Benefit Risk assessment

 

What are the benefits and risks?

 Benefits are clinically meaningful improvements to a patient, health state, or quality of life.

 The risk can encompass a variety of factors, including the absence of expected benefits, potential dangers or hazards to the patient, adverse events, both direct and indirect harm, and the frequency and severity of side effects. It also extends to harm caused to non-patients or the general public, unacceptable damage to the patient, and the loss in efficacy compared to current therapies. Additionally, risks may include the negative aspects of a drug, pharmacokinetic interactions, insufficient treatment duration, the probability of adverse events or harm, negative impacts on the patient’s quality of life, failure to meet clinical endpoints, and drug intolerability.

 The integrated benefit-risk evaluation should be performed for all authorized indications and should incorporate the evaluation of risks in all use of the medicinal product (including use in unauthorized indications).

Benefit-risk assessment: why is it needed?

Ø  Simplifies product understanding

Ø  Easy to utilize in multiple documents

Ø  Makes an impact

Ø  Adds credibility

What are the components of B-R?

Ø  How does the disease impact patient population

Ø  How does the disease impact patients' quality of life

Ø  What are the current treatment options, and are they meeting the patients

Expectations?

Ø  What are the key benefits, and how do they impact the patient's functions, quality, and survival?

Ø  How these benefits provide clinically meaningful benefits in the patient population and a subset of the population

Ø  Risks

Ø  What are the known risks, and how are they quantified (reversibility, treatability, and Preventability)

Ø  What are unknown risks, and how may they change in a marketing scenario if approved

Ø  Are there any more risk minimization measures required beyond labeling?

Ø  If yes what are those and how they can be addressed with meaningful risk minimization strategy

Which documents need a B-R assessment?

1. PSUR/PBRER

2.RMP

3. Clinical modules as a part of MA application

4. Ongoing evaluations for any documents that require an understanding of product performance in terms of risks and benefits.

How to draft a B-R assessment?

1. Current understanding of disease indication ( epidemiology, pathophysiology, complications, prognosis, impact on patients' quality of life mortality and morbidity, incidence, duration, and impact on public health)
2. Current therapies:  Available options with details of availability, access, affordability, benefits, risks, tolerability, convenience, and preference in the patient populations, subpopulations and also noting any regional differences

Ø  Benefits: Clinical importance of the benefit (impact on patient's clinical conditions and disease ), the time course of benefits ( time to onset, continuous effect of product), variability of key benefits (age, sex, ethnic origins etc)

Ø  Risks: Risks are adverse events or unfavorable events should be considered especially in terms of their occurrence in study drug vs placebo, comparator etc (in percentage), reversibility, tolerability, preventability, seriousness and severity.  Describe the ability to manage, prevent or treat risks and also describe variability factors (age, sex, concurrent therapies)

Written by:

Dr.Shraddha Bhange.

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References:

Ø  EMA- ICH Topic E2C(R1), PSUR

Ø  International Conference on Harmonisation. ICH Harmonised Tripartite Guideline, Periodic Benefit-Risk Evaluation Report (PBRER) E2C (R2), 2012. http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Efficacy/E2C/E2C_R2_ Step4.pdf. Accessed August 11, 2015

Ø  European Medicines Agency (EMA). Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report (Rev 1). 2013. http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2013/04/WC500142468.pdf. Accessed August 11, 2015.

Ø  International Conference on Harmonisation. E2C(R2) Implementation Working Group ICH E2C(R2) Guideline: Periodic Benefit-Risk Evaluation Report Questions & Answers, 2014. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Efficacy/E2C/E2C_R2_QAs_Step4.pdf. Accessed August 11, 2015.

Ø  European Medicines Agency (EMA). Benefit-risk methodology project. Work package 1 report: description of the current practice of benefit-risk assessment for centralised procedure products in the EU regulatory network. London: EMA; 2009. http://www. ema.europa.eu/docs/en_GB/document_library/Report/2011/07/ WC500109478.pdf. Accessed August 11, 2015.

Ø  European Medicines Agency (EMA). Benefit-risk methodology project. Work package 4 report: benefit-risk tools and processes. London: EMA; 2012. http://www.ema.europa.eu/docs/en_GB/ document_library/Report/2012/03/WC500123819.pdf. Accessed August 11, 2015.

Ø  Food and Drug Administration (FDA). Structured approach to benefit-risk assessment in drug regulatory decision-making. http:// www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrug UserFee/UCM329758.pdf. Published 2013. Accessed August 11, 2015.

Ø  Coplan PM, Noel RA, Levitan BS, Ferguson J, Mussen F. Development of a framework for enhancing the transparency, reproducibility, and communication of the benefit–risk balance of medicines. Clin Pharmacol Ther. 2011;89:312-315

Ø  European Medicines Agency (EMA). Benefit-risk methodology project. Work package 4 report: benefit-risk tools and processes.

 

Biosimilar products

 Biosimilars definition

EU definition of Biosimilar "A biosimilar is a biological medicine that is highly similar to another biological medicine already approved in the EU (called 'reference medicine') in terms of structure, biological activity and efficacy, safety, and immunogenicity profile (the intrinsic ability of proteins and other biological medicines to cause an immune response).

Biosimilars are called Follow-on biologics, BIOSIMILARS, similar biological medicinal products, follow-on protein products, BIOGENERICS, and biologics, or BIOPHARMACEUTICALS.

Biosimilars and Generics differences

Biological products are very similar to reference biologics but not identical. Generics, on the other hand, are chemically synthesized and hence have identical medicinal ingredients compared to reference products.

Biological products are large, complicated, relatively unstable molecules that are often mixtures of different isoforms with a complex production and purification process, while generics are smaller, stable molecules that are easier to manufacture.

Safety concerns for biologicals often concern infections, malignancies, and reactions related to immunological events. Safety concerns for small molecules are known to be often related to the classes ‘Cardiac disorders’, ‘Hepatobiliary disorders’, ‘Blood and lymphatic system disorders’, and ‘Nervous system disorders’.

Switching or substituting a biosimilar is more complicated than switching or substituting simple generic molecules since this could involve a change in product and device, leading to safety concerns during administration (device design is also proprietary). With simple generics, switching is easier and may only require patient education on changes in appearance.

Biosimilars regulations

USA

•        Analytical evidence that is comparable to the source, animal studies, clinical research and the identification of the mechanism of action

•        Guidance v 351 (k)

INDIA

•        Studies on biological activity, clinical research, preclinical research and immunogenicity

•        Guidance CDSCO

EU

        

•        Clinical investigations, preclinical research, biological activity, purity, physiochemical characteristics and studies on immunogenicity

•        Guidance

v CHMP/437/04

v EMEA/CHMP/BWP/49348/2005

v EMEA/CHMP/BMWP/403

 

Biosimilars advantages

•        Affordability

•        Accessibility

•        Less cost than reference biologics

•        Lower costs of development

 

Biosimilars and PV

Data Sources

•        Specialized (hospital) setting

•        Patient and disease specific Registries

•        Randomized clinical trials

•        Switch therapy information

•        Batch number information

•         

ICSR

•        Complex adverse events & immunological events may arise from minor variations in structure, such as glycosylation

•        Difficulty in the establishment of a causal association

•        Dosing & administration issues

•        Drug-device combination safety

•        Causality – class & compound effects

•        Onset time, previous therapy, life-threatening & chronic illnesses

•         

RMM & aRMM

•        Additional risk minimization measures may be required apart from those for the reference product.

•        Prospective surveillance registries

•        Post-approval pharmacoepidemiologic studies and PASS

•        Randomized clinical trials

•        Targeted follow-up questionnaire

•        Educational materials for HCPs

•        Medication guide for patients,

•         

 

Written by:

Dr.Shraddha Bhange.

Connect with me Via the comments below. (I do not respond to Facebook messages)

Support the cause of better rural education with me: ThinkSharp Foundation http://thinksharpfoundation.org/#home

 

References

 

 Biosimilar medicines: Overview | European Medicines Agency (EMA)

What are biosimilars? | Biosimilar Basics | Biosimilars Council

Biosimilar vs. Generic: The 4 Core Differences (and Similarities) - GoodRx

Pharmacovigilance of biosimilars – Why is it different from generics and innovator biologics? - PMC

Frontiers in nonclinical drug development: biosimilars - PubMed

Safety considerations of biosimilars - Australian Prescriber

 

 

 

 

 

 

Pregnancy and lactation labeling rule (PLLR)

1. What is PLLR :

FDA published the Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling referred to as the “Pregnancy and Lactation Labeling Rule. Other regulatory authorities also seek this type of analysis in terms of updating the label documents from a pregnancy, breastfeeding, and lactation perspective

PLLR is an analytic tool for evaluating safety data concerning Reproductive, Pregnancy, and lactation risk sections. This evaluation will then help comprehensively present the data on product labels so that the HCP understands the risk quickly and makes clinical decisions based on the same.

This section in the label will also allow consumers and patients to make informed decisions for themselves and their children.

Once the evaluation of PLLR is submitted to the FDA, the label needs to be updated as per the current section requirements. The FDA will approve it, and consequently, it will be added to the labels.

 2. Where is it required:

For a product label USPI, SmPC (e.g. addition to label or labeling update), patient leaflets.

If there are additional risk minimization measures for pregnancy and lactation, then adding to the Dear Health Care Professional letter

 3. Regulatory background :

The Food and Drug Administration (FDA) is amending its regulations governing the content and format of the "Pregnancy," "Labor and delivery," and "Nursing mothers" subsections of the "Use in Specific Populations" section of the labeling for human prescription drug and biological products. The final rule requires the removal of pregnancy categories A, B, C, D, and X from all human prescription drugs and biological product labeling. For human prescription drugs and biological products subject to the Agency's 2006 Physician Labeling Rule, the final rule requires that the labeling include a summary of the risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation. The final rule eliminates the "Labor and delivery" subsection because information about labor and delivery is included in the "Pregnancy" subsection. The final rule requires that the labeling include relevant information about pregnancy testing, contraception, and infertility for health care providers prescribing for females and males of reproductive potential

 4. What are data points utilized to write PLLR

• Global Safety database
• Literature search
• Clinical data
• USPI- current

 5. Why and how is it prepared

1.               Review and summary of the available published literature regarding the drug’s use in pregnant and lactating women and the effects of the drug on male and female fertility 

2.               A cumulative review and summary of relevant cases reported in the pharmacovigilance database from the time of product development to the present

3.               A summary of drug utilization rates amongst females of reproductive potential (e.g. aged 15-50 years) calculated cumulatively since initial approval

4.               An interim or final report of an ongoing or closed pregnancy registry (if applicable), pregnancy cases from clinical trials

Based on the above results, each section is drafted, and then a conclusion is reached regarding the risks the product carries when used in pregnant, lactating, or reproductive-age females.

Written by:

Dr.Shraddha Bhange.

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References:

Pregnancy and Lactation Labeling (Drugs) Final Rule | FDA

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HHE (Health Hazard Evaluation)

1. What is HHE 

HHE is a tool for classifying a voluntary recall by a pharmaceutical company. Pharma companies will perform this evaluation, which will be submitted to the FDA, to determine the risk to the public from the defective product and appropriate actions for the pharmaceutical company and the FDA to take to protect public health.

HRA is a tool for predicting possible harm from a defective or malfunctioning device. The assessment helps the FDA and the firm determine if any actions are necessary, such as recalling the devices or notifying the public about the risk.

2. When is HHE written 

HHE is written when there is a product quality issue or a formal request from the FDA.

 3. What are the components and steps of HHE?

Components for assessment for HHE

Qualitative and quantitative outputs from the safety database for the search terms related to the problem (AE-adverse event, PQC product quality complaint, LOE Lack of efficacy etc)

•        Support of internal and external data sources as but not limited to 

•        Literature

•        Competitors’ products

•        RA (Regulatory Authority) database

Steps in HHE: 

•        Collaboration and participation in risk mitigation measures for a recommendation for further steps

•        Plan for Submission to the regulatory agency

•        Implementation of risk minimization measures and additional risk minimization measures

•        Monitor and evaluate the comments from Regulatory if any

 4. Regulatory actions for HHE (High level)

1.      Once the MAH/Pharma submits the HHE data to the FDA

2.      FDA will have an internal team of physicians and engineers to evaluate the response and carry out the same exercise

3.      based on this determination, the Food and Drug Administration will assign the recall a classification

4.      Recall classification e.g. Class I, Class II, or Class III, to indicate the relative degree of the health hazard of the product being recalled or considered for recall.

 5.  Sections in HHE (MAH):

1.  MAH details

2. Product details

3. Device issues

4. Association of AE with this particular device issues

5. What is the impact of this AE in patients i.e. serious, reversible, preventable, treatable etc

6. Can this device issue be easily identified by the patient population?

7. Mechanism of action of this issue

8. Impact on the patient population 

9. Mitigation of this risk that can happen due to this device issue

Written by:

Dr.Shraddha Bhange.

Connect with me Via the comments below. (I do not respond to Facebook messages)

Support the cause of better rural education with me: ThinkSharp Foundation http://thinksharpfoundation.org/#home

References:

Health Hazard Evaluations (HHEs) and Health Risk Assessments (HRAs) | FDA 

Description of the Health Hazard Evaluation Program - The Health Hazard Evaluation Program at NIOSH - NCBI Bookshelf (nih.gov)

 

What skills are important in PV other than PV?

What skills are essential in PV other than PV?

1. What is PV?

Pharmacovigilance is the science and activities relating to detecting, assessing, understanding, and preventing adverse effects or any other medicine/vaccine-related problem.

2. Scientific skills vs supporting skills

1. Regulatory guidance: Scientific skills like GVP modules, CIOMS, and ICH -GCP guidance documents should be clearly known at a high level, to say the least. However, these are very detailed, so memorizing them is not an expectation; knowing how to interpret them in daily PV activities is.  

2. ICSR: ICSR is not limiting the knowledge to only 4 minimum criteria and how to do case processing. ICSRs also need to understand the criticality of each ICSR in the product safety file. For Seriously unlisted cases, especially any ICSR that can potentially be a signal, a critical assessment of labeling, seriousness, and causality is the first step. But going beyond this is essential as well. Product quality complaints, off-label use, and increased complaints related to product packaging issues also impact patient safety. For e.g., a lot of ICSRs with patients unable to open packaging issues for an asthmatic drug is a potentially severe issue, as this may cause asthma patients to not get the correct dose at the right time during an asthma attack. 

3. Aggregate reports: The starting point is PSUR, PBRER, and DSUR basics from regulatory guidance documents for the template and expectations understanding. However, for a PV professional to author, review, or contribute to PSUR requires many analytical skills. We need to know what the baseline safety profile of the product is, how to correlate sales volume data against the number of adverse drug reactions reported, have a clear strategy regarding which risk will need cumulative vs interval analysis, what articles to include, and how and which topics can be closed are some key answers to find for each aggregate report to then conclude if there is any change in the benefit-risk profile of the drug.

4. Signal detection: As much as every new PV professional wants to jump into signal management, knowing the signal management process through regulatory guidance is just the beginning. Identifying, validating, and proposing a signal outcome requires a thorough understanding of medical, scientific, and drug safety profiles. 

5. Risk management plan (RMP) and risk management measures:

 RMP is a big topic in PV, where all the pieces of PV come together for patient safety.  Identification of risk, proposing appropriate risk minimization measures, and evaluating those measures that are sufficient and effective for patient safety is a collective effort of everyone working in PV and also other departments. Every MAH has to ensure a favorable benefit-risk profile for each drug. To ensure this, it is essential to know how to scientifically put the risks associated with the drug with appropriate risk minimization measures to get MA approval or to continue the MA approval. 

6. Other: Some country-specific or local requirements are also necessary, primarily if you work on a product marketed in these territories. Health Hazard Evaluation Report, PLLR, REMS, PSMF. As PV works very closely with regulations, it is essential to know the regulatory requirements like MA application, CTD modules, MA dossier qualification, and post-submission expectations from the regulatory authorities. You are submitting NDA, ANDA, or for a new indication of a previously approved drug.

3. Supporting skills that are a must 

Having only scientific skills is necessary, but complementary skills that will help you implement your assigned tasks effectively and productively are also essential. 

In the world of PV, activities can most often not be planned as they depend on external factors—how many AEs are reported and when, what and when regulatory agencies send questionnaires, etc.

Hence, time management and prioritization are a must. PV also needs to collaborate with every department in a company (RA, Clinical) and an outside company (RA). Stakeholder management, influencing, negotiation, and good communication skills help a lot when implementing any PV process and ensuring its effectiveness. 

Other skills valuable in any other career, such as Presentation, leadership, and knowledge of Excel and Word, are also essential in PV.

4. Supporting skills based on role and KPI : 

Some skills are more critical than others for some roles within PV.

ICSR: Excel, safety database, time management, coding.

Aggregate: Stakeholder management, Excel, analytical skills, literature review

Signal: Looking at multiple datasets for meaningful patterns and trends. Signal database, RA database combing and downloading, statistics and epidemiology

RMP and REMS: Knowing HCP patterns and behaviors to understand which RMM and aRMM will be effective, visualizing, project management, influencing, negotiation, and assertiveness.

5. Where to find tools to develop? 

Coursera, UDEMY, and YouTube are probably PV academy training institutes for online and offline tools. 

6. How to ensure continuous development of supportive skills

The most significant source of learning is doing by learning. If you are in ICSR and want to develop aggregate skills, ask to contribute a few sections and listings in PBRER. Ensure that you stay up to date with regulatory guidance, but before that, ensure you are thorough with internal company SOP on the area of development you are focusing on. 

Written by:

Dr.Shraddha Bhange.

Connect with me Via the comments below. (I do not respond to Facebook messages)

Support the cause of better rural education with me: ThinkSharp Foundation http://thinksharpfoundation.org/#home.

Reference:

Pharmacovigilance training materials | European Medicines Agency (EMA) (Europa. eu) 

Training resources (who. int)

Everything You Need To Know About A Career In Pharmacovigilance - Mentoring

Agreement to avoid ugly disagreements SDEA

 What is SDEA 

A service data exchange agreement (SDEA) is an agreement between two companies that ensures the roles and responsibilities of each company are clearly defined, especially related to the pharmacovigilance process. 

This agreement is necessary due to business requirements, such as pharmaceutical companies having to have partners in some countries instead of selling themselves or buying or selling their molecules to others. Often, an MAH may only be involved in distribution, marketing, or manufacturing. Knowing and defining who will do what in the PV process becomes essential in all such scenarios. This is also a requirement from regulatory agencies during audits or inspections.

 2. Types of SDEA 

As defined in the above image, there are various types of agreements. The most important and necessary one is between two MAHs. The SDEA can also have other supporting documents that may be used to define granular details, timelines, how to exchange information, etc. 

 3. When, who, and how do we write 

SDEA is written or drafted very early once the business agreements are signed. Usually, the pharmaceutical company with the global license or MAH initiates the SDEA. 

The SDEA should be finalized and signed before the first batch is in the market (worst case), but earlier is better. The safety database, SOP, Work instructions, and team readiness—in a nutshell, the PV system should be live and ready to onboard or delegate the product.

 4. Elements of SDEA

SDEA elements, as seen in the above image, are minimal basic requirements that must be defined. This is not an exhaustive list, and further granularity is required depending on the product, its risk minimization measures, local RA regulations, etc. Other factors that need to be addressed are BCP (Business Continuity Plan), Termination, confidentiality, etc.

 5. Challenges and Solutions

Challenges:

1. Data privacy can be challenging, especially if local laws vary.

2. Confidentiality policies may have differences that may be contradictory to SDEA terms

3. Meeting regulatory compliance requirements as per local laws and each company's policies

Solutions:

1. Regulatory adherence: Helps companies meet legal obligations at local laws. 

2. Efficient collaboration: Once roles and responsibilities are clearly defined, it helps meet local and global regulatory requirements.

3. Data quality:  Maintains safety data's accuracy, completeness, and timeliness.

4. Clarity: Confidentiality and data privacy should be clearly defined to avoid any inspection and audit findings.

Having SDEA is of utmost importance so that both companies and parties work and collaborate together. This will ensure that there are no ugly disagreements later.

Written by:

Dr.Shraddha Bhange.

Connect with me Via the comments below. (I do not respond to Facebook messages)

Support the cause of better rural education with me: ThinkSharp Foundation http://thinksharpfoundation.org/#home

References:

Guideline on good pharmacovigilance practices (GVP) Module I – Pharmacovigilance systems and their quality systems (Europa. eu) 

Pharmacovigilance Agreements: Negotiating Safety Data Exchange Timelines: To Agree to Disagree? That is the Question | Therapeutic Innovation & Regulatory Science (springer.com) 

https://pvdrugsafety.com/2021/11/pharmacovigilance-agreements-pvas-and-safety-data-exchange-agreements-sdea/ 

Literature review in pharmacovigilance

1. Why is a literature review required:

A literature review for continuously monitoring the product's safety profile is a regulatory authority requirement across all countries. However, it goes beyond meeting compliance requirements as it helps MAH/Pharma companies utilize real-world data in various other documents, e.g., new indication applications, better understanding of the risks, and introducing or adjusting risk minimization measures as the safety profile changes. Literature serves as a source of information outside the company database. 

 2. Which databases are used for literature: 

The European Union has published a list of active substances (drugs) that need to be monitored in the literature. Other regulatory agencies may or may not have such an explicit list or name of drugs published; however, when a product has active PSUR, RMP, or any risk minimization measures, it becomes pertinent to have a literature review for those products. A literature review for identifying cases/ICSR is required for all products; hence, having one database for literature is mandatory. However, the industry standard is to have at least 2 databases, and whenever required, especially for MAH in European countries, local literature in the local language also becomes mandatory.

3. Literature search strategy:  Literature search strategy depends on three critical factors.

1. Phase of development of product and the status of the product

    A product that is an originator and still in a clinical development phase may require a class search or a search focused on toxicology, animal studies, etc., as the real-world data may be limited. However, for a generic product with a well-developed safety profile, the search will be limited to molecules and collecting natural clinical settings usage and patient outcomes.

The most common and required terms are adverse event, class and product terms, pregnancy and breastfeeding, and pregnancy outcomes.

2. Literature database 

This also drives the way we use search terms and the technical aspects, such as using the correct characters.

3. Local vs. Global Literature

The search strategy will also change based on local or global search. In the case of specific terms used locally in clinical publications, those will need to be targeted. 

4. Broad vs narrow search strategy

 The search strategy can be broad or narrow depending upon where the articles will be used and for what. When the risk is not established or not characterized, we usually use signal validation in the broad search. However, we use narrow when the risk is well known, and we want only certain aspects to be characterized, e.g., prevalence in specific populations. 

 4. Where are literature articles utilized 

The literature in PV is not limited to ICSR or signal management. It can be utilized for aggregate reports, e.g., PSUR, DSUR, etc. Additionally, for new indication applications, designing a study to determine which study safety outcomes and Benefit risk assessment.

 5. Points to consider for literature articles 

 5.1 ICSR

Validating an article as an ICSR from literature is the same as in any case: 4 minimum criteria. However, the same 4 minimum criteria must be relevant to the literature source. 

Product: Is your product available in this market/country? 

Is the literature article date or use of the product mentioned in the article after the product was launched in that country/market? 

Does the article mention the brand name or have the same composition as your product? 

We need to address these questions before adding this to the safety database.

Event: Add only events that occurred with company products or events after the company product was started. Add events that the author attributed to the company product.

Reporter and Patient: This criterion has no change per se except that patient identifiers must be available in the article. A table of patients with their age/gender, categorized into products they have taken or events that occurred. In a nutshell, we need to know that there were separate patients.

 5.2 Aggregate safety reporting

Articles that need to be included in the PBRER depend on multiple factors, e.g., sections in the PBRER, i.e., sections 9 or section 15, or 16. It also depends on the baseline safety profile of the product, what we know about the individual risk, and what outcome is expected from that section or risk. If it's a second PSUR, is there any particular request from PRAC? Generally, articles with large populations, varied/diverse patient populations that were not studied, specific outcomes, and changes in severity, seriousness, and frequency will be included. Articles that provide more information on the mechanistic action of drugs (previously unknown) or articles that provide new or relevant disease pathophysiology will also be included.

Written by:

Dr.Shraddha Bhange.

Connect with me Via comments below. (I do not respond to Facebook messages)

Support the cause of better rural education with me:ThinkSharp Foundation http://thinksharpfoundation.org/#home

References:

1. Detailed   guide regarding the monitoring of medical literature and the entry of relevant information into the EV database by the EMA (Europa. eu)

2. Welcome - Embase

3.MEDLINE   (nih.gov)

4. Allied    and Complementary Medicine Database (AMED) | EBSCO