PharmaReform on Amazon Kindle has explored a broad range of challenges and issues affecting the pharmaceutical industry.  The intent of the blog posts has been to encourage and stimulate thinking about how to address industry shortcomings while finding more patient- and healthcare customer-friendly approaches to marketing and selling prescription drugs in an increasingly complex business environment.

Reviewing the functional  diversity of running a drug company from manufacturing to research, the author provides an industry insider perspective to the commentary, suggestions, and recommendations for transforming drug companies into innovative profitable businesses in the evolving new healthcare market while reestablishing public trust and credibility.

Over 100 blog post articles, organized by topic (see Table of Contents),  are included in this e-book format (Amazon’s Kindle) providing a more convenient portable document for readers who prefer keeping, retrieving, and reviewing them as a reference.

Is Big Pharma Manufacturing Expertise Becoming a Misnomer?

We all depend on pharmaceutical manufacturing to produce our prescription drugs that are consistent in formulation, safe, and not contaminated with foreign materials or potentially harmful pathogens.

Anybody who has done pharmaceutical manufacturing, especially biologics or sterile injectable prescription drugs, knows how challenging it is to repeatedly get it done right in large scale.  From engineering and process controls to supply chain and inventory management to quality systems the expertise required to consistently produce high quality, regulatory compliant prescription drugs is perhaps one of the most unappreciated critical success factors for a pharmaceutical company.   If you can’t make it you can’t sell it.

This expertise is a core competency that has clearly been taken for granted by Big Pharma senior executives.  This lack of appreciation for manufacturing expertise is evident every time a pharmaceutical company faces a recall or needs to shut down due to “quality issues.”   Perhaps best exemplified by the now well publicized drug shortage situation, the inability to manufacture these life saving prescription drugs is putting patient lives at risk.   The lack of appreciation for the complexities and challenges of pharmaceutical manufacturing manifests itself in these shortages.

So what does it take to do high quality, safe, and regulatory compliant prescription drug manufacturing?  It takes a broad range of expertise (not just well trained technicians and operators), significant ongoing capital investment in facilities and equipment, and rigorous, almost obsessive quality systems.  These are not the places pharmaceutical executives  should be looking to cut costs.  And worse,  generic drug pricing generally don’t allow for the levels of continuous investments I believe are necessary in people (expertise), facilities, equipment, and quality systems.

But what about Big Pharma?  Well, who had the expertise?  Who had the robust quality systems?  I’ll even add … who had the proprietary insight into the nuances and complexities of making a particular prescription drug.  Big Pharma.   At least they did until they decided to take manufacturing expertise for granted.  Unfortunately, Big Pharma continues to close manufacturing facilities, outsource more to contract manufacturers, and retire or let go much of their manufacturing expertise.  And, this expertise and know-how doesn’t necessarily get transferred from Big Pharma to the manufacturers that will be making the generic versions of their products.

I often wonder how generic drug manufacturers or even contract manufacturers who take over manufacturing a prescription drug figure out, understand, and know how to deal with all the nuances and complexities of making a particular prescription drug.  Again, if you’ve done pharmaceutical manufacturing, you know how much is learned by doing hundreds and thousands of batches over years of experience.   Perhaps those who are challenged with making the drugs that are now in shortage are finding this out the hard way.  Unfortunately, it is patients who are now suffering and dying because pharmaceutical manufacturing is harder and takes more expertise than most pharmaceutical company executives appreciate.

How Pharmaceutical Companies can help Increase FDA Productivity

First, I am not going to defend the FDA or ignore its organizational dysfunction and seemingly antiquated review processes.  No doubt, the agency is underfunded and lacking in the necessary expertise to carry out its broad and geographically disperse responsibilities.   At the same time there are steps the pharmaceutical industry could take to help increase FDA productivity.

Historical precedent would suggest that pharmaceutical companies are more interested in getting products to the market than making sure their products are safe, effective, or even needed.  They tend to do the absolute minimum to get through the regulatory approval process (fastest, easiest indication first), hoping to argue there way through questionable safety data and relying on marketing to find expanded revenue opportunities in patients for whom they have little or no proof of efficacy or safety.   Some of the antics reported in the trade and lay press would suggest that pharmaceutical companies are continuously trying to find new ways to “game” the system.  If you need the details, there is a good review of the past forty years of industry missteps and flagrant disregard for regulatory expectations in the book Pharmaplasia™.   It is clear that the FDA has been put on high alert police mode by what historically has appeared to be an out-of-control, intentionally non-compliant, almost defiant pharmaceutical industry that can’t be trusted.

In this context, is it any wonder that the FDA is skeptically cautious, more demanding for proof of claims, and sometimes even slow and seemingly uncommitted when it comes to product approvals and issuance of guidance documents yet deliberate and critical, albeit intermittent and inconsistent in their enforcement?

Here are five steps the pharmaceutical industry could take to help improve the regulatory process and FDA efficiency.

  1. Focus on Innovation
  2. Makes safety issues easy for the FDA to understand
  3. Make manufacturing quality an organizational priority
  4. Commit to ethical and regulatory compliant marketing and sales
  5. Establish a base of credibility

Focus on Innovation

Despite the sunk costs of discovering and developing a product that companies hoped would turn out better than it did, don’t bog down the FDA review process with products that have little or no clinical benefits over what is already available on the market.  If you feel compelled to bring a comparable product to market, don’t try to make it sound better than it really is to substantiate a higher price.  Again, trying to angle for a labeling claim advantage that doesn’t really exist consumes FDA time and resources.

Make safety issues easy for the FDA to understand

It is mind-blowing to me that pharmaceutical companies can get to a final advisory board meeting prior to an expected approval and find out there is a concern and unanswered questions about an animal toxicology study or clinical finding?  Well, maybe the company was hoping it would just slip by and nobody would notice the data or they thought they could argue their way through the questionable or disturbing data.  Why not be proactive, anticipate the concern and just get the data to prove it’s not an issue?  Well, maybe companies still believe in the “don’t look for it unless it is a regulatory requirement” theory because they might find something they don’t like or can’t explain.  I appreciate the need for speed in development but you have at least 3 to 5 years after a product starts clinical studies to sort out any safety issues.  That is, if you really want to take the risk to understand the basic sciences of the concern or potential problem.

Make manufacturing quality an organizational priority

First, the answer to industry manufacturing issues is not lower quality standards, fewer FDA inspections, or less rigorous, less critical inspections.  In fact, I am a proponent of maintaining high quality standards,  more frequent and more rigorous inspections, including of foreign facilities.

As challenging as pharmaceutical manufacturing can be, I don’t see why pharmaceutical companies should expect anything other than a clean slate, no 483’s,  when the FDA inspects their facilities.  With appropriate management manufacturing expertise and robust quality systems in place, avoiding 483’s should not be a matter of chance or wishful thinking but rather a matter of fact.  Clean, high quality, cGMP – compliant manufacturing would make FDA inspections (and follow-up) easier, less laborious, and less time consuming.

Commit to ethical and regulatory compliant marketing and sales

“Pushing the regulatory envelop” and “off-label” promotion can drive revenues and increase your market opportunity but also puts tremendous additional workload on the FDA.   So much so that it is clear that pharmaceutical companies have taken advantage of this burden by trying to be clever in their advertising and promotions knowing full well the FDA can’t police everything and the chances of being caught are remote.  Even if caught, the consequences are minimal (a “slap on the hand” in the form of a letter) unless the Department of Justice pushes for some financial penalty.  And then,  it just becomes a cost of doing business.  Unfortunately, pharmaceutical companies may feel they will be at a significant commercial disadvantage if they don’t “push the regulatory envelop” because “everybody is doing it.”

An industry-wide commitment to ethical and regulatory compliant marketing and selling would make non-compliant outliers more obvious and allow FDA to focus resources  on the more egregious and potentially harmful marketing and sales activities.

Establish a base of credibility

If the pharmaceutical industry were trusted, credible, and committed to regulatory compliance the FDA would not have to spend as much time, effort, and resources trying to sort out the “gamers” from bona fide efforts to bring safe and effective innovative new products to market, to maintain high quality manufacturing standards, and to market products in compliance with the approved label claims.  Yes, I believe there are companies and their CEOs who profess this to be their intent, but the historical record suggests there are few who have been able to deliver or credibly live up to this commitment.

Banning Pharmaceutical Sales Representative Access to Physicians

Pharmaceutical companies are held legally and financially accountable for making sure their drugs are used appropriately and that physicians and patients are aware of and understand the risks associated with their prescription drugs.

Product liability litigation against pharmaceutical companies often feature how the pharmaceutical company insufficiently or inaccurately informed physicians  (often highlighting what the sales representative said or didn’t say and the brochure used) about the appropriate use of products (right patients, right dose) or communicated misleading understatements or outright omissions of the risks associated with prescribing those drugs.  Companies who can demonstrate they did everything they could to accurately and comprehensively inform the prescribing physician, especially about the risks involved in the plaintiff claims, are generally afforded some degree of legal protection under what is called the “learned intermediary” doctrine.

An increasing number of healthcare systems, hospitals, and academic medical centers are banning pharmaceutical sales representatives from their institutions.  Some group practices and even individual physicians are also placing restrictions on pharmaceutical representatives.  The intent is often to control the influence of sales representatives on physician prescribing but also to preclude representatives from distracting physicians and consuming practice time with interactions that are perceived to have little or no value.

Whatever the reason for limiting sales rep access to physicians, I am wondering how pharmaceutical companies could possibly be expected to fulfill and demonstrate their “duty to warn” responsibilities when institutions and physicians have decided to ignore and outright refuse one of the historically most effective means of communicating product information.  Will the package insert information now be the basis for appropriately “informing” the medical community and satisfy the “learned intermediary” doctrine?

Again, I am not a lawyer but I wonder what the courts and patients are going to say when a pharmaceutical company facing a “failure to warn” product liability charge demonstrates that their package insert clearly delineates the appropriate use and potential risks and they did everything they could to get the information to the physician but they were banned or denied access.  What are physicians going to tell their suing patients when the pharmaceutical company representatives testify that they tried repeatedly to get time with the treating physicians  to discuss the risks and benefits of the drug but were prohibited by policy and rejected at the office or hospital.

If healthcare systems and physicians make the decision not to include pharmaceutical company representatives in their drug education process are they also assuming more liability when pharmaceutical companies defend themselves by demonstrating that healthcare systems and physicians “chose” not to be informed or educated by the company?   They may in fact feel this is no big deal, they’ll just do their own educating.  But if physicians and healthcare systems assume this responsibility and take the deep pockets of the pharmaceutical company  “off the table” , are they really ready to assume the financial consequences or will patients seeking compensation and their lawyers be less quick to file these product liability suits?

What can FDA really do about drug shortages?

President Obama is reported to have issued an executive order for the FDA to fix the drug shortage.  But, what can the FDA do, realistically?  Giving advanced notice of an impending shortage won’t help, especially with the current shortage.  And, even if FDA had authority and power to force manufacturers to continue manufacturing, how do you do that if quality of manufacturing or lack of cGMP (current Good Manufacturing Practices) compliant active pharmaceutical ingredients (API) are the problems?

The drug shortage problem has been evolving over the past 5 years or so and was inevitable given the market pressures on generic drug pricing and a market expectation for FDA approved products to be manufactured under rigorous cGMP conditions affirmed by FDA facility inspections (remember heparin?).

First, I believe the root cause of most of the drug shortages is the lack of financial incentive (profitability) to ensure a continuous supply of product to the market.  This is mostly not a Big Pharma issue with high margin branded products.  The majority of drug shortages are for generic drugs and many are injectable products (difficult to manufacture).  Generic does not necessarily mean easy or cheap to manufacture.

So, why don’t generic drug companies just raise their prices?  Well, perhaps the biggest factor is Medicare pricing and the 6% price increase cap in any 6 month period but also the aggressive price negotiations by Pharmacy Benefits Managers, pharmacy chains, hospital purchasing groups, and wholesalers.   Besides the manufacturing logistic challenges, the Medicare price increase cap leaves little incentive to ramp up production in the face of a shortage.

If low profit margins accentuated by the challenges and expense of maintaining manufacturing quality are to be blamed for these shortages,  what can FDA do?

First, FDA could be more lenient about the expectations and enforcement of cGMP requirements.  This might be a reasonable option where compliance issues are minor administrative deficiencies that should be in place but may not be as tidy as FDA and cGMP regs might require.  If administrative record keeping and paperwork issues are keeping otherwise high quality products off the market, FDA could provide some relief, at least temporarily.  My guess is this is not the case in most current drug shortage situations with manufacturing quality and FDA concerns being of a more serious nature.  And, to ignore cGMP entirely (e.g., don’t inspect so you don’t find)  is not a viable option where patient safety is at risk.

A more reasonable option, if the manufacturer really wants to continue manufacturing, would be to have the FDA work closer on an expedited plan for resolving regulatory concerns about safety or quality manufacturing issues.  Similarly, the FDA could work with interested alternative manufacturers to facilitate an accelerated approval of facilities, processes, and drug application.

I’m somewhat skeptical about fixing manufacturing issues because the investment (accelerated cash spend in short period of time) to resolve the issues may be far more than the market might be willing to pay for in terms of higher prices.  And with higher prices, even if manufacturers could raise prices to sufficiently profitable levels, comes the potential for market criticism and resentment because you are charging more than they used to pay.  Raising prices on prescription drugs, even when warranted, is a “no win” for manufacturers.

FDA could require filing “continuity of supply” plans with new drug approvals, brand or generic.  No viable alternative plan, no approval.  Besides being difficult to enforce, it won’t help the near-term drug shortages.

I’ve also read about building government stockpiles of “critical medicines. “  I’m not sure about the practicality of this in terms of how much supply for how long.  Would you stockpile months or year supplies? This might provide some modest initial financial incentive to the chosen manufacturers and these stockpiled drugs would also need to be replenished once they expire.  Managing this process and determining which manufacturer will get the contract at what price for a particular product, however, could undermine the purpose and viability.

The problem with most of the proposed solutions is they don’t address the root cause …  lack of financial incentive to ensure a continuous supply.

If the products that are now on the shortage list were priced at or maybe even priced slightly below the historic branded prices, I’m certain most would not be in short supply.  Manufacturers would already have “continuity of supply” plans in place. They would be making absolutely sure they made the necessary investments to ensure cGMP compliance.  They would make sure their active pharmaceutical ingredient (API) suppliers were sufficiently incentivized to ensure a continuous supply.  And if there was an anticipated problem, they would be working diligently around the clock and making any necessary investments to ensure supply to the market.  The FDA can not fix these financial incentive issues, regardless of the regulatory authority the President or Congress might want to bestow on the agency.