Pediatric Drug Development
For this lecture we’re g oing to be looking at pediatric drug development. A drug development in pediatrics can be quite challenging due to the unique concerns within this population.
First, let’s define the pediatric population, and this is defined from birth to 16 years. The reason that pediatric drug development can be challenging is that there are fundamental differences between growing and developing children and adults. These include differences to drug response, differences in the toxicity profile, rates of drug development, and also the trials that we do to assess safety and efficacy in children are different. Or the way we design them are different than in adults.
Children are also considered a vulnerable population, and according to ethical codes of conduct we need to protect children. Clinical trials create risk for any subject within the study, however children may be exposed to increased risk just because of their age and developmental status. However, not conducting clinical trials creates risk for all children, because then physicians don’t know how to dose the products.
So, as a result of these challenges, product labeling frequently failed to provide directions for safe and effective use in pediatric patients. This led to a situation where clinicians were either reluctant to provide drugs to pediatric patients because they didn’t know how to dose them correctly, or if they did provide drugs to patients, they were dosed inappropriately because dosing was arbitrarily chosen and selected.
Therefore, need existed for regulations to avoid adverse drug reactions in children, but also to ensure that the doses provided to children were efficacious and that children weren’t being untreated. So as a result, physicians prescribe drugs, usually off-label, for the pediatric population. A result of this was exposing children to drugs that were untested in the pediatric population because they were solely tested at end results. From the perspective of pharmaceutical companies, they’re usually not interested in gaining labeling in children just because it’s a small target population, so there isn’t any great revenue stream there. There’s also concerns about adverse events that could potentially cause issues where the drug, as a whole …
So this was realized within the medical community and within FDA. So FDA made some changes in order to encourage companies to put a pediatric labeling on their products. In 1979, a section was added which required labeling providing direction for pediatric use. And this labeling notified physicians that below a certain age that the safety and efficacy of the drug had not been established in this group of patients. And then in 1994, a regulation required manufacturers of marketed drugs to survey their existing data and determine whether the data was sufficient to support pediatric use. If so, the manufacturers were required to submit a supplement to their license containing that data to change their label. If not, then the manufacturers had to change the label to read safety and effectiveness in pediatric populations has not been established. However, both of these requirements were viewed by industry and the agency as being voluntary. There was not any enforcement mechanism. And because of this viewpoint, they were insufficient to bring about change.
In 1997 the FDA Modernization Act was signed into law. This provided an incentive for manufacturers to change their labeling to include the pediatric population. This provided market exclusivity for an additional six months to manufacturers who voluntarily conducted and submitted to FDA pediatric studies of their drugs. However, this still left significant gaps in obtaining the data for these studies and in changing the labeling.
This is due to the fact that products that did not have specific existing patent or exclusivity protection, this marketing exclusivity couldn’t be prolonged because there wasn’t any protection to prolong. Some drugs were also not included, such as antibiotics and also biological products licensed under the Public Health Service Act. Some manufacturers simply chose not to perform these studies because they had no interest and the exclusivity wasn’t worth it to them. Also, this exclusivity provision could only be used once with respect to an active ingredient.
If additional studies were required, then the exclusivity provision did not kick in so there was no economic incentive. This provision of the Modernization Act expired on January 2002.
In 1999, the Pediatric Rule became effective, and these regulations can be found in 314 for NDAs, and 601 in BLAs. This rule required regulations, or established regulations that required pediatric studies. And these are for products that are likely to be commonly used in children, or that represent a meaningful therapeutic benefit over existing treatments. Marketing applications for new active ingredients, new indications, new dosage forms, new dosage regimens, and new routes of administration have to contain a pediatric assessment, unless a waiver or deferral has been obtained. And this pediatric assessment needs to be conducted through clinical trials.
Manufacturers also get regulatory benefits from the Pediatric Rule in that they receive early consultation with the agency during the investigational study. And it’s also a benefit to the agency, because it provides FDA with the ability to require the development in a pediatric formulation, which is also a challenge when it comes to giving drugs to children, especially oral drugs in that they don’t readily swallow pills. So we need to develop usually liquid formulation for this population.
The Pediatric Rule can also be required for already marketed drugs, and these are drugs that are used in a substantial number of pediatric patients, and where inadequate labeling can pose significant risks, and a substantial number of patients, [inaudible 00:00:28] 50,000 pediatric patients in the United States, with a disease or condition for which the drug is indicated. And these are also in patients that would provide … where the therapy would provide a meaningful benefit over existing treatments, and this means a significant improvement in the treatment, diagnosis, or prevention of disease as compared to a marketed product. The Pediatric Rule, however, doesn’t apply to orphan drugs, and it doesn’t apply to generic drugs.
In 2002, the Best Pharmaceuticals for Children Act was signed into law, and this reauthorized the Exclusivity Incentive Program enacted through the FDA Modernization Act. And this, once again, established a voluntary testing legislative framework. FDA must determine that the pediatric testing provides health benefits to that population in order for the agency to request that this testing be done. If FDA does determine that there’s health benefits, then FDA makes a written request to the manufacturer to conduct the study. The manufacturer then agrees to conduct the study within the appropriate timeframe. And then then manufacturer conducts tests and submits the reports to the FDA. So, there’s a process that needs to be followed here in order for these studies to be conducted.
A best also authorized NIH to fund studies and established a private fund. And it also gave FDA some enforcement ability. If the agency felt that the product needed to be reformulated, for the pediatric population and if labeling changes are needed to be made. And the manufacturer didn’t want to make these changes or to do any reformulation studies. Then the FDA has the ability to take this request to the advisory committee. If the advisor committee agrees with the agency and the manufacturer still refuses, then enforcement action can be taken by the FDA.
Now the downside within this law is that it doesn’t extend to biological products. The awarding of study contracts doesn’t extend to biological products or certain antibiotics. And public funding is dependent on yearly congressional appropriations. Now this was reauthorized in 2007 and this law sunsets in 2012.
In 2002, there was an important court case where the district court for this District of Columbia held that FDA had exceeded its statutory authority when issuing the Pediatric Rule. And the court suspended its implementation and enjoined its enforcement. And once again, we find physicians with those pediatric patients having limited treatment options.
A physician once again had this issue with off-label use and during this court case the plaintiffs argued that FDA does not have the authority to require manufacturers to conduct studies of drugs for uses that they do not intend to seek or devise formulation for these uses.
The court concluded that the legal basis did not exist for the Pediatric Rule and FDA had exceeded their statutory authority. As a result of this court case FDA enacted PREA in 2003 and they codified elements of the suspended Pediatric Rule and attempted to fill the gaps left by the Pediatric Rule suspension. This was retroactive back to 1999 when the Pediatric Rule was first enacted.
However, as we design these studies, we need to take in consideration the specific needs of the population and address any ethical issues in trial design considerations that are unique to pediatric studies.
So let’s get into drug development, and exactly when to conduct pediatric studies, and how to conduct pediatric studies, now that we’ve got all these histories.
So we conduct pediatric studies for life threatening conditions when no adequate treatment is available. And before we conduct these studies, we need to make sure that we have initial safety data. So we first have to study the drug in adults. And these pediatric studies usually begin in phase one or in phase two. So they begin early in drug development, but once you’ve already gone into a first in human study and then adult population. Now for less serious diseases, you may conduct these studies later in drug development.
In some cases, you also may not begin these studies until after approval, due to scientific and ethical issues. And there are certain cases when you may not conduct pediatric studies, where a product has not shown any benefit over an adequately labeled product, or the therapeutic need is low, or where the risk of exposing pediatric patients to a new product may not justify conducting these studies. Or you may conduct them once a safety profile has been well-established in adults, so you may even wait until after your product is well into phase three or already on the market before you conduct these studies.
When one is scoping out their drug development program, one needs to have discussions with the FDA very early on regarding their pediatric indication and regarding the studies. If you’re developing a product for life threatening or severely debilitating illness, then these development plans should be discussed with the agency during the pre-IND meeting.
For other products, these plans should be submitted to the agency at the end of a phase two meeting, prior to going into your pivotal studies in phase three.
Waivers can be granted, FDA can grant either full or partial waivers. If the product does not represent a meaningful, therapeutic benefit over existing treatments and is not likely to be used in a substantial number of pediatric patients, then a full waiver is granted. If the studies are impossible or highly impractical, because there’s a low number of patients or because these patients are geographically dispersed, again, a full waiver can be granted, or if there’s strong evidence that products would be ineffective or unsafe in the pediatric age group. Also, for some diseases we don’t see the diseases in the pediatric population, so of course then you would also not need to conduct clinical trials for patients in the pediatric population.
A partial waiver can also be granted and this is when studies aren’t conducted in specific age groups. So you may conduct studies, for example, in patients 16 years old or older and exclude all patients below the age of 16. Partial waivers are granted using the same sort of thinking as a full waiver and the conditions are when there doesn’t seem to be a meaningful therapeutic benefit over existing treatment, the product is not likely to be used in a substantial number of patients or the studies are impossible or highly impractical, once again, due to the number of patients or because of the disbursement of the patients geographically throughout the US. There’s strong evidence that the product isn’t effective or unsafe in the pediatric age group. But also, if a manufacturer has attempted to develop a pediatric formulation and those attempts have failed. For example, some oral drugs may not dissolve well enough to have a liquid formulation. Therefore, you can receive a partial waiver based on that.
Clinical trials in the pediatric population can also be deferred until after the BLA or NDA has been filed. And, there’s various factors feeding in to this decision. One factor is that agency wants to make sure that the drug approval isn’t held up because you’re doing studies in the pediatric population. So, you don’t want any waiting here or any drugs being held up for patients in need because there isn’t a pediatric label put in place. There’s also the need for the drug, which is a factor in the decision making process. The availability of sufficient safety data to initiate pediatric trials. You may need to wait until after your product is on the market and you’ve got sufficient data in adults before you initiate these studies. There’s also the nature and extent of data to support a pediatric labeling, the existence of substantiated differences in enrolling patients, differences between adults and pediatrics, and also the evidence of technical problems in developing pediatric formulations. It may take longer for you to develop your formulation than you had anticipated.
Now, FDA also has enforcement action that they can take if pediatric studies weren’t conducted. But the drug may be considered to be mis-branded or not approvable. If the drug is mis-branded, the agency can issue an injunction. They can prosecute individuals or they can seize the product and prevent it from being distributed. However, these enforcement actions are only taken in rare cases because the agency doesn’t want to deprive patients of a useful medical product. Any issues that come up in this area can be presented and discussed with the pediatric advisory committee.
Now, the Pediatric Advisory Committee advises and makes recommendations to the Commissioner regarding pediatric research, regarding ethics, and the design and analysis of pediatric therapeutics, labeling disputes, labeling changes, adverse events, et cetera, et cetera.
Other considerations in the design of clinical studies for pediatrics is that your IRB must have pediatric expertise and also that placebo controlled study may be difficult to conduct if their use doesn’t place the pediatric population at increased risk. This is also a challenge to the pediatric … to the conduct of pediatric studies. It may be difficult to conduct a pediatric study using an already marketed product as a comparator because most of the products are labeled for adults and not the pediatric population. So this requires the use of a placebo study or the use of a placebo which can also cause ethical issues to arise when one uses a placebo in a vulnerable population.
The preclinical studies that we do prior to doing a pediatric trial is different from the preclinical studies that we do to support a trial in the adult population because of the development stage of this pediatric population. So, we need to select animals that exhibit the same developmental characteristics as the pediatric population that we’re going to … that we’re going to be studying and using in our clinical study. So, we use young animals to support the preclinical safety evaluation for these studies. And, the focus of the preclinical safety evaluation is on the potential effects of the drug on growth and development. And we only do these studies when we haven’t conducted studies already that can provide support for these clinical studies, or to further investigate issues that have arisen in previous preclinical, or perhaps, our clinical studies.
And these studies may be conducted separately in juvenile animals or one may conduct toxicology studies to support an adult indication but amend the design of that study to include juvenile animals. And when we design these animal studies, we need to ensure that the age of the pediatric population of the clinical study is going to be adequately represented in the developmental stage of the animals. And-
There’s other considerations before we do these studies or in the design of these clinical studies in general. What one consideration is, of course, the intended or likely use of the drug in children. If it’s not going to be used in children, then, of course, we don’t do these studies.
Another is the timing of the dose in relation to phases of growth and development. Animals develop a lot faster than humans, and it’s very important that that dose be given right at the right time or you’re going to miss that window of opportunity.
One also needs to consider the potential differences in pharmacological and toxicological profiles between the mature and immature systems. And also, of course, we always need to consider differences between animals as they are relative to the clinical population and to humans in general.
When we think about the age of the animals to use in these studies, we need to consider, too, that the younger the pediatric population is that we’re going to study in our clinical study, the more dynamic and faster their growth rate is. So we need to make sure that that animal population is adequately represented.
This is a chart looking at the age of various animal models and the development that occurs. And this is used to demonstrate just the age difference, the developmental differences, between these animal models and humans. For example, if you’re doing a clinical study in pediatric population that is entering puberty or within puberty, which is about 11 to 12 years for us humans, then you’re going to be doing your preclinical study in monkeys that are between two and a half and three years old, and dogs that are between six and eight months, or, yeah, eight months of age, and rats that are two to three months old, and in a mouse that’s 35 to 45 days. And then this chart also shows you if you’re doing lung studies what age you’re looking at in rats and mice to be comparable to the human. And also if you’re doing studies looking at for example the growth hormone and looking at growth, which is frequently measured by ossification of the long bones, in this case the femur, then you also have a comparable time to the human and to the animal models.
A lot of ethical issues come up in the design of clinical studies for this population. And, these ethical issues need to be addressed and there’s various ways that we address them. In the composition of the IRB, we ensure that there are members of the IRB who are knowledgeable in the conduct of the pediatric studies, in the development of pediatric patients, in psychological issues, and then of course, in all the ethical issues.
When we recruit patients, we need to be sure that the recruitment process is free from inappropriate inducements. And, these inducements can be not only to the study participant, but also to the parent or legal guardian of that study participant. As with all drugs, or as with all clinical studies, any monetary compensation is reviewed by the IRB and it has to be approved by the IRB. Informed consent can be challenging because the pediatric subject is frequently unable to provide informed consent. So, the consent is obtained from the individual’s parent or a legal guardian. And, this person needs to assume responsibility for the participation in clinical studies.
Participants need to be fully informed to the greatest extent possible about the study in a language that they can understand and in terms that they can also understand. If the participant is of an age where they are intellectually mature, then they should personably sign and date the written informed consent. In all cases, as with all clinical studies, participants should be made aware of the right to decline to participate, or their ability to withdraw from the study at any particular time.
Attention should also be paid to signs of undue distress in these patients because of their age, they may be very young, and they may not be able to clearly articulate their distress as adults do.
Distress of course needs to be minimized in any clinical study. But we do special things to minimize distress in this pediatric population. We should that personnel who are conducting the study have an understanding, and are skilled in dealing with the pediatric population, and their age-appropriate needs.
We do these studies in a comfortable physical setting. And this physical setting includes play equipment, furniture, activities, and food that is appropriate to the age of the subjects.
In order to decrease distress, we also conduct these studies in a familiar environment where participants normally receive their care. So we try not to make a lot of changes. And we take various approaches to minimize discomfort, such as usually using topical anesthesia to place IV catheters, we use the dwelling catheters rather than doing repeated venipunctures for blood sampling. And we try to lessen the number of samples that we take by taking a protocol specific blood samples when routine clinical samples are taken.
So, in summary, developing drugs for pediatrics can be challenging just because pediatric patients are different than adult patients due to the developmental stage that they’re in and the rapid growth that they’re undergoing, and also psychologically. FDA regulations require that pediatric information be included in the drug labeling, and so we need to conduct studies in the pediatric population.
Here’s some references, if you’d like to have, for the reading on the topic.
And if you have any questions please contact me at my email address. Thank you.