Moving forward: biologics and biocomparables in Mexico
Biological drugs and the legislation and regulation surrounding them are topics that have provided more than one headache to governments around the world. If the fight between innovators and generic companies over non-biological medicines has always been more a matter of industrial property, when a biological medicine is involved, regulatory concerns increase the complexity of the debate.
Biological medicines cannot be treated in the same way as non-biological medicines by the domestic health authorities, because the usual standards for safety, efficacy and quality are not suitable for proving that one particular biological medicine is a generic version of another, previously authorised one.
With these problems in mind, each country has been developing its own legislation. In some cases, domestic governments may follow what other countries are doing (the US, the EU, etc), but in the case of Mexico, the government, through the Ministry of Health and COFEPRIS (the department in charge of granting marketing authorisations for new drugs) has chosen the following solution.
A decree was published in October 2011 amending the General Health Law (LGS) and its regulations including new provisions for the approval of biologics and biocomparables. As well as providing definitions for both biological medicines (innovators) and biocomparables (generics), the main implications of the decree can be summarised in the following points:
- A provision stating that Mexico will allow for the approval of follow-ons as ‘biocomparables’, regulated in more detail than before.
- A biocomparable drug usually makes reference to a previously registered innovator drug. If the innovator drug has not been authorised in Mexico, a previously registered biocomparable drug can now be used as a reference. The significance of this provision is that a biocomparable drug can be the first drug of its kind in Mexico, rather than the innovator drug, in the event that a developer delays a request for approval.
- Concerning prescription requirements, a provision now states that prescriptions must contain the international non-proprietary name (INN) of the active ingredient. The commercial name is optional.
- Clinical trials for innovator biological drugs must take place in Mexico in all cases where the drug will be manufactured in Mexico. For drugs manufactured abroad, the Ministry of Health can request that a clinical trial take place in Mexico, when a Biologic Products Committee considers that this step is necessary.
- In the case of the approval of biocomparable drugs, preclinical and clinical trials can be requested by COFEPRIS. The use of the wording ‘can be’, instead of making the provision compulsory, elicited a good number of opinions from the generic medicine industry. Furthermore, the lack of provisions clarifying when and how the preclinical and clinical trials are to be requested is still a topic of discussion.
- The reach of biocomparability clinical trials will now be supported by evidence of the active ingredient characterisation and, as that ingredient characterisation improves, the number of trials required will decrease.
- An eight-year Bolar-type exemption is included concerning requests for approval of biocomparables when an innovator drug is covered by a patent (the Bolar exemption enables the data from studies, tests and trials of the innovator drug to be used in the approval process of biocomparables without this use amounting to patent infringement).
- For non-biological products, a Bolar-type exemption is included in the LGS that provides a three-year window for generic application of medicines protected by a patent. Within this three-year period, applying for a generic will not be considered an infringement, an applicant may obtain marketing authorisation the day aft er the patent/s expire, provided that the rest of the regulatory provisions are met.
- Once an authorisation request for either innovators or biocomparables has been approved by the corresponding committee and submitted, COFEPRIS has a 180-day period to make a decision on the application (it also has the option to issue a single request for additional information, which must be complied with in 100 days from the date of the request).
Upon the expiration of these periods, applications are considered refused unless they have been specifically approved (negativa ficta). Negativa ficta is one of the solutions that the Mexican law provides for particulars when the government is silent to a request. Through this legal method, any particular that does not receive a response from the government may assume that the petition was denied and therefore may appeal before the proper courts.
While this is not the best solution it is clearly a good way to prevent people waiting forever for a decision from an administrative agency.
“THE TESTS FOR SAFETY, EFFICACY AND QUALITY MUST BE MADE BY AN AUTHORISED THIRD PARTY RESEARCH CENTRE IN ORDER TO GET A MARKETING AUTHORISATION FOR A BIOCOMPARABLE MEDICINE.”
Under the above scenario, and considering the lack of a proper regulation for the process and requirements to be met in order to obtain marketing authorisation for biological drugs and biocomparables, a second round of legislation was made by the Mexican government.
On September 20, 2012, the Ministry of Health published the Emergency Mexican Official Standard NOM-EM-001-SSA1-2012, with the intention of having at least a provisional regulatory instrument, establishing the characteristics and/or specifications for biological and biocomparables products and processes when these may present a risk to the safety of people or damage to human health.
The Ministry of Health established a six-month period for this regulation to be in force until a definitive regulation is enacted.
The emergency regulation established so-called ‘good manufacturing practices’, technical and scientific characteristics to be met by biological drugs and their biopharmaceuticals, to demonstrate their safety, efficacy and quality. Likewise, the requirements to carry out biocompatibility and pharmacovigilance studies were included in this regulation.
It is worth noting that due to the circumstances that motivated the issue of the emergency regulation, in March 2013 the Ministry of Health considered it necessary to publish an extension notice for the regulation of six months.
Also, during 2012, COFEPRIS issued two different guidelines in regard to this matter:
- A requirement for acknowledgement of stability studies conducted abroad regarding biological and biocomparables import medicines; and
- Guidelines for biocomparable medicines.
In the guidelines, COFEPRIS set forth some other rules that said medicines must comply with when seeking marketing approval, including that the tests for safety, efficacy and quality must be made by an authorised third party research centre in order to get a marketing authorisation for a biocomparable medicine.
In the Mexican system, as in many other countries, laws and in particular federal laws provide only general provisions in regard to all the matters that are to be regulated. These provisions are usually completed by the regulations of the law, and finally by rules that are made by the agency in charge of applying the law’s provisions.
Therefore in Mexico, biological and biocomparable medicines now have a general regulation, that it is integrated in the four-level legislation system mentioned above. However, this framework is not yet complete and the way in which it is implemented raises some questions and concerns.
In fact, there is a bill pending with the Mexican Congress to include a new provision, Article 222 bis of the LGS. That bill is focused on solving problems related to the non-interchangeability (substitution) of biological drugs in the health sector and thereby improving pharmacovigilance programmes for medications.
Furthermore, the bill is designed to meet the constitutional objectives related to the public purchase of goods on the best terms of pricing and quality for the public health system.
The regulatory framework related to the purchase of drugs includes provision in the regulations that govern the Coordinating Commission for Negotiation the Price of Medicines. This agreement was modified through the Federation’s official Gazette dated August 23, 2012, including, among other provisions, the negotiation of prices of products when there is only one offered or with regard to those which have no technically reasonable substitutes, mentioning biological products specifically as they cannot be interchangeable due to their nature.
Another bill currently under discussion in the Health Commission of the Mexican Congress seeks to have electronic control of all medicines in Mexico, including a two-dimensional code and some colour-labelling provisions for different medicines.
This bill also seeks to treat as a felony the sale of expired medicines. In summary, biocomparable medicines are among the hottest topics in regard to life sciences legislation in Mexico. Although some provisions have been enacted, there are many things left to do and many of these are currently under discussion in the industry and the government.
Daniel Sánchez is a partner at Olivares & Cia. He can be contacted at: dsb@olivares.com.mx
Victor Ramirez is an associate at Olivares & Cia. He can be contacted at: vrl@olivares.com.mx
