Welcome to the June 2016 issue of FREYRFOREWORD!
A monthly round-up of the latest happenings and updates from Freyr.
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:
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.
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:
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:
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 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.
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:
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:
“‘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.
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.
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:
Companion diagnostics additionally identify patients for those a therapy may be ineffective, produce serious adverse advents — thus hoarding payers the burden of
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
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
Objectives of Pharmacovigilance
Statistics pertaining to Product Recalls due to Poor Safety
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)
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.
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
Note: No two case numbers will be identical to each other. Every case number will be unique and different from others.
2. Case Processing
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
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
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
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
Fatal case: 7 days of MRD (Manufacturer Receipt Date)
7. Case Closed/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”.
|As an organization, we at Freyr, have always placed the highest value on our business associations and partnerships. It has been our guiding principle to identify newer opportunities and create exceptional engagement excellence for our clients that transform into long-term relationships. As always, it is a great pleasure to announce the New Wins of this quarter.|
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