Insofar as I have an opinion on politics, I'm against it. Generally it runs in its own noisy part of the world, involves a lot of unnecessary angst and drama, and at the end of the day has little to no influence on my day to day life. It is best ignored. I'll talk about it a little today because it seems likely that some upheaval lies ahead for the regulation of medical development in the US, and by extension that portion of the rest of the world that has outsourced much of its medical regulation to the US. The Department of Government Efficiency and related factions have yet to turn their eyes in earnest to the FDA, but they seem likely to do so.
One old idea that appears ripe for revival is have the FDA cease to require proof of efficacy for new drugs, and only enforce proof of safety before permitting use in the market. By extension, this also implies preventing the FDA from attempts to sabotage the already permitted off-label use of existing approved therapies for new indications. The various payers in the system, everything from medical insurers to individuals, could then make their own decisions as to the proof and standards of efficacy they would like to see upheld before paying for a treatment. It would go back to being a market with a plurality of opinions on any given drug and use case in question, rather than having to accept the dictates of one set of bureaucrats, one size fits all.
One present manifestation of this ethos is the Right to Try law in Montana, which states that any drug that passes a phase 1 safety trial is open for use by any patient - though in practice obtaining that drug would be challenging for any novel therapeutic, requiring cooperation on the part of the developer that the leadership of that company might justifiably view as a risk to their ongoing relationship with the FDA. However, one could envisage a world in which this Right to Try approach effectively becomes federal law in the US, because that is a fairly simple change from the point of view of the executive branch: just alter the way the FDA behaves, and all clinical trial activity beyond phase 1 is optional. At that point, the incentives on developers change considerably, and the complexity thereafter is left to evolve in the market of consumers and payers.
It seems likely that the immediate response of the largest insurance companies and other payers would be along the lines of "great, but keep on running phase II and phase III clinical trials that demonstrate efficacy if you want us to pay for your medicines." I'd expect this to result in only short-term chaos for the network of investments, valuations, and stock prices that depend upon medicine being very expensive to bring to the clinic, and thus only short-term opposition from large investors, pharma entities, and other vested interests with political influence and lobbying capital to spend. After matters settle down to be more or less a continuation of the status quo, at least at first, greater freedom will emerge over time: payers will selectively defect from the consensus regarding standards for efficacy, where they feel it is justified, biotech and pharma companies will gain a much greater freedom to bring new medicine to the market earlier and at a lower cost than would otherwise be the case, and patients would gain the choice of earlier access. All of this is already happening via medical tourism for a small number of people and organizations; adding the option to do this in the US would greatly broaden access.
Another possible path forward is to make the US clinical trial ecosystem look a lot more like that in Australia. This would require more extensive changes to the regulatory system, which may or may not meet with opposition. In Australia there is no central government body akin to the FDA with the role of assessing and approving every phase 1 safety trial. Instead a competing market of specialized clinical sites and institutional review boards exists to assess and approve proposed new drugs and clinical trials, balancing their incentives to receive business versus their incentives to minimize harm to patients. Since something like 10% of all phase 1 trials worldwide are conducted in Australia, at something like half the cost and a fraction of the time required for approval in the US, it is a system that appears to work fairly well. Setting this up in the US would require dismantling regulations applying to institutional review boards and removing the FDA function of up-front vetting and approving of trials. As before, this change would likely produce short-term chaos and scrambling, but if the end goal remained to work towards the same present format of data and reporting that results from clinical trials, then the existing marketplace of contract research organizations (CROs) that run trials and package data would adapt, form standards, and those standards would likely look very much like the present status quo, at least at first. Moving forward, competition and freedom to choose would allow a greater plurality of options to emerge.
A harder and more disruptive change would be to alter the way in which the production of drugs is regulated in order to reduce the costs of compliance. Regulating manufacture under the banner of Good Manufacturing Practice (GMP) is sizable chunk of the work conducted by the FDA, and conforming to FDA requirements on manufacturing processes is certainly a very large slice of the cost and effort required to bring a drug to the clinic. The guidelines put out by the FDA are standard and vague. Every single class of drug has accumulated over years and decades a deep and very detailed culture and tradition of non-public material and experience among consultants and regulators to describe the precise details of an acceptable interpretation of those vague standards. This cannot be discovered without engaging with regulators and consultants at considerable expense. Further, the requirements for GMP manufacture of any given drug class tend to expand over time, as efforts to remove any novel assay or other addition that regulators and consultants have seen used widely will be opposed.
Trying to change GMP requirements runs into a range of problems: firstly, there will be a great deal of political opposition from those who hold the unreasonable fear that any change to GMP regulation will make drugs unsafe; secondly, there will be a great deal of political opposition from large organizations that use the high cost of compliance to reduce competition, the usual problem of regulatory capture; thirdly, the specific interpretations of compliance that have become so very costly have very little do with the published regulations, vary widely by drug type, are very complicated, are are near entirely documented privately, making them hard to target; fourthly, many smaller countries reference US GMP standards and rely upon them to inform their own medical regulation, essential outsourcing that function.
To return to Australia, for example, the consensus that has emerged among institutional review boards, clinical trial running CROs, and clinical sites, is that the drug used in a phase 1 clinical trial should be manufactured to GMP-like quality. What "GMP-like" means in practice is that the FDA has accepted the proposed technical/scientific details of the manufacturing process and quality control assays, the drug batch is manufactured using that process and those assays, but the manufacture is not conducted with the very expensive addition of the full audit trail, checking in triplicate, form-filling, checkboxes, and validation at every step that is required for a process to be GMP grade. In drug manufacture circles this is called an engineering batch, and in present practice is the last full scale non-GMP batch that successfully tests all of the manufacturing processes and passes all of the quality assurance tests. The engineering batch is usually used for toxicity studies in animals that are conducted as a part of submitting an IND proposal to the FDA - except that in Australia one can also use the engineering batch for a phase 1 safety trial in human volunteers.
If engineering batches are safe enough for humans in Australia, why not everywhere else? Why not have the minimum regulated safety requirement for medicines at any stage of approval or commercial use be that manufactured batches be made as if engineering batches? This would reduce manufacture cost by 50% for many drug classes. The batches would still have to pass quality testing that has been reviewed by regulators, institutional review boards, and others. The answer to the question "why not?" is probably that (a) this would be a hard change to make, politically, and (b) while it is easy to state the change in a single sentence, actually wrangling into shape the vague regulations and hidden details of the present state of the art regarding compliance would be challenging.
But it seems likely that we shall see how this all turns out!
View the full article at FightAging
