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.