FDA drug manufacturing
Shortages of drugs, especially generic injectables, continue to cause significant harm to patients. A new Congressional report offers the best account to date of the shortages and provides details confirming my earlier post. The story in essence is this:
The FDA began to ramp up GMP rules and regulations under the new commissioner in 2010 and 2011 (see figure at left (N.B. this includes all warning letters not just GMP so it is just illustrative, AT added). In fact, the report indicates that FDA threats shut down some 30% of the manufacturing capacity at the big producers of generic injectables. The safety of these lines was not a large problem and could have been handled with a targeted approach but instead the FDA launched a sweep against all the major manufacturers at the same time. These problem have been exacerbated by a change in Medicare reimbursement rules and by the rise of GPOs (buying groups) which reduced the prices of generics. Thus, in response to the cut in capacity, firms have shifted production from less profitable generics to more profitable branded drugs, so we get shortages of generics rather than of branded drugs.
Add to these major factors a few unique events such as the FDA now requiring pre-1938 and pre-62 drugs to go through expensive clinical trials, the slowdown of ANDAs and crazy stuff such as DEA control over pharmaceutical manufacturing and you get very extensive shortages.
WP: Doctors, hospitals and federal regulators are struggling to cope with an unprecedented surge in drug shortages in the United States that is endangering cancer patients, heart attack victims, accident survivors and a host of other ill people.
Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA. The FDA has inadvertently caused drugs long-used in the United States to be withdrawn from the market and its “Good Manufacturing Practice” rules have gummed up the drug production process and raised costs.
Here, for example, is an analysis from the summary report on drug shortages by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP).
Several drug shortages (e.g., concentrated morphine sulfate solution, levothyroxine injection) have been precipitated by actual or anticipated action by the FDA as part of the Unapproved Drugs Initiative, which is designed to increase enforcement against drugs that lack FDA approval to be marketed in the United States. (These drugs are commonly called pre-1938 drugs, referring to their availability prior to passage of the Food, Drug, and Cosmetic Act of that year.) Some participants noted that the cost and complexity of completing a New Drug Application (NDA) for those unapproved drugs is a disincentive for entering or maintaining a market presence. Other regulatory barriers include the time for FDA review of Abbreviated New Drug Applications (ANDA) and supplemental applications, which are required for changes to FDA-approved drug products (e.g., change in source for active pharmaceutical ingredients API, change in manufacturer). Manufacturers described this approval process as lengthy and unpredictable, which limits their ability to develop reliable production schedules.
and on GMP:
Manufacturing-related causes that contribute to drug shortages are multifactorial. Inability to fully comply with GMP, which results in production stoppages or recalls, was considered a major cause.
The Federal Food and Drug Administration (FDA) has been stepping up its quality enforcement efforts — levying fines and forcing manufacturers to retool their facilities both here and abroad. Not only has this more rigorous regulatory oversight slowed down production, the FDA’s “zero tolerance” regime is forcing manufacturers to abide by rules that are rigid, inflexible and unforgiving. For example, a drug manufacturer must get approval for how much of a drug it plans to produce, as well as the timeframe. If a shortage develops (because, say, the FDA shuts down a competitor’s plant), a drug manufacturer cannot increase its output of that drug without another round of approvals. Nor can it alter its timetable production (producing a shortage drug earlier than planned) without FDA approval.
Thus, it’s not any one thing that is causing the shortages but an accumulation of rules and regulations. The system plods along when all is normal, but when a novel situation develops the market can no longer adapt quickly and efficiently. As Michael Mandel puts it:
No single regulation or regulatory activity is going to deter innovation by itself, just like no single pebble is going to affect a stream. But if you throw in enough small pebbles, you can dam up the stream. Similarly, add enough rules, regulations, and requirements, and suddenly innovation begins to look a lot less attractive.
Add to all these pebbles the fact that various price controls have become more binding over time and thus have reduced the profits from being in the business at all and you have a recipe for deadly shortages.
If I understand correctly, a biologic is “any medicinal product manufactured in, extracted from, or semisynthesized from biological sources,” and a biosimilar is a copy of a biologic. Think of a biosimilar as harder to make than a generic drug and also requiring separate FDA approval. Here is Wikipedia:
Unlike the more common small-molecule drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to changes in manufacturing processes. Follow-on manufacturers do not have access to the originator’s molecular clone and original cell bank, nor to the exact fermentation and purification process, nor to the active drug substance. They do have access to the commercialized innovator product.
Here is a Rand piece on the potential cost savings from biosimilars (pdf), but in percentage terms they do not become nearly as cheap as generic drugs, maybe 65-85% of the price of the original.
Zarxio was the first biosimilar approved by the United States, and the global biosimilars market could hit $55 billion by 2020. Here is yesterday’s FT story about biosimilars draining away sales.
Here is a paper by Blackstone and Fuhr:
Various factors, such as safety, pricing, manufacturing, entry barriers, physician acceptance, and marketing, will make the biosimilar market develop different from the generic market. The high cost to enter the market and the size of the biologic drug market make entry attractive but risky.
Will cell therapies, which are relatively new and also hard to copy with biosimilars, save Big Pharma from the forthcoming patent cliff?
There are 11 biologic drugs that will face biosimilar competition in the next several years, according to data compiled by Evercore ISI. These drugs, which treat ailments from cancer to rheumatoid arthritis, raked in more than $50 billion combined in 2014.
The FDA is outlining biosimilar approval pathways, although the issue seems to be receiving almost zero attention from the outside world.
Angell: The question of innovation–you said that some people feel, economists feel, [the FDA] slows up innovation: The drug companies do almost no innovation nowadays. Since the Bayh-Dole Act was enacted in 1980 they don’t have to do any innovation….
Roberts: But let’s just get a couple of facts on the table…[The] research and development budget of the pharmaceutical industry is, in 2009, was about $70 billion. That’s a very large sum of money. Are you suggesting that they don’t do anything–that that’s mostly or all marketing? That they are not trying to discover new applications of the basic research? It seems to me basic research is an important part. Putting that research into a form that can make us healthier seems to be a nontrivial thing. You think they are–what are they doing with that money?
Angell: If you look at the budgets of the major drug companies–just go to their annual reports, their Security and Exchange Commission (SEC) filings, you see that Research and Development (R&D) is really the smallest part of their budget. If you look at the big companies you can divide their budget into 4 big categories. One is R&D, one is marketing and administration; the other is profits, and the other is just the cost of making the pills and putting them in the bottles and distributing them. The smallest of those is R&D.
Notice that Angell first claims the pharmaceutical companies do almost no innovation then, when presented with a figure of $70 billion spent on R&D, she switches to an entirely different and irrelevant claim, namely that spending on marketing is even larger. Apple spends more on marketing than on R&D but this doesn’t make Apple any less innovative. Angell’s idea of splitting up company spending into a “budget” is also deeply confused. The budget metaphor suggests firms choose among R&D, marketing, profits and manufacturing costs just like a household chooses between fine dining or cable TV. In fact, if the marketing budget were cut, revenues would fall. Marketing drives sales and (expected) sales drives R&D. Angell is like the financial expert who recommends that a family save money by selling its car forgetting that without a car it makes it much harder to get to work.
Later Angell tries a third claim namely that pharma companies do no innovation because their R&D budget is mostly spent on clinical trials and, “it’s no secret how to do a clinical trial.” I find this line of reasoning bizarre. I define an innovation as the novel creation of value, in this case the novel creation of valuable knowledge. Is Angell claiming that clinical trials do not provide novel and valuable knowledge? (FYI, I have argued that the FDA is overly safety conscious and requires too many trials but Angell breezily and nastily dismisses this argument). In point of fact, most new chemical entities die in clinical trial because what we thought would work in theory doesn’t work in practice. Moreover, the information generated in the clinical trials feeds back into basic research. Angell’s understanding of innovation is cramped and limited, she thinks it begins and ends with basic science in a university lab. Edison was right, however, when he said that genius is one percent inspiration and ninety-nine percent perspiration–both parts are required and there is no one-way line of causation, perspiration can lead to inspiration as well as vice-versa. Read Derek Lowe on the reality of the drug discovery process.
Angell infuses normative claims to the industrial organization of the pharmaceutical industry. Over the past two decades there has been an increase in the number of small biotechnology companies, often funded by venture capital. Most of the small biotechs are failures, they never produce a new molecular entity (NME). But a large number of small, diverse, entrepreneurial firms can explore a big space and individual failure has been good for the small-firm industry which collectively has increased its discovery of NMEs. The small biotechs, however, are not well placed to deal with the FDA and run large clinical trials–the same is also true of university labs. So the industry as a whole is evolving towards a network model in which the smaller firms explore a wide space of targets and those that hit gold partner with one of the larger firms to pursue development. Angell focuses in on one part of the system, the larger firms and denounces them for not being innovative. Innovation, however, should be ascribed not to any single node but to the network, to the system as a whole.
Angell makes some good points about publication bias in clinical trials and the sometimes too-close-for-comfort connections between the FDA, pharmaceutical firms, and researchers. But in making these points she misses the truly important picture. Namely that new pharmaceuticals have driven increases in life expectancy but pharmaceutical productivity is declining as the costs of discovering and bringing a new drug to market are rising rapidly (on average ~1.8 billion per each NME to reach market). In my view, the network model pursued on a global scale and a more flexible and responsive FDA, both of which Angell castigates, are among the best prospects for an increase in pharmaceutical productivity and thus for increases in future life expectancy. Nevertheless, whatever the solutions are, we need to focus on the big problem of productivity if we are to translate scientific breakthroughs into improvements in human welfare.