How exactly does a medicine get approved? (Part 5 of 5)

Episode 5: The Light At the End of the Tunnel

Here are links to Parts 1, 23, and 4.

Almost there! Almost there!


Pediatric medicine

Finally we arrive at my original intended subject, pediatric medical products. It may seem trite and obvious, but children aren’t little adults. Growing bodies demand adjustable or revisable implants–a daunting issue if it means repeated surgeries. Immature organs sometimes process drugs differently, meaning dosing is not simply a matter of scaling up or down by weight. Rapidly proliferating cells in growing bodies are more sensitive to mitotic disruption, thus chemotherapy agents can offer unique risks. For all these reasons and more, clinical evaluation of a therapy in adults cannot be directly translated to safety and efficacy for children.

For one telling example, consider Reye’s Syndrome. While the exact cause of the condition is still unclear, it seems that childrens’ organs process fatty acids differently from those of adults, and this can be exacerbated by the combination of aspirin and certain viral infections. The resulting syndrome includes swelling of the liver and brain and can be fatal. The condition is virtually unheard of in adults, suggesting a developmental change that protects mature organs from the condition.

Despite these key driving factors, conducting a clinical trial in pediatric populations is far from easy. Children are considered a ‘vulnerable population’ by the Helsinki Accords, primarily because they may not be able to make fully informed decisions about their health and therefore cannot provide informed consent to participate in a clinical study. However most ethicists consider the parents to be somewhat vulnerable as well, as our natural tendency to protect our children can sometimes compromise our decision-making abilities. A convincing charlatan and a desperate parent can make a dangerous combination.

In 2002, the US Congress passed the Best Pharmaceuticals for Children Act, which encouraged voluntary labeling of drugs for pediatric use and allowed the FDA to request studies in certain situations. In 2003, Congress went a step further with the Pediatric Research Equity Act, which authorized the FDA to require evaluation of drug safety and efficacy in pediatric populations. In exchange, FDA could offer an additional six months of market exclusivity to qualifying products. Manufacturers can request an exception from PREA if it would be unfeasible (generally because a product is useless in children due to its design, or the rarity of the condition in children).

Both BPCA and PREA expired on October 1, 2012, and Congress failed to renew either Act. It is difficult to assess whether they had a positive impact upon pediatric health, but it would appear that they incentivized additional scientific study, as evidenced by reports from both the GAO and George Washington University. Both indicate a small but measurable increase in the number of products approved with pediatric data, but neither report clearly differentiates between studies with definitive results versus those with negative or indeterminate findings.

There’s a bit of good news for patients (including children) with rare diseases. If a disease manifests itself fewer than 4,000 Americans per year, a device can qualify for a Humanitarian Device Exemption (HDE), gaining various incentives, grants, and accelerants through the regulatory and development process. Similar Orphan Disease incentives exist for drugs to treat or prevent diseases affecting fewer than 200,000 Americans per year. Some conditions are prevalent in adults but rare in children; as such, targeted therapies can gain HDE or Orphan Disease support for development and commercialization.

Without BPCA and PREA incentives, what happens if a condition doesn’t qualify for HDE or Orphan Disease exemptions? At present, manufacturers can either conduct a study in children or simply ignore those cases and leave the decision up to the caregiver. Unfortunately the return on investment for a pediatric trial is limited, and (understandably) few parents are willing to sign their children up to test an experimental therapy unless the existing options are unacceptable. So few manufacturers opt for that route, and we must frequently rely upon small studies, case reports, and extrapolation from adult studies.


The Future

So where do we go from here? I don’t have any easy answers, but there are some points to consider. Pediatric medical conditions are thankfully rare, but that means that it is difficult to obtain sufficient safety and efficacy data for the current regulatory systems. How can a manufacturer recoup up to a decade of intensive bench research, three to four clinical trials, plus several million dollars in regulatory filing fees when they’re seeking to treat a few dozen children a year?

One option is government subsidization of research and development activities. Various pundits have advocated a shift in research towards universities with commercialization incentives, and a few discoveries have succeeded under this model. However universities–while exceptional at initial discovery–are very poorly positioned to make the investment of time and money required to advance those discoveries beyond the laboratory. The incentives for promotion and tenure, degree conferment, and paper publication are sometimes in direct conflict with the incentives for commercial development.

Another option is to move the barriers for approval. Antibiotics suffer from a similar problem, in that the commercial incentive to develop them is limited. Various authors, including Senator Orrin Hatch of Utah, have proposed creating an alternative pathway for certain drugs. In brief, manufacturers would have to demonstrate safety (Phase I and II trials) prior to commercial launch in a limited population, then conduct very careful monitoring of patients afterwards. The bar for market withdrawal of the product would be lowered such that small but clear evidence of adverse side effects would be enough to shut the product down. This would allow products to get onto market faster and at less cost while still ensuring tight monitoring. The model has currently been proposed for drugs, but if successful it could be extended to devices as well.

As of this writing, the 21st Century Cures Act has moved from committee to the House floor. This bill could substantially overhaul the FDA, including provisions on innovation incentives, novel clinical trial designs (including a version of Senator Hatch’s proposal), accelerated review, and pediatric research (amongst others; for a comprehensive review, see here). The bill was passed by House committee in May, and could come for a floor vote soon (as of June 30, gives it a 53% chance of being enacted); however there is some concern that FDA may currently lack the required funding to implement these changes.

As a final note, next-generation cures will pose yet another challenge. Personalized medicine, combined diagnostic/therapeutics, precision medicine, engineered organs, stem cells, nanomedicine, and other efforts don’t easily fit within the existing framework. We can either wait for the first products to emerge and then build a responsive system, or we can be proactive and develop systems that can accommodate novel products. FDA’s typical response (which I personally received in a conversation on this topic) is, “if they American public wants those changes, they’ll implement them via Congress.”

All we know for certain is that the current model doesn’t work. As I mentioned at the outset, I have focused on the US situation here, but comparable issues arise in virtually every jurisdiction worldwide. Hopefully the future will continue to bring new advances in health for all of us. Meanwhile, arm yourself with knowledge. Understand both the push and pull that simultaneously drives and inhibits innovation. Lobby your government representatives to change policy. Engage in the debate. Healthcare improves when an informed consumer makes intelligent decisions and takes an active role in their treatment.


Topher is a nerd, scientist, bioengineer, photographer, costumer, dog trainer, beer brewer, and a lot of other nouns. He has too many degrees and too many hobbies because it’s all fun and interesting, and … squirrel!

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