Monitoring safety of drugs:Pregnancy and Breastfeeding

 Pharmacovigilance in terms of monitoring safety of drugs in pregnant and breastfeeding mothers is very critical and also different. 

For knowing safety profile of drug during pregnancy or breastfeeding we are dependent on pharmacologic or chemical class of drug, or animal studies or clinical trials data.

Why critical?

1. Almost all clinical trials for registering new drugs exclude pregnant and breastfeeding women. So data is not available regarding effects of drug on this population easily.

2. Special clinical trials and data collection methods are required to monitor effects of drug on this population.

Hence to know safety profile of drugs during pregnancy, post marketing surveillance is major source of data. This is collected after the drug has been approved and used by pregnant women voluntarily when they know they are pregnant or when they used drugs without knowing in advance they were pregnant. 

Usage of drugs during pregnancy and breastfeeding is different than when used in general population for 2 reasons:

1. Use of drugs has to be thought in terms of its risks and benefits to mother and child both.

2. Risk of disease if left untreated without administering drug has to be weighed for both mother and child.

E.g. if breastfeeding is continued to benefit baby, is the risk greater to infant from receiving milk with drug excreted from mother in it or the mother's disease left untreated pose more risk in terms of quality of milk?

ICSR:

The route of administration in baby case (ICSR) is transplacental/transmammary and event is exposure in utero/Drug exposure via breast milk . The route of administration for the mother case is to be coded in correct fields in parent/child section .The outcome and event coding should correlate to correct patient i.e. baby and parent. 

Some important fields for cases are: Gestational age, Ultrasound results (in narrative), Use of other drugs especially teratogens, Outcome of pregnancy.It is also important to link cases.

It is also critical to know when to create 2 cases i.e. parent and child and when only 1 i.e. parent. The key to remember is usually if there is an adverse event for baby then 2 cases and if no adverse event then on;y 1 i.e. parent case. E.G.

1.  A pregnant women with abortion then only 1 case of mother with event abortion. However if its full term pregnancy and foetal death is outcome then 2 cases.

2. A pregnant women delivered baby with foetal abnormality then 2 cases baby and mother.

Expedited reporting of cases (parent and baby) follows same timelines. Cases with no adverse event or non serious preganancy cases, cases with termination of pregnancy are usually reported in PSURs/PBRER's.

Aggregate reports: 

PBRER/PSUR for product the frequency and template remains same for the drug concerned. The additional data to be included about drug use in pregnancy and breastfeeding should be described in relevant sections. The data sources is the ICSR received from spontaneous source, literature, pregnancy registries, studies etc where an pregnancy or breastfeeding exposure is reported with or without adverse pregnancy outcome.

Another additional section is drug utilisation by age group wherein it should be monitored if reproductive age group patients were exposed to the product to have data regarding quantitative exposure for this group.

The risk/benefit section should describe the cases of pregnancy and breastfeeding exposure and its relevance to safety profile of drug. If pregnancy and breastfeeding exposure is one of the safety concern in RMP then its important to mention the data relating to it in detail especially what is status of risk minimisation measures already implemented or if planned.

It is important to mention pregnancy/breastfeeding exposure as missing information in RMP and to monitor it.

Pregnancy registries: 

Different types of registries are maintained wherein data is collected regarding women who have been exposed to drugs during pregnancy and for drugs with longer half life's before pregnancy, male exposed to such drugs where pregnancy occurs following it, birth registers, birth defect registries etc.

When studied appropriately they provide very useful information in generating signal or at least signal hypothesis.

Studies conducted to study pregnancy and breastfeeding exposure and data collected from it. This study should be planned in structured manner and outcomes to be collected with longer follow ups (6-12 months at least after pregnancy period and include baby follow up too).

References:

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-good-pharmacovigilance-practices-product-population-specific-considerations-iii_en.pdf

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-exposure-medicinal-products-during-pregnancy-need-post-authorisation-data_en.pdf

https://www.ncbi.nlm.nih.gov/books/NBK208605/

https://www.fda.gov/science-research/womens-health-research/list-pregnancy-exposure-registries

Written by:

Dr.shraddha Bhange.

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Basics learnings from MDR (Medical Device Regulation)

Recently while discussing with colleague regarding device regulations, I realized much is not know about this topics. And decided to share my learnings via my blog to open a dialogue and learn more.

1.       What is medical device?

It is any instrument which is used in diagnosis, prevention, monitoring, prediction, prognosis, treatment, alleviation of disease ,injury or disability. Primarily it is an agent which does not alter or work on  pharmacological, immunological or metabolic systems of human body, but which assists this systems in its function.

Let's look at key points mentioned in EU-MDR for monitoring safety of medical devices (European Union's Medical Device Regulation document).

What is combination product?

21 CFR 3.2 (e) Definitions

(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity

(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device, device and biological, or biological and drug product. [single entity]

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use. [cross-labeled ]

·        1.  Reporting post market surveillance of serious incidents and field safety corrective actions through the electronic system:            

•  any serious incident involving devices made available in EU, except expected side-effects which are clearly documented in the product information and quantified in the technical documentation
•  any field safety corrective action in respect of devices made available in EU (includes actions from third country if the reason for the field safety corrective action is not limited to the device made available in the third country).
• All serious related incidents no later than 15 days after MAH (Marketing Authorisation Holder*) become aware of the incident.
• All serious related incident which pose serious public threat no later than 2 days after MAH become aware of the incident.
• Serious related death incident, no later than 10 days after MAH become aware of the incident.
• Inform field safety corrective actions in same timeframe as above before implementing them except in case of urgency when it can be notified after implementing.
• Serious incidents and field safety corrective action which are identified and documented or a implemented and are common they may be submitted as periodic summary reports instead of individual serious incident reports, after consultation with the competent authorities.

HiHighlight:       

      MDRs are required when a manufacturer (or representative) becomes aware of information that reasonably suggests that their marketed medical device has or may have caused or contributed to a death, serious injury, or has malfunctioned and likely to cause or contribute to a death or serious injury if malfunction were to recur.

MDR Report Requirements:

5-Day MDR Report, described in 21 CFR 803.53(a), which requires a MDR to be filed no later than five business days following the occurrence of an event that necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health

30-Day Device Malfunction Report, described in 21 CFR 803.20(b)(3)(ii), which must be filed no later than 30 days after receipt of a report of the malfunction of a device; this requirement applies only to certain permanently implantable, life-supporting or life-sustaining  medical devices

 

2.  Recording and reporting of adverse events that occur during clinical investigations:

             The sponsor shall fully record all of the following:

• adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation;
• any serious adverse event;
• any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate;
•  any new findings in relation to any event referred above.

3. Other documents required:

• Post market surveillance plan (PMCF) is necessary except for custom-made device and is part of technical documentation.
• Clinical evaluation report is required
• PSUR required for class IIa, class IIb and class III devices. For class IIb and class III devices update the PSUR at least annually. For class IIa devices update the PSUR when necessary and at least every two years. For class III devices or implantable devices, submit PSURs as specificed with other assessment documentation during registration. For devices other than mentioned, PSURs should be made available upon request of competent authorities (CA).
• Trend analysis is required: any statistically significant increase in frequency or severity of non serious or listed side effects that can alter benefit-risk analysis. The MAH should inform such to competent authorities and also mention how to manage it.
•   Field safety notices: Report containing UDI,SRN and field safety corrective action prepared by MAH and submitted to HCP and users after approval form CA.
• RMP ( risk management plan) for each device is required.
• For implantable devices and for class III devices, other than custom-made or investigational devices, the manufacturer shall draw up a summary of safety and clinical performance (equivalent to SmPC) to the public via Eudamed. This document should have UDI-DI and SRN if available other content remains same as of SmPC for drugs. This document should be made available on Eudamed (European database on medical devices).
• .   * Also include manufacturer/distributors.

4. Terminologies and requirements:

•   Having a Unique Device Identification (UDI) system in place which allows to trace the device throughout the system.The UDI shall be used for reporting serious incidents and field safety corrective actions .
•    SRN (Single Registration Number) generated from electronic database by Competent Authority  while registering device for MAH
• Eudamed is used for maintaining registration, manufacturer details,clinical investigation,certificates,pharmaocivgilance etc by Member States, notified bodies, economic operators and sponsor.
• ‘incident’ means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect
• ‘serious incident’ means any incident that directly or indirectly led, might have led or might lead to any of the following:

  (a)the death of a patient, user or other person,

 (b)the temporary or permanent serious deterioration of a patient's, user's or other person's state of health,

(c)a serious public health threat;

(d) any of the above

5.   Regulatory representative:

•   a diploma, certificate or other evidence of formal qualification in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices;
•   four years of professional experience in regulatory affairs or in quality management systems relating to medical devices.
•   at least two years of professional experience within a relevant field of manufacturing.
•   Micro and small companies do need to have this person within their organisation but have a person on contract permanently and continuously at their disposal.

References:

https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0745&from=IT#d1e1058-1-1

Written by:

Dr.shraddha Bhange.

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

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