Clinical trial labels and worldwide regulatory requirements

Clinical and regulatory professionals are closely watching EU Clinical Trial Regulation (EU-CTR) No 536/2014. This regulation was approved in April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. The application of the Regulation will occur in May 2016, depending on timely development of the required IT by the EMA.

Important topic for labeling professionals is the content of the labeling of the Investigational Medicinal Product (IMP) provided in EU CTR 536/2014 annex VI.

This regulation introduces new term Auxiliary Medicinal Products (AMP) instead of Non Investigational Medicinal Products (NIMP) and also explains authorized and unauthorized AMP. Labeling requirements for unauthorized AMP are also given in the regulation.

The correct labeling of an IMP or clinical trial label is an important and integral part of the conduct of a clinical trial. The labeling has implications not only for the safety and protection of the subjects but also for the identification, traceability and adequate use of the IMP as well as the identification and proper documentation of the clinical trial. Regulatory requirements provide guidance and added value with respect to these purposes.

So what it takes to review labeling contents against regulatory guideline and local requirements?

Is it just to compare labeling contents versus list of requirements in guideline? And mark the contents which are not added per guideline? There is more to it......like review storage conditions per regional requirements, check format of the sentence which gives critical information to patients and review standard term usage of dosage form to mention a few.

Before regulatory review, one need to confirm if the trial is blinded or open; If the primary and secondary packaging intended to remain together and whether product will be or not be taken home by the subject. Based on the confirmations reviewer amends the contents.

Sometimes guidelines just give general direction, for example it states “Particulars should appear in the official language(s) of the country”. If the country has more than one official language it becomes tricky in terms of compliance with regulations and requires local demographic understanding, clinical trial requirements knowledge to reach the conclusion.

Local best practices and requirements are again reviewer need to be updated with. Sometime local requirements do not have a foundation of a guideline but do follow some best practices. Like in some Latin American countries it is recommended to mention on label the term “Not for sale”.

IMP labeling is complex and companies need to face wide range of requirements. They include regulatory compliance, regional language and a quick and efficient manner to avoid disturbance to supply chain network. 

If you would like to avail our regulatory services on IMP labeling reviews for worldwide markets please contact us on suprabhanaralkar@iregconsulting.com

By: Suprabha Naralkar, Prinipal Consultant,   iReg Consulting LLP - See more at: http://regaffairspro.blogspot.in/

From XEVPRM to IDMP.......................................a lot to comply

On 15 December 2010, the European Parliament issued Regulation No 1235/2010 amending earlier regulations 726/2004 and 1394/2007. Although this regulation focused on pharmacovigilance, it also directed to set up and maintain a list of all medicinal products for human use authorized in the EU and to comply with this regulation in 2012. The regulation itself did not include any mandate about the format which needed to be used and the EMA decided to use the Article 57 format or eXtended EudraVigilance Product Report Message (XEVPRM) format to store date in Extended EudraVigilance Medicinal Product Dictionary (XEVMPD).  

On June 19, 2012 Regulation (EU) No 520/2012 was issued, specifically stating reference to the ISO norms 11615, 11616, 11238, 11239 and 11240 as the terminology to be used for communication of pharmacovigilance and medicinal product information. The implementation stated from July 1, 2016.  This is how; ISO Identification of Medicinal Product (IDMP) put forward as regulatory framework.

In light of the above developments, the current Art57/XEVPRM format will be replaced with the formats, terminologies and standards as defined by the ISO IDMP standards.

ISO IDMP Standard was developed in response to a worldwide demand for internationally harmonized specifications for Medicinal Products.

IDMP is a key regulatory framework that developed under the umbrella of the ISO organization. European region is the only one mandating compliance with IDMP at this point of time but once the IDMP standards get adopted across different regions, it will enable consistent data entry, thereby providing regulators the means to compare data across regions for consistency, particularly in the case of global companies.

These standards include a variety of regulatory activities related to development, registration and life cycle management of medicinal products, as well as pharmacovigilance and risk management.

So how XEVPRM works?

XEVPRM is based on XML files.  Basically your software will gather together all your product licence information and any related data about organisations etc, put it into XML format, and create a ZIP file from it, along with any documents that are also required. You will then send this file to the EMA. EMA will process this file per their rules and review and update their database with your valid information and generate EV codes for the new records. Then it will create an acknowledgement file that will say which data it found to be valid and which is invalid. Finally it sends the file back to you. Your software will then read this file and use it to update your database with the EV Codes that it has allocated to your data.

IDMP will also require software implementation but it is far more comprehensive than XEVPRM. Comparative analysis of IDMP requirements Vs. XEVMPD given below shows IDMP is a far more broad set of standards vs. XEVMPD.

XEVMPD	IDMP	IDMP data Source
Medicinal product	Medicinal product	Regulatory Knowledge, RIM System
Regulated document	Regulated document Version	Regulatory Knowledge, RIM, ERP Systems
Medicinal Product name	Medicinal Product name Country/language	Regulatory Knowledge, RIM System
Medicinal product classification	Medicinal product classification Manufacturer/Establishment Marketing authorization holder Manufacturing operation Medicine regulatory agency	Regulatory Knowledge, RIM System
Marketing authorization Marketing authorization procedure Marketing authorization application	Marketing authorization Marketing authorization procedure Marketing authorization application Marketing status PSUR	Regulatory Knowledge, RIM System
Packaged medicinal product Device	Packaged medicinal product Device Device batch identification Batch identifier Shelf life/storage Device nomenclature Package Container Package component Manufactured item Other characteristic Physical characteristics Device batch identification	Labeling/ERP Systems
Pharmaceutical product Route of administration	Pharmaceutical product Route of administration Pharmaceutical product characteristics PHPID set	Regulatory Knowledge, RIM System
Specified substance Reference strength Ingredients Strength Substance	Specified substance Reference strength Ingredients Strength Substance	CTD Module 3, Quality Systems
Clinical particulars Therapeutic indication	Clinical particulars Therapeutic indication Undesirable effects Contraindication Interaction Interactant Population specifics Other therapy Specifics	Regulatory Knowledge, Labeling, Pharmacovigilance, Clinical
New requirement Scope expanded Same

Reference to above table, data will exist in multiple places; some of it will be in the supply chain system, and some of it will have to be gathered from clinical documentation and the regulatory submission information. All that data will have to be extracted and made ready for IDMP. To comply with the IDMP standards; companies will need to do data assessment, Preparation to meet the gaps, software selection and implementation of the system.

The EMA expects to have draft guidance in June 2015.

Personalized medicines

Illumina MiSeqDx …there is a lot of excitement among physicians and researchers about this medical device clearance by US FDA. This is a compact DNA sequencer …..And has the potential to make the personalized medicines a reality.

The DNA sequencers will enable physicians to take a comprehensive look at a patient’s genetic blueprint to search for a wide range of variations or changes that increase risk of disease, drive the disease process, and/or affect response to medications and other treatments. Such information has the potential to benefit patients in many ways.

Personalized medicines - “A form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease.” – National Cancer Institute, NIH

The concept of personalized medicines is not new as over the period it is been observed that patients can respond to various medicines very differently. Throughout history, the practice of medicine has largely been reactive. Even today, we have to wait until the onset of diseases and then try to treat or cure them. And because we don’t fully understand the genetic and environmental factors that cause major diseases such as cancer,  our efforts to treat them are often imprecise, unpredictable and ineffective.

Personalized medicines involve uses of two medical products – a diagnostic device and a therapeutic product. For example, an oncologist might use results of a sequencing scan to choose the chemotherapy drug that is most likely to work. 

Unique genome details, RNA sequencing which provides information about alternative gene spliced transcripts, post-transcriptional modifications, gene fusion, mutations and changes in gene expression are some evolving technologies show a silver line for personalization of medicines.

Personalized medicine may change future healthcare cost and patient care in several ways like, shift the emphasis in medicine from reaction to prevention; predict susceptibility to disease, improve disease detection, preempt disease progression; customize disease-prevention strategies; prescribe more effective drugs  and avoid prescribing drugs with predictable side effects; reduce the time, cost, and failure rate of pharmaceutical clinical trials, and eliminate trial-and-error inefficiencies.

For example, the drug, Ivacaftor is for the patients with a specific genetic mutation which causes Cystic fibrosis (CF) – a disease that impairs lungs and digestive system.  Ivacaftor works by helping to restore the function of the protein that is made by the mutated gene. It allows a proper flow of salt and water on the surface of the lungs and helps prevent the buildup of sticky mucus that occurs in patients with CF and can lead to life-threatening lung infections and digestive problems. There are hundreds of known mutations that can lead to CF and out of that Ivacaftor targets one such mutation in patients…so there is lot to achieve on this pathway…

Adaptive Licensing

In the month of March the European Medicines Agency (EMA) launched its adaptive licensing pilot project.

So what is Adaptive licensing...

Adaptive licensing is a new approach to licensing medicines, which is still in the early stages of development. In this model, licensing is based on stepwise learning under conditions of acknowledged uncertainty, data and regulatory evaluation. This is in contrast to traditional drug-licensing approaches, where an experimental therapy is transformed into a fully evaluated therapy at the moment of licensing.

The adaptive licensing approach, sometimes called staggered approval or progressive licensing, is aimed at improving timely access for patients to new medicines especially when there are no satisfactory alternative therapies. Adaptive licensing builds on existing regulatory processes and intends to extend the use of elements that are already in place, including scientific advice, centralised compassionate use, the conditional marketing authorisation mechanism (for medicines addressing life-threatening conditions), patients’ registries and pharmacovigilance tools that allow collection of real-life data and development of risk management plans. Ongoing medicine development programmes submitted by companies should be experimental medicines in the early stage of clinical development, i.e., prior to the initiation of confirmatory studies.

This approach could allow approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions.

AL will take into consideration impressive preliminary animal/human data; positive benefit risk; commitment of sponsor to conduct further studies after initial MA; adequate infrastructure to observe AL etc. Thus AL is designed to manage the entire life span of a drug, during which data continue to be generated on the product through various ways, including active surveillance and additional studies after initial and “full” licensing.

Refer below link for more information.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/03/news_detail_002046.jsp&mid=WC0b01ac058004d5c1

 

First medicine on Castleman disease a rare disorder gets EMA approval

Castleman’s disease is an uncommon lymphoproliferative disorder that may be localized to a single lymph node (unicentric) or occur systemically (multicentric). It is a non-cancerous growth of the lymph nodes and related tissues, but it is associated with a higher risk of a type of cancer called lymphoma.

Affected patients have an increased risk of infection, kidney failure and certain cancers. Castleman’s disease is life threatening, especially for patients with more than one affected lymph node. The most common Symptoms are high fevers, anemia, weight loss, loss of appetite, and low white blood cell counts, which may to be due to the overproduction of interleukin 6.

Sylvant (siltuximab), a medicine for the treatment of adult patients with multicentric Castleman’s disease who are HIV negative and human herpesvirus‑8 (HHV‑8) negative have received European Medicines Agency (EMA) recommendation for MAA under orphan legislation. The active substance of Sylvant is siltuximab, a human‑mouse chimeric monoclonal antibody that specifically binds to and neutralizes human IL-6 with high affinity.

There are currently no medicinal products authorized in the European Union (EU) for the treatment of Castleman’s disease. In clinical trials, Sylvant has shown its ability to reduce tumour burden and improve the symptoms of the disease with a safety profile.

The CHMP opinion on Sylvant will now be sent to the European Commission for adoption of a decision on an EU-wide marketing-authorization.

For more details refer http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/03/news_detail_002048.jsp&mid=WC0b01ac058004d5c1

 

The tough road ahead for Biosimilars or follow-on-biologics

I may call it a coincidence...that on women’s day I am posting this blog about a drug on breast cancer. I was just assessing the regulatory perception of the news and its relevance to the women in India...oh but before that let’s get to the core news.

On 5 February, Delhi high court restricted Biocon and Mylan from claiming similarity to the Roche breast cancer drug HERCEPTIN® in India.

The new biosimilar product was to be launched under the trade name Hertraz by Mylan and as CANMAb by Biocon in early 2014 under co exclusive rights for the product in India.

Biocon and Mylan have challenged Roche’s contention, insisting that the package insert is duly approved by the drug authority. The approval of what is essentially a generic version of the targeted drug came three months after Roche's patent on HERCEPTIN® expired in India.

Significance of the approval was that it was the first biosimilar trastuzumab to be accorded regulatory approval.

Monoclonal antibodies (MABs) currently represent the fastest growing segment within the biopharmaceutical industry. Biosimilar manufacturers face many challenges considering the complicated structure and larger size of MABs. Moreover, this market is dominated by leading players and making market entry a difficult plan for biosimilar manufacturers. Regulatory Authority’s concern about transparency and safety with patients are also likely to be critical in a competitive and dynamic environment.

 In addition to the above challenges currently an issue on International Non-proprietary names (INN’s) is fetching attention on international platform.  Under the WHO's current INN policy, nonglycosylated biosimilar receive the same INN as the reference drug, as they're considered highly similar. But glycosylated biosimilar, considered comparable but distinct, get a suffix – such as alpha or beta – added to the INN.

 Debate is on whether Biosimilars should be treated as unique products with uniquely distinguishable International Non-proprietary names. Generic drug makers that are getting into the market want Biosimilars treated as generics, which means they would have the same INN as the reference product. But companies with extensive experience in developing biologics think distinguishable names are necessary because no two biologics are expected to be identical.

Future of biosimilar of HERCEPTIN® in India is unknown yet, but the importance of the fact that an access to affordable and safe medicines to women in India cannot be ignored.

E-cigarettes will not be controlled as medicinal products in Europe

On 8 October 2013, European Parliament adopted anti-smoking bill but refused to control e-cigarettes as medicinal products.

Electronic cigarettes will therefore continue to be available in tobacco shops or specialist stores, with the exception of any brands claiming curative properties. They will also be banned for sale to minors and no advertising allowed.

The parliament’s vote will set the stage for negotiations with the EU’s member states over final legislation.

Refer following links for more information.

http://www.europarl.europa.eu/plenary/en/texts-adopted.html

http://www.eubusiness.com/news-eu/health-tobacco-law.qse