Safety narrative is a short story or a safety summary about a particular subject participated in a clinical study and experienced safety event which qualify under the criteria, such as Death, Serious Adverse Event (SAE), AE(s) leading to discontinuation of study, and AE of special interest.

As per the International Council of Harmonisation (ICH), E3 guidance for Clinical Study Report (CSR) structure and content, the CSR Section 12.3.2 or Section 14.3.3 should contain a brief subject narrative describing the event. The placement of the narrative in the CSR section depends on the number of narratives. The narratives count always depends on the type of clinical study, number of participants and the number of events that fall under narrative criteria; usually, the late phase studies have more number of narratives.

When the number of narratives is very high, they are prepared as a separate entity called as attachment to CSR section 14.3.3. The preparation of narratives is carried out as a separate narrative writing project either by the sponsor company itself or outsourced to medical writing group of a Clinical Research Organization (CRO). Safety narratives are prepared from Phase 1 to Phase 4 clinical studies.

Narrative and its Content

Narrative writing is an art that expresses the medical information clearly and effectively. It involves collating the relevant information from several source documents, and liaising with medical experts to describe the safety summary about a particular subject who participated in a clinical study.

As per ICH E3 (Section 12.3.2 or Section 14.3.3), a narrative should describe:

• Demographic data of the subject
• Medical history and concomitant medications
• Study drug administration timing
• Description of the event(s) (nature, intensity and outcome)
• Relevant laboratory measures
• Action taken with the study drug in relation to the event(s)
• Treatment for the event(s)
• Causality decision of Investigator and Sponsor

The above-specified information will be extracted from one or more source files as following: Council for International Organisations of Medical Sciences [CIOMS] form, Case Report Form [CRF], FDA Med Watch Form, Data Clarification Form [DCF], summary tables, and listings.

Challenges of Narrative Writing Projects

The narrative writing projects are executed as teamwork between the sponsors and CROs have to reach the goal of submitting the study results at the earliest. In most of the therapeutic confirmatory studies conducted for marketing approval, preparation of the narratives is the last and the most critical step in the dossier preparation. Listed below are the challenges that various stakeholders come across.

Challenges for the Clinical Research Organizations (CROs)

For CROs, completing narrative writing projects within a pre-specified timelines and budget while providing excellent quality can be a stringent task. Considerable effort of project management and resource management activities is involved before and during the narrative writing project execution.
These are short-term projects (up to 3 months), and the CRO has challenge in keeping and getting the trained resources along with:

• Maintaining/Providing MW resource count for the project
• Involving/allocating required resources in a short span of time
• Providing project/study specific trainings and updates
• Providing adequate communication channels
• Defining process flow and getting it approved by the Sponsor
• Identifying key person from the sponsor team who takes the ownership
• Using resources without affecting other MW projects
• Tracking and managing the entire project

Challenges for Sponsors

For sponsors, finding a CRO with an adequate resource count, hands on experience & capability and therapeutic area knowledge is a challenge. Getting high-quality documents within specified time, but without compromising company policies, SOPs and confidentiality are other major challenges in addition to:

• Identifying the number of narratives before the project (at least approximate number), to decide whether it can be executed in-house or should be outsourced to CRO
• Planning the activities and deciding the timeline
• Defining the responsibilities for CRO MW and in-house reviewer
• Template design/format of the narrative
• Deciding outsourcing cost and budget allocation
• Providing the reviewers, including clinical team and Medical experts
• Performing sponsor’s quality check/quality assurance, if any planned

Challenges for Medical Writers

Narratives describe the whole story of the subject/participant in predefined restricted format. It is quite challenging from the medical writer’s perspective because different types of data such as demographics, study drug administration, medical history, event(s) description, associated lab, concomitant medications, outcome and causality assessment details are put together within the agreed template (might be full text, semi-tabulated, or automated narratives) which has to be completed in stringent timelines.

Rework is the biggest challenge in narrative writing projects due to inappropriate sources, intermediate change requests, updating template and adding the new requirements during the drafting stage. Other common challenges that medical writers come across are:

• Adapting to new style guide and the meeting the Sponsor’s reviewer expectation
• Fulfilling the template and style guide requirements
• Delivering the narratives in stringent timelines
• Achieving daily target (number of narratives per day/week)
• Understanding multiple source documents
• Involvement of multiple reviewers
• Management of multiple drafts
• Unclear or illegible source data (hand written CRFs, CIOMS)
• Undergoing multiple project-specific trainings or attending multiple update meetings
• Complexity of the narratives (example: Oncology narratives consist of several numbers of events, multiple concomitant therapies and hospitalizations)

The narrative writing projects are executed as teamwork, and has several challenges as compared to the other medical writing projects. A proper forecasting, planning, coordination, and execution is the key to success for Narratives.

The accelerating costs of drug discovery, development and drug promotion continues to concern the pharmaceutical sector. This has been compounded by the initiation of personalized medicine and its demand for individualized products. In contemplation to satisfy the demands presented by this new prototype, the next generation of drugs needs to be safe & efficacious and the pharmaceutical companies must assemble more genotype and/or phenotype-engrossed therapeutic agents.

Personalized medicine is the adaptation of treatment, based on a patient’s genetic or somatic heredities and holds the promise of transforming healthcare. Companion diagnostics, many of which are molecular genetics assays, are critical tools in the accomplishment of personalized medicine. Information resulting from these tests provides for customizing definite therapies based on the genetics of the disease.

Molecular genetic companion diagnostic assays are befitting more pertinent and imperative in an environment of amplified regulatory guidance in their development and application. The advancement of Companion Diagnostics seems to offer a set of tools as well as the presage of relevant biological and clinical information that concentrates on many challenges that the pharmaceutical companies must overcome.

Personalized Medicine

Personalized medicine is a therapeutic model using molecular profiling technologies for tailoring the accurate therapeutic strategy for the correct person at the right time, and determines the predisposition to disease at the population level and to deliver appropriate and stratified prevention. The vital concept in this definition is molecular profiling that encompasses the use of a biomarker.

Biomarker

A biomarker can be defined as “a representative that is empirically gauged and assessed as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.”

Various types of biomarkers can be classified as per their purpose:

• Predisposition biomarkers – to assess the possibility of a disease (e.g. BRCA1 for breast cancer)
• Diagnostic biomarkers – to identify a specific disease (e.g. HCV RNA after infection)
• Prognostic biomarkers – to predict the course of disease (e.g. HER2 for breast cancer)
• Monitoring biomarkers – to assess the track of disease progress (e.g. BCR-abl for monitoring the treatment response in patients with chronic myeloid leukemia)
• Predictive biomarkers – to predict the response or reactions to a pharmaceutical drug (e.g. BRAF-V600 for melanoma patients)

Patients react contrarily to the same pharmaceutical drug, at standard prescriptions. An assessment for a predictive biomarker that is allied with a pharmaceutical drug (Rx) is called a companion diagnostic (CDx). FDA defines a companion diagnostic as “an in vitro diagnostic device that stipulates information that is necessary for the safe and effective usage of a corresponding therapeutic product.”

FDA has emphasized four areas in which a companion diagnostic may be indispensable to the protected and operative use of a therapeutic product to:

• Identify patients likely to benefit from the therapeutic product;
• Identify patients predisposed to compounded risk for serious adverse reactions as a result of treatment with the therapeutic product;
• Monitor response to therapeutic product for the purpose of correcting treatment (eg; dose, discontinuation) to accomplish enhanced safety or effectiveness; and
• Identify patients in the population for whom the therapeutic product has been effectively considered, and found nontoxic and efficient, i.e., there is sufficient info regarding the protection and efficiency of the therapeutic product.

Companion Diagnostics

“‘Companion diagnostic’ means a device precisely anticipated for the selection of patients with a previously diagnosed condition or predisposition as appropriate or inappropriate for a particular therapy with a medicinal product or a range of medicinal products.”

Companion diagnostics are a part of personalized medicine and will likely endure to swiftly surge in number and application to disease areas. First companion diagnostics were sprung in the 1980s and in the face of substantial preliminary cynicism from drug developers in case of segmenting a drug’s market through a diagnostic was advisable.

The viable accomplishment of drugs such as Gleevec® (imatinib) and Herceptin® (trastuzumab), which implicate testing with companion diagnostics beforehand they can be recommended, has proceeded the entire companion diagnostic field forward.

From an initiation of a handful of diagnostics, the field has augmented to include several therapeutic areas and the number of combinations has propagated by 12-fold.

Applications of Companion Diagnostics

The considerable application of companion diagnostics is to support the choice of most appropriate pharmaceutical drug for a given patient. Patients might react in a different way to the same pharmaceutical drug. One subgroup of patients may not respond, alternate subgroup might respond partially while a third subgroup might experience adverse drug reactions. Trial- and-error is one inquisitive to find which subgroup a patient belongs to. A trial-and-error approach can be tedious and prolonged, and patients with a life threatening disease may be despaired before the appropriate pharmaceutical drug is identified.

The potential of predictive biomarkers is the capability to ascertain patients who benefit or who are at threat of suffering from a pharmaceutical drug before initiation of treatment, thereby improving patients’ health.

A second application of companion diagnostics is during pharmaceutical drug development. If the association between a predictive biomarker and a new pharmaceutical drug is discovered initially, subgroup-specific drug development is possible as patient population is expected to yield higher efficacy rates with smaller sample sizes and, hence, may also lower trial costs. In theory, even development time could be of the pharmaceutical drug development process.

However, in practice generally subgroup-specific development is initiated only after a phase III study has failed and a subgroup analysis has revealed the prominence of the stratifying patients. In such a scenario, costs and development time would be increased. However, using a companion diagnostic may allow a moderately small group of responders to gain access to an efficacious pharmaceutical drug that would otherwise never have received a marketing authorization.

Regulatory Approval and Certification

In Europe regulatory pathways for pharmaceutical drugs and accompanying companion diagnostics are alienated. Marketing authorization applications for pharmaceutical drugs have to be submitted to the Committee for Medicinal Products for Humans Use (CHMP) within the European Medicines Agency (EMA). Based on the evaluation and endorsement of EMA, the European Commission then concedes a single marketing authorization valid in every member state of the European Union.

The association with a companion diagnostic test is stipulated in the pharmaceutical drug label. It is important to note that EMA recommendations on the pharmaceutical drug label do not specify a particular test and therefore any validated test can be used. A pre-marketing approval is not required for companion diagnostics. Commercial companion diagnostics are classified as in vitro diagnostics (IVDs) in Europe and consequently have to be in compliance with the respective ‘IVD directive’ (98/79/EC). Compliance with the IVD directive is indicated by a CE marking.

Self-certification by the manufacturer is sufficient in most cases to acquire a CE marking. Laboratories which develop their own biomarker tests for in-house use, so-called in-house tests or laboratory developed tests are exempted from CE marking requirements.

The IVD directive is presently under revision. The European Commission’s proposal for a Regulation on IVDs introduces a risk classification that classifies companion diagnostics as Class C device (high individual risk and/or moderate public health risk). Class C in vitro diagnostics require a compulsory review by a notified body.

“Notified Bodies are the recognized third party bodies that can accomplish conformity assessments laid down in the relevant harmonized European standards or European Technical Assessment”.

Manufacturers should submit a clinical evidence report to a notified body that demonstrates, analytical performance, scientific validity and where applicable, clinical performance. The review process of the clinical evidence report involves consultation with a national competent authority or EMA. The competent authority or EMA have 60 days to give their opinion which might be protracted once by further 60 days on scientifically valid grounds according to the proposal issued in September 2012 by European Commission.

Challenges

One of the considerable challenges to impending growth in companion diagnostics is aligning the inducements of all stakeholders. A major carter of growth will be the economic incentives for drug developers to brace their products with diagnostics. Diagnostic companies are caught between the contradictory demands of foremost stakeholders, payers/providers and pharmaceutical companies.

Regulators are also grueling in aligning development timelines between drugs and diagnostics. In order to endure and thrive, diagnostic companies must contemplate more broadly about companion diagnostics. They should also have to continue the process of global expansion and consolidation that the industry has by now instigated. Despite of potential obstacles, companion diagnostics became one of the dampest areas of deal making in the diagnostic space in recent times, and the future trends continue to look progressive.
Fig 1: Necessary alliances to develop a successful companion diagnostic. 

Benefits of Companion Diagnostics

Companion diagnostics stipulate individual, treatment-essential information; health care payors (both public and private) and patients stand to benefit considerably from the evolution of the companion diagnostic device industry.

The benefits include:

• Earlier therapeutic intervention,
• Hasty disease detection and risk characterization/classification/assessment,
• Ability to execute enhanced disease monitoring and improved monitoring of therapies anticipated for chronic use.

Companion diagnostics additionally identify patients for those a therapy may be ineffective, produce serious adverse advents — thus hoarding payers the burden of
(i) Paying for a medicine that does not act and
(ii) Paying costs correlated with treating potentially serious side effects.

Conclusion

Companion diagnostic device and the personalized medicine market, endure to progress in extent and significance to health care providers, patients, and payers of health care, and the market will surge in value. Manufacturers of companion diagnostics will capitalize significant progressive resources and should therefore, confer with legal counsel to

• Edifice an optimum regulatory pathway that will lead to FDA approval;
• Obtain the widest possible patent coverage; and
• Augment the benefit of any available patent term extension.

Overview

Pharmacovigilance is a branch of Pharmacological Science, which deals with safety, detection, assessment, understanding, and prevention of an adverse effect of a drug.

History of Pharmacovigilance

​1968: WHO drug monitoring program was laid
1964:  UK “Yellow Card” system for reporting adverse effects was implemented
2000: WHO UMC provided guidelines for setting up a Pharmacovigilance Centre.

Objectives of Pharmacovigilance

• Improve patient care and safety.
• Improve public health and safety
• Encourage safe, rational and appropriate use of drugs
• Promote understanding, education and clinical training in Pharmacovigilance.

Statistics pertaining to Product Recalls due to Poor Safety

Basic Concepts

Adverse Event

Any untoward medical occurrence that may be present during the treatment with a pharmaceutical product at any dose, but does not necessarily have a causal relationship with this treatment.

Adverse Drug Reaction

A response which is noxious and unintended, and occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease or for the modification of physiological function which necessarily has a causal relationship with the drug.

Source of ICSRs

Individual Case Safety Reports can be obtained from two sources, either from a Solicited Source or an Unsolicited Source.

Solicited Reports includes reports from marketing programs, customer engagement programs, and surveys etc.

Unsolicited Reports includes reports from patient, pharmacist, physician, lawyer, nurse, caregiver, social media, email and fax, literature, and journals etc.

Timelines for ICSR Submission

Fatal case: 7 days of MRD (Manufacturer Receipt Date)
Serious case: 15 days of MRD
Non-serious case: 90 days of MRD

Kindly Note: Every Adverse event irrespective of its seriousness has to be reported to the Regulatory Authority. Serious cases reporting will be expedited to the Regulatory Authority, whereas non-serious cases will go in the form of Periodic Safety Update Reports (PSUR) to RA.

All the adverse events reported will be documented in Adverse Event Monitoring Form and then entered into a Safety Database. From Safety Database, reports will be generated and submitted to the Regulatory Authority.
The different types of Safety Database are as follows:

• Argus Safety Database ( created by Oracle)
• ARISg Safety Database (created by Aris Global)
• AERS (Created by Oracle)
• Clintrace

Kindly Note: Argus Safety Database and ARISg Safety Database are widely used, however AERS and Clintrace are the legacy databases which are still in use by few MAHs.

Flow Chart for Case Processing:

Let us discuss in brief about the steps involved in Case Processing:

1. BookIn/Case Receipt/Case Triage
In this step, the information received pertaining to AE will be analyzed to check whether the case is valid or invalid i.e. Case Triage. The case is valid if it fulfills the minimum criteria is processed and the minimum information required in terms of Patient, Reporter, and Suspect Drug and event, is present. The case is invalid if it does not fulfill the minimum criteria. After entering this minimum information, a unique case number is generated.

Note: No two case numbers will be identical to each other. Every case number will be unique and different from others.

2. Case Processing
In this step, complete information pertaining to case will be entered into safety database. This step includes Full Data Entry which includes details like demography, previous and ongoing medical history, concomitant medical history, and brief narrative (case history) and laboratory investigations. Coding of events and Suspect Drug products with MedDRA (Medical Dictionary for Regulatory Activities) and “Company Drug Dictionary” (CDD) /WHODD (WHO Drug Dictionary) respectively is also undertaken. If there is any discrepancy or missing information, a query is generated, after which the case is routed to next step in workflow i.e. Quality Control or QC.

Note: If the Suspect Drug product is Company Product Drug (CPD), it will be coded with “Company Drug Dictionary” (CDD) and if the Suspect Drug Product does not belong to a particular company, it will be coded with “World Health Organization Drug Dictionary” (WHODD).

3. Quality Control
This is one of the integral part of Case Processing. This step deals with, “Checking the consistency of the information entered in database, hand written text with narratives, special characters in case, E2B validation errors and also appropriateness of any query generated”. If any inconsistency is observed, it will be corrected promptly and the case will be routed for the next workflow i.e. Medical Review.

Note: E2B validation errors will lead to “Delayed Submissions”. Hence, it is utmost important that all the validation errors are eliminated from the case.

4. Medical Review/Case Assessment
This is the step wherein, “Causality Assessment” is carried out. Medical Review can be only carried out by an allopathic physician. Based on the information available and confounding factors, medical review is done to determine the causality. It can be either, “Related or Unrelated or Probable or Not Associated”. The Medical Reviewer can use his discretion and medical judgement to assess the causality. Once the Causality Assessment is done by a medical reviewer, the case is routed for a next workflow i.e. Final Case Review or Data Validation. If the medical reviewer has any comments or suggestions, those will be incorporated and addressed in the next workflow.

Note: The relationship between a Suspect Drug and an event is referred to as, “Causality”. It can be either, “Related or Unrelated or Probable or Not Associated”. Causality Assessment directly impacts the Regulatory Submission.

5. Final Case Review/Data Validation
This is the step where Case Processor receives the case from a Medical Reviewer. The Case Processor in this step ensures that all the comments and suggestions are properly incorporated and addressed. Once every discrepancy and comment is addressed, the case is ready for Regulatory Submission.

Note: Final Case Review/Data Validation is the step where the case will be ready for Regulatory Submission. It is utmost important that all the changes and suggestions are properly addressed as given out by Medical Reviewer as there will be no QC after this step.

6. Regulatory Submission
This is the step where the case will be submitted to Regulatory Authority. Once the case is submitted, it will have a status of either, “Case Closed or routed for Awaiting Follow-up”.
Note: The timelines for the case submissions to regulatory authority are as follows:

Fatal case: 7 days of MRD (Manufacturer Receipt Date)
Serious case: 15 days of MRD
Non-serious case: 90 days of MRD

7. Case Closed/Awaiting Follow-up
This is the final step in Case Processing. Once the regulatory submission is done, the case is either “Closed” or routed to “Awaiting Follow-up”. If there is no pending information from a Reporter, the case will be locked and closed. If there is any information pending from a reporter, then the case will be routed to, “Awaiting Follow-up”.

Note: If the case is Closed or Locked, and for the same case if additional information is received then, “the case is unlocked and the whole process of Case Processing continues till the report is submitted to Regulatory Authority”.

STRATEGIC SUBMISSION SERVICES IN CANADA FOR UK-BASED COMPANY

• Freyr bags a strategic submission and publishing project from a leading UK based pharmaceutical company. We will be providing NeeS submission and publishing services for Canada.

CLAIMS TO A UK-BASED COSMETIC COMPANY

• Freyr to provide assessment services for Cosmetic Claims to a UK based, Fast growing Cosmetic Product Company. We are helping the client in reviewing cosmetic claims in the US for 45 products across multiple markets.

SUCCESSFUL HARMONIZATION OF LABELING UPDATES FOR A US BASED, GLOBAL $50+ BN, PHARMACEUTICAL COMPANY

Successful Approvals through EU-Centralized Procedure Delivered For All 24 European Languages for 2 Products

Explore how Freyr supported client with additional resources for performing translation QC for 2 products (24x2 EU languages) providing standardization of global labelling processes to build efficiencies.

BENEFIT HIGHLIGHTS

• Supported client for seeking approvals through EU-Centralized Procedure by performing
• Translation QC for all 24 European languages for 2 products (24x2) simultaneously in strict timelines

BUSINESS IMPERATIVES

Client was looking for a strategic partner to outsource key regional labelling activities listed below:

• Quality Check of EU Product Information with quick turnover
• Base Document Creation of Regional Prescribing Information for Rest of World
• EU Labelling – Linguistic Review
• US Labelling – SPL creation
• Package Component Labelling

CHALLENGES

• Extremely quick TAT for high volume of translation QC for 24 European languages for 2 products simultaneously.
• There was a need to capture institutional knowledge from client SMEs due to lack of process documentation.
• Widely different process/guidelines across geography
• Collaboration with multiple stakeholders across the globe for each product
• Training/live job coordination with offshore team during transition by onshore Freyr team and track multiple activities (visual QC, base document/variations) within the strict timelines

FREYR SOLUTIONS & SERVICES

• Freyr worked to seek approvals through EU-Centralized Procedure by performing Translation QC for all 24 European languages for 2 products (24 x2) simultaneously in strict timelines
• 4 member team travelled to UK and started live job on the same day after only one translation QC document  training
• Freyr customized  and integrated process as per client requirements and also gave greater visibility to client by delivering metrics (such as schedule/effort variance, productivity etc.) to measure the quality of the task in client-Freyr SharePoint
• Train the trainer model was implemented by absorbing knowledge effectively and transfer knowledge to offshore team
• Identified single point of contact for each region for effective communication and issue resolution

CLIENT BENEFITS

• Freyr supported at a critical point of time when the client needed additional resources for performing translation QC for 2 products (24x2 EU languages) with quick TAT
• Program will provide the client the ability to ramp-up and ramp-down resources based on volume requirement

First successful NDA-Medical Device Submission Made with Reduced Delivery Time from 50 days to 16 Days

BENEFIT HIGHLIGHTS

• First successful NDA-Medical Device Submission
• Reduced Delivery Time from 50 days to 16 Days
• Zero Defect, High Quality Delivery
• Fastest Turnaround Time

BUSINESS IMPERATIVES

• The company is known for its popular sports and energy drinks, such as “Pocari Sweat” and “Oronamin C”. Freyr is associated with the client’s Regulatory Affairs and related technology services for an array of submissions and related activities in CSRs, NDAs, INDs and LCM
• The team provided support to a critical and highly strategic New Drug Application (NDA). A medical device submission which utilizes Aripiprazole + an ingestible event marker (IEM) targeting Schizophrenia known as MIND1
• MIND1 (Medical Information Device 1) System does not represent the proposed trade name, but, within this application it will be referred to as MIND1. The proprietary name is ABILIFY MIVU™
• MIND1 is a combination of Aripiprazole (an atypical antipsychotic) embedded with an IEM that communicates with a Patch (a wearable sensor) and a medical software application. It is intended for the treatment of schizophrenia, manic and mixed episodes associated with bipolar I disorder; and adjunctive treatment of MDD

CHALLENGES

• The submission being executed by the client was an extensive  one
• The company’s Style Template was not utilized when documents were prepared by their resources, which led to a delay in approvals and issuance of documents to publishing
• Several rounds of republishing due to delays in approvals of documents
• Resources required to review the same files various times, due to the rework and reapproval of documents
• Multiple versions of the same files were uploaded to the DMS instead of up versioning
• Preventable time spent on tracking down current versions of files
• Imperative changes delayed due to FA leads not providing responses to queries in a timely manner

FREYR SOLUTIONS & SERVICES

• Establishing an Account level PMO to manage individual projects
• Introducing a balanced mix of onshore and offshore resources thus providing 24x7 support to meet stringent timelines
• Deploying experienced industry professionals to quickly understand project requirements and start performing in short turnaround time
• Assisting the client to increase productivity by deploying knowledgeable Document level Publishers.
• Providing support to fix font issues, which is a major error in Validation reports.
• Helping the client to maintain submission trackers and issue logs, throughout the submission, which are intended to help keep track of the submission until delivery

CLIENT BENEFITS

• Freyr reduced the overall turnaround time from 50 days to just 16 days
• Swiftest document preparation and validation of the submission for a cost-competitive submission
• A single Point of Contact throughout the submission process which reduced confusion and decreased surplus time and man hours spent per each document
• High productivity with quick turnaround time
• Delivery of over 1400 man hours were utilized for this submission
• Ahead of-schedule and defect free delivery