A somewhat controversial new law was passed by Congress and signed by the President in late 2016 known as “The 21st Century Cures Act.” It runs some 314 pages in the Congressional Record. It is still being analyzed and there is much in it on efficacy, technology, devices and more. It makes significant changes in drug and device regulation with a time frame running five years and longer.
There are many, many other sections in this act and they have been nicely summarized by many other groups and firms. See, for example, the 3 summaries on the excellent FDA Law Blog from the firm of Hyman, Phelps & McNamara, PC at:
Their summary of the changes regarding devices can be found here.
Here are some of my comments on drug safety (DS) and pharmacovigilance (PV).
Drug Safety Surveillance
What there is very little of is drug safety surveillance. In fact, the safety part is on page 106 in its entirety:
There is another brief reference on page 138 encouraging the use of high tech for drug safety surveillance.
The section copied from the Federal Register is not interpretable as published. So, here’s what the actual changes will now read as best I can tell. This is the section from 21USC355(k)(5) as referenced above.
(5) The Secretary shall—
(A) conduct regular, bi-weekly screening screenings of the Adverse Event Reporting System database and post a quarterly report on the Adverse Event Reporting System Web site of any new safety information or potential signal of a serious risk identified by Adverse Event Reporting System within the last quarter;
(B) report to Congress not later than 2 years after September 27, 2007, on procedures and processes of the Food and Drug Administration for addressing ongoing post market safety issues identified by the Office of Surveillance and Epidemiology and how recommendations of the Office of Surveillance and Epidemiology are handled within the agency; and
Alas, I tried to find the referenced 21USC355 amended section 2074 and failed. I tried multiple Google searches and could not locate the changed section with the appendix of the act or elsewhere. Nonetheless, the intent of the CURES act here is to make sure that whatever the amended section calls for will be published on the internet including “guidelines, developed with input from experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that detail best practices for drug safety surveillance for drugs using the Adverse Event Reporting System and make available the criteria for posting of AE signals.”
(C) on an annual basis, review the entire backlog of postmarket safety commitments to determine which commitments require revision or should be eliminated, report to the Congress on these determinations, and assign start dates and estimated completion dates for such commitments.
(D) preparing, by 18 months and making publicly available on the Internet website established under paragraph (1) best practices for drug safety surveillance activities under this section or under section 351 of the Public Health Services Act after approval of a drug or after use of the drug by 10,000 individuals, whichever is later, a summary analysis of the adverse drug reaction reports received for the drug, including identification of any new risks not previously identified, potential new risks, or known risks reported in unusual number;
As best I can tell that’s it on DS and PV! Minor changes in drug safety. Perhaps there is more in the CURES act but someone else will have to try to find it!
Comment: As you can see from the above the wording of the law is incredibly non-user friendly and one must go into the Food Drug and Cosmetic Act to try to figure out what these changes actually mean and how the new section of the FDC Act will read.
Other Sections & Their Implications for DS & PV
The basic goal of the entire act is to get important drugs that have shown some level of effectiveness/efficacy to market more rapidly. The act aims to have FDA and the public find more innovative ways to study drugs and obtain information in ways other than the classic clinical trial methodology. The act puts in new requirements for “patient-focused drug development”.
FDA is given up to 5 years to issue guidances on methodological approaches for collection of patient experience data throughout the drug development process to help in submissions and for benefit-risk evaluations. FDA is also directed to establish a process for the development and use of new drug development “tools” including biomarkers and clinical outcome measures.
There are requirements for new methods for drug development of rare diseases and orphan drugs. There are also provisions for FDA to make drugs more available during development under expanded access policies.
There are provisions for better access to “regenerative advanced therapies” (e.g. cell therapies, therapeutic tissue engineering products, human cell and tissue products and more).
There are requirements for antimicrobial (antibiotic) development allowing a “limited population pathway” in which FDA may approve a critically needed drug even if “there is a lack of evidence to fully establish a favorable benefit-risk profile in a broader patient population”.
So what are the implications of all of this?
First, the basic goal is to make needed drugs and devices available to the public more quickly. This, of necessity, means fewer studies, clinical trials and real-life experience in humans before approval. The data may now come largely from small groups of patients stricken with a particular disease. There may be little information about use of such drugs in the general population with this disease or in patients with other diseases. There is the implication and stated goal that much more data will now need to be derived after marketing or after the drug is made available to the public.
To me, the critical issue here is that such expanded and compassionate use will be based primarily on efficacy criteria. There will be less safety data. One can argue whether biomarkers rather than outcomes are sufficient or appropriate as parameters for drug approval. Benefit-risk analyses will be harder to do with less data. But this is the wave of the future and we will see drugs made available to the public based on limited efficacy data and minimal safety data.
This is the critical issue in terms of safety: there will be less and less safety data on drugs approved or made available by these alternate mechanisms.
It is well known that even fairly large sized NDA/BLA submissions with thousands of patients are inadequate to determine the safety profile of the drugs. Even in today’s world of controlled trials, rare serious adverse events are not be picked up in the clinical trials and are only discovered over many years time after marketing. FDA has shown that safety label changes are made for the most part during the first 7-10 years after marketing but important safety issues are sometimes found many decades later. The safety profile of a drug is never “completed” though it gets more and more solid over the years.
We will now see drugs approved where the benefit-risk evaluation is weak on the risk side. There is nothing necessarily wrong with this so long as we understand and accept that there will be serious and even fatal AEs occurring since the safety profile is less understood when patients start using the drug.
This has large implications for the world of DS and PV. Some questions then:
- Will FDA require tighter safety reporting of expanded access and early use of drugs which are approved or made available by these alternate means?
- Since there is a call for more access to data, more transparency and internet access, how will this be done? Will patients’ information be made available broadly? Will patients be able to check an internet site weekly or so to see how this new drug they’re using is being experienced by other patients?
- What will be the mechanism and threshold to make changes in patient use such as dose or scheduling changes, withdrawal etc? And how will it be done? Will all patients be kept in a registry?
- Will the clinical trial safety data be made more available for all drugs, not just these alternate pathway drugs? Will this data be put into FAERS or elsewhere? Will it be user-friendly?
- How will signals be tracked? How will the benefit-risk evaluations be done? And by whom? What will be published on the FDA’s website as well as sponsors’ websites? What about use outside the USA?
- How will benefit-risk evaluations be done by companies? What will happen if the sponsor feels the risk is too high but FDA and the public disagree? Will companies be obliged to use these new routes to approval even if they do not want to?
- Will PADERs and DSURs be altered to accommodate this? Will new reports be required?
- How will prescribers be “qualified” to prescribe the drug? Will there be limitations on who can prescribe and requirements for registration of the prescribers and patients with tracking of safety data?” If a patient is refused use, can he/she appeal? Will we see social media petitions and outcries?
- Will insurers cover the drugs? What will the malpractice and litigation implications be?
- What will happen when the first “disaster” occurs? When several patients die early and quickly on a minimally tested drug?
This is a fascinating and, in many ways, commendable approach to alter classic drug and device development to get, hopefully, needed drugs to market for very ill patients more quickly. There are both more benefits and more risks. FDA, the companies, the medical world and the public though will need to come to terms with the very serious implications of getting drugs with much less safety information to very ill patients.
