Pharmalink Consulting - Worldwide Regulatory Affairs

Before we examine the main theme of our latest newsletter, we would like to take this opportunity to thank all of our clients and staff worldwide for your tremendous support throughout 2009 – we really appreciate it. We would also like to wish you all the very best for the coming year.

Regulatory piece

Over-the-Counter (OTC) drug products are an expanding part of the pharmaceutical industry. Between 2004 and 2008 the compound annual growth rate of the global market was 4%. The global OTC market grew at a rate of 3.9% in 2008 to reach a value of $104.2 billion. Supplying a product in an OTC form gives the public greater access and choice in medication for common, minor ailments; this gives the public a greater opportunity for self-diagnosis and treatment resulting in a decreased burden on healthcare providers.

This article gives a comparison of the POM to P switch processes in US and UK.

The US process – an overview

In the US, there are more than 300,000 marketed OTC drug products in over 80 therapeutic categories of OTC drugs. As with prescription drugs, CDER (Center for Drug Evaluation and Research) regulates OTC drugs to ensure that they are properly labeled and their benefits outweigh their risks. Within CDER, the Office of Nonprescription Drug Products reviews OTC drugs primarily. There are 2 different regulatory pathways to file for an OTC drug:

• Legally marketed under a New Drug Application (NDA) or an abbreviated NDA (ANDA). An OTC product new to the marketplace is regulated under the NDA process. [21 CFR 314] and FDA approval is required prior to marketing. An example of this would be a drug previously only available by prescription can be marketed as an OTC product if approved under an “RX-to-OTC switch” NDA. As with any NDA, the application may require clinical studies, a user fee and will require post-approval maintenance. Labeling is unique to the marketed drug. There may be marketing exclusivity.

• Legal marketing is in compliance with an OTC drug monograph. Monographs are based on the active ingredients, as opposed to the NDA, which is based on the drug product. A monograph could be viewed as a “recipe book”. The OTC drug product contains active ingredients that are “generally recognized as safe and effective” (GRASE). Should a drug be marketed under monograph, pre-approval is unnecessary. [21 CFR 330]. If there is no final monograph established for the OTC drug product, then the NDA procedure must be followed. Clinical studies are not required, there is no user free, the labeling is the same for all similar drugs and there is no marketing exclusivity.

The safety and effectiveness standards are the same for OTC products as they are for prescription drugs plus the consumers must be able to self-diagnose, self-treat, and self-manage the condition. To assist consumers’ understanding on the appropriate use of the product, the OTC label has specific standardized requirements on what is required and how this information is to be presented. [21 CFR 201.66] The format of the label is called “Drug Facts”.

The UK process – an overview

In the UK there are three separate legal categories for medicinal products, each successive step signifying an increase in the assurance of patient safety; Prescription Only Medicines (POM) can only be dispensed to patients holding a valid prescription with a registered pharmacist being present on the premises; Pharmacy Only Medication (P) is dispensed at the discretion of the pharmacist depending on each customer; General Sales List (GSL) medication is available to be sold with no pharmacy training required as the product is generally considered safe for most people when taken correctly, this classification is more akin to the OTC status seen in the US..

A drug containing a new active ingredient in the UK is usually, when first authorized, categorized as POM. If, following experience gained during use, it can be demonstrated that the medicine is safe for use with pharmacist supervision and available for sale as category P, further experience may support the progression to GSL status. In the UK, Reclassification of a substance normally follows a request from the company which holds a marketing authorization for it. However, requests can be made by any interested party, such as a professional body, or be initiated by the MHRA.

In the UK, before a drug can be switched from POM to P to GSL, certain criteria must be met for each step downward. For the POM to P step, Ministers must be satisfied that it would be safe to supply the drug without a prescription. This means that the drug no longer meets any of the following criteria (Medicines Act 1968, section 58A):

• Is likely to present a direct or indirect danger to human health, even when used correctly, if used without the supervision of a doctor; or
• Is frequently and to a very wide extent used incorrectly, and as a result is likely to present a direct or indirect danger to human health; or
• Contains substances or preparations of substances of which the activity requires, or the side effects require further investigation; or
• Is normally prescribed by a doctor for parenteral administration (that is, by injection).

A product can only become GSL once the step has already been made to P. Similarly to the POM to P switch, before a medicine can be switched from P to GSL, Ministers must be satisfied that it ‘can with reasonable safety be sold or supplied otherwise than by or under the supervision of a pharmacist’ (Medicines Act 1968, section 51).

Applications to reclassify medicines are evaluated by the MHRA, with advice from a suitable expert committee (currently the Commission on Human Medicines (CHM)), as necessary. Where it is considered that the proposed reclassification may safely be made, wide public consultation, via the MHRA website takes place. Interested organizations will be notified when a new consultation has been added to the website. Responses to the consultation are evaluated by the MHRA and advice is sought from the CHM only if a new safety issue is raised during consultation. Following a successful reclassification proposal, the change of legal status will be conferred on the product that is the subject of the application for switching. All other products with the same active substance will need to make a separate application to follow suit.

There are 3 regulatory pathways in the UK:

COMPLEX PROCEDURE: A major change requiring Committee referral will be allocated to the complex procedure. This process will generally take up to 180 calendar days, not including the consultation. Applications will be assessed by the MHRA Secretariat, and submitted to the relevant committee for consideration. If reclassification is recommended, consultation will take place with interested parties via the MHRA website on a rolling cycle as and when applications are made. Provided that no outstanding issues remain following the consultation procedure, action as in the Standard procedure will be instigated. Notification and opportunity for appeal will be given if reclassification is not recommended.

STANDARD PROCEDURE: A change not requiring Committee referral will be allocated to the Standard procedure. This process will generally take up to 120 calendar days, not including the consultation. Valid applications will be submitted immediately for consultation, via the MHRA website, to interested parties including members of the relevant committees. Interested parties will be notified of new consultations. Applications will only be submitted for formal review by the advisory committee if issues are raised as a result of the consultation process or of the review of the supporting data by the MHRA Secretariat. Members of the relevant committee may also request that the full application be referred to another committee or to the Medicines Commission (MC). Such committee referral will, of necessity, lengthen the time to final determination. The applicant may also be approached for additional information in relation to specific concerns and any such action would again increase the time required to determine the application. Upon determination, the applicant will be informed of the outcome. Favourable decisions on applications will be implemented depending on what type of application was submitted, by including the new legal classification in the grant of the new MA, the renewed MA or the variation to the existing MA. Reclassified products will then be listed in the next available Medicines Act Information Letter (MAIL) and on the MHRA website. In the case of applications not approved, the reasons for the decision will be notified to the applicant who will also receive the assessment report. Applicants will be given the opportunity to appeal by written representation to MC.

Me Too Application: A “me-too” application based on an analogous product, which has already completed the reclassification procedure, may be dealt with simply as a variation. For these purposes, an analogous medicinal product is a medicinal product, which has a United Kingdom marketing authorisation or a Community marketing authorisation and which—

(a) has the same active ingredient, route of administration and use;

(b) has the same strength or a higher strength;

(c) has the same dosage or daily dosage, or a higher dosage or daily dosage; and

(d) is for sale or supply at the same quantity or a greater quantity, as the medicinal product in relation to which the application is made.

Follow on “me too” reclassifications (not supported by full data) for products where an analogous product has already been reclassified are dealt with by the variation procedure. There is no public consultation or referral to the advisory committee for these applications.

Consultation and advice

• Public consultation with interested parties for a 4 or 6 week period (6 weeks for Complex applications) will take place at different points in the two procedures. Consultation will take place immediately in the Standard procedure and will be based on the applicant’s ‘Reclassification Summary’ (see below). In the Complex procedure, public consultation will only take place after the advice of the committee has been sought and they have recommended that reclassification should take place.
• The advisory committee is invited to comment on straightforward (Standard) applications during the public consultation period. Complex applications are submitted for advice in the first instance and released for consultation following positive advice. Standard applications on which issues have been raised in consultation may also require committee advice. There is a right of appeal to the MC on applications refused.

As a more commercially driven product an OTC pack will require a significant re-design from the basic statutory information presented in the POM pack in order to make it attractive to consumers. The Proprietary Association of Great Britain (PAGB) offers a pre-vetting scheme for MAHs looking to update their artwork from prescription to OTC format. This consists of providing the new OTC artwork along with the currently approved POM artwork and a copy of the SmPC. The PAGB will assess the new artwork for consistency with the SmPC and against their code of practice. Once approval is granted it can be used to support expedited MHRA approval by supplying the approval document along with the following statement in the background section of the application form “application submitted for expedited assessment of pack redesign following pre-approval by PAGB”.

Consultants with OTC experience (available in 2010)

US based Senior Regulatory Consultant with Project Management Skills

• Extensive experience in OTC drug regulatory affairs with experience supporting monograph and NDA drugs, dietary supplements and cosmetics.
• Experience with a variety of drug therapeutic categories with focus on upper respiratory.
• Hands-on experience in Rx to OTC switch, NDA’s, sNDA’s, dNDA’s, IND’s and FDA interactions.
• Demonstrates a keen sense of urgency and effectively manages complex situations.
• Worked in the advertising and promotion areas throughout this time.
• Latest role included responsibility for the regulatory support for the growth (novel advertising claims; new product development) and maintenance (advertising; labeling) of two very well known brands post approval. “

UK based Senior Regulatory Consultant with Project Management Skills

• Extensive experience in managing OTC brands for Consumer Healthcare companies including the registration of line extensions and all post approval activities.
• Ability to build key relationships to enable seasonal products to be launched within project deadlines to maximise sales for clients.
• Possesses excellent communication skills in successfully challenging Regulatory Authorities including the PAGB to enable better medicinal claims for products and save costs at manufacturing sites.
• Management of Consumer Healthcare product portfolios at a regional (CEE) and local (UK) level
• Preparation and submission of BROMI and PIQ article 61(1) Variation packages
• Preparation and submission of Abridges Applications in the EU.

UK Based Senior Regulatory Executive

• Project Management and delivery of New Global OTC Product launches and New Dosage forms within a challenging project team
• Post Maintenance of Product licences for both Generics (OTC) and Prescription Only licensed products through the MHRA portal system
• Responsible for dealing with acquisition of products from other manufacturers in order to harmonise product  licences details and information, e.g. Application for change of ownership
• Filing Type I and Type II variations globally for licences granted through national,  MRP and Centralised Procedures
• Reclassification of medicines from POM to P and P to GSL.

Indian Based Senior Regulatory Executive

• EU Variations, renewals and manufacturing site transfers
• Working knowledge of product registrations in regulated and non-regulated market
• Experience in product registration in Europe, CIS countries, Latin America, USA and Asian market and have experience in ANDA, CTD and PIL preparation
• Participation in product registration in Asean CTD and CTD format for European, CIS, Asian countries and South Africa market.

Biologics

Pharmalink organizes training for our staff on a regular basis. A recent training program was a workshop series on biologics
The training course was a 3 day workshop and was divided into three Modules:
Module 1- Biotechnology Products in the Pharmaceutical Industry Market
Module 2 – Manufacturing and testing of biologics
Module 3 – Biosimilars, follow on biologics

As this is such a vast topic we have provided a short basic review of the subject from a US perspective, including what are biologics, an overview of the regulations and development issues that apply to biologics, followed by a few lines on biosimilars.

A US perspective – Overview

Biological products, like other drugs, are used for the treatment, prevention or cure of disease in humans. In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products are generally derived from living material -human, animal, or microorganism, are complex in structure, and thus are usually not fully characterized.
These medications are usually one of three types:
º Substances that are (nearly) identical to the body’s own key signaling proteins, eg the blood-production stimulating protein erythropoetin, or growth-stimulating hormone.
º Monoclonal antibodies. These are similar to the antibodies found in the human immune system, but they are “custom-designed” (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type.

º Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology.
Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.” FDA regulations and policies have established that biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products. Biological products subject to the PHS Act also meet the definition of drugs under the Federal Food, Drug and Cosmetic Act (FDC Act). Hormones such as insulin, glucagon, and human growth hormone are regulated as drugs under the FDC Act, not biological products under the PHS Act.

Development and regulations

Following initial laboratory and animal testing that show that investigational use in humans is reasonably safe, biological products can be studied in clinical trials in humans under an investigational new drug application (IND) in accordance with the regulations at 21 CFR 312. If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted as part of a marketing application. A biologics license application (BLA) is required for biological products subject to licensure under the PHS Act. Like a NDA (New Drug Application) filing for drugs, a 356h form is completed for a BLA submission.

Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product.
Among other things, safety and purity assessments must consider the storage and testing of cell substrates that are often used to manufacture biologics. A potency assay is required due to the complexity and heterogeneity of biologics.
Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product’s safety, identity, purity and potency. Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture. Since there is a significant difference in how biological products are made, the production is monitored by the agency from the early stages to make sure the final product turns out as expected.

The regulations regarding BLAs for therapeutic biological products include 21 CFR 600, 601 and 610.
Biologics are subject to provisions of both the FD&C Act and the PHS Act. Because of the complexity of manufacturing and characterizing a biologic, the PHS Act emphasizes the importance of appropriate manufacturing control for products. The PHS Act provides for a system of controls over all aspects of the manufacturing process. In some cases, manufacturing changes could result in changes to the biological molecule that might not be detected by standard chemical and molecular biology characterization techniques yet could profoundly alter the safety or efficacy profile.

Biosimilars

Biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes, unlike the more common small molecule drugs. The follow-on manufacturer does not have access to the originator’s molecular clone and original cell bank, nor to the exact fermention and purification process. In addition, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that generic versions of biologics might perform differently than the original branded version of the drug. Hence, unlike most drugs, generic versions of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. Notable exceptions include several of the earliest biopharmaceuticals made via recombinant DNA technology, including biosynthetic ‘human’ insulin and human growth hormone, which are grandfathered under the U.S. Federal Food, Drug & Cosmetic Act. By comparison, vaccines and most other biotech drugs are governed under the Public Health Services Act, which would need to be amended by U.S. Congress and signed into law by the President to allow for generics.
In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed “similar biological medicinal products”. This procedure is based on a thorough demonstration of “comparability” of the “similar” product to an existing approved product.

Pharmalink Consultants Available

UK based Biologics Consultant – available to assist you from September 2009. A biotechnology graduate with 8 years experience in Regulatory Affairs and extensive working knowledge of Biosimilar and Biotech products. Having worked on several time and business critical projects, she has assisted in ensuring projects completed on time and below budget. Skills include:- working knowledge of EU procedures ( Centralised, Decentralised, National and MRP) ; PILs and SmPCs; fluent in English, French, Spanish, Catalan, Russian and Arabic.

US based Biologics Consultant – now available to assist you with your BLA and sBLA regulatory needs. Over 7 years experience with biologics. Extensive knowledge of both US and international regulations. In addition has a solid working knowledge of clinical affairs, manufacturing and CMC for products in several therapeutic areas. Worked with products in both the pre-approval and post-approval stage. Based on the East coast and available to work in the US and international locations. Fully bilingual in English and Spanish.

We have recently seen an increase in requests for consulting roles in Asia. We currently have colleagues based in Dubai, Kuala Lumpur and Japan, all working on a large compliance project. In addition several of our projects have required our consultants to work remotely and provide specific regional advice on regulatory requirements for Asian and Latin American countries. If you need assistance with regulatory project work in these regions, please contact:
Asheesh Bhimsaria at our AsiaPac office – +91 22 4030 9595
Kevin O’Toole at our UK office – +44 (0)1628 860300
Stephen Loughrey at our US (New Jersey) office – +1 973 218 2725