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European Pharmaceutical Contractor

Age Concerns

FDA regulation section 505(b)(2), improves the development of paediatric and geriatric drugs, by providing effective and speedy routes to approve new applications for these patient populations.

It comes as no surprise to anyone in the industry that drugs intended for paediatric and geriatric populations are challenging for pharmaceutical companies. For one thing, individuals can only be labelled as paediatric or geriatric for so long, which means the long-term need for these customised dosage forms is limited. For another, niche drugs traditionally cost more to develop. Paediatric clinical trials in particular are more complicated and expensive, typically involving different endpoints and requiring a greater number and diversity of participants, spanning in age from prenatal to late teens. Additionally, clinical trials involving children mean recruiters must essentially enlist up to three people – a child and potentially two guardians – for each available slot.

The challenges of developing drugs for unmet needs in speciality populations involve ethical, logistical and technical considerations. In many cases, developing niche drugs is more complicated and less remunerative, but that doesn’t remove the moral obligation for drug development companies and doctors to provide pharmaceuticals that are safe and effective for both their oldest and youngest patients.

One method that can help meet the demand for drugs specifically formulated and approved for paediatric and geriatric populations – and do so faster and at a lower cost – is an effective regulatory process in the US called 505(b)(2).

The Challenges of Off-Label Prescribing

Only about a third of paediatric prescriptions have adequate labelling information to guide their use, hence off-label use of medicines has become, unfortunately, a necessary part of paediatric medical practice. Off-label prescribing includes the use of drugs for un-approved indications or with a different age group, dosage, frequency or route of administration. It also includes the administration of extemporaneous formulations (such as oral suspensions made from adult tablets) with untested bioavailability and stability.

When no other option is available, paediatricians may prescribe an adult medication to a child by estimating the appropriate dosage and method of administration. On one hand, this offers a treatment to a suffering patient who may have no other option. On the other, it may subject the patient to significant risk, based on approximate calculations about the child’s metabolism and the pharmacokinetics of the drug.

Penicillamine is a good example of a less-than-optimum formulation being prescribed off-label for paediatric use. Penicillamine tablets are large and must be crushed to administer to children, leading to uncertainty of the actual dose delivered. Dosing of penicillamine is also required for extended periods of time, and the crushed tablet is foul-smelling with an unpalatable taste.

A Liquid Solution

One area of particular interest is the reformulation of products into a liquid dosing form. In children, this route of administration provides flexibility to customise the dose, allowing individualised therapy according to the child’s age, weight and specific recommended goal. In geriatric patients, a liquid route of administration can make a real difference for the 15 per cent of seniors who suffer from dysphasia (difficulty swallowing). In addition, because senior patients often require specialised doses of certain medicines, developing a version that can be administered in variable doses is often beneficial.

Overcoming the technical difficulties of formulating some compounds in liquid form can be perplexing, especially when palatability is an objective, but, for many situations and patient populations, a liquid form represents the best and most efficacious treatment. No patient, whatever their age, can be relied upon to maintain a course of medicine they find unpleasant.

How 505(b)(2) Can Help Fill the Gap

Section 505(b)(2) of the US Federal Food, Drug, and Cosmetic Act was established by the Hatch- Waxman Amendments of 1984 to allow sponsors to obtain approval of new drug applications (NDAs) containing investigations of safety and effectiveness that were not conducted by or for the applicant. These investigations can include information for drugs approved by the FDA – or information from any other reliable data source. The section was added to avoid unnecessary duplication of studies already performed; however, sponsors must still provide any additional data necessary to ensure that differences from the reference drug do not compromise safety and effectiveness.

Although it took 20 years to clear all the legal hurdles to make this a viable development strategy, 505(b)(2) today can provide relatively fast approval for a wide range of products, especially for those that represent a limited change from a previously approved drug.

Assuming two of the biggest hurdles to creating drugs to serve paediatric and geriatric populations are development cost and time, 505(b)(2) often offers an optimum solution.

Simplified Testing Requirements

The 505(b)(2) process involves studies of bioavailability and usually only relatively small patient safety and efficacy trials. Because the drug is already known in one population or indication, the clinical testing process is typically shorter and less costly than for a new drug compound. The clinical testing process can be completed in as little as three years after the pre-IND meeting with the FDA.

Applications under 505(b)(2) are for either a new chemical entity/new molecular entity (NCE/NME) or changes to previously approved drugs such as dosage form, strength, route of administration, formulation or dosing regimen. As an additional incentive to pharmaceutical companies, the 505(b) (2) applicant may qualify for three, five or even seven years of market exclusivity, depending on the type of information included in the NDA.

A Significant Marketing Opportunity

By instituting 505(b)(2), the US Congress hoped to increase the number of approved drugs available on the market by easing requirements of the approval process for drugs about which something is already known. Beyond the benefits to society of a greater variety of available drugs, 505(b)(2) represents a substantial marketing opportunity, not only for Big Pharma and existing patent holders, but also for smaller, virtual organisations.

For example, Congress passed the Pediatric Rule in 1999 that states, in part, that each application for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration – even if it is an abbreviated new drug application (ANDA) – has to contain data to establish safety and efficacy among relevant paediatric subpopulations if the drug is appropriate for children. Because there is no requirement to own rights to the adult drug on which a formulation may be based, the 505(b) (2) process presents an opportunity for a smaller pharmaceutical company to repurpose existing drugs to service this more specialised market while enjoying some period of marketing exclusivity.

A Practical Example

Currently, the analgesics used to treat acute pain in children include acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs) and opioids. The analgesic efficacy of acetaminophen and NSAIDs is often inadequate to treat paediatric postoperative pain in cases such as dental extraction, tonsillectomy and adenotonsillectomy. On the other hand, the use of opioid analgesics for postoperative analgesia in children has been shown to significantly increase the time to, and reduce the amount of, pain cessation.

An analgesic for acute pain in children should be available in an oral formulation with high potency, not cause respiratory depression and have a favourable adverse event profile.

Approvals Under 505(b) (2) Growing

Bringing a modified version of an existing drug to market through 505(b)(2), although potentially much faster and less costly than starting with a new compound, is still a demanding process requiring a thorough understanding of the FDA and how it works. However, in the fiscal year 2006, approximately 20 per cent of new drugs were approved through the 505(b)(2) process. Three years later, 50 per cent of the new drugs approved in the US were based on this strategy. Some are predicting that by 2012 this will have increased to 80 per cent. For many products and companies, 505(b)(2) offers a clear path to approval, a differentiated product and some period of marketing exclusivity. The rising tide of drugs approved under this strategy is testament to its growing importance in the drug development market.

Children and the elderly deserve to have drugs that are proven safe and efficacious, in appropriate dosage forms and labelled specifically for their use. The Section 505(b)(2) method provides a pathway to make more and better drugs available more quickly and economically.

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Pete Joiner is CEO of Madeira Therapeutics. With a 30-year history in sales, sales management and marketing for pharmaceutical companies, Pete has launched over 15 major pharmaceutical products. Pete was previously a part of the senior management team at Alliant Pharmaceuticals and has a BEng in Electrical Engineering and an MBA in Industrial Management from the University of Cincinnati. Email:

Ken Phelps is Chief Scientific Officer at Madeira Therapeutics, and President and CEO of Camargo Pharmaceutical Services. Ken used more than 30 years of experience in the health science and services industry to found Camargo in 2003. He is an industry expert in 505(b)(2) FDA submissions and has aided in the successful approval of numerous compounds. Prior to founding Camargo, Phelps held a number of executive level assignments in quality control; project management; and regulatory, clinical and medical affairs at Duramed Pharmaceuticals (now Barr Pharmaceuticals). Ken has a BSc in Chemistry from the University of Nebraska. Email:
Pete Joiner
Ken Phelps
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