The Product Pipeline and Clinical Trials: Bringing a Drug to Market
September 6 and 8, 2005

Readings and Other Activities: NEW:Drugs in '05: Much Promise, Little Payoff

1. Clinical Trials from CenterWatch Clinical Trials
2. Orphan Products: Hope for People With Rare Diseases FDA Consumer, 2003
3. Be sure to 'interact with' the FDA's New Drug Development Process (click on any button or phrase on diagram for more info)
4. Biotech 101: The Road to FDA Approval: Adam Feuerstein, TheStreet.com, July 5, 2004
Science 29 July 2005: Special Issue on Drug Discovery
5. 29 July 2005: Sending Pharma Better Signals;
6. 29 July 2005: The Hunt for a New Drug: Five Views From the Inside;
7. 29 July 2005: Productivity Counts--But the Definition Is Key

(Note: a PDF) "The Century of Biology Begins with 369 Biotechnology Medicines in Testing for More Than 200 Diseases: By using the body's own tools and weapons to fight disease, pharmaceutical and biotechnology companies are developing more and better medicines. A survey by the Pharmaceutical Research and Manufacturers of America (PhRMA) found 369 medicines in the pipeline that meet the definition of "biotechnology medicines": they use proteins and other substances produced in the human body to counter disease. All together, the biotechnology medicines in the pipeline target more than 200 diseases."

I. Steps in the Product Pipeline:

1. Discovery Research: ($155-225 M), ~ 5.5 years!!!

• Lead compound screening: Promising target or lead molecules are identified and tested as candidates for drug development.($15M - $35M)
• Discovery testing: Does the drug candidate work in animal cells - if so for how long ($20M - $40M)
• Scale-Up: Can drug be manufactured safely & economically ($82M - $100M)
• Stability and Formulation: Is drug adequately stable in chemical, light, moisture, and during formulation into tablets and capsules. Does the compound's solubility allow it to be absorbed in therapeutic concentrations in the body.($38M - $50M)

2. Pre-clinical: ($65M - $90M) ~ 4 years!!

• Use results from in vitro experiments (cell cultures) and in vivo animal models to determine the activity of a drug under many different conditions before it can be tested in humans.
• FDA will want to see "(1) a pharmacological profile of the drug in living cells/animals; (2) information about toxicity of the drug in at least two species of animals, and (3) short-term toxicity studies ranging from 2 weeks to 3 months."
• If things look promising at this point (no effects from long-term chronic use or carcinogenicity), the company will file a US Patent Application (to protect their promising new drug candidate from use or commercialization by others), and may possibly international patent applications as well. (Note: In the US, the "First to Invent" gets the patent; in almost all other countries, the "First to File" gets the patent. This is why is is crucial that people in industry keep up-to-date, signed lab notebooks! More about this when we talk about patents!
• When and if the patent is granted (~ within 2 years or so?) the 20-year patent protection clock starts ticking, even though the product will NOT be to market for another 6-8 years!!! The Hatch-Waxman act can 'give back' some of that time by extending the patent for 1/2 of the years the drug was under development and testing.

3. File an IND to the FDA: If the company or laboratory decides to pursue human studies, it must first submit an Investigational New Drug application to the FDA for approval. The FDA's Center for Drug Evaluation and Research (CDER) reviews the IND, and The Center for Biologics Evaluation and Research (CBER) regulates biological products.

• The IND must provide pre-clinical data to justify the testing of the drug in humans:
  • Animal Pharmacology and Toxicology Studies,
  • Manufacturing Information
  • Clinical Protocols and Investigator Information
• Here is a chart of the IND review process and all the steps that have to be completed before clinical trials can begin - yikes!
• 30 days after receipt by the FDA, the IND is given either a "safety acceptable to proceed" OR a "clinical hold decision".
• The IND must be filed annually until the clinical testing is over.
• About 85% of all IND applications move on to begin clinical trials.

Next Step: Clinical Trials: testing experimental drugs in humans.

4. Phase I clinical trials (~$10 M or more)

• Examine drug safety and pharmacology and metabolism, determinine drug regimen.
• Only 1 in 2,500 compounds ever makes it to this stage.
• Participants (usually normal, healthy volunteers) are closely scrutinized for harm caused by the medicine.
• These trials are small in scope (20 -100 patients), but they also give researchers an opportunity to begin to understand how the drug will work = dosage, side effects, absorption and excretion.
• Further trials and development can only take place if Phase I trials show the drug to be "reasonably safe" for normal, healthy humans.

5. Phase II clinical trials (~$25 M- $35 M)

• Confirm safety, determine efficacy in humans over the short term, and help set up parameters (e.g. dosage) of Phase III trials.
• 100 - 300 paient volunteers who suffer from the illness are recruited.
• Phase II trials are typically placebo-controlled and double-blinded: neither the patient nor the physician know which is the drug and which is the placebo.

6. Phase III clinical trials (often $100 M or more!)

• Pivotal in establishing safety and effectiveness of a drug in a large group of volunteers over the long term.
• Typically double-blinded, placebo-controlled and involve ~500 - 3,000 patients over many months or even years, in Medical Centers around the country.
• Risks are usually minimal because safety has been established.
• The large scope of these trials gives researchers and physicians opportunity to identify rare side effects of treatment, if any.
• Very expensive in terms of time, money and effort.
• However, Phase III trials are the principle criterion for FDA approval.

7. File an NDA with the FDA: The FDA must review all drugs and clear them for marketing, mandated by the Prescription Drug User Fee Act (PDUFA), a law passed in 1992 that allows the FDA to charge drug companies a fee for reviewing their NDA / BLA.

• New Drug Applications (NDAs) typically contain 120,000 pages of data and take the FDA a median of 12 months to review.
• Biologics License Application (BLAs) are similar, and are used for biologics (most biotechnology drugs!) drugs derived from living sources.
• Often, the FDA requires companies to provide more data, answer difficult questions and defend statements that they wish to include in their product labeling.
• The FDA advisory committees either approve the drug, denies approval, or sends the company back to redo portions of its clinical trials before ruling.
• The following letter codes describe the review priority of the drug:
  S- Standard review for drugs similar to currently available drugs (60 days to accept or reject the NDA for review, FDA action at ~10 months.)
  P- Priority review for drugs that represent significant advances over existing treatments. (45 days to accept or reject the NDA for review, FDA action at ~6 months.)
• Biotech stock prices hang in the balance during this time -- between phase III clinical studies and the NDA decisions - the dreaded "Refuse-to-file" (RTF) letter can set a company back for months or years ! (Better than having an unsafe product on the market, though!)
• We just can't go here, but if you want to read the story about the FDA's Refuse-to-File letter to Imclone (the sad tale of "Insider pessimism" involving Martha Stewart - formerly inmate Stewart, Samuel Waksal - now inmate Waksal and others), see Securities and Exchange Commission v. Martha Stewart and Peter Bacanovic.

8. Phase IV trials: Conditional approval after the drug or treatment has been marketed...

• Measure the drug's impact on patient sub-groups / population (especially children, the elderly, pregnant women)
• Supply information on as-yet undetected adverse outcomes, especially in sub-group populations.
• Provide additional information on the drug's long-term morbidity and mortality profile.
• Phase IV trials can be conducted voluntarily OR at the request of the FDA. The FDA has the right to make Phase IV studies a condition of market approval.
• While phase IV trials are conducted, the company can begin to market its product.

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Some variations on the basic theme...

1. Speeding things up: Since 1997, the FDA has been approving drugs at almost twice its usual rate (6 months rather than 10 months), thanks in part to money provided by the drug industry to speed the drug review process.

• Fast Track Review: Investigators work closely with the FDA; can submit individual parts of the NDA to the FDA one at a time to speed approval.
• Priority Review: The FDA has 45 days to accept or reject the NDA for review, and has a target date for FDA action at 6 months. Priority Review is typically indicated for products that address unmet medical needs.
  
  • Real life example; 2004: From Biotech 101: The Road to FDA Approval: The "PDUFA clock" starts on the day the NDA is filed with the FDA. Biotech firms typically issue press releases when drugs are filed, so it's relatively easy for investors to count forward six months from that day to find the date by which the FDA must issue its decision, often referred to as the "PDUFA date."
  • On May 25, 2004, the FDA granted "priority review" status to Antegren, the MS monoclonal antibody drug to Biogen Idec (BIIB:Nasdaq) and Elan Pharmaceuticals (ELN:NYSE) . The companies submitted Antegren to the FDA on May 25; thus the drug's PDUFA date falls on or around Nov. 25". Stay tuned!
  • November 23, 2004: FDA Approves Tysabri® (Natalizumab, Formerly Known As Antegren) For Relapsing Forms Of MS 
  • This year Jun 21, 2005: REVLIMID gets Priority Review Status for the Treatment of Myelodysplastic Syndromes
    U.S. Food and Drug Administration (FDA) has granted a Priority Review designation to its New Drug Application (NDA) for REVLIMID with a Prescription Drug User Fee Act (PDUFA) date by October 7, 2005.
    
• Accelerated Development / Review: For drugs that promise a significant advantage over existing drugs for serious or life-threatening illnesses, or for illnesses for which no therapy exists. A key feature of this process: manufacturers must continue testing after approval to demonstrate that the drug does benefit the patient (if not, the FDA can withdraw the product).

2. Compassionate Use: An alternative to clinical trials for desperately ill patients.

• Sometimes MDs and patients can lobby (or pressure) a company for access to experimental medications before the drug has approval, to save the life of a critically ill patient.
• The company usually has valid reasons for refusing compassionate access - giving an experimental drug to a few people before it is proved wastes resources, time, and money (and the drug itself) that could be spent on determining whether the drug works.
• However, if it is designed well, a compassionate access program can produce enough data to help the drug win FDA approval.
• For a person to receive drugs through compassionate access, their doctor applies to the pharmaceutical company and FDA via a Treatment IND, and approval is considered on a case-by-case basis.

3. The Orphan Drug Act of 1983,

• The FDAs attempt to encourage the development of new drugs for the treatment of rare diseases, such as Huntington's disease, ALS (Lou Gehrig's disease), Tourette syndrome, and muscular dystrophy, Gaucher's disease.
• These diseases afflict so few patients (less that 200,000) that it may not be economically feasible for pharmaceutical companies to compete in these markets. The FDA has approved ~240 orphan drugs since 1983.
• The ODA guarantees the developer both a seven year exclusive right to sell an orphan drug before other competitors would be allowed to compete in that market (market exclusivity), and lucrative tax incentives.
• Cerezyme - that's some orphan drug!!!!! "Cerezyme is Genzyme's (GENZ) treatment for Gaucher's disease, a rare genetic condition marked by an enlarged liver and spleen, low red blood cell counts, and thinning of bones. Genzyme charges roughly $170,000 per patient for the full treatment. Even though Genzyme's patent protection for this drug expired years ago, 60 percent of the estimated worldwide market of ~4,000 patients still take Cerezyme. See the link - Who Pays?
• REVLIMID (above) is another such drug - for those with a 5q chromosomal deletion - but has many indications that may be approved at a later date.

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Misc:

Who can conduct clinical trials and who pays for clinical trials? (go to link)

• Government agencies: National Institutes of Health (NIH), National Cancer Institute;
• Private industry (pharmaceutical and biotech companies);
• Individual physicians or health care institutions such as health maintenance organizations (HMOs);
• Organizations that develop medical devices or equipment.
• The sponsor of the research hires physicians to conduct the clinical trial. Physicians are typically paid on a per-patient basis.
• The medical care is often provided free to the patient. Patients may also be paid a small fee to participate in a clinical trial.

Informed consent (information from link)

"The process of learning the key facts about a clinical trial before deciding whether or not to participate.

• Why the research is being done.
• What the researchers want to accomplish.
• What will be done during the trial and for how long.
• What risks are involved in the trial.
• What benefits can be expected from the trial.
• What other treatments are available.
• The fact that you have the right to leave the trial at any time."
  

Who can participate in a clinical trial (inclusion and exclusion criteria)? (information from link)

• "Before you join a clinical trial, you must qualify for the study.
• Guidelines are based on such factors as age, type of disease, medical history, and current medical condition.
• Some research studies seek volunteers with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. .
• The factors that allow you to participate in a clinical trial are called inclusion criteria and the factors that keep you from participating are called exclusion criteria. It is important to note that inclusion and exclusion criteria are used to identify appropriate participants and keep them safe.
• The criteria help ensure that researchers will be able to answer the questions they plan to study."
  

Something to keep in mind when and if you become an MD...the best physicians keep themselves aware of the clinical trials at their Medical Center and at those in surrounding areas. This could mean the difference between life and death for patients who qualify, and as well, further the cause of scientific knowledge needed to bring a new drug to market.

Clinical Trials program at Indiana University School of Medicine
Center Watch Clinical Trials Listing - anything appeal to you?

Should Drug companies post BOTH their positive and negative results of clinical trials?

Two Studies, Two Results, and a Debate Over a Drug New York Times, June 3, 2004
Merck Says It Will Post the Results of All Drug Trials New York Times, Sept 6, 2004

Check the news this coming week about a House subcommittee about publishing unfavorable clinical trial results.

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II. Timelines!

FromThe Drug Development and Approval Process : It takes 15 years on average for an experimental drug to travel from the lab to U.S. patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

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ANDA = "Abbreviated New Drug Approval - is used by potential manufacturers of a generic copy of a previously approved drug. Once approved as bioequivalent (comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use), an applicant may manufacture and market the generic drug product." (Can't go here, but...Discount Drug Plan Announced: "Ignoring a federal ban on prescription drug imports, Gov. Rod Blagojevich announced Tuesday, Aug 17, that the state of Illinois is creating an online clearinghouse of pharmacies to help Illinois residents purchase drugs from Canada, Ireland and the UK" .

Indicting the Drug Industry's Practices New York Times, Sept 6, 2004 Ouch! A scathing attack on the implications of the Bayh-Dole Act of 1980 that changed the way university discoveries could be patented, and how "patent shenanigans have reshaped the drug business". More on this when we talk about Tech Transfer on 9 Nov !

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IV. A few notable pipelines:
Some of the drugs in these pipelines will go on to become huge winners, while others will crash and burn! Note: BEWARE the WAYYY over-used term ROBUST (as in 'robust pipeline'). Sounds great to investors, but it is a pretty data-less adjective!

V. Feeling LUCKY? If you had money to invest in one of these companies, which would YOU pick, and why?? That's our next topic!!!