Until January 1st, 2009, forty million Americans had relied on CFC (chlorofluorocarbon) inhalers to help them breathe. CFC inhalers have been used worldwide for about 50 years, and have a proven track record of safety and effectiveness. The FDA ban on CFC inhalers is unprecedented: it is the first time in U.S. history that the government has banned a proven life-saving medication for non-medical reasons.

The FDA claimed that the new HFA inhalers (that were designed to replace CFC inhalers) were just as safe and just as effective as the old CFC inhalers. We know from many studies listed in our HFA MDIs: Just The Facts, from Medwatch data, and from patient and doctor comments, that the new HFA inhalers are less safe and less effective than the old CFC inhalers. Please read more comments on our Mad As Hell page.

1. Despite what the FDA, The Gang Of Nine, and the drug manufacturers claim, the new HFA inhalers have different inactive ingredients and different impurities than CFC inhalers.
   
   
2. In 1994, at the suggestion of the drug manufacturers, the FDA used a watered-down regulatory approach (the so-called “bridging” approach) for the pre-clinical and clinical trials of HFA inhalers. And until as late as 1999, FDA officials are on record expressing continuous concern about the need for large-scale real-world post-marketing studies.
   
   
3. Due to opposition from the drug manufacturers, the FDA banned CFC inhalers without requiring that any large-scale, real world U.S. post-marketing studies of HFA inhalers be done. We believe that the CFC albuterol ban is illegal because FDA Final Rule 21 CFR 2.125 requires 1) "adequate U.S. post-marketing data" proving the safety and effectiveness of Proventil HFA and Ventolin HFA, specifically, and 2) that this U.S. postmarketing data prove that "patients are adequately served" by these inhalers, and we believe that no such data exists. In fact, three years of FDA MedWatch data shows just the opposite. HFA inhalers work for some of the patients who were well-controlled by CFC inhalers, but not all. For many thousands of patients, the ban of CFC inhalers was a huge step backwards in the management of their asthma or other pulmonary disease.
   In fact, Schering-Plough itself says this about its product, Proventil HFA: "Rapid heart beat, vomiting, chest pain, and palpitation occurs more frequently with Proventil HFA (than with CFC albuterol)."

CFC inhalers have been on the market for fifty years. We know that they are safe and effective. We have no idea what the long term side effects of HFA inhalers will be. All physicians who treat asthma and pulmonary patients know how hard it is to find the right combination of drugs to treat any given patient. Doctors should be free to prescribe the medication that works best for each individual.

The new HFA inhalers have different inactive ingredients and impurities, some of which are known to be harmful.

HFA and CFC inhalers deliver virtually the same active ingredient (for example, albuterol base in CFC inhalers and albuterol sulfate in HFA inhalers). However, they have different inactive ingredients and impurities – which patients inhale along with the active ingredient. Over the course of two years, Dr. Jenkins (currently the Director of the FDA Office of New Drugs), repeatedly expressed concern about the safety of these inactive ingredients:

DR. JENKINS (FDA): "you need to remember that the new (HFA inhaler) formulations are new drugs, they often have different excipients (inactive ingredients), and different devices, so there are additional needs for more extended studies for those for safety purposes, as well as durability of the efficacy response." (p. 302, 1997 PADAC meeting).

DR. JENKINS (FDA): "There are documented cases where patients may be responding to an excipient, for example, an inactive ingredient that's in one formulation that's not in another formulation. So I should have put that in as a caveat, and there's obviously also physiologic differences between different beta agonists. Some have more selective beta adrenergic effects than others. So I was trying to target more on efficacy, but recognizing that there are potential differences and adverse event profiles because of the molecule or because of the formulation." (p. 194 1999 PADAC meeting):

For example, some of the new HFA inhalers contain ethanol, a known asthma trigger (bronchoconstrictor and inflammatory effect).

“Whereas the direct contact of ethanol with the bronchial mucous caused bronchospasm, the consumption of alcohol had never caused the patient’s asthma to worsen. Various effects on the bronchial tone after the ingestion of ethanol have been documented and approximately 30% of asthmatics report an exacerbation in their symptoms (5). In an animal model, it has been shown that ethanol can trigger bronchoconstriction through TRPV1 (transient receptor potential vanilloid-1) activation of the airway sensory neurons in the brochi (6). Our findings suggest that bronchospasm is caused by ethanol-induced TRPV1 activation [in humans].” (Bronchospasm induced by inhalant corticosteroids: the role of ethanol).

"In conclusion, we have demonstrated that EtOH [ed. ethanol] stimulates peptidergic primary sensory neurons in the guinea pig airways by TRPV1 activation. This excitatory effect of EtOH, distinct from that of AcH, results in neurogenic inflammatory responses that may contribute to the mechanism of EtOH-induced asthma." JPET 309:1167-1173, 2004.

Worse, the ethanol in the current HFA inhalers comes from corn, which is a known allergen in its own right. Corn allergies can lead to an asthma attack and/or anaphylaxis.

Each brand of HFA also has its own unique mix of impurities. The inactive ingredients and inhaler components combine with each other to create potentially dangerous extractables and leachables (which are only one category of inhaler impurities). A joint study between researchers at the FDA and inhaler manufacturers identified the following sources of extractables and leachables:

“metal components, e.g., MDI valve components, canisters, residual cleaning agents, organic surface residues, e.g., heavy oils or surface treatments of any type that are in contact with the formulation or the patient, coatings on internal canister surface, elastomeric container/closure system components, e.g., gaskets, seals, etc., chemical additives, including antioxidants, stabilizers, plasticizers, etc., trace level contaminants and reaction products contained within chemical additives, monomers and oligomers from the elastomer, secondary reaction products from the curing process, plastic/polymeric container/closure system components, e.g., plastic, MDI valve components, mouthpieces, plastic container material, chemical additives, including antioxidants, stabilizers, plasticizers, etc., trace level contaminants and reaction products contained within chemical additives, monomers and oligomers from the polymeric material, pigments, processing aids, e.g., chemicals applied to surfaces of processing/fabrication machinery, or directly to components, mould release agents, lubricants.” (Safety Thresholds and Best Practices for Extractables and Leachables In Orally Inhaled and Nasal Drug Products, p 5, Table 1).

Forty million Americans will inhale these new inactive ingredients and impurities for the rest of their lives. Their doctors should be allowed to prescribe the inhaler that is safest and most effective for them.

Keep reading to learn how the FDA watered-down its own regulations for pre-clinical and clinical trials and fraudulently found (in our opinion) that Proventil HFA and Ventolin HFA met all of the requirements of FDA Final Rule 21 CFR 2.125 before it banned CFC albuterol inhalers.

You can also go to our HFA MDIs: Just The Facts page for studies showing that the new HFA inhalers are less safe and less effective than the old CFC inhalers.

The HFA inhalers were not adequately tested for safety and effectiveness.

On March 31, 2005, FDA decided to ban CFC albuterol inhalers effective January 1, 2009 (technically, the EPA banned albuterol inhalers after the FDA removed them from the list of "essential uses" of ozone-depleting substances). They claimed that HFA inhalers were a safe and effective replacement. At the time of its decision there were:

• No large scale, real world U.S. post-marketing studies of HFA albuterol.
  
  
• No U.S. studies that lasted more than one year (and most lasted less than 3 months).
  
  
• No U.S. studies on patients with severe asthma, lung cancer, COPD, or cystic fibrosis.
  
  
• No U.S. studies on pregnant women, patients with other illnesses, or the elderly and only two-four week studies on children.
  
  
• Most disturbing of all, the HFA-134a propellant itself was never tested on asthma and pulmonary patients in the IPACT-1 study or any other study that we know of. It was only tested on healthy volunteers. Healthy people don’t have the severe allergies or hyper-reactive and/or inflamed airways that asthma patients have.

The HFA inhaler manufacturers formed IPAC (International Pharmaceutical Aerosol Consortium) in 1988 to find a replacement for CFC inhalers. IPAC convinced the FDA to let them use a new “bridging” approach for the HFA inhaler pre-clinical and clinical trials instead of the larger, more rigorous traditional studies previously required before approving any new drug on the market.

Dr. LUMPKIN (FDA): “…the Division of Pulmonary Drug Products agreed with IPAC that a "bridging" approach was appropriate for the pre- clinical testing of the new formulations of propellant, drug substance, and inactive ingredients. This "bridging" approach substantially reduces the regulatory requirements for pre-clinical studies to be conducted prior to approval for each new non-CFC MDI product.” (Testimony before the Subcommittee on Health and Environment, House Committee on Commerce, July 30 1997.)

Dr. JENKINS (FDA): "A more limited or bridging approach was developed for the pre-clinical safety testing of the new [ed. HFA inhaler] formulations... " (p 22, 1997 PADAC meeting).

Dr. JENKINS (FDA): "Similar to the preclinical safety battery... the recommended clinical development programs for the most part represent a bridging approach." (p 23, 1997 PADAC meeting).

These bridging studies lasted only twelve weeks to a year. They only included a small sample of younger patients with mild to moderate asthma. Both Dr. Meyer and Dr. Jenkins, who supervised the FDA program for the ban of CFC inhaler since 1996, expressed concern that the HFA inhaler clinical trials were likely to miss problems. They emphasized the importance of doing post-marketing studies of HFA inhalers.

  DR. MEYER (FDA): "I think clinical trials, well-controlled (pre-approval) clinical trials tell you a lot, but they don't tell you certainly everything, and particularly they're very well-groomed (younger, healthier) patient populations that are taken into them. They're the only the patient populations for which the drug is indicated, and I think we're very much interested in the post-marketing period about what happens in the patients who are using it for other indications off-label or more severe patients than were the clinical trials or younger or older, so on. And then, finally, just due to some of your statistical limitations, if you have a database of a thousand patients, you're not likely to pick up a very rare event. So if there was some rare reaction to the formulation, we wouldn't pick that up in clinical trials, unless we were quite lucky, either." (p. 140, 1999 FDA PADAC meeting).

Notice that Dr. Meyer said that even a thousand-patient study would not pick up rare complications – the HFA inhaler clinical trials used less than 300 patients in the test arms.

DR. JENKINS (FDA): "Well, if you go back and look, remember that the pre-approval clinical trials are very rigorously controlled. They have very selective entry criteria. So you actually generally end up with mild to moderate asthmatics who are fairly compliant with their medications, and they're in a rigorous 12-week clinical trial with a low of follow-up. A post-marketing type of study that may be of a simpler design might be more of a general practice type of study, where you in some way randomize patients in practice to one therapy or the other, but you're kind of following how the drugs are actually used and not proscribing so much up front about entry criteria, exclusionary criteria, indications, et cetera. It's kind of that type of more simple design, real-world (older, sicker patients) type of experience." (p. 156, 1999 FDA PADAC meeting).

At the 1997 and 1999 FDA PADAC meetings, FDA Drs. Jenkins and Meyer repeated the same refrain: CFC inhalers should not be banned based solely on the limited pre-approval clinical trials. The FDA needed large scale post-marketing data.

DR. JENKINS (FDA): "There is all the other criteria that have to be met (for FDA approval of HFA inhalers), of patient acceptability, serving patient needs... safety data from the large postmarketing experience..." (p.257, 1997 PADAC meeting).

DR. MEYER (FDA): "I think when you add on the issue that this may be the product [HFA inhalers] that leads to a safe and effective product that contains CFCs no longer being able to market, it may change the balance some [in favor of requiring postmarketing studies of HFA asthma inhalers]. (p.170, 1999 FDA PADAC meeting).

DR. JENKINS (FDA): "I think a point we all need to keep in mind is that normally, when we are approving new drugs, whether it be a new molecular entity, a new formulation of an existing drug, we're approving that thinking that it's going to go into the market and become part of the overall armamentarium for the disease. This (HFA inhalers) is a different paradigm, where these products are being specifically developed to replace existing products (CFC inhalers). So when we approve these non-CFC alternative products, there's an intent through the Montreal Protocol and the Clean Air Act that if those are acceptable to patients, they're (HFA asthma inhalers) going to replace the old products, and part of the question we're trying to get answers from you are, how can we be certain that we're not going to make things worse? We certainly may not be able to address some of the concerns that are out there now, but I don't think we want to make things worse by making a determination that the alternative product (the HFA asthma inhalers) meets patient needs, and you declare the CFC product as no longer essential, and the CFC product goes off the market, and then you find out that maybe it (the HFA inhalers) really didn't meet patient needs. So it's a very different paradigm, and that's why we're asking these difficult questions." (p. 172, 1999 FDA PADAC meeting).

DR. MEYER (FDA): "We'd want to know that there's adequate patient acceptance (of HFA inhalers). I think that it is important to realize, and I'm sure most of you all do, that the drug approval process does assure that the product is sufficiently safe and effective for its intended use, but that's rather different from knowing that in millions of patients, it will provide them the same kind of benefit or use as the current CFC inhaler products." (p.44, 1999 FDA PADAC meeting).

After saying for years that large-scale, real world U.S. post-marketing studies of HFA inhalers were important, the FDA inexplicably reversed its position on March 31, 2005. It banned CFC inhalers without mandating any U.S. post-marketing studies. In the next section, we explain how this is a direct violation of U.S. law and FDA regulations.

Did the FDA violate the law when it banned CFC inhalers?

U.S. regulations require that the FDA find that there is adequate U.S. post-marketing data on HFA inhalers (specifically, Proventil HFA and Ventolin HFA) before banning CFC albuterol inhalers. Adequate post-marketing data is especially important because the FDA already watered-down its own regulations on HFA inhaler pre-clinical and clinical trials by substituting the “bridging” regulatory approach.

Here are the two (out of four) legal requirements that we believe were not met when the FDA made its decision to ban CFC albuterol:

(iii) Adequate U.S. postmarketing use data is available for the non-ODS product(s) (specifically, Proventil HFA and Ventolin HFA); and

(iv) Patients who medically required the ODS product are adequately served by the non-ODS product(s) containing that active moiety and other available products;” FDA Final Rule 21 CFR 2.125.

On June 10th, 2004, the FDA held the final PADAC meeting (Pulmonary Allergy Drug Advisory Committee) to determine whether or not Proventil HFA and Ventolin HFA met the requirements of FDA Final Rule 21 CFR 2.125. Dr. Swenson, a pulmonologist, explicitly asked for some post-marketing data. Dr. Meyer, the FDA official who worked with Dr. Jenkins in managing the CFC ban since 1996, replied that the FDA had some data from other countries. He also hinted at the existence of one or two U.S. studies which he was unable or unwilling to provide to the committee. These studies have never been released to the public. As we pointed out above, FDA Final Rule 21 CFR 2.125 specifically requires U.S. studies be used, and not foreign data.

DR. SWENSON: "Just for the agency, we really didn't see any data regarding the safety and the track record (of Proventil HFA and Ventolin HFA). Can you give us a brief synopsis? I suspect, because they have been out as long as they have, they are probably safe. But can you tell us so from your data monitoring?" (2004 PADAC meeting p.243).

DR. MEYER (FDA): "I think for the purposes of the proposed rule, we really didn't contest that this was not the case. In other words, these products have substantial worldwide experience. We have some postmarketing, formal postmarketing data, available [Dr. Meyer is refering to studies in other countries, there is no US postmarketing data], particularly for the 3M product (Proventil HFA) as well as some analyses for the GSK product (Ventolin HFA). At this point, the postmarketing experience that we have seen, both from more formal data and from the informal safety reporting, is that these products do not appear to be substantially different from the CFC products in terms of how they perform. So we have not expressed any concern in that regard." (2004 PADAC meeting p.244).

Why wasn’t Dr. Meyer concerned? In the previous section, we saw that he and Dr. Jenkins (current Director of the FDA Office of New Drugs) strongly suggested that post-marketing data for HFA inhalers should be collected before banning CFC albuterol. They repeated their concern on this issue in both the 1997 and the 1999 PADAC meetings.

We don’t know why Dr. Meyer did not express any concern at the 2004 PADAC meeting. We do know that Dr. Meyer has recently left the FDA for a well-paid position at pharmaceutical giant Merck.

We don’t know why the FDA decided to ban CFC albuterol without first having mandated that U.S. post-marketing studies be done.  We do know that Dr. Jenkins, who was the FDA’s lead official on the CFC inhaler ban, is now the Director of the FDA Office of New Drugs.  He now claims to be very concerned about long-term post-marketing studies for any new drugs that are used to treat chronic illnesses.

"We are thinking about what the implications of these new data and these new findings are for all chronically used drugs….It's changing how we look at how much data you need to get a drug approved [the FDA] might look at more requirements for large studies after approval." (2008 Dr. Jenkins, interview with Susan Heavey, Reuters).

We now know from many studies (that are posted in our HFA MDIs: Just The Facts), from Medwatch data, and from patient and doctor comments, that the new HFA inhalers are less safe and less effective than the old CFC inhalers.