In late February of this year, the US Food and Drug Administration released its Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics. Unlike traditional clinical studies, which require that the elements of the protocol are immutable throughout the study,
adaptive trials can include elements that can be changed mid-trial, so long as the conditions under which changes are made
and the nature of those changes are established in the study design.
Adaptive trials promise to lower trial costs and speed up the development process by reducing the number of trials that must
be conducted and increasing the probability that a trial will reach the desired endpoint. They are indicative of the growing
complexity of clinical research as bio/pharmaceutical companies respond to the growing concern over the cost and safety of
new drugs. Companies must confront an expanding range of challenges when developing and testing new drug candidates. Some
of those challenges include:
- demonstrating superiority over existing therapies: this is becoming a touchstone for regulators concerned about the quality
of new drugs coming to market and third-party payers unwilling to add new drugs to formularies unless they provide a tangible
- reducing trial costs: decreasing the costs of drug development is imperative as bio/pharmaceutical companies endure declining
revenues in the phase of patent expirations and fewer approvals
- expanding subject populations: the need to find sufficient numbers of trial subjects, combined with the desire to expand into
new markets, has pushed bio/pharmaceutical companies to recruit more and more patients in emerging markets, including Latin
America, Eastern Europe, India, and China
- bringing more biologics into the clinic: as the clinical performance of traditional small-molecule compounds wanes, bio/pharmaceutical
companies have increased their focus on biologics as the source of new drug approvals.
These challenges have increased the complexity of clinical trials. Examples of this increased complexity include the expanding
number of clinical trials in which new drug candidates are tested against active controls (approved, marketed drugs); clinical
trial designs incorporating more arms (patient sub-groups); adaptive trials; and the growing number of sites per study.
CLINICAL SUPPLY CHAIN CHALLENGES
The increased complexity of clinical trials is posing new challenges across the supply chain.
Packaging complexity: large multi-arm studies greatly increase the number of packaging configurations needed to conduct a trial. A study with at
least one active control, one placebo, and a development candidate can easily have six or more packaging configurations, depending
on the protocol. If the study is being conducted in multiple countries, labeling the packages to incorporate multiple languages
is an additional challenge.
Forecasting complexity: large multi-country studies make clinical supply forecasting very difficult. For example, estimating how many kits will be
required in each country means being able to forecast enrollment rates with some accuracy, which is extremely difficult. Adaptive
trials further complicate the problem.
Logistical complexity: shipping clinical supplies to multiple countries raises problems such as transportation and storage under good manufacturing
practice (GMP) conditions. Because of the growing number of biologics, maintenance of temperature conditions across the supply
chain, i.e., cold chain management, has become a major concern.
CLINICAL SUPPLY ARMS RACE
The growing complexity of clinical trials and the clinical supply chain has opened up an "arms race" in the clinical supply
chain industry because participants are competing to offer the most sophisticated capabilities. For instance, clinical packagers
are investing millions in information systems that can track individual packages from the warehouse shelf through every step
in the supply chain, all the way to the clinic or physician's office where the patient receives his drug supply.
In addition, supply chain complexity has boosted the importance of a range of specialty providers and services across the
supply chain. Some examples are below.
- Comparator sourcing companies that specialize in procuring drugs used as active controls in clinical trials. This is an intricate undertaking because bio/pharmaceutical
companies often require large quantities of a drug from a single manufacturing lot when conducting active control trials.
- Courier companies that specialize in shipping materials to clinical sites and depots around the world. This is a booming business, with high
double-digit growth rates.
- Clinical supply depots that provide GMP-compliant storage for packaged clinical supplies. Depots enable bio/pharmaceutical companies to ship multiple
kits to a country at one time, reducing shipping and customs-clearing costs, and ensuring timely delivery to patients. Once
an ancillary service offered by a few contract research organizations (CROs), clinical supply depots now are a critical link
in the supply chain.
The ability to deal with the complexity of the clinical supply process has shifted the balance of power in the clinical supply
chain to CROs, especially the major clinical packagers and logistics services providers. Being able to handle clinical supply
chain complexity requires major investments in information technology and specialized packaging and labeling equipment. It
also rewards companies with the know-how to devise sophisticated solutions for complex supply chain problems and the experience
to accurately and safely implement those sophisticated solutions.
Only companies that handle hundreds of clinical supply projects annually can use the experience to devise and implement those
sophisticated solutions and afford to make the necessary investments. There is no way that bio/pharmaceutical companies can
hope to match those capabilities in their in-house clinical supply operations.
Jim Miller is president of PharmSource Information Services, Inc. , Springfield, VA, 703.383.4903,