defined patterns of liver injury, and/or there are reliable measures on which risk management and monitoring can be based upon.

Are ALT & AST Elevations Really Liver Function Tests

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Liver biochemical tests are very commonly performed in clinical studies/clinical practice. These tests include:

  • Alanine/aspartate aminotransferases (ALT/AST), Alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT)
  • Bilirubin, Albumin
  • Prothrombin time (PT), International normalized ratio (INR)

These tests are commonly used for the diagnosis and evaluation of acute and chronic liver disease, irrespective of the ethology.

  • Liver Injury Vs. Liver Function

There are two separate concepts for drug-induced liver injury: severity of liver injury and the grade of liver function impairment

  1. Liver Injury Indicators:

    • Tests: ALT (Alanine Aminotransferase) and AST (Aspartate Aminotransferase): Elevated levels of ALT and AST indicate liver cell damage, suggesting liver injury.

  2. Liver Function Impairment Indicators:

    • Tests: Albumin, PT (Prothrombin Time), INR (International Normalized Ratio), and Bilirubin: Decreased albumin or increased PT, INR, or bilirubin levels indicate impaired liver function.

Therefore, the term Liver function tests (LFTs) being used for elevations of ALT and AST is somewhat of a misnomer because these enzymes do not represent liver function but rather indicate the damage of liver cells. On the other hand,

albumin, bilirubin, and vitamin K-dependent clotting factors represent synthetic function of the liver. The decreased synthesis of clotting factors by the liver may lead to prothrombin time (PT) prolongation and an increase in the

international normalized ratio (INR).

Some of the commonly used scores to predict mortality in patients with cirrhosis such as the Child-Pugh score and Model for End Stage Liver Disease (MELD) score do not use AST, ALT, or ALP but instead use INR, bilirubin and albumin in

Child-Pugh score and INR and bilirubin in MELD score.

The following table reflects a summary of the commonly used serum liver tests in clinical studies/clinical practice:

Liver Injury Tests

Category Test Conditions Associated with Abnormal Liver Injury Tests Site of Localization
Hepatocellular Injury ALT Hepatocellular injury, muscle injury, rhabdomyolysis Liver, cardiac muscle, skeletal muscle
AST Hepatocellular injury, muscle injury, rhabdomyolysis, haemolysis Liver, cardiac muscle, skeletal muscle, brain, kidney, RBC
Cholestasis ALP Cholestasis, biliary injury, bone disorders, late pregnancy Liver, kidney, bone, intestine, placenta
GGT Cholestasis, biliary injury, alcohol intake, obesity, smoking Liver, pancreas, kidney, intestine, spleen, prostate
Total Bilirubin (Direct + Indirect) Direct > Indirect: Hepatocellular injury, cholestasis; Indirect > Direct: Haemolysis, Gilbert’s syndrome Circulates in blood in unconjugated (indirect) form and undergoes conjugation (direct) in the liver

Liver Function Tests

Test Site & Function Conditions Associated with Abnormal Liver Function Tests
Albumin Main protein produced by the liver, circulates in serum, and maintains serum oncotic pressure. Acute Liver Disease: Albumin synthesis usually preserved. Chronic Liver Disease: Low serum albumin indicates cirrhosis.
PT/INR Indicates the function of vitamin K-dependent clotting factors mainly synthesized in the liver. Test measures the extrinsic coagulation pathway. Aids in the diagnosis of both acute and chronic hepatic disorders.

The below table indicates a pattern of alterations of liver injury tests and liver function tests in hepatocellular injury & cholestasis:

TEST HEPATOCELLULAR INJURY CHOLESTASIS
Liver Injury Tests
ALT/AST ++/+++ 0/+
ALP 0/+ ++/+++
Total Bilirubin 0/+++ 0/+++
Liver Function Tests
PT/INR Prolonged Prolonged
Albumin -/—- 0

Stopping Rules for the Drugs in Premarketing Clinical Studies for Hepatotoxicity:

In clinical trials, it is often difficult to determine when the study drug should be stopped. This is because transient increase of ALT or AST are quite common and progression to severe DILI or acute liver failure is usually uncommon, stopping the study drug on an increase in ALT or AST greater than 3xULN may be unnecessary. For most individuals, the liver appears capable of adapting to injury by chemical substances, which may render a person tolerant to the drug despite continued exposure. Stopping a drug at the first indication of mild injury does not allow knowledge if adaptation will occur, as it does for drugs such as tacrine, which cause liver injury but do not cause severe DILI. On the other hand, if there is marked increase in serum aminotransferases or there is evidence of functional liver impairment (as indicated by rising INR or bilirubin) which represent substantial liver injury, continuing with the study drug appears unacceptably dangerous.

Hence, the USFDA guidance mentions that in the premarketing clinical studies, discontinuation of the study drug should be considered if any of the following occurs:

  • ALT or AST >8 x Upper Limit of Normal (ULN)
  • ALT or AST >5 x ULN for more than 2 weeks
  • ALT or AST >3 x ULN and (Total bilirubin >2 x ULN or INR >1.5)
  • ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

It is important to note that these stopping rules are guidelines and may further evolve based on advances in medical research and knowledge. The safety of study participants should always be the top priority, and the final decision to stop a study due to hepatotoxicity will be made by the study sponsor in consultation with multiple key stakeholders including regulatory agencies, investigators, and independent safety monitoring committees.

Annual Summary Reports for Health Canada: Overview, Requirements, Format and Submission

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What is an Annual Summary Report (ASR)?

It is a comprehensive assessment of all known safety information for a marketed drug or natural health product. The ASR is prepared by the market authorization holder (MAH) to provide an update on the worldwide safety profile at defined intervals post-authorization.

Which type of Products require an Annual Summary Report (ASR)?

  1. Products regulated under the Food and Drug Regulations (as per section C.01.018 of the food and Drug Regulations)

The MAH must, on as annual basis and whenever requested by the Minister of Health, conduct a concise, critical analysis of the adverse reactions (ARs) and serious adverse reactions to a drug and prepare a summary report relating to the reports received during the previous twelve months Products regulated under the Natural Health Products Regulations (as per Natural Health Products Regulations, Section 24, Reaction Reporting, C.R.C., SOR/2003-196).

 

  1. Products regulated under the Natural Health Products Regulations (as per Natural Health Products Regulations, Section 24, Reaction Reporting)

The MAH/licensee must, on an annual basis, prepare and maintain a summary report that contains a concise and critical analysis of all

domestic ARs to a natural health product, and all foreign serious unexpected ARs to a natural health product, reported during the

previous twelve months.

When does the requirement to prepare ASR begin for the MAH/Licensee?

The requirement to prepare ASRs begins on the date that the MAH first sells the product in Canada.

The term Sells includes offer for sale, expose for sale, have in possession for sale and distribute, whether or not the distribution is made for consideration. (Ref: Sec. 2, Food and Drugs Act).

The MAH should specify the selected 12-month period for the ASR.

Health Canada prefers that the ASRs be prepared with harmonized Data Lock Points (DLPs) based on the International Birth Date (IBD) of the active substance. The MAH should refer to the EU reference dates (EURD) lists if they are unable to identify the IBD.

The date of the first licensing in Canada may be used for natural health products.

Is there a requirement to submit prepared ASR to Health Canada?

The ASRs are to be submitted to Health Canada under certain circumstances:

  1. Upon Request by Health Canada
  2. To fulfill a Commitment

When preparing the report, the MAH must determine whether or not there has been a significant change in the benefit—risk profile of the drug. The current interpretation of benefit—risk profile is a reflection of the overall balance of the product’s potential benefits with its identified risks as revealed through safety and efficacy evidence, and through consideration of how that evidence contextualizes with real world conditions of use on the market. If the MAH concludes that there has been a significant change in the benefit—risk profile, they must notify the Minister without delay, in writing, unless this has already been done. The primary focus should be on the clinical significance of such a change.

Health Canada expects that a copy of the ASR be provided with the notification letter if the report shows that there has been a significant change to the benefit-risk profile.

If Health Canada determines that an examination of the safety and/or effectiveness of a drug are warranted, a request may be made to the MAH under C.01.018(5) and (6) of the Food and Drug Regulations to submit an ASR, and/or the case reports (Council for International Organizations of Medical Sciences [CIOMS] preferred) of all adverse reactions that are known to the MAH.

All ASRs must be maintained by the MAH on site or be easily accessible and, when requested, be submitted to Health Canada within 30 calendar days unless otherwise specified.

Health Canada requests that relevant unique Canadian identifiers (DIN, DIN-HM, NPN) be included in ASR reports, to make it easier to link the report to other information about the marketed product.

For the NHPs, If the Minister has reasonable grounds to believe that the natural health product may no longer be safe when used under the recommended conditions of use, the Minister may request any summary reports, interim summary reports and all adverse reactions for which a case report is required, to be submitted to Health Canada within 30 days after the day on which the request is received by the MAH/licensee.

Does Health Canada expect the MAH to discuss quality/ Good Manufacturing Practices (GMP) problems in the ASR?

ASRs are not expected to discuss quality/ Good Manufacturing Practices (GMP) problems unless they result in adverse clinical outcomes. GMP related safety issues should be distinguished from ingredient related safety issues.

What are the Acceptable Annual Summary Report Formats?

Depending on the type of the product and the preference of the MAH, several formats are considered to be acceptable for the preparation of ASRs.

The information included in the ASR will vary depending on the adverse reaction data known to the MAH. If a section cannot be completed, this should be noted and explained.

What are the Acceptable Annual Summary Report Formats?

Depending on the type of the product and the preference of the MAH, several formats are considered to be acceptable for the preparation of ASRs.

The information included in the ASR will vary depending on the adverse reaction data known to the MAH. If a section cannot be completed, this should be noted and explained.

  • Periodic Benefit -Risk Evaluation Report (PBRER) Format (ICHE2C (R2))
  • Periodic Safety Update Report (PSUR) Format (ICHE2C (R1))
  • Non – ICH Annual Summary Report Format

What should be the format of the Annual Summary Report for the NHPs?

Although the ICH format is preferred for the preparation of ASRs, a simpler format is also acceptable for annual summary reports for NHPs.

Following sections are expected by Health Canada in non-ICH format ASRs prepared for NHPs:

  • Introduction
  • Summary of changes (if any) to what is known about the product’s safety, based on information collected during the reporting period.
  • Core reference safety information, preferably Company Core Safety Information (CCSI)/ Company Core Data Sheet (CCDS), if available. If these are not available, other documentation that reflects the core safety knowledge of Canadian licensed products should be included such as the product monograph, or approved labelling information/terms of market authorization. The type of document should be identified.
  • In Information about significant domestic or foreign regulatory actions (if any) bearing on safety during the reporting period.
  • Patient exposure (see ICH E2C(R2) for details), including Canadian exposure. Basic information would include sales information.
  • A critical analysis covering:
    1. All known adverse reactions occurring inside Canada
    2. Serious unexpected adverse reactions inside or outside Canada during the previous 12 months at a dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying organic functions in humans.
  • A conclusion regarding the product’s real-world safety

Should MedDRA be used in the ASRs?

MAHs are encouraged to use Medical Dictionary for Regulatory Activities (MedDRA) terminology to analyse and present data.

How many days after the Data Lock Point (DLP) should the ASR be prepared?

The ASR should be prepared 70 days from the data lock point. In any case, the ASR must accurately reflect the actual collection and analysis performed and the information used.

Is there a requirement for Canadian Specific Sections in the ASR? How should they be presented in the report?

Regional differences may exist in the aggregate reports, even though standardized periodic summary reports (i.e., PBRERs and PSURs) are used globally.

The MAH should consider the need for a Canadian—specific section when preparing an ASR for submission to Health Canada. The following is Canadian specific data:

  • Adverse drug reactions occurring in Canada
  • Information such as the epidemiology of the medical condition(s) or risk factors that reflect the authorized indication(s) in Canada in cases where it varies from the authorized indication(s) in other jurisdictions
  • References to the latest available version of the Terms of Market Authorization (e.g., Canadian Product Monograph (CPM);
  • Information present in the Licensed Natural Health Product Database; finished product labelling) information related to Canadian patient exposure
  • Post-marketing experience in the Canadian context
  • A discussion of pharmacovigilance activities within the Canadian context
  • Verification of AR records against Health Canada’s Canada Vigilance Database; and Information that is applicable to the Canadian context, in relation to risk minimization strategies and evaluation of effectiveness of risk minimization activities.

Canadian-specific section(s) can be prepared in the form of a Canadian-specific summary report or as an appendix or annex to an already prepared summary report.

How to submit the Annual summary reports?

The Annual Summary Reports should be provided to Health Canada in electronic-only format. The submissions should be provided in either English or French.

  • eCTD Format Requirements

Health Canada strongly recommends that electronic documents be provided in electronic common technical document (eCTD) format. ASRs provided in eCTD format should be prepared using applicable sections of the Guidance Document: Preparation of Drug Regulatory Activities in Electronic Common Technical Document (eCTD) Format published on the Health Canada Web site.

  • Non-eCTD Format Requirements

Alternatively, Health Canada will also accept electronic documents in “non-eCTD electronic—only” format. ASRs provided in “non—eCTD electronic-only” format should be prepared using applicable sections of the Guidance Document: Preparation of Regulatory Activities in the” Non-eCTD Electronic-Only” Format published on the Health Canada Web site.

Drug Induced Liver Injury in Premarketing Clinical Trials

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DILI (Drug Induced Liver Injury) is a rare but potentially fatal adverse drug reaction.

DILI is a very common cause of acute liver failure in North America and Europe, a key reason for the failure of a drug to obtain marketing authorization, and a common cause of post-marketing restrictions and product withdrawals.

The evaluation of DILI is critical because most drugs that cause severe DILI do so infrequently and usual drug development databases with up to a few thousand subjects exposed to a new drug will not reveal any cases.

Such databases, on the other hand, may show evidence or signals of a drug ‘ s potential for severe DILI if clinical and laboratory data are properly assessed for evidence of lesser injury that may not be severe but could predict the ability to cause more severe injuries.

For the past 50 years, DILI has been a very common cause of safety-related drug marketing withdrawals.
Here are some examples of such drug withdrawals:

  • Tolcapone, troglitazone, trovafloxacin, bromfenac, nefazodone, lumiracoxib and sitaxentan.
  • Drugs that were not approved in the United States because their hepatotoxicity was identified during European marketing – ibufenac, perhexiline, alpidem.
  • Drugs that were not approved in the United States because premarketing data revealed the possibility of severe DILI: dilevalol, tasosartan, ximelagatran.

Mechanism and Types of DILI

Drugs can cause liver injuries through varied mechanisms. These injuries are similar to almost all known liver diseases, and there are no pathognomonic findings, even on liver biopsy, that confirm a diagnosis of DILI

DILI can look like almost any type of acute or chronic liver disease. Hence, when DILI is suspected, additional clinical and laboratory information should be obtained for differential diagnosis of the cause. The mechanisms and the risk factors for DILI are poorly understood in most cases.

Despite their rarity, both idiosyncratic and indirect DILI can lead to severe and sometimes fatal liver injury.
Most of the drugs withdrawn from the market for hepatotoxicity have caused death or transplantation at frequencies in the range of ≤1 per 10,000, so that a single case of such an event rarely would be found even if several thousand subjects were studied.
Severe DILI cases rarely have been seen in drug development programs of significantly hepatotoxic drugs.

DILI reactions are usually categorized as follows:

DILI Categories

Signals of DILI and Hy’s Law

Hy’s Law is essentially a translation of Zimmerman’s finding that hyperbilirubinemia
caused by pure hepatocellular injury is an ominous sign of a drug’s potential to
cause substantial liver injury.

In a summary, Hy‘s Law cases consist of the following three elements:

  1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above the ULN of aminotransferases (ATs) ALT or AST than the (nonhepatotoxic) control drug or placebo.
  2. Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum Total bilirubin (TBL) to >2xULN, without initial findings of cholestasis (elevated serum ALP).
  3. No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury.

According to Hy‘s law, there is a 10–50% risk that a patient will develop acute liver failure (ALF), which can lead to death or liver transplantation.

The presence of even one or two such cases in a clinical trial programme is significant because it indicates a higher risk for idiosyncratic ALF in a postmarket population treated with the same medication under equivalent conditions

Severity of DILI

The National Cancer Institute’s grading system of Common Toxicity Criteria for Adverse Events (NCI-CTCAE) may be useful for signal detection and identification of changes in liver tests at the individual and aggregate levels in a clinical study. However, these criteria do not specifically correlate with hepatocellular function or clinical outcome. These criteria were not developed specifically for DILI, and their severity grading is not stratified by risk levels

For the assessment of post-marketing cases of suspected DILI, a five-level categorical scale with specified clinical and laboratory test results has been used by the NIH Drug Induced Liver Injury Network (DILIN) and the United States Food and Drug Administration (U.S. FDA). The same is mentioned below:

 

DILI is challenging to predict during the drug development process. The underlying mechanism of DILI are incompletely understood.

For intrinsic DILI, some of the potential risks can be flagged by preclinical models and in vitro test systems, but these are not very useful in assessing the risk of idiosyncratic DILI.

Considering severe DILI is generally rare, finding one case may require the treatment of thousands of people from diverse patient populations.

Due to the limited number of clinical trial subjects, monitoring the standard serum liver tests to detect milder liver injury can be considered the predominant approach to predict the risk of possible DILI in clinical trials.

Considering that there may be varied mechanisms of DILI and different clinicopathological phenotypes, a systematic collection of adequate diagnostic datasets along with a focused causality assessment performed by clinical professionals having expertise in this area is required for the evaluation of each potential case of DILI in clinical trials.

 

Hy’s law & Drug Induced Liver Injury – Part II

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Drug-Induced Liver Injury Occurrence

  1. Most frequent cause of acute liver failure in North America and Europe.
  2. No definite causative agent has been attributed in several cases.
  3. Underlying mechanisms are still unclear and hence is difficult to predict during drug development.
  4. May mimic almost any known type of liver disease.
  5. Rare yet potentially life-threatening.
  6. Key reason for drugs to fail to achieve marketing authorization, frequent cause for post-authorization restrictions and product withdrawals.
  • Monitoring of standard serum liver tests to detect milder liver injury is the main approach to anticipate a possible DILI risk in Clinical Trials.
  • Evaluation of each potential DILI case in clinical trials requires a systematic collection of adequate diagnostic datasets and a rigorous assessment for causality, performed by clinical experts in this area.
  • The evaluation of DILI is critical because most drugs that cause severe DILI do so infrequently and usual drug development databases with up to a few thousand subjects exposed to a new drug will not reveal any cases.
  • Such databases, on the other hand, may show evidence or signals of a drug’s potential for severe DILI, if clinical and laboratory data are properly assessed for evidence of lesser injury, that may not be severe but could predict the ability to cause more severe injuries.

FDA’ s eDISH Program for Hepatotoxicity Assessment

Hy’s Law and eDISH Development: The Hy’s Law principle served as the foundation for the FDA’s creation of the ‘eDISH’ software program, designed to evaluate Drug-Induced Serious Hepatotoxicity.

Step-Based Approach:

  1. Data from case reports are examined for peak values of liver enzymes ALT and TBL over the observation period. These values are plotted on an x-y chart as logarithm10 multiples of elevations above the upper limits of the normal reference ranges (ULN).
  2. For an individual patient, time course of ALT, TBL, AST, and ALP are plotted together for visual comparison.
  3. A medical text narrative, written by a skilled physician, provides additional context about the patient’s condition. This narrative helps estimate the most likely cause of abnormal findings and assesses the probability of drug-induced hepatotoxicity.

Causality Assessment:

Requires considering of multiple potential factors.

Several possible causes are common and Insufficient to simply label cases as ‘confounded.’

Estimated likelihood is categorized as ‘probable’ if the likelihood is over 50% and higher than all other causes combined.

Sufficient information and thorough patient investigation are essential to rule out alternative causal factors.

Note: The upper right quadrant doesn’t automatically define cases as ‘Hy’s Law’; It identifies patients as of unique importance. Further clinical information is essential for a comprehensive medical diagnosis aimed at identifying the most likely cause of the observed findings.

Approach to the diagnosis of DILI

Conclusion:

  1. DILI is a key concern for regulators, drug developers, and physicians, and is difficult to predict during drug development process.
  2. As severe DILI is generally rare, finding a single case may require treatment of thousands of people from varied patient populations.
  3. The clinical trials present an exclusive opportunity to detect hepatotoxicity and cases of potential DILI with a study drug prior to its use in general population.
  4. Monitoring the liver test abnormalities is useful for assessing trends over time and to analyse imbalance between study drug and placebo/comparator groups.
  5. Due to the limited number of subjects in a clinical trial, monitoring the standard serum liver tests to detect milder liver injury can be considered a predominant approach to predict the risk of possible DILI in clinical trials.
  6. Considering that there may be varied mechanisms of DILI and different clinicopathological phenotypes, a systematic collection of adequate diagnostic datasets along with a focused causality assessment performed by clinical experts is required for evaluation of each potential case of DILI in clinical trials.

Hy’s law & Drug Induced Liver Injury – Part I

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Drug-Induced Liver Injury Occurrence

  1. Most frequent cause of acute liver failure in North America and Europe.
  2. No definite causative agent has been attributed in several cases.
  3. Underlying mechanisms are still unclear and hence is difficult to predict during drug development.
  4. May mimic almost any known type of liver disease.
  5. Rare yet potentially life-threatening.
  6. Key reason for drugs to fail to achieve marketing authorization, frequent cause for post-authorization restrictions and product withdrawals.
  • Monitoring of standard serum liver tests to detect milder liver injury is the main approach to anticipate a possible DILI risk in Clinical Trials.
  • Evaluation of each potential DILI case in clinical trials requires a systematic collection of adequate diagnostic datasets and a rigorous assessment for causality, performed by clinical experts in this area.
  • The evaluation of DILI is critical because most drugs that cause severe DILI do so infrequently and usual drug development databases with up to a few thousand subjects exposed to a new drug will not reveal any cases.
  • Such databases, on the other hand, may show evidence or signals of a drug’s potential for severe DILI, if clinical and laboratory data are properly assessed for evidence of lesser injury, that may not be severe but could predict the ability to cause more severe injuries.

Hy’s law

Hy’s Law cases have the following three components:

  • The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or placebo.
  • Among trial subjects showing such AT elevations, often with ATs much greater than 3 x ULN, one or more also show elevation of serum TBL to >2 x ULN, without initial findings of cholestasis (elevated serum ALP).
  • No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury.

This observation formed a basis for the development of the e-DISH plot by the U.S. FDA.

Translation of Zimmerman’s observation that pure hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver injury.

Recognition of the importance of altered liver function, in addition to liver injury, began with Zimmerman’s observation that drug-induced hepatocellular injury (i.e., aminotransferase elevation) accompanied by jaundice had a poor prognosis, with a 10 to 50percent mortality from acute liver failure (in pre-transplantation days).

Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population.

USFDA has been using Hy’s law rigorously to screen out potentially hepatotoxic drugs for almost 20years, and “since 1997 did not have to withdraw a single drug approved after 1997 because of post-marketing hepatotoxicity”.

*  1. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol(2019), https://doi.org/10.1016/j.jhep.2019.02.014

2.EVOLUTION OF THE FOODANDDRUG ADMINISTRATION APPROACH TO LIVER SAFETY ASSESSMENT FOR NEW DRUGS: CURRENT STATUS AND CHALLENGES. JOHN R. SENIOR.DRUG SAF (2014) 37 (SUPPL 1):S9–S17

Any potential Hy’s Law cases should be:

  • Handle das a serious unexpected adverse event associated with the use of the drug.
  • Reported to the FDA/Regulators promptly (i.e., even before all other possible causes of liver injury have been excluded).
  • Reporting should include all available information, especially that needed for evaluating the severity and likelihood that the drug caused the reaction, and, should initiate a close follow-up until complete resolution of the problem and completion of all attempts to obtain supplementary data.

Time Lag:

  • Combined elevation of ALT or AST and TBL may not be concurrent elevation.
  • Typically, ALT or AST elevation are followed by bilirubin elevation (delay of up to 4 weeks).

Time course of elevations – ALP elevations:

  • “Pure” hepatocellular injury initially may show secondary ALP elevations due to intrahepatic cholestasis.
  • Hence, cases with increased ALT or AST and TBL, associated with increased ALP, cannot automatically be discarded as not matching Hy’s law criteria.
  • Additionally, ALP values >2 x ULN were not found to decrease the risk of ALF in patients fulfilling Hy’s law in the Spanish DILI registry.

R Ratio and ALP:

  • Both ALP activity and the R ratio should be considered in the exclusion of cholestatic or mixed type injury.

Direct vs Indirect Bilirubin:

  • Hepatocellular dysfunction is indicated by increased direct, i.e. conjugated bilirubin only.
  • Conditions such as haemolysis, or drug-related enzyme inhibition may lead to increase in indirect, i.e., unconjugated bilirubin.
  • Hence, fractionated bilirubin should be assessed since cases with predominantly unconjugated mild hyperbilirubinemia would not qualify as potential Hy’s law cases.

Conclusion

  1. DILI is a key concern for regulators, drug developers, and physicians, and is difficult to predict during drug development process.
  2. As severe DILI is generally rare, finding a single case may require treatment of thousands of people from varied patient populations.
  3. The clinical trials present an exclusive opportunity to detect hepatotoxicity and cases of potential DILI with a study drug prior to its use in general population.
  4. Monitoring the liver test abnormalities is useful for assessing trends over time and to analyse imbalance between study drug and placebo/comparator groups.
  5. Due to the limited number of subjects in a clinical trial, monitoring the standard serum liver tests to detect milder liver injury can be considered a predominant approach to predict the risk of possible DILI in clinical trials.
  6. Considering that there may be varied mechanisms of DILI and different clinicopathological phenotypes, a systematic collection of adequate diagnostic datasets along with a focused causality assessment performed by clinical experts is required for evaluation of each potential case of DILI in clinical trials.

Risk Evaluation and Mitigation Strategy (REMS) Compliance & Inspection

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REMS are Enforceable under Section 505-1

  • REMS must be fully operational before drug introduced into interstate commerce.
  • Drug is deemed to be misbranded (Section 502(y)) – If the applicant holder fails to comply with approved REMS.
  • FDA can impose civil monetary penalties for violations of the FD&C Act – 303(f) (4).

Objectives of Rems Compliance Programme

  1. Assess compliance with the requirements of Section 505-1.
  2. Assess compliance with the requirements mentioned in REMS approval letter.
  3. Document the company’s or contractor’s implementation of the REMS.
  4. Verify the accuracy of the REMS assessment information submitted to the FDA.

 Penalties

  • FDA may impose civil monetary penalties of up to $250,000 per violation of REMS requirements, not to exceed $1 million in a single proceeding (Section 303(f)(4)(A)).
  • Civil monetary penalties may increase if the violation continues more than 30 days after FDA notifies the applicant holder of the violation.
  • The penalties double for the second 30-day period and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million per proceeding.
  • The Centre for Drug Evaluation and Research (CDER) Office of Scientific Investigations (OSI) takes the lead on enforcement when firms do not comply with REMS requirements.

REMS Inspections

  • REMS inspections are conducted to determine compliance with Section 505-1 of the Act, and the REMS approval letter for the specific product.
  • Inspections under this program are domestic and are generally preannounced.

 

FDA may consider a risk-based approach to select REMS programs each year for inspection. The following factors may generally be considered in the risk-based approach:

  1. REMS with elements to assure safe use (ETASU);
  2. REMS with identified issues or violations from a previous REMS inspection.
  3. REMS with approved modifications since the last inspection.
  4. REMS that have been identified by the Office of New Drugs (OND) or Office of Surveillance and Epidemiology (OSE) with recognized issues.
  5. REMS with issues identified during review of the REMS Assessment Report.
  6. REMS that have never been inspected; and
  7. REMS not inspected in the last 2-3 years.

 

Each Risk Evaluation & Mitigation Strategy (REMS) is unique and hence may have different elements and tools for risk mitigation. The inspection may focus on the requirements of FDA approved REMS.

Medication Guide

   Do you know what FDA may look for during REMS Inspection?

  • The REMS requires that the company develops a Medication Guide (per 21 CFR 208) that defines requirements for patient labelling for human prescription drugs.
  • Under 21 CFR 208 and in accordance with Section 505-1 of the Act, the company must make sure that the Medication Guide is available for distribution to patients at the time of dispensing the drug.
  • Medication Guide should be in non-technical language, in a standardized format (font size, headers, etc.), and provided in addition to General Information Sheets.

 

  1. Is the Medication Guide being distributed to each patient when the drug is dispensed?
  2. FDA may collect a copy of the Medication Guide in the version or format (hardcopy) that is provided to each patient & verify that is identical to the copy at REMS@FDA
  3. Documentation of the Company’s activities related to the assessment of healthcare provider’s and patient’s understanding of the messages communicated in the Medication Guide.
  4. Any documentation the Company has regarding procedures to identify, report and correct failures to adhere to distribution and dispensing requirements.

Communication Plan

  1. The REMS may require that the company develops a communication plan targeted to healthcare providers.
  2. A communication plan informs, educates, and raises awareness of risk.
  3. A communication plan includes tools for distributing information about the risks included in the REMS, including risk messages and messages related to operations and requirements to assure safe use (505-1(e)(3)).
  4. Some examples of REMS tools mentioned in a communication plan are:
    1. Dear Healthcare Provider (DHCP) letters, REMS letters, or letters addressed to HCPs through professional organizations.
    2. REMS website; REMS Factsheets.
    3. Patient counselling tools for HCPs; or Journal information piece.

Certain aspects that might be evaluated during an inspection

  1. Were the distribution dates of the Communication Plan consistent with the dates provided in the REMS document?
  2. Method of distribution of the Communication Plan tools?
  3. FDA may collect a copy of all Communication Plan tools and may verify they are identical to the documents appended to the REMS.
  4. Source and accuracy of the mailing lists used to distribute letters to the target audience? Corrective actions taken to ensure return mailings were reissued.
  5. The number of REMS tools (e.g., REMS Factsheets, Patient counseling kits) distributed by company’s personnel during follow-up visits with HCPs during the specified time-period after REMS approval?
  6. Were the professional journal communications in the journal as per the dates provided in the REMS document?
  7. Is the REMS Website fully operational and Is the communication plan available on the REMS website, if applicable?
  8. Documentation related to the assessment of targeted REMS stakeholder’s (e.g., HCP, patient, pharmacist) understanding of the information communicated by the REMS program (e.g., knowledge surveys for analysing HCP’s understanding of REMS program requirements).
  9. Documentation of the company’s activities for surveillance of the risks addressed by the REMS program (e.g., Drug utilization information, Post marketing case reports)?

Navigating Risk Evaluation and Mitigation Strategy (REMS) Audits Inspections

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What is REMS?

Per the USFDA, REMS is defined as:
– A required risk management plan that uses risk minimization strategies beyond professional labelling to ensure that the benefits of the drug outweigh the risks.

How Rems Requirement Came into Force?

Historical Background

  1. On September 27, 2007, the FDA Amendments Act (FDAAA) was enacted as a Public Law 110-85.
  2. Title IX, Subtitle A, Section 901 of the statute created a new Section 505-1 of the FDC Act (the Act).
  3. This act authorizes FDA to require persons submitting or holding certain applications to submit a proposed REMS as part of such application, if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks (Section 505-1(a)).
  4. The REMS program is a statutory program of the Act and does not have a code of federal regulations (CFR) designation.

Factors the USFDA may Consider if a Drug Requires REMS

Per Section 505-1(a)(1) of the FDC Act, the following factors are considered to determine if a drug requires REMS:

  • Approximate population size expected to use the drug.
  • Seriousness of the disease/condition intended to be treated with the drug.
  • Expected benefit of the drug with respect to the disease/condition being treated.
  • Expected or actual treatment duration.
  • Seriousness of any potential or known adverse events that may be related to the drug and the background incidence of such events in the population.
  • Whether the drug is a new molecular product.

Tools FDA requires to ensure Risk Mitigation & attain goals of REMS (Section 505-1(e)) – FDA requires the following tools to mitigate the risks of the drug & and attaining the goals of REMS

  • Information to Patients

–  Medication Guides (21CFR 208)

–  Patient Package Inserts (Section 505- 1(e)(2))

  • Information to Healthcare Providers

– Communication Plan (Section 505-1(e)(3))

(Section 505-1(f)(3)) If the tools mentioned above under section 505-1(e) are not considered adequate for risk mitigation, FDA may require more restrictive measures, termed Elements to Assure Safe Use (ETASU).

ETASU A Healthcare Providers
ETASU B Pharmacies
ETASU C Certain Healthcare Settings
ETASU D Documentation of Safe Use
ETASU E Monitoring
ETASU F Registry

How to assure safe use of the drug under ETASU B, C & D.

The REMS that include ETASUS under the following Elements, an Implementation System is required under Section 505-1(f)(4):

  • ETASU Element B (Pharmacies)
  • ETASU Element C (Certain Healthcare Settings)
  • ETASU Element D (Documentation of Safe Use)

Implementation System

Should be in place, through which the company is able to take reasonable steps to monitor and evaluate REMS implementation by healthcare providers, pharmacists, and others responsible for implementing those elements, & work upon to improve them.

REMS Supporting Document

Additional details about Implementation system are included in REMS Supporting Document which is a document prepared by the company that includes a comprehensive description of the rationale and supporting information for REMS content; however, it is not part of the approved REMS.

REMS Assessments

  1. NDAs and BLA applicant holders are required to perform and submit REMS assessments as per the intervals described in the approved REMS.
  2. FDAAA specifies the minimal timeframe (18 months, 3 years, and 7 years) for the submission of assessments from the date of the initial approval of the REMS (section 505-1(d)).
  3. The provision for scheduled REMS assessments does not apply to ANDAs
  4. In the Approval Letter, FDA provides the applicant holder with a comprehensive assessment plan, addressing the specific content areas in the REMS to include, at a minimum, in their assessment report. FDA provides the applicant holder with the schedule and the timeframe for performing REMS Assessments.

Assessments are also required:

  • When the applicant holder submits a supplemental application for a new indication for use, OR
  • When FDA determines, an assessment is needed to evaluate whether the approved strategy should be modified to ensure the benefits of the drug outweigh the risks of the drug, OR
  • To minimize the burden on the health care delivery system that is complying with the strategy (section 505-1(g)(2)).
  • Additionally, applicant holders may voluntarily submit an assessment of the REMS at any time (section 505-1(g)(1)).