ABSTRACT
Obtaining marketing authorizations (MAs) for drugs in the Latin American (LATAM) countries is very country specific. Organizations must chart out a successful global regulatory strategy to understand the pharmaceutical regulatory environment in LATAM in order to address complex and evolving ad-hoc requests from reviewers in a bid to avoid expensive delays for local product launches.

From a global perspective, the commercial significance of markets is increasing and it is
imperative for the pharmaceutical industry to cope with the regulatory requirements to ensure their place in the market. The registration dossier has quality, safety and efficacy data, which holds significant importance.

The International Conference on Harmonisation’s (ICH) Common Technical Document (CTD) can serve as a resource for most local MA applications. In addition, a large amount of mandatory and highly country-specific documentation (related to infrastructure, legal documents, stability studies, labeling, etc.) requires strategic planning and allocation for timely local approvals. Organizations can face challenges owing to identification of actual requirements due to frequent changes in regulations, unclear expectations, etc.

The pharmaceutical industry will benefit if they have clear visibility of the country-specific requirements and health authorities (HAs) expectations in LATAM and also improve their planning activities when submitting the global MA applications. This will also help in managing internal expectations and offer patients in the region faster access to therapies.

INTRODUCTION
The LATAM pharmaceuticals market has seen a phenomenal rise over the last decade and has been mostly dominated by European and US-based multinational companies who have found a fertile ground here. This has also led to growth of local drug regulations due to the rapid introduction of high-technology medicines into import, export and distribution networks. It has also become critical for each HA to guarantee medicines reaching local patients are in compliance with specific standards of quality, safety and efficacy.

Each LATAM HA has strengthened its health legislation which is a continuous evolving process; however variation in drug registration processes causes time-consuming and costly obstacles for companies. The article tries to focus on MAs for prescription drugs (including biologics/biotech). Latin American countries must harmonize their basic vocabulary on pharmaceutical products and reach agreement on the technical procedures needed to ensure the quality of multisource products.

LATAM PHARMACEUTICAL MARKET
As of May 2012, Latin America has a market size of $66bn and it is extremely difficult to penetrate the pharmaceutical market. To gain momentum in these markets it is important to address different regulations between countries in the region and the various components required to register a product from country to country.

Adaptation and Growth
Emerging markets have long served as low cost manufacturing destinations pharmaceutical companies who pay low wages to manpower and less stringent adherence to environmental, health and safety regulations. Countries in emerging markets are now taking steps to adapt their regulations to compete with highly regulated markets like the EU and the US. Brazil and Mexico are spearheading this growth which has given impetus to countries in Latin America to establish their place in the market.

Location
All the LATAM countries put together have a population of 582.5 million and they constitute Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama in Central America; Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela in South America.

More than 20 countries and territories including Aruba, the Bahamas, Cuba, the Dominican Republic, Haiti, Jamaica and Trinidad and Tobago. The first language of most Latin Americans is Spanish, except Brazil where Portuguese is spoken. There is a marked diversity of influences and also the politics to a certain extent contribute to the HAs’ idiosyncrasies.

Pharmaceutical Trends: Growing Domain of Generics Market
Branded and unbranded generics are expected to grow faster than patent protected and non-protected branded drugs. Pharmaceutical sales in the areas of vaccines, oncology, high cost medicines, biologicals and rare diseases are rising fast. There is an increasing demand for drugs; urging the region to increase drug access in spite of intensifying cost containment measures. There is also an emergence of a new biosimilars market offering opportunities and consistent regulatory challenge for biopharmaceutical producers in many LATAM markets.

Pharmaceutical Market Overview
Brazil, Mexico, Argentina and Colombia are considered as the top Latin American economies and pharmaceutical powers. As a pharmaceutical market overview, Latin American sales in 2011 were at $62.9 bn (Source: WHO 2012). Latin America also faces westernized health risk trends such as hypertension, obesity, cancer, ischemic heart diseases and diabetes posing challenges to domestic and international pharmaceutical companies catering to these markets. Companies are looking into emerging science, new products and services, shifting demographics, evolving regulations while transformed business models trigger increased stakeholder expectations.

Drug Registration Process: Limitations
LATAM’s drug registration processes are not harmonized. Through the initiative of the Pan American Health Organization (PAHO) via the Pan American Network for Drug Regulatory Harmonization (PANDRH) harmonization efforts have been ongoing for the past fifteen years. Recommendations for a number of key topics (including Pharmacovigilance and pharmacopoeias) were generated by PANDRH to strengthen local HAs and regional regulatory harmonization however each
country has its own unique regulatory requirements.

There are also country specific challenges to pharmaceutical companies seeking market penetration in the region as there is no regional “CTD” application. Each MA application must be planned and executed as per requirements of each country’s HA. PAHO has recognized five national reference authorities from Argentina, Brazil, Colombia, Cuba and Mexico for the LATAM region.

The Term Generic: Different Connotations in Different Countries
The term “generic” means different things between and within countries. Most policy-makers, consumers, and many health professionals use the terms “generic” and similar interchangeably, which is confusing. Brazil has 1033 generic pharmaceuticals while rest of the Latin American countries have few drugs proven to be therapeutically equivalent or interchangeable with the proprietary product.

In Argentina, the term “generic” is used indiscriminately causing confusion. The Minister of Health- Argentina announced an initiative through a resolution 326 and law 25.549 to promote the use of generic drugs, competition and to lower prices, resulting in increased accessibility. However national and provincial medical associations opposed the policy owing to ambiguity of the term “generic” and stated that none of the drugs sold as generic drugs in the country had proven bioequivalence as required by law. The government’s initiative was to explore if expensive branded originals could be replaced with similar drugs, which were offered in markets under branded and International Nonproprietary Names (INN). Medical associations thought that the quality of the similar drugs was questionable and hence opposed the policy.

Classification of Pharmaceutical Products in LATAM Region
Some countries developed a typology that includes three types of drugs: original, similar and generic while others use a binary classification of branded and generic products. The World Health Organization (WHO) has proposed a different typology: single source and multisource pharmaceuticals. Single source pharmaceuticals usually identified with a brand name correspond to the original drugs (usually on-patent). Multisource pharmaceuticals, identified by the INN or by brand names, can be produced by multiple pharmaceutical firms and include drugs that are pharmaceutically equivalent and may or may not be therapeutically equivalent to the original drug.

Merging of the categories of similar drugs and generic drugs offers several advantages. Drug regulatory agencies must check the efficacy of medicines supplied to ensure they are safe. For multisource drugs, currently there is no agreement on the tests that each pharmaceutical product should undergo for it to have met acceptable efficacy and safety standards. For some products it is sufficient to document that the new product is pharmaceutically equivalent to the original drug; in other cases therapeutic equivalence needs to be proven. Clinical trials, in vitro or through pharmacodynamics studies can be used to prove therapeutic equivalence; however this has several implications in terms of costs, technical capacity and time.

Also drug companies opt for lengthy testing if they want to restrain competition while other drug companies who want to expedite availability of cheaper versions of drugs which is sufficient to guarantee efficacy and safety of drugs opt for limited testing. There is also confusion on classification of pharmaceutical products commonly used in Latin America as there is a lack of consensus on classifying these products, across pharmaceutical industry experts. In addition, pharmaceutical industry experts had different interpretations of the word bioequivalence. As of now LATAM countries are trying to reach agreement on the type of tests to be carried out ahead of approval of commercialization of multisource drugs.

Curious Case of Brazil: Difficulties Encountered in Making These Types of Determinations
In September 1999: Resolution number 391 was passed which stated, “Bioequivalence must be proved for a product to be registered as generic.

Modification of Requirement for Proving Bioequivalence
In February 2002: Resolution 10, which mandated creation of a guide to substitute bioequivalence testing with other tests to demonstrate the interchangeability of the new product with reference drug. Resolution 10 included a list of medicines that for safety reasons could not be registered as generic drugs. (Uruguay has a similar list and Colombia is considering adopting one.) In March 2002: Resolution 84 “modified the list of products identified in resolution 10.” Other issues under discussion in Brazil include the determination of the minimum number of volunteers needed to demonstrate bioavailability and bioequivalence in clinical trials.” Furthermore, as there is a lack of consensus on the term “generic”, carrying out comparative cross national studies of generic policies looks impossible.

Drug Registration
Regulatory regime in LATAM countries can be divided into three categories

Time Frame for Product Registration

Conclusion
There are major differences between countries in the LATAM region as there is no centralized or harmonized procedure for drug registration. The LATAM market will continue to be the focus along with other emerging markets as quality requirements and cost of compliance continue to increase globally. Manufacturers continue to seek ways to decrease costs and capitalize as it may lead to partnership opportunities as governments try to increase their local capabilities to decrease healthcare expenditures. The LATAM market is expected to see regional investment and signing of new deals for biologics, high potency, and cytotoxic medications. Foreign market and established players can benefit from developing their manufacturing and expertise in this growing region.

In today’s uncompromising regulatory climate it is imperative for companies to produce accurate scientific, medical and regulatory documents. Regulatory writing- a discipline that evolves with new and updated regulations and guidelines. Medical writers are specialized in writing all kinds of high quality regulatory documents. It must be noted that a single medical writing document is the culmination of many hours of hard work by study teams, and is essential to creating high quality documents. Poorly written regulatory documents may lead to delays in regulatory approval, costing time and money for the sponsor.

It is important that all regulatory documents are presented in a clear and unbiased manner. Regulatory medical writers must adhere to stringent regulatory requirements while keeping in mind the needs, preferences and styles of sponsors/study teams. Regulatory medical writing plays a large role across the evidence generation continuum and also adds a lot of value in the production of clinical trial documentation.

The medical writers can aid in all steps right from protocol development to the submission process. In short regulatory medical writing is of key importance in developing and conveying the strategic message of the data and is an integral part of clinical research. A clinical development program is deemed successful if it has proper documentation of research plans and results.

Regulatory Medical Writing is an activity of writing / communicating clinical and scientific data. The process involves writing regulatory documents like protocol, Clinical Study Report (CSR) narratives, Safety Update Report, Investigator Brochure (IB), Investigational New Drug (IND), New Drug Application (NDA) submissions and other documents as per Common Technical Document (CTD) or eCTD that are submitted to regulatory authorities for approval. It also involves writing commercial documents like abstracts, manuscripts, posters, oral presentations for Congress/ Conferences/ International Meetings, educational slide sets and training modules for medical professionals

Medical Writer: The Importance of Producing High  Quality Documents

Highly skilled medical writers can play a role in every step of the data analysis and document preparation process. A medical writer can efficiently take up the writing tasks from the technical staff and help hasten the document development process. The writer must also ensure that scientific and medical communication materials are clear, concise, scientifically accurate and fully compliant with regulations, industry best practices.
Medical writer needs to produce high quality documents in a short time with respect to the CRO perspective. Client Pharma companies deal with the production and testing of drugs, but presenting this information to the HA is crucial and lies in the hands of the medical writer.

Understanding Client Requirements:
Medical writing projects follow basic end-to-end steps, which typically start off with a kick-off meeting. For large or complicated projects, the internal team should first arrange and meet for the internal kick-off meeting so that the whole team is on the same page when client
introductions are made. This helps every member understand the client requirements, which in turn gives the client the confidence that the team is well organized and understands the project.

The most important fundamental for both the medical writers and the client lies in here, which is the ‘Expectations’. Expectations should be outlined to the extent possible before actual writing is even initiated; which include

•The number of drafts?
• Input the client intends to provide?
• How often will the client provide input?
• Any other specific requirements?
It is also important to discuss with the client, the list of  reviewers from different line functions (i.e. statistician would assist in the statistical part], DMPK expert [Drug Metabolism and Pharmacokinetics, would assist in the PK part; etc.]). The respective timelines should also be discussed with the client.

• Database lock (DBL) point or data cut-off date, as applicable
• Availability of final source documents
• Date by when the client wants the drafts
• Date by when the client wants the final deliverable

Draft Preparation and Significance of Internal Review:

The medical writing team should work within the realistic timelines to ensure that there is no delay from their end at any instance. Usually there are one or two draft deliverables, followed by the final to client deliverable document. Mostly comprehensive templates and the corresponding source documents are provided by the client, after which medical writer needs to add relevant information into the corresponding sections of the working template.
The medical writer must have regulatory knowledge (for example, knowing what information is required in the efficacy section of a Clinical Overview); experience with client preferences (example, (1) for agency submissions, client A prefers that all data is presented individually from all phase 1 studies, not just an overall, pooled phase 1 summary; (2) when target population for a compound is an elderly population, client prefers devoting more text to adverse events that may be especially concerning to an elderly population).

Also, interpretation of the results in the form of tables, listings, figures is a skill and an aspect which needs strong attention to every detail, hence requires the medical writing expertise. In some cases, together with template, the client also provides a model document to ensure the medical writer prepares the working document in line with the model. Any doubts which arise while preparing the draft document should be carefully handled, by initially utilizing the internal experience, best practices, lessons learnt, knowledge sharing etc. It is only then the medical writer should generate the list of queries-to-client. An internal review to improve the quality of document always plays a significant role before the client review wherein it is checked for flow, adherence to client template and relevance of subject matter. Always impose a pre-discussed deadline to schedule a review so as to keep work on track.

Adherence to Style Guide (Client Specific)
It is the medical writer’s job to prepare a clean-read (spell-check, grammar, formatting, accuracy of citations, cross-referencing etc. adhering to the client style guide) deliverable document before sending to the client for  feedback.

Importance of Comment Logs and Client  Review:

The writer must provide comment logs along with drafts which communicates the exact input needed from the client in a systematic manner. Through the addition of client responses to the log, any misunderstood issues if there are any can be quickly cleared ensuring the team and the client are on the same page. A good draft should be so prepared that it may need only minor changes post-review, rather than substantial revision. Scheduling a comments resolution meeting with the client is exceptionally important to discuss ‘Why and Why not’ to address a major comment, in a tricky situation and a consensus is reached.

A medical writer should prepare the minutes-of-meeting (MoM), post-meeting and should circulate among all the participants so that all the members are on the same page of understanding, to keep track of the agreed points in the meeting and for documentation purpose. Comments from multiple client reviewers ‘within’ a single line function should be handled sensitively and thus it is better to initially agree upon, before sending the document for review, as who will provide the comments and who will act a spectator, so that the latter could be marked in CC of the email.

Finalizing Draft and QC Review:

By the final draft, the writer must keep track of multiple versions, consolidate comments and any feedback from the client should be integrated into the document. Before it is delivered, it should also go through a formal  quality control (QC). This is where the entire content is thoroughly checked against sources for accuracy, consistency, completeness; which can be anything from  an email with wording provided by the client, to the number of adverse events provided in client table, to agreed upon responses in a comment log or comment resolution meeting. Documentation of the communication happened throughout the entire writing and reviewing period is
highly important.

Conclusion:
CROs have a wide spectrum of customers who all have different requirements in terms of templates, language, presentation, etc. Such a variety of customers bring diverse indications to work on, whether it is hypertension, Alzheimer’s disease, psoriasis or a vaccine. Medical writers within a CRO can therefore be exposed to a wide variety of documents (and indications) in a short timeframe.

In the end, clients will prefer to work with a CRO that have medical writers who consistently produce high quality documents in the promised time frame. A quality document delivered a week late, does no good to the client. And the converse is also true - A document completed on time, but if it’s less than stellar, then the client may move their business elsewhere. With so many CROs out there, pharmaceutical companies have their pick of medical writers to work with, so the measured index of productivity is to consistently deliver quality documents in a systematic and timely fashion.

• Provide eCTD submissions and publishing services for Europe based, global $15+ Bn, pharmaceutical company
• Undertaking multiple projects pertaining to NeeS and eCTD submissions services for Middle East

LABELING MANAGEMENT SERVICES FOR $2+BN, BIOTECHNOLOGY COMPANY

• Awarded regulatory labeling management services support contract by a US based, global $2+ Bn, biotechnology company
• In-scope activities include development and management of client’s Company Core Data Sheet (CCDS) using Freyr Label, a proprietary CCDS tracking & distribution tool

STRATEGIC REGULATORY SERVICES FOR EUROPE BASED HEALTHCARE COMPANY

• Provide end-to-end regulatory services for a Europe based, fast growing healthcare company
• Regulatory services that include end-to-end product registrations (medical devices, medicinal products and food supplements) in Middle East followed by all GCC countries.
• Undertake QPPV support for medicinal product, variations submissions for medicinal products in Middle East and offshore support for regulatory activities in EU

BUSINESS HIGHLIGHTS

• Reduction of time spent analyzing information
• Identification of competitive advantages in an increasingly complex regulatory landscape
• Enabled the client to plan for multi-country filings, stay ahead of guidelines

BUSINESS IMPERATIVES

• Generation of market and product portfolio specific regulatory intelligence
• Development of a primary intelligence strategy to address key regulatory intelligence questions
• Validate secondary information using first-hand information and generate in-depth insights about recent and upcoming regulations that could potentially impact target product list

CHALLENGES

• Address the Identified gaps obtained through Primary and Secondary sources
• Define a streamlined process for compliance driven regulatory intelligence for multiple parameters in target countries

FREYR SOLUTIONS & SERVICES

• Freyr’s indigenously developed RegInsight tool was customized as per the requirement of the client
• Search was conducted for each and every ingredient
• Trainings were provided on the use of the tool and Adhoc Customizations done to meet individual team requirements
• Brainstormed the client on the requirements to provide inputs to the development team
• All results were reviewed by the team and inputs shared with RA Team to deliver high quality services

CLIENT BENEFITS

• Reduction of time spent analyzing information by starting from one central point
• Identification of competitive advantages in an increasingly complex regulatory landscape for global drug development
• Enabled the client to plan for multi-country filings, stay ahead of guidelines, compare existing and emerging products, identify new indications for client’s product
• Access to safety alerts, Qualitative and Quantitative changes to improve product specifications in different countries

BUSINESS HIGHLIGHTS

• Faster Time to Approval
• Successful ANDA submission within 3 weeks
• Increase in cost benefits by 70%

BUSINESS IMPERATIVES

• The client is engaged in the regulatory approval and commercialization of "super-generic" drugs and "bio similar" biotechnology products.   
• The primary mission is to gain approvals in North America, Latin America and Europe for a significant pipeline of low cost, high quality, life-saving medical products.
• Client was looking for rapid delivery timelines.

CHALLENGES

• Find a reliable partner, who is comfortable working with global / virtual teams, to help with the immediate objective of ANDA submission  
• Ensure that the selected partner has the capabilities to be a long-term strategic Regulatory Submissions entity

FREYR SOLUTION & SERVICES

• Submission roadmap creation
• Granular Document-level publishing
• Report-level Publishing (Clinical Study Reports)
• Submission-level publishing and eCTD XML backbone creation
• Ongoing Life cycle maintenance of Client’s ANDA Application

CLIENT BENEFITS

• Freyr offered a 24 X7, follow-the-sun, global delivery model to address the aggressive timelines
• Successful ANDA submission within 3 weeks
• Cost benefits, upwards of 70%
• Played an important role in accelerating ahead of competition – Faster Time to Approval