A new perspective essay, published in PLOS Medicine, proposes an improved method for governmental agencies to regulate drug authorization. The essay’s authors describe a number of problems arising from the current relationship between regulatory bodies—specifically the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA)—and the business interests that sponsor drug development.
They note inconsistent guidelines used by the health authorities and a lack of transparency from the pharmaceutical industry. The essay describes an alternative route for drug approval designed specifically to address such issues, utilizing the “registered report” publishing format grounded in open science principles. The researchers, led by Florian Naudet, a psychiatrist and researcher at the Université de Rennes 1, state:
“Systematic investigations demonstrate that approvals based on weak and limited evidence are the rule rather than the exception.”
Aside from the inherent problems of potentially inefficacious or even unsafe drugs getting to the market, the authors of the perspective essay point out that when these kinds of issues occur often, it damages public confidence in medicine more broadly. This is particularly pressing at the current moment; as against the rule described above, the researchers write, “there are notable instances where approval was based on strong evidence, such as the recent case of Coronavirus Disease 2019 (COVID-19) vaccines.” Questionable practices by drug regulators and developers can deteriorate trust in all medical products, regardless of how legitimately the authorization process functions in any particular case.
Oversight during the drug approval process is largely in the hands of the developers. As the researchers write: “When requesting marketing authorization for their drug products, pharmaceutical companies are allowed to choose the indication, design the trials, and choose assessments.”
In other words, the businesses build their own tests for their own products. This can lead to numerous issues with clinical trials, like control groups being given a placebo, even when treatment-as-usual is already far superior. Drug companies also retain power over reporting, meaning unfavorable results may be spun for publication or even omitted.
The primary change recommended in the essay is a shift to the “registered reports” model for peer review and publication. In the status quo, advisory committees assembled by regulatory bodies only review research near the end of the process, essentially forming a single gatekeeper immediately before authorization.
With registered reports, an earlier round of review would take place after the study design but prior to actual clinical trials. At this stage of review, the researchers explain, “health authorities would be required, a priori, to pose research questions that matter (in terms of patients, interventions, comparator, outcome, and study design) and define adequate criteria for success, with no possibility of bending the rules after data collection.”
If a proposed registered drug approval program passed this initial stage of peer review, the developers would be authorized to proceed with clinical trials as usual. Following the trial period, the second round of review would occur at the normal time (after completing all trials and data analysis, but immediately preceding authorization). However, with registered reporting, this set of reviewers will be able to refer to the proposed methods and criteria for success articulated in the earlier round. The assessments will thus be placed in the hands of the regulators rather than designed by the drug companies.
A second, likely more contentious suggestion by the researchers is for all resultant data to be shared via clinical trial registries, which they say “are in a privileged position to expand toward incorporating more comprehensive open science tools empowering Findability, Accessibility, Interoperability, and Reusability (FAIR) access to any study-related data.” They propose uploading information obtained in all drug trial research, regardless of final approval by the regulators, in full transparency.
To foster such a huge shift in practice, the researchers note the ideal would be international encouragement to adopt registered reports and share data on clinical trial registries. But, of course, the researchers are fully aware of the pushback these changes would face. Beyond the lobbying of legislators, they explain, “because much agency funding comes from drug company user fees, sponsors may be reluctant to lose control over the process by which trial results, which they have long regarded as ‘trade secrets,’ are disseminated.”
Recognizing that pharmaceutical companies are highly motivated by their bottom line, the researchers suggest the registered reporting method could start off as optional, being incentivized by the streamlining of authorizations across all collaborating national agencies. The researchers also add, “A more important incentive is that approval via this pathway honors the ethical duty of all stakeholders toward trial participants who altruistically put themselves at risk and can hence strengthen trust in science.” These incentives could provide a competitive advantage in marketing, offsetting any costs to adhere to stricter standards in the drug development process.
The new pathway proposed in the perspective essay would yield more consistency from governmental regulatory bodies and greater transparency from the pharmaceutical industry. If the barriers to implementation can be overcome, the use of registered reporting would ensure drug authorization would take all evidence into account and would be based on assessments created through peer review by regulators rather than formed by the same businesses developing the drugs. Gradually, this transparent process may also help to rebuild public trust in medicine.
Naudet, F., Siebert, M., Boussageon, R., Cristea, I. A., & Turner, E. H. (2021). An open science pathway for drug marketing authorization—Registered drug approval. PLoS Med 18(8): e1003726. https://doi.org/10.1371/journal.pmed.1003726 (Link)
Undermining by Pharma or by the Drug Regulators themselves?
It may be a bit of both. From my interpretation of the article, the researchers were pointing out loopholes exploited by Pharma. However, it could certainly be added that the regulators undermine their own stated purposes by allowing these practices to continue.
Thank you for reading!
Ben: If the intersections between the interests you have are variable, then how can one expect the consistency of purpose to become stable? One may even presume that an area is weak, when in fact the space may be learning, powering up, so to speak, to go and attempt to engage the mindset held? Then if a government, empowered by the rule of law, how to foster a space for healing?
To think of the issue at an international level from a neuro perspective surely will flesh out some questions that help develop new nerve cells, perhaps yet identified? Or at least recharging the old?
Pharmaceutical companies have to follow a protocol that they submit to the FDA. This protocol is reviewed by the agency and by an Institutional Review Board, which is supposed to protect study participants. The drug company and the FDA collaborate on many aspects of the study.
Yet the drug companies still sometimes get approval for drugs that are poorly conducted. My question is will adding another layer of reviewers to what is already an extensive process really lead to better trials?
I agree that making trial data accessible is a good idea, but that it probably won’t happen. Nonetheless, the information already available in published studies often gives us enough information to see whether the trials are well done. Often it’s obvious they’re not.
I also think the public is generally unaware of the limited effectiveness of many of the drugs they take. I don’t think some people’s reluctance to get a COVID vaccine is because of a mistrust of medicine in general.
While any reform that might result in more safe and effective drugs getting approved and used and fewer (or no) unsafe and ineffective drugs getting approved and used would be valuable, this whole topic is virtually meaningless without looking at the larger context.
First, we have drug companies and others turning “medicine” into a profit-making profession instead of a healing profession. As long as that situation continues, what chance does an individual have of getting better when they go to a doctor?
Second, we have “doctors” who focus entirely on bodies, leaving out all other relevant factors, of which there are many. When someone gets hurt or sick they should get an ethics interview to see if they are connected to a suppressive person (such as a doctor!). The current system will never stomach that much emphasis on actually getting well!
Being a corrupt government official has become the norm, as has the practice of bribing or blackmailing government officials. In such a degraded moral climate, how can we expect any of these parties to actually care about those who approach them seeking help?
People involved in medicine (“body health”) or psychiatry (“mental health”) are in a perfect position to see that these systems don’t work and need to be changed. But they are in a terrible position to have any real concept of how much change is needed. And so “reforms” never are enough to bring real change.
The concept of “open science” is a bold new idea already being applied in some other areas of study. But if Science never opens itself up to the areas it should study but has chosen to neglect, then nothing much will come of this concept. You don’t effect change by looking at the situation from the same viewpoint that resulted in the problem in the first place. These people need a whole new viewpoint on what science should be and how life really works.
What is being proposed is a small but important tweak to what currently occurs.
Presently, these things are typically discussed at an end of phase II meeting. Plus there may be special protocol assessments.
Any agreements regarding the trials must be reduced to writing, included in the approval package released by the FDA and may only be changed with regards to the size or design of the trial but not other aspects by the division director and only if justified.
One thing that is understood and is included in the law on accelerated approval is that the any differences must be “clinically meaningful”. In other words a statistically significant improvement is not good enough for you can always get a statistically significant improvement if you enroll enough people but that doesn’t mean it means anything.
Examples of this are with depression where in the past changes in the HAM-D not only had to be statistically different from placebo but also had to reach a value of 12 and be a 50% decrease from baseline.
For mania this would be a difference of 4 on the YMRS, a difference of 2 simply isn’t good enough to make a practical difference.
So even though these were kind of understood in the past and were done much of the time, I see no problem in making it a requirement. To avoid the times where there’s a problem, e.g. Aduhelm and Exondys 51.
Higher standards would be an improvement, in that fewer truly useless drugs will get to market. But it doesn’t really address the fundamental problem in psychiatry, namely that we are dealing with subjective phenomena and pretending that we can objectively “diagnose” something that has no objective reality in the physical universe. So if we say the HAM-D scores need to be a 50% decrease from baseline, there is nothing to stop investigators from diddling with the data to create the apparency that there is such an improvement. There is also the problem of “negative” studies being buried and only the “positive” studies being published. This is, of course, anti-scientific in so many ways, including the idea that a study that proves a drug ineffective is “negative.” We SHOULD be after objective evidence, not a particular “positive” outcome. But that’s just the starter. The whole system is so corrupted, it’s hard to know what can be done to fix it.
I greatly appreciate all the thoughts on this report! Thanks to everyone. Overall, the biggest thread I’m picking up is everybody’s frustration with this struggle between reform and revolution. I wrote my MA thesis on drug policy reform, so I’m right there with you all. I’m ready for an overhaul that brings about justice and ethical treatment for users of mental health services, and drugs in general. But I’m equally hopeful about any reforms along the way that may help improve lives. For instance, I keep hoping the current administration pulls through on earlier promises to release all federal prisons with non-violent marijuana charges and expunging their records. So, while I understand it won’t be the solution to everything, I do think registered reporting would be a step in the right direction.