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A new survey of 55 biotech and pharmaceutical firms in both the North American and European markets by Premier Research reveals that the biggest problem those companies are facing in complying with pediatric regulations is that there may not be enough children who are both accessible and can meet often stringent study criteria to participate in the required clinical trials.
The survey also reveals confusion with the pediatric trial rules as well as a lack of awareness and understanding by biopharma companies about the extent to which regulatory agencies in the United States and Europe are willing to amend or revise obligations on compliance issues and timing.
North American survey results
Patient recruitment is number one concern in Pediatric Research Equity Act studies
Premier Research, a global contract research organization (CRO) which works with biotech, pharmaceutical, and medical device corporations, reported that nearly three-quarters (72%) of survey respondents in the United States feel that identifying a sufficient number of pediatric patients for PREA* studies is a major challenge.
Nearly six in 10 (56%) said pediatric patient recruitment is the number one area where they need help from a CRO in satisfying PREA requirements. "The FDA recognizes that it can be difficult to recruit kids," Premier Research VP, Regulatory Affairs and Pediatric Consulting Charli Sanders, MD, said, adding that the agency is receptive to tools like population pharmacokinetic modeling and extrapolation of information from adult studies to help fill in the gaps. In the right hands, she noted, existing research tools and data can sometimes be used to modify a PREA requirement.
"Studying drugs in children is a scientifically demanding task," said Sanders, who is also a practicing pediatrician. "As much as pediatric studies have helped, the reality is that they're harder to conduct than adult studies. Indeed, children's hospitals and care facilities as well as clinical practices are being bombarded in the search for pediatric patients to join these studies. It's really challenging."
For many, filing tax return is less confusing than PREA
Respondents said they found complying with PREA rules to be confusing—so much so that one in four (26%) said that dealing with federal tax returns is less confusing than dealing with PREA.
The survey indicated that two in 10 (17%) do not understand the regulations for pediatric clinical trials at all. Six in 10 (59%) said they only "somewhat understand" PREA. One in 10 (10%) have never even heard of PREA, which has been on the books since 2003 and is up for renewal this November.
"Many companies are in a quandary about PREA," Sanders said. "Our survey shows that fewer than two in ten fully understand the rules. Many are seeking outside expertise on PREA. In terms of modifying PREA obligations on behalf of biopharma firms, we're one of the few who have experience in guiding companies through the process."
"Preventative consultation' is key to managing PREA
While two-thirds of the respondents already work closely with the FDA for PREA, about one-third (34%) either did not know how to conduct a PREA compliance discussion with the FDA or were not aware that there may be room to amend or revise their PREA obligation.
"For that expressed reason, we recommend an initial consultation that often will include a clinical feasibility analysis of the product as it relates to children," Sanders said. "When appropriate, it also may be helpful to invest in pediatric pharmacometric work up front that could potentially eliminate the need for more expensive and elaborate clinical trials down the line. This is particularly valuable if the simulations offered can demonstrate to the regulatory authority's satisfaction that a larger trial is not necessary. Call it 'preventative consultation.'"
About four in 10 (39%) strongly or fairly strongly believe that the method for securing PREA waivers or deferrals should be easier. Some six in 10 (61%) strongly or fairly strongly felt that simplifying the rules would improve companies' understanding of PREA rules. Nearly two in 10 (17%) strongly or fairly strongly believed that the enforcement process could be a lot clearer.
Sanders added that to build its preventative consultation practice, Premier Research works closely with pharmacometric statisticians, who contribute a skill set that few other CROs can offer.
Ironically, about four in 10 (36%) said complying with PREA is only a moderately high priority, while one in 10 (12%) admitted that it is a relatively low priority. Only half (52%) said it is a high priority.
Companies outsourcing PREA compliance to CROs
Nearly all respondents (92%) said that having an independent analysis of their PREA obligation by a firm that specializes in dealing with PREA could save time and money and might result in the granting of an exemption.
About seven in 10 (67%) have either had to hire outside consultants or more staff to handle PREA's complex regulatory requirements. Nevertheless, three in 10 (31%) said that PREA has not caused them to change anything. Almost none (6%) have dropped a drug trial because of the PREA expense.
PREA causing R&D budgets to spike
"What most companies don't want to hear about PREA compliance is that you cannot start a pediatric clinical trial soon enough," Sanders said. "Studies take time. And they cost money—there is 'sticker shock.' Around 1990 you could do a pediatric study for perhaps $3 million. Today, that same study, updated to include all the necessary medical and HIPAA compliance, risk management, ethics and data review board oversight, pharmacovigilance, and GCP-related components, might come in just under $20 million."
Half (52%) of survey respondent said they have had to increase their R&D budgets because of PREA requirements. Only 23% thought that slashing the cost of running pediatric clinical trials was highly important.
When it comes to protecting investments in drug patents, six in 10 (60%) strongly or fairly strongly said there should be a longer extension of patent exclusivity.
European survey results
Survey results from biopharmaceutical companies that operate in Europe were similar to the results from the US respondents when it came to the issue of finding an adequate number of pediatric patients.
More than seven in 10 (73%) feel strongly that finding enough children to participate in trials is a problem.
In fact, nearly six in 10 (56%) identified pediatric patient recruitment as the number one area where they needed help from a CRO in satisfying the Paediatric Regulation's PIP requirements.
Confusion around pediatric clinical trial rules mirrors United States
About two in 10 (21%) do not understand the European Medicines Agency (EMA) regulations for pediatric trials at all. About six in 10 (55%) said they only "somewhat understand" PIP. Finally, 6% have never even heard of PIP.
Fewer than two in 10 (18%) said they fully understand PIP.
Premier Research Executive Director of European Regulatory Affairs Susan Bhatti, PhD, noted that, "Development of a sound strategy for PIP is vital, but for many companies it is also a huge burden in the drug development process," she said. "That is why working with a CRO that knows the process intimately and can offer expert guidance, including a deep understanding of how to effectively work with the Paediatric Committee, is becoming the norm."
While two-thirds of the respondents already work closely with the EMA on PIP issues, about one-third (34%) either did not know how to conduct a PIP compliance discussion with the Pediatric Committee or PDCO or Bhatti noted, were not even aware there was room to modify their PIP if this is properly justified.
Nearly all respondents (90%) say that having an independent analysis of their PIP obligation by a CRO that specializes in dealing with the Pediatric Regulation might well save time and money and, according to Bhatti, help to secure deferrals or waivers for paediatric studies.
About seven in 10 (66%) have either had to hire outside consultants or more staff to handle the Paediatric Regulation's complex regulatory requirements. Nevertheless, roughly three in 10 (35%) said that the Paediatric Regulation has not caused them to change anything.
Companies say rules should be simplified, Clarified
Only about one in 10 (9%) have scaled back new drug development to pay for PIP studies. Half (50%) have had to increase their R&D budgets because of PIP requirements.
About three in 10 (26%) said complying with the Pediatric Regulation is only a moderately high priority, while one in 10 (4%) admitted that it is a relatively low priority. Only half (54%) said it's a high priority.
About seven in 10 (68%) strongly or fairly strongly believed that the method for securing PIP waivers or deferrals should be easier—this is an issue that is far more important in Europe than in the United States.
Seven in 10 (70%) strongly or fairly strongly felt that simplifying the rules would improve companies' understanding of PIP rules. Nearly four in 10 (37%) strongly or fairly strongly believed the enforcement process could be
much clearer—another area of difference with US market rules.
Finally, the same number in Europe as in the United States strongly or fairly strongly believed there should be a longer extension of patent exclusivity.
Editor's Note: The European counterpart to PREA (Pediatric Research Equity Act of 2003) is the aediatric Regulation of 2007, which requires biotech and pharmaceutical companies to submit a Pediatric Investigation Plan, or PIP. Results of the European portion of Premier Research's survey follow the section on North American results.