Back ground

Comparators are an integral part of product development process in pharmaceutical / Biologic industry

Comparator sourcing has become an “Achilles Heel” in the product development process off lately. As competition to develop bio-similar has increased, so has the demand for Comparators increased

History of Clinical trails / product development process is full of stories about trails getting stuck, delayed, abandoned due to non-availability of comparators.

Regulatory Senario

Regulators, National Health Authorities (NHA) and CROs are equally to be blamed for current confusion in comparator sourcing.

At the core of Comparator sourcing are two words with different interpretations which lead to confusion and cost escalation “Sourced” and “Licensed”

Difference between “Sourced” and “Licensed”

Terms used in guidelines issued by NHAs are “Sourced” from SRA (Stringent Regulatory Authority) markets. These are defined as North America, EU, Australia, Japan, South Africa. For the purpose of this white paper we will refer to US / EU as SRA countries

While the CRO industry interprets Sourced as Licensed in SRA.

Since comparator sourcing is largely an outsourced activity done by CROs, the sponsor is unable to pass on industry specific knowledge such as the ‘product registration’ or CTD dossiers or the role of CPP or CoPP (Certificate of Pharmaceutical Product) in registration of product in RoW (Rest of the World) countries.

The words “Sourced” is often confused with “Licensed” in the clinical trial industry.

Sourced can mean manufactured or Originates in SRA country.

While licensed means for sale in the pharmacies of a particular SRA country.

In order to explain this difference better, lets consider the following example for Rituximab.

Rituximab is manufactured by Roche Diagnostics in Germany and sold in Global markets including India under various brands by Hoffman LA Roche.

In the EU it’s marketed as MabThera, while in India it’s Ristova

Now in order for Roche to sell it’s product in India it will have to undergo a process called “Product registration”.

Product registration is a process followed by NHAs to obtain all Administrative, Non Clinical, Clinical and CMC details about the company and product before granting marketing authorisation for a product.

These registration requirements are commonly called CTD dossier. A CTD dossier normally has 5 modules

Module 1 – General Information:

One of the requirement of this module is for certificate called: CPP

CPP is a certificate developed under WHO Certification scheme in 1975 and most recently revised in 1997.

Detailed information can be read here :http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/guidelines/en/CPP

requirement as adopted by Indian CDSCO here : http://www.cdsco.nic.in/writereaddata/Guidance%20documents.pdf


CPP is a mandatory certificate for all CTD dossiers and is taken as a proof of QSE (Quality, Safety and Efficacy) of the product and also as an evidence of GMP.

In case CPP is missing, the manufacturer has to undertake Clinical validation, Safety, Efficacy studies in destination market as well as the manufacturing facility will have to be inspected by the inspectors form the NHA in order to obtain marketing authorisation.

CPP ensures that the product being registered in RoW markets is same in QSE as the one in Origin.

Once the regulator of importing country is satisfied that product being offered is same in Origin and destination a Marketing authorisation is granted.

Commercial Facts:

A comparator licensed in SRA country is not going to add any value to the development process but only add cost.

For Example : Cost of Rituximab 500mg in Germany is about 2900 Euros while in India it’s 1100 Euros.

For a Bio similar development where comparator cost constitutes over 30% of the cost, this can mean considerable cost savings and shorter time to market due to ease of availability of comparators from RoW markets as compared to SRA markets.

What the regulators are looking for in product development process is Comparators “Sourced” or Manufactured in SRA countries, so that the Bio similar that is developed too is of highest SIMILARITY.

CROs drafting protocols should be careful while interpreting the terms such as “Sourced” and “Licensed”.

So is there any difference in drugs “Sourced” from Germany as compared to “Licensed” in Germany.

Answer : No and Yes

NO : The registration process involving CTD dossiers are pretty cumbersome and thorough.

The process is designed to pick out variations and differences and every document has to be Legalised, Notarised, Apostile, etc….

Any variations results in deficiencies letters, rejection or even inspections. Manufacturers are very careful to avoid these and follow a principle of One product One Dossier world wide.


A product licensed in SRA will be a country specific pack.

The pack will be in local language – for the example used above it will be a German pack

Will carry the German PZN number and any warning or specific instructions mandated by German regulator at the time of granting Marketing authorisation.

Advantages of sourcing from RoW markets.

Key advantages :

  1. Price : Pharma majors follow a differential pricing strategy in SRA and RoW markets – this can be used to the advantage of the developer
  2. Quantity : Quantities of 500s, 1000s etc… are easily available in RoW markets such as India as compared to SRA markets due to more controlled supply chain in SRA countries.
  3. Batches : Multiple batches / Single batches – what ever the requirement, it’s easier to meet them from RoW markets as compared to SRA markets.

The difference between Sourced and Licensed is now clear.

“Sourced” can be manufactured in SRA country but also sold in other RoW markets – it does not loose it’s QSE or GMP parameters merely by the fact that it’s sold in RoW markets.

To reach those RoW marketed the product sourced in SRA has undergone a thorough administrative scrutiny to ensure that product is same in Origin and Destination.

While Licensed is a country specific pack, meant for a A particular market.


Such as counterfeit, GDP compliance etc… can be effectively addressed by working with WHO cGDSP certified wholesalers such as GNH India, who are among very few from India to be certified by SGS France for their WHO cGSDP practise.


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