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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.

Postmarketing Adverse Drug Experience (PADE) Inspections – Part II

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Legal Framework of PADE Inspections

  1. LAW: Federal Food, Drug and Cosmetic Act (FDCA)
  2. Title 21 of the Code of Federal Regulations (CFR)
  3. FDA’s Current Thinking

Inspectional Observations: USFDA 2023

1 21 CFR 314.80(b) Failure to develop written procedures Written procedures have not been developed for the [surveillance] [receipt] [evaluation] [reporting to FDA] of post marketing adverse drug experiences.
2 21 CFR 314.81(b)(1)(ii) Failure to meet specifications An NDA-Field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established for it in the application.
3 21 CFR 314.80(c)(1)(i) Late submission of 15-day report. Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information.
4 21 CFR 314.80(c)(1)(ii) Failure to investigate serious, unexpected events Adverse drug experiences that were the subject of post marketing 15-day reports were not [promptly] investigated.
5 21 CFR 314.80(c)(2) Late submission of annual safety reports Not all annual periodic adverse drug experience reports have been submitted within 60 days of the anniversary date of the approval of the application.
6 21 CFR 314.80(c)(2)(ii)(A) Incomplete periodic safety report Failed to submit a periodic report containing

  • [a narrative summary and analysis of the ADE information for the reporting interval in the report.]
  • [an analysis of the post marketing 15-day Alert reports submitted during the reporting interval.]
  • [a history of actions taken since the last report because of adverse drug experiences.]
  • [an index with a line listing of your patient identification code and adverse reaction term(s) for all ICSRs you submitted for the reporting interval.]
7 21 CFR 314.80(d) Failure to submit scientific article A postmarketing 15-day Alert report based upon scientific literature was not accompanied by a copy of the published article.
8 21 CFR 314.80(j) Failure to maintain records Failed to maintain for a period of 10 years records of all adverse drug experiences known to you, including raw data and any correspondence.
9 21 CFR 314.81(b)(2) Timely submission An annual report was not submitted [each year] [within 60 days of the anniversary date of U.S. approval of the application] to the FDA division responsible for reviewing the application.

Ref: Number of 483 issued from the System*

Inspections ending between 10/1/2022 and 9/30/2023
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-observations

Written Procedures Must Address

  1. Surveillance
    • Account for all sources
    • Spontaneous
    • Solicited
    • Internet sources (firm sponsored)
    • Literature …and more!
  2. Receipt
    • ADE info
    • Initial
    • Follow-up
    • Receipt from any source
  3. Evaluation
    • Seriousness
    • Expectedness
    • Relatedness
    • ADEs from any source
    • Follow-up procedures
  4. Reporting
    • 15-day Alert Reports
    • Non-expedited individual case safety reports (ICSRs)
    • Aggregate Reports
    • All info must be submitted electronically

Ref: Postmarketing Drug Safety and Inspection Readiness June 19, 2018. Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance (SBIA) Webinar. USFDA

Written Procedures

  1. Develop written procedures for the surveillance, receipt, evaluation, and
    reporting of postmarketing safety information, including procedures for
    managing safety information with contractors and business partners, as
    applicable.
  2. Written procedures should be maintained and followed.
  3. Determine if written procedures provide for complete, accurate, and timely reporting of safety data to FDA.
  4. Regulations pertaining to the requirements for written procedures: 21 CFR 4 310.305(a), 21 CFR 314.80(b), and 21 CFR 600.80(b).

Surveillance

  • Determine if the firm is monitoring potential sources of adverse event information
  • Determine if the firm is surveilling both foreign and domestic sources.
  • Determine if the firm is promptly reviewing all postmarketing safety information received from any source


Many other sources such as firm-sponsored websites, firmsponsored social media, legal cases, product complaint files etc.

  • The timeline for submission of adverse experiences to FDA begins the day that the applicant, nonapplicant, or its contractors or business partners, obtain the minimum data set for a valid adverse event report.
  • The minimum dataset required to consider information reportable is
    • an identifiable patient
    • an identifiable reporter
    • a suspect product and
    • an event.
  • The date of receipt must be accurately determined and documented for the receipt of initial and follow-up information received by any method (for example, by phone, electronic mail, postal mail, fax, literature, websites, or employees).

Evaluation

Determine how:

  • Safety information from any source is evaluated to determine if an adverse experience is present.
  • Adverse experience reports are evaluated to establish if each report is spontaneous or solicited.
  • All adverse experiences, both spontaneous and solicited, are evaluated for seriousness and expectedness.
  • For adverse experiences originating from solicited sources, determine how the causal relationship between the product and the adverse experience is assessed.
  • If adverse experiences that are both serious and unexpected are promptly investigated and if all attempts to obtain additional information are documented.

Reporting

  1. Spontaneous adverse experiences, foreign or domestic, that have been evaluated as both serious and unexpected are submitted to FDA no later than 15 calendar days from the initial receipt of the information.
  2. For solicited adverse experiences, foreign or domestic, determine if all adverse experiences that have been evaluated as serious, unexpected, and possibly related to the suspect product are submitted to FDA no later than 15 calendar days from initial receipt of the information.
  3. Review 15-day Alert reports submitted late to the Agency.
  4. For each late report, the firm should provide justification for why the reports were late and appropriate corrective actions, if applicable.
  5. Domestic spontaneously reported non-expedited ICSRs are being submitted to FDA with or before the Periodic Report.
  6. The firm is in possession of any adverse event data that were not reported to the Agency as required.

Stay tuned for Part III, where we will explore the safety reports.

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.

Automation Solution – UNITYdx™

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Essential Automation Solution Components Technology

  • Digital Monitoring of Safety Communications with site
  • Tracking of Delivery Receipts and Acknowledgement Compliance
  • Custom Configurations for Site Reminders and Email templates
  • Complete Logical Separation of Sponsor (Customer) data
  • Secure login using Multi-Factor Authentication
  • Pre-Validated as per GAMP-5 guidelines
  • Permission-based Access Control for Software Features, Read-only access
  • 21CFR Part11 compliant Audit Trail Maintenance

 

Solution Drivers

  1. High Volume Communication that requires Tracking
  2. Highly Available Infrastructure – Secure, with Backup and Redundant Servers
  3. Secure Communication, Complete Audit Trail and Tracking
  4. Configurable, Regulatory Compliant

 

Service

  • Simplified sync with Safety Systems via E2B R3 XML upload, EDI connection
  • Automated assessment of Regulatory, Site and EC/IRB reporting timelines via Reporting Rules
  • Detailed Compliance Reports with case-level and site-level as well as aggregated data presentation
  • Custom Templates for Site Notifications and Reminders
  • Cross-Reporting for multi-country trials
  • Retrospective Reporting for New Sites joining a study
  • Trial, Contact, Site and Product Masters for rapid integration with Safety and Clinical Databases

 

Benefits of Automation in Safety Document Distribution

    Safety Document* Distribution Solution for Clinical Sites (* 7/15-day SUSARs,

DSURs, USRs)

  1. Safety Document Distribution with Digital Tracking:

    • ENHANCED COMPLIANCE TRACKING
      User-friendly dashboard with study/ site/ product-specific filters for data and reports

  2. Secure Transmission of Reports

    • SECURE TRANSMISSION
      21 CFR Part11 compliant, Sign-in via secure access code received on verified email

  3. Reduce Human Effort and Probability of Error

    • GREATER PROCESS EFFICIENCY
      Automatic tracking and reminders, Cross-reporting, Retrospective reporting. Can be integrated with a CTMS for real-time updates

 

About UNITYTMdx

Soterius offers its in-house tool SUSAR Notification, UNITYTMdx, which automates the sending and tracking of SUSARs to the Clinical Trial Sites. System integration and standardization allow UNITYTMdx to work with any standard safety database. Multi-channel communication hub ensures prompt, compliant, efficient, and secure communication between Clinical Trial sites, Safety Teams (CROs and Sponsors), and Clinical teams.

 

Challenges in Manual process of SUSAR Notifications

  • Lack of regulatory compliant audit trails
  • Excel-based tracking prone to data integrity issues
  • Super busy Sites and Investigators do not respond
  • Maintenance of contact information on Excel prone to error
  • Multiple emails for1 SUSAR in case of multiple studies at a Site.
  • Institutional policies block email delivery notifications

 

Implementation Strategies

Transition, Integrations and Training

Key Takeaways

  1. Regulatory Compliance: Prompt SUSAR communication; Inspection Findings
  2. Manual Process of SUSAR Reporting is prone to errors, inadequate documentation and lack of audit trails
  3. Automation enhances process efficiency, mitigates risks in ensuring compliance and saves time and effort
  4. Ensuring data security with robust measures to protect sensitive information related to SUSAR notifications
  5. Successful Implementation needs a partner with Safety, Validation and Quality Assurance Expertise
  6. Aim is to have a Robust, Efficient and Compliant Solution for SUSAR / Safety Document Communication

Transforming Clinical Trial Safety: Regulatory Expectations & Inspection Findings for Site Notifications for SUSARs

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US-FDA (United States Food and Drug Administration)

The sponsor must notify all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting as follows:

 

1 (c)(1)(i) : Serious and unexpected suspected adverse reaction.

 

2 (c)(1)(ii) : Findings from other studies (other than those reported under paragraph (c) (1)(i) whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug

 

3 (c)(1)(iii) : Findings from animal or in vitro testing: that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure

 

4 (c)(1)(iv) : Increased rate of occurrence of serious suspected adverse reactions.

 

Health Canada

Sponsors should refer to ICH Guidance Documents E6: Guideline for Good Clinical Practice and E2A: Clinical Safety Data Management for safety reporting requirements to Qualified Investigator(s) and their Research Ethics Board(s).

The reporting of SUSARs to investigator(s)/institutions(s) and to the IRB(s)/IEC(s) should be undertaken in a manner that reflects the urgency of action required and should take into consideration the evolving knowledge of the safety profile of the product. Reporting of SUSARs to the investigators/institutions should be made in accordance with regulatory requirements.

 

Urgent safety issues requiring immediate attention or action should be reported to the IRB/IEC and/or regulatory authority/(ies) and investigators without undue delay and as specified in regulatory requirements.

Investigator Responsibility: Specifying that the investigator/institution should promptly report to the IRB/IEC

    • deviations from the protocol to eliminate immediate hazards to the trial participants
    • changes increasing the risk to participants and/or significantly affecting the conduct of the trial
    • all suspected unexpected serious adverse reactions (SUSARs) in line with applicable regulatory requirements;
    • new information that may affect adversely the safety of the participants or the conduct of the trial.

 

European Medicines Agency

  1. Article 17(1)(d) of Directive 2001/20/EC provides that ‘the sponsor shall also inform all investigators’. The information should be concise and practical. Therefore, whenever practicable the information on SUSARs should be aggregated in a line listing of SUSARs in periods as warranted by the nature of the research project/clinical development project and the volume of SUSARs generated. This line listing should be accompanied by a concise summary of the evolving safety profile of the IMP.
  2. Sponsor responsibilities: Reporting of suspected unexpected serious adverse reactions (SUSARs) to the Ethics Committee.
  3. The purpose of the reporting obligation towards the Ethics Committee is to make the Ethics Committee aware of SUSARs that have occurred in the territory of the Member State concerned

 

Medicines & Healthcare products Regulatory Agency

  • SUSAR 7/15 Day Reports

    Sponsor should report to the relevant ethics committee Fatal or Life Threatening SUSARs within 7 days and any other SUSARs within 15 days of first awareness of the reaction.

A sponsor shall ensure that, in relation to each clinical trial in the United Kingdom for which he is the sponsor, the investigators responsible for the conduct of a trial are informed of any suspected unexpected serious adverse reaction which occurs in relation to an investigational medicinal product used in that trial, whether that reaction occurs during the course of that trial or another trial for which the sponsor is responsible.

  • Annual list of suspected serious adverse reactions and safety report

    As soon as practicable after the end of the reporting year, a sponsor shall, in relation to each investigational medicinal product tested in clinical trials in the United Kingdom for which he is the sponsor furnish the licensing authority and the relevant ethics committees with a list of all the suspected serious adverse reactions which have occurred during that year and a report on the safety of the subjects of those trials.

 

Inspection Findings – USFDA

Program Area: Bioresearch Monitoring

2022: Failure to provide all participating investigators with a written IND safety report

2017: Failure to provide FDA and all participating investigators with an adequate written IND safety report

 

Challenges in Manual process of SUSAR Notifications

  • Excel-based tracking prone to data integrity issues
  • Maintenance of contact information on Excel prone to error
  • Institutional policies block email delivery notifications
  • Multiple emails for 1 SUSAR in case of multiple studies at a Site.
  • Super busy Sites and Investigators do not respond.
  • Lack of regulatory-compliant audit trails.

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)).

Signal Detection in Early Phase Clinical Drug Trials

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Why Should You Perform Signal Detection in Early Phase Clinical Drug Trials?

The term ‘pharmacovigilance’ has conventionally been related with post-marketing activities; however, it is also equally applicable to the pre-marketing process for collecting, managing & assessing safety information during clinical development of the molecule. Similarly, the concepts of signal detection and assessment, risk assessment and risk minimization are as applicable to the pre-marketing scenario as they are to the post-marketing scenario.

The importance of this is evident from the following examples:

 

  1. Drugs not approved in USA

–  Examples of drugs not approved in USA as premarketing experience provided evidence of the potential for severe DILI e.g., Dilevalol, Tasosartan, Ximelagatran.

 

  1. Drugs withdrawn from market worldwide after initial regulatory approval

–  E.g., Rimonabant, Rofecoxib, celecoxib etc.

The safety information generated at the end of clinical development program should be extensive enough to permit comprehensive regulatory review and determination of benefit-risk profile for supporting marketing approval. The information should be comprehensive so that product label can be adequate to provide prescribers & patients adequate information for safe use of the drug.

 

What Do the Regulators Say?

USFDA 21CFR312.32 USFDA Draft Guidance on Sponsor Responsibilities
June 2021

Sponsors must adopt a systematic approach to safety surveillance to meet IND safety reporting requirements and enhance quality of safety reporting.
Such an approach involves promptly reviewing, evaluating, and managing safety information from all sources, including animal studies, clinical investigations, scientific literature, professional meetings, foreign regulatory authorities, and commercial marketing experience.

USFDA 21CFR312.56 USFDA Draft Guidance on Sponsor Responsibilities June 2021

– The sponsor’s review should involve assessing data from all sources and monitoring the progress of investigations:

  • To identify previously undetected potential serious risks (§312.56(a)).
  • To update investigator’s brochure, protocol, and consent forms with new information.
  • As necessary, to take measures for protecting subjects (e.g. monitoring, modifying dosing, or participant selection) (§312.56(d)).

 

CIOMS Working Group VI

– The purpose of ongoing safety evaluation during drug development is to ensure that important safety signals are detected early and to have a better understanding of benefit-risk profile of study drug.
Sponsors should develop a system to analyse, evaluate and take actions on the safety information on a continuous basis. This is to ensure the earliest possible detection of safety concerns and allow suitable risk minimization.

 

Systemic Approach for Signal Detection

Essential Elements for Effective Signal Detection in a Clinical Development Program

  • Early Initiation is Crucial
  • Written Process Required for Review
  • Multidisciplinary Safety Management Team (SMT)
  • Data from Licensing Partners to be Considered
  • Project Management Function
  • Background Incidence
  • Ready Data Accessibility
  • Initiative Proactive Strategy
  • Establish Timeframes and Milestones
  • Decision Making
  • Advisory Bodies

 

Signal Detection: Effective Data Review

Below are some of the key points that support effective data review during signal detection process in a clinical development program:

 

Parameters Overview
Analyse all AEs – Serious and Non-serious The safety analysis is complete when all adverse events (serious and non-serious) are reviewed, with a greater emphasis on those leading to treatment discontinuation
Review of Individual Cases Individual case analysis is essential for safety analysis. SARs and AESIs are important for detecting safety signals. Consider patient population, drug indication, and disease history during analysis.
Aggregate Review of Safety Data Aggregate review helps analyse evolving safety information, comparing interval and cumulative data. Data should be analysed per dose, cohort, gender, age, etc.
Review of Clinical Lab Data Laboratory tests are useful for screening subjects, early detection of organ toxicity & detection of potential toxic effects. Special focus should be on lab values correlating with organ toxicity e.g., endocrine abnormalities, hepatotoxicity etc.
Adverse Events of Special Interest (AESI) The protocol should define AESIs, emphasizing identification, monitoring, and reporting. Includes events like rhabdomyolysis or hair loss.

 

Structure of Safety Management Team

Development Risk Management Plan (DRMP)

A Development Risk Management Plan (DRMP) is a natural extension of high-quality pharmacovigilance. In DRMP, a compound-specific approach should be adopted, possibly as part of the broader Clinical Development Plan. It should contain early documentation of identified, expected, or potential risks, along with strategies for addressing them throughout development. As appropriate, the DRMP may develop into a post-marketing risk management plan.
The DRMP is a guide for safety surveillance during development and is not a legal or regulatory document; however, the following two actions must be considered during development of the process:
Recognize the potential for legal discovery of DRMP and ensure appropriate
language clarifying its status as a working document.

  1. Recognize the potential for legal discovery of DRMP and ensure appropriate language clarifying its status as a working document.
  2.  Establish robust processes, including project management to ensure the diligent execution of the action plans.

The DRMP should include the following sections: anticipated product profile, epidemiology, non-clinical safety experience, clinical safety experience, identification and assessment of known or anticipated risks, identification and assessment of potential new risk, and actions and/or plans for evaluating and mitigating risk.

 

Conclusion

The concepts of signal assessment, risk assessment and risk minimization are as
applicable to pre-marketing scenario as they are to the post-marketing scenario. The purpose of ongoing safety evaluation is to ensure that safety signals are detected early and to obtain an understanding of benefit-risk profile of the drug. Signal detection during clinical trials is usually performed based on clinical judgement, since there is limited data available during premarketing clinical trials. The three basic attributes for signal detection includes quick medical assessment, periodic aggregate assessment, and safety evaluation of completed unblinded trials. To ensure effective signal management, it is important to establish an effective system, beginning early, having proactive approach, analysing all serious and non-serious events, periodic reviews by scientific committees, and prompt decision making.