Pipeline and Clinical Trials:
Bringing a Drug to Market
September 6 and 8, 2005
and Other Activities:
'05: Much Promise, Little Payoff
Trials from CenterWatch Clinical Trials
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
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
How does a drug candidate (recombinant or otherwise) get through
the federal regulatory processes and finally make it to market?
(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
- 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)
($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?)
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
- The IND must be filed annually until the clinical testing
- About 85% of all IND applications move on to begin clinical
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
- 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
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
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
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
- The FDA advisory committees either approve the drug, denies
approval, or sends the company back to redo portions of its clinical trials
- 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.
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.
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.
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
- On May 25, 2004, the FDA
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.
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).
Use: An alternative to clinical trials for desperately
- 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
- 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
- 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
(above) is another such drug - for those with a 5q chromosomal deletion -
but has many indications that may be approved at a later date.
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
- 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
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
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
Clinical Trials Listing - anything appeal to you?
Should Drug companies post BOTH their positive
and negative results of clinical trials?
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
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.
Laboratory and animal studies
20 to 80
100 to 300
1000 to 3000
Assess Safety and biological activity
5,000 compounds evaluated
= "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 !
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
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!!!
1. For each stage of the Drug Developmant
and Approval Process, be sure to know how many years, how much $$, and
how many patients (where applicable) would be involved at each stage.
2. Distinguish between an IND and an NDA
3. Explain the three process that can speed up FDA approval. .
4. Describe compassionate access and when it is used.
5. Explain the Orphan Drug Act, why it was implemented, and how it provides
an incentive to pharmaceutical companies.
6. Distinguish between inclusion and exclusion criteria for a clinical